“Selected from” is used herein according to common patent application drafting terminology, to introduce a list of elements among which an item is selected. Any occurrence of “selected from” in the specification may be replaced by “selected from the group comprising or consisting of” and reciprocally without changing the meaning thereof.

“Solvate” refers to molecular complex comprising a compound along with stoichiometric or sub-stoichiometric amounts of one or more molecules of one or more solvents, typically the solvent is a pharmaceutically acceptable solvent such as, for example, ethanol. The term “hydrate” refers to a solvate when the solvent is water (H₂O).

“Therapeutic agent”, “active pharmaceutical ingredient” and “active ingredient” refer to a compound for therapeutic use and relating to health. Especially, a therapeutic agent (e.g., a compound of the invention) may be indicated for treating and/or preventing a disease, preferably an infectious disease. An active ingredient may also be indicated for improving the therapeutic activity of another therapeutic agent.

“Therapeutically effective amount” (in short “effective amount”) refers to the amount of a therapeutic agent (e.g., a compound of the invention) that is sufficient to achieve the desired therapeutic or prophylactic effect in the patient to which/whom it is administered.

“Treat”, “treating” and “treatment” refer to alleviating, attenuating or abrogating a condition and/or disease and/or any one of its attendant symptoms, e.g., an infectious disease.

DETAILED DESCRIPTION
Compounds

This invention relates to a compound of formula (I)

[Image Omitted]

- wherein Y, Y², L, R¹and Z¹are defined hereinafter in the detailed description.

In the compounds of formula (I) as described hereinafter in the detailed description, unless otherwise indicated, any alkyl group (which encompass alkylene group) may be “optionally substituted”, i.e., each hydrogen atom bound to a carbon atom in the alkyl moiety can optionally be replaced by at least one low-molecular weight substituent such as, for example, a substituent selected from halogen, cyano, hydroxy, oxo, amino, —O—(C₁-C₆) alkyl, —NH—(C₁-C₆) alkyl and —N—((C₁-C₆) alkyl)₂. Only substitutions wherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the (C₁-C₆) alkyl group(s) present in the substituents are not themselves further substituted. Preferred substituted alkyls include alkyls substituted by one or more fluorine atom(s) and/or hydroxy such as, for example, trifluoromethyl.

In the compounds of formula (I) as described hereinafter in the detailed description, unless otherwise indicated, any cyclyl group (i.e., cycloalkyl, heterocycloalkyl, aryl or heteroaryl group) may be “optionally substituted”, i.e., each hydrogen atom bound to a carbon atom in the cyclyl moiety can optionally be replaced by at least one low-molecular weight substituent such as, for example, a group selected from halogen, cyano, hydroxy, oxo, amino, —(C₁-C₆) alkyl, —CH₂—O—(C₁-C₆) alkyl, —CH₂—NH—(C₁-C₆) alkyl, —CH₂—N—((C₁-C₆) alkyl)₂, —O—(C₁-C₆) alkyl, —NH—(C₁-C₆) alkyl and —N—((C₁-C₆) alkyl)₂. Only substitutions wherein the resulting molecule is chemically stable are encompassed by this definition. Typically, the (C₁-C₆) alkyl group(s) present in the substituents are not themselves further substituted. Preferred substituted cyclyl groups include cyclyl substituted by substituted by one or more fluorine atom(s) and/or hydroxy such as, for example, difluorocyclopropyl.

In the formulae represented herein, the dotted line ---- represents the point of attachment of the depicted moiety to the main molecular structure.

Y¹Definitions

In formula (I) above, Y¹is a bicyclic heteroaryl. According to one embodiment, Y¹is a 9- to 11-membered bicyclic heteroaryl. According to one embodiment, Y¹is a 9- or 10-membered bicyclic heteroaryl. According to one embodiment, Y¹comprises two fused rings selected from 5-membered heteroaryls and 6-membered heteroaryls.

According to one embodiment, Y¹comprises two fused rings, said rings consisting of:

- a first 5- or 6-membered heteroaryl ring selected from:
  - formula (Y¹-0-1-A-a)

[Image Omitted]

- - - wherein G^Ais selected from C—R²and N, G^Bis selected from C—R³and N, and G^Cand G^Dare independently selected from C—R², C—R³and N (wherein R²and R³are independently as defined hereinbelow), and
  - formula (Y¹-0-1-A-b)

[Image Omitted]

- - - wherein G^Aand G^Bare independently selected from C—R², C—R³and N, and G^Eis selected from O, S and N—R⁴, in particular from O and N—R⁴(wherein R², R³and R⁴are independently as defined hereinbelow), and
- a second ring selected from 5-membered heteroaryl, 6-membered heteroaryl and aryl, wherein the second ring is fused with G^Aand G^B, G^Band G^C, G^Cand G^D, or G^Band G^Eof the first ring, to form the 5-membered heteroaryl, 6-membered heteroaryl or aryl.

According to one embodiment, Y¹is a 9- or 10-membered bicyclic heteroaryl selected from the following group of formulae (Y¹—I)

[Image Omitted]

- wherein A¹, A², A³, A⁴, A⁵, A⁶and A⁷are each independently selected from C—R⁷and N; A¹, A⁹, A¹⁰and A¹¹are each independently selected from C—R⁷and N; G¹is selected from C—R³and N; G²is selected from O and N—R⁴; and B is selected from O, S and N—R⁵. “(ScX)” means “(Scaffold n° X”).

According to one embodiment, Y¹is a 9- or 10-membered bicyclic heteroaryl selected from the following group of formulae (Y¹—I′)

[Image Omitted]

- wherein A¹, A², A³, A⁴, A⁵, A⁶and A⁷are each independently selected from C—R⁷and N; A¹, A¹, A¹⁰and A¹¹are each independently selected from C—R⁷and N; G¹is selected from C—R³and N; G²is selected from O and N—R⁴; and B is selected from O, S and N—R⁵. “(ScX)” means “(Scaffold n° X”).

According to one embodiment, Y¹is a 9- or 10-membered bicyclic heteroaryl selected from the following group of formulae (Y¹-Ia)

[Image Omitted]

- wherein A¹, A², A³, A⁴, A⁵, A⁶and A⁷are each independently selected from C—R⁷and N; A¹, A⁹, A¹⁰and A¹¹are each independently selected from C—R⁷and N; G¹is selected from C—R³and N; and B is selected from O, S and N—R⁵. “(ScX)” means “(Scaffold n° X”).

In one embodiment, when A¹, A⁹, A¹⁰and A¹¹are present, at least one of A¹, A⁹, A¹⁰or A¹¹is N. In one embodiment when A⁵and A⁶are present, when A⁵and A⁶are C—R⁷, then B is not S. In one embodiment when A⁵, A⁶and A⁷are present, when A⁵, A⁶and A⁷are C—R⁷, then B is not S. In one embodiment, G¹is N.

According to one embodiment, Y¹is a 9- or 10-membered bicyclic heteroaryl selected from the following group of formulae (Y¹—I-1)

[Image Omitted]

- wherein A¹-A⁴, A⁶, A⁷, G¹and R²are independently as defined herein.

According to one embodiment, Y¹is a 9-membered bicyclic heteroaryl selected from the following group of formulae (Y¹—I-2)

[Image Omitted]

- wherein A¹-A⁴, A¹-A¹¹, G¹and G²are independently as defined herein.

According to one embodiment, Y¹is a 9-membered bicyclic heteroaryl of formula (Y¹-0-2)

[Image Omitted]

- Wherein G¹is selected from C—R³and N, B¹-B⁵are selected from O, S, and any one of A⁵, A⁶or A⁷as defined herein; and B¹-B⁵form together a 5-membered heteroaryl, i.e., the bonds between B¹-B⁵are so arranged that the cycle is aromatic and at least one among B¹-B⁵is selected from O, S and N—R⁵.

According to one embodiment, Y¹is a 10-membered bicyclic heteroaryl of formulae (Y¹-Ia-1)

[Image Omitted]

- wherein A¹-A⁴, G¹and R²are independently as defined herein.

In Y¹as defined herein, R²is selected from hydrogen, halogen, cyano, amino, hydroxy, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —OR¹⁵, —(C₁-C₆) alkylene-OR¹⁵, —O—(C₂-C₆) alkylene-OR¹⁵, —NR¹⁶(C₂-C₆) alkylene-OR¹⁵, —NR¹⁷R¹⁸, —(C₁-C₆) alkylene-NR¹⁷R¹⁸, —O—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —(C₁-C₆) alkylene-SO₂—NR¹⁷R¹⁸, —NR¹⁶—SO₂—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷—SO₂—R¹⁵, —C(O)—NR¹⁷R¹⁸, —(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —O—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶C(O)—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —C(O)—R¹⁵, —C(O)OR¹⁵, —(C₁-C₆) alkylene-C(O)OR¹⁵, —O—(C₁-C₆) alkylene-C(O)OR¹⁵, —NR¹⁶—(C₁-C₆) alkylene-C(O)OR¹⁵.

In one embodiment, R²is a —(C₁-C₆) alkyl such as, for example, methyl, iso-propyl, ethyl or alkyl, wherein the alkyl is optionally substituted by at least on fluorine atom. Preferred substituted —(C₁-C₆) alkyls include difluoromethyl and trifluoromethyl.

In one embodiment, R²is hydrogen. In one embodiment, R²is a —(C₃-C₇) cycloalkyl such as, for example, cyclopropyl optionally substituted by at least one methyl, hydroxy or fluorine atom. In one embodiment, R²is a —(C₃-C₇) heterocycloalkyl such as, for example, tetrahydrothiophene or tetrahydrofuran, optionally substituted by at least one methyl. In one embodiment, R²is a heteroaryl such as, for example, thiophene or furan optionally substituted by at least one methyl or ethyl. In one embodiment, R²is a —(C₃-C₇) heterocycloalkyl such as, for example, morpholine optionally substituted by at least one methyl, hydroxy or fluorine atom.

In Y as defined herein, R³is selected from halogen, cyano, amino, hydroxy, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —OR¹⁵, —(C₁-C₆) alkylene-OR¹⁵, —O—(C₂-C₆) alkylene-OR¹⁵, —NR¹⁶(C₂-C₆) alkylene-OR¹⁵, —NR¹⁷R¹⁸, —(C₁-C₆) alkylene-NR¹⁷R¹⁸, —O—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —(C₁-C₆) alkylene-SO₂—NR¹⁷R¹⁸, —NR¹⁶—SO₂—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷—SO₂—R¹⁵, —C(O)—NR¹⁷R¹⁸, —(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —O—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶C(O)—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —NR¹⁶—(C₂—C₆) alkylene-NR¹⁶C(O)—R¹⁵, —C(O)—R¹⁵, —C(O)OR¹⁵, —(C₁-C₆) alkylene-C(O)OR¹⁵, —O—(C₁-C₆) alkylene-C(O)OR¹⁵, —NR¹⁶—(C₁-C₆) alkylene-C(O)OR¹⁵.

In Y¹as defined herein, R⁴is selected from hydrogen, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-aryl, —(C₁-C₆) alkylene-heteroaryl, —(C₁-C₆) alkylene-OR¹⁵, —(C₁-C₆) alkylene-NR¹⁷R¹⁸, —(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —(C₁-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —(C₁-C₆) alkylene-C(O)OR¹⁵, and —(C₁-C₆) alkylene-OC(O)—R¹⁵.

In one embodiment, R⁴is hydrogen.

In Y¹as defined herein, R⁵is selected from hydrogen, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-aryl, —(C₁-C₆) alkylene-heteroaryl, —(C₁-C₆) alkylene-OR¹⁵, —(C₁-C₆) alkylene-NR¹⁷R¹⁸, —(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —(C₁-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —(C₁-C₆) alkylene-C(O)OR¹⁵, and —(C₁-C₆) alkylene-OC(O)—R¹⁵.

In one embodiment, R⁵is a —(C₁-C₆) alkyl such as methyl. In one embodiment, R⁵is an aryl such as, for example, phenyl optionally substituted by at least one halo or methyl.

In Y¹as defined herein, R⁷is independently selected from hydrogen, halogen, amino, hydroxy, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —OR¹⁵, —(C₁-C₆) alkylene-OR¹⁵, —O—(C₂-C₆) alkylene-OR¹⁵, —NR¹⁶(C₂-C₆) alkylene-OR¹⁵, —NR¹⁷R¹⁸, —(C₁-C₆) alkylene-NR¹⁷R¹⁸, —O—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷R¹⁸, —SO—R¹⁵, —SO₂—R¹⁵, —SO₂NR¹⁷R¹⁸, —(C₁-C₆) alkylene-SO₂—NR¹⁷R¹⁸, —NR¹⁶—SO₂—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶—SO₂—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷—SO₂—R¹⁵, —C(O)—NR¹⁷R¹⁸, —(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —O—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶—(C₁-C₆) alkylene-C(O)—NR¹⁷R¹⁸, —NR¹⁶C(O)—R¹⁵, —(C₁-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —O—(C₂-C₆) alkylene-NR¹⁶C(O)—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-NR¹⁷C(O)—R¹⁵, —C(O)—R¹⁵, —C(O)OR¹⁵, —(C₁-C₆) alkylene-C(O)OR¹⁵, —O—(C₁-C₆) alkylene-C(O)OR¹⁵, —NR¹⁶—(C₁—C₆) alkylene-C(O)OR¹⁵, —OC(O)—R¹⁵, —(C₁-C₆) alkylene-OC(O)—R¹⁵, —O—(C₂-C₆) alkylene-OC(O)—R¹⁵, —NR¹⁶—(C₂-C₆) alkylene-OC(O)—R¹⁵or —NR¹⁶—C(O)OR¹⁵.

In one embodiment, R⁷is hydrogen. In one embodiment, R⁷is a —(C₁-C₆) alkyl such as, for example, methyl.

In one embodiment, R⁷is (C₃-C₇) heterocycloalkyl such as, for example, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted 1,4-oxazepanyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl or optionally substituted 2-oxa-5-azabicyclo[2.2.2]octan-5-yl. In one embodiment, the (C₃-C₇) heterocycloalkyl is substituted by one or two —(C₁-C₆) alkyl such as, for example, one or two methyl.

In R², R³, R⁴and R⁷as defined herein, R¹⁵, R¹⁶, R¹⁷and R¹⁸are each independently selected from hydrogen, —(C₁-C₆) haloalkyl, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-heteroaryl, and —(C₁-C₆) alkylene-aryl; and/or two groups selected from R¹⁵, R¹⁶, R¹⁷and R¹⁸form together a cycle selected from —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl and heteroaryl.

In one embodiment, Y¹is a 10-membered [6,6]bicyclic heteroaryl.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-1)

[Image Omitted]

- wherein R², R³and R⁷are independently as defined herein.

In one embodiment, Y¹is a 9-membered bicyclic [6,5]heteroaryl.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-2)

[Image Omitted]

- wherein R², R³, R⁵and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-3)

[Image Omitted]

- wherein R², R³, R⁵and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-4)

[Image Omitted]

- wherein R², R³, R⁵and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-5)

[Image Omitted]

- wherein R², R³and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-6)

- wherein R², R³and R⁷are independently as defined herein.

[Image Omitted]

In one embodiment, Y¹is a 9-membered bicyclic [5,6]heteroaryl.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-7)

[Image Omitted]

- wherein R²and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-8)

[Image Omitted]

- wherein A¹, A², A A⁴and R⁴are independently as defined herein.

In one embodiment, Y¹is selected from optionally substituted naphthyridine (such as, for example, optionally substituted 1,7-naphthyridine, 1,6-naphthyridine or 2,7-naphthyridine), optionally substituted 1H-pyrazolo-pyrimidine, optionally substituted 2H-pyrazolo-pyrimidine, optionally substituted benzimidazole, optionally substituted benzoxazole, optionally substituted imidazo[1,2-a]pyrazine, optionally substituted imidazo[1,5-a]pyrazine, optionally substituted imidazo[4,5-b]pyridine, optionally substituted pyrazolo[1,5-a][1,3,5]triazine, optionally substituted pyrazolo[1,5-a]pyrazine, optionally substituted pyrido[2,3-d]pyrimidine, optionally substituted pyrido[3,2-d]pyrimidine, optionally substituted pyrido[3,4-d]pyrimidine, optionally substituted oxazolo[4,5-b]pyridine, optionally substituted oxazolo[4,5-c]pyridine, optionally substituted oxazolo[5,4-b]pyridine, substituted oxazolo[5,4-c]pyridine, optionally substituted quinazoline, optionally substituted quinoline, and optionally substituted phthalazine.

In one embodiment, Y¹is optionally substituted 1H-pyrazolo-pyrimidine. In one embodiment, Y¹is 1H-pyrazolo-pyrimidine. In one embodiment, Y¹is optionally substituted 2H-pyrazolo-pyrimidine. In one embodiment, Y¹is 2H-pyrazolo-pyrimidine. In one embodiment, Y¹is selected from optionally substituted pyrido[2,3-d]pyrimidine, optionally substituted pyrido[3,2-d]pyrimidine and optionally substituted pyrido[3,4-d]pyrimidine. Y¹is selected from pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine. In one embodiment, Y¹is optionally substituted quinazoline. In one embodiment, Y¹is quinazoline.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-1a)

[Image Omitted]

- wherein R²and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-2a)

[Image Omitted]

- wherein R², R⁵and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-3a)

[Image Omitted]

- wherein R², R⁵and R⁷are independently as defined herein.

In one embodiment, Y¹is selected from the following group of formulae (Y¹-4a)

[Image Omitted]

- wherein R², R⁵and R⁷are independently as defined herein.

In one embodiment, V is selected from the following group of formulae (Y¹-5a)

[Image Omitted]

- wherein R²and R⁷are independently as defined herein.

In one embodiment, Y¹is optionally substituted phthalazine (such as, for example, phthalazin-1-yl).

In one embodiment, the bicyclic heteroaryl in Y¹is substituted by one or two —(C₁-C₆) alkyl such as, for example, one or two methyl.

Y²Definitions

In formula (I) above, Y²is a monocyclic heteroaryl or aryl. According to one embodiment, Y²is a 5- or 6-membered heteroaryl. According to one embodiment, Y²is a 5-membered heteroaryl.

According to one embodiment, Y²is selected from the following group of formulae (Y²-0)

[Image Omitted]

- wherein R¹², R¹³and R¹⁴are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, —(C₁-C₆) alkyl, —CH₂—O—(C₁-C₆) alkyl, —CH₂—NH—(C₁-C₆) alkyl), —CH₂—N—((C₁-C₆) alkyl)₂, —O—(C₁-C₆) alkyl, —NH—(C₁-C₆) alkyl) and —N—((C₁-C₆) alkyl)₂.

According to one embodiment, Y²is selected from the following group of formulae (Y²—I)

[Image Omitted]

- wherein R¹², R¹³and R¹⁴are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, —(C₁-C₆) alkyl, —CH₂—O—(C₁-C₆) alkyl, —CH₂—NH—(C₁—C₆) alkyl), —CH₂—N—((C₁-C₆) alkyl)₂, —O—(C₁-C₆) alkyl, —NH—(C₁-C₆) alkyl) and —N—((C₁-C₆) alkyl)₂.

In one embodiment, Y²is selected from the following group of formulae (Y²-1)

[Image Omitted]

- wherein R¹², R¹³and R¹⁴are independently as defined herein.

In one embodiment, Y²is selected from optionally substituted thiadiazole, optionally substituted thiazole and optionally substituted thiophene. In one embodiment, Y²is selected from thiophene, fluoro-thiophene, thiadiazole and thiazole.

In one embodiment, R¹²and R¹³, or R¹²and R¹⁴, are selected from hydrogen and (C₁-C₃) alkyl. In one embodiment, R¹²and R¹³, or R¹²and R¹⁴, are each hydrogen, i.e., Y²is a divalent unsubstituted thiophene.

L Definitions

In formula (I) above, L is selected from —(CR¹⁰R¹¹)_n, —(C₃-C₇) cycloalkyl and —(C₃-C₇) heterocycloalkyl, wherein n is an integer ranging from 1 to 10; and R¹⁰and R¹¹are independently selected from hydrogen, halogen, hydroxy, amino, —(C₁-C₆) alkyl, —O—(C₁-C₆) alkyl, —NH—(C₁-C₆) alkyl and —N—((C₁-C₆) alkyl)₂.

According to one embodiment, n is an integer selected from 1, 2, 3 and 4.

According to one embodiment, R¹⁰and R¹¹are independently selected from hydrogen, halogen, hydroxy, amino, —(C₁-C₃) alkyl, —(C₁-C₂) haloalkyl, —(C₁-C₂) hydroxyalkyl, —(C₁-C₂) aminoalkyl, —O—(C₁-C₄) alkyl, —NH—(C₁-C₃) alkyl and —N—((C₁-C₃) alkyl)₂.

In one embodiment, L is selected from —(C₄-C₇) cycloalkyl and —(C₄-C₇) heterocycloalkyl. In one particular embodiment, L is selected from —(C₅-C₆) cycloalkyl and —(C₅-C₆) heterocycloalkyl.

In one embodiment, n is an integer selected from 1, 2 and 3. In one embodiment, n is an integer selected from 1 and 2. In one embodiment, n is 1. In one embodiment, n is 2.

In one embodiment, R¹⁰and R¹¹are each independently selected from hydrogen and (C₁-C₃) alkyl. In one embodiment, R¹⁰and R¹¹are each hydrogen.

Z¹Definitions

In formula (I) above, Z¹is selected from (C═O)—R⁹, S(O)—R⁹and S(O₂)—R⁹. According to one embodiment, Z¹is selected from (C═O)—R⁹and S(O₂)—R⁹,

In Z¹as defined herein, R⁹is selected from amino, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-aryl, —(C₁-C₆) alkylene-heteroaryl, —(C₁-C₆) alkylene-OR²¹, —(C₁-C₆) alkylene-NR²³R²⁴, —(C₁-C₆) alkylene-C(O)—NR²³R²⁴, —(C₁-C₆) alkylene-C(O)—NR²³R²⁴, —(C₁-C₆) alkylene-NR²²—C(O)—R²¹, —(C₁-C₆) alkylene-C(O)OR²¹, —OR²¹, —NR²³R²⁴, —NR²²—(C₂-C₆) alkylene-OR²¹, —NR²²—(C₂-C₆) alkylene-NR²³R²⁴, —NR²²—(C₁-C₆) alkylene-C(O)OR²¹.

In R⁹as defined herein, R²¹, R²², R²³and R²⁴are each independently selected from hydrogen, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) halocycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl, heteroaryl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-heteroaryl, and —(C₁-C₆) alkylene-aryl; and/or two groups selected from R²¹, R²², R²³and R²⁴form together a cycle selected from —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, aryl and heteroaryl.

In one embodiment, R⁹is selected from methyl, tert-butyl, cyclopropyl, O-tert-butyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, methoxymethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, phenylmethyl, phenyl 2,2-difluorocyclopropyl 2,2,3,3,3-pentafluoro-propyl, H₂N-methyl, N-methyl-NH-methyl, methylazetidinyl, 1-hydroxyethyl (e.g., (S)-1-hydroxyethyl or (R)-1-hydroxyethyl) and pyrrolidinyl. In one embodiment, R⁹is selected from cyclopropyl, hydroxymethyl, (S)-3,3,3-trifluoro-2-hydroxypropyl, 2-hydroxypropan-2-yl, 1-hydroxycyclopropyl, 2,2-difluorocyclopropyl and 2,2,3,3,3-pentafluoro-propyl.

R¹Definitions

In formula (I) above, R¹is either a singular non-cyclic moiety, or R¹is merged with another moiety in formula (I) to form an heterocycloalkyl comprising at least one nitrogen atom.

According to a first embodiment of the invention, R¹is selected from hydrogen, —(C₁-C₆) alkyl, —(C₃-C₇) cycloalkyl, —(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) cycloalkyl, —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, —(C₁-C₆) alkylene-OR¹⁹and —(C₁-C₆) alkylene-NR¹⁹R²⁰, wherein R¹⁹and R²⁰are each independently selected from hydrogen, —(C₁-C₆) alkyl and —(C₃-C₇) cycloalkyl; or R¹⁹and R²⁰form together a cycle selected from —(C₃-C₇) cycloalkyl and —(C₃-C₇) heterocycloalkyl.

According to a second embodiment of the invention, R¹and one of R¹⁰or R¹¹from together a (C₃-C₇) heterocycloalkyl comprising at least one nitrogen atom;

According to a third embodiment of the invention, R¹and R⁹(as defined herein in the definition of R⁹) form together a (C₃-C₇) heterocycloalkyl comprising at least one nitrogen atom.

In one embodiment, R¹is selected from hydrogen and (C₁-C₃) alkyl, preferably R¹is hydrogen or methyl. In one embodiment, R¹is hydrogen. In one embodiment, R¹and one of R¹⁰or R¹¹form together a 5- or 6-membered heterocycloalkyl comprising one nitrogen atom. In one embodiment, R¹and one of R¹⁰or R¹¹form together a pyrrolidine. In one embodiment, R¹and R⁹from together a 5- or 6-membered heterocycloalkyl comprising one nitrogen atom. In one embodiment, R¹and R⁹form together a pyrrolidinone or a morpholin-3-one.

Specific Compounds

According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 below.

TABLE 1

Cpd #
Structure
Name

1

[Image Omitted]

N-((5-(2-((2-isopropylquinazolin- 4-yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

2

[Image Omitted]

N-((5-(2-((2- cyclopropylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

3

[Image Omitted]

N-((5-(2-((2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

4

[Image Omitted]

N-((5-(2-((2- (methoxymethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

5

[Image Omitted]

N-((5-(2-((1,6-dimethyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

6

[Image Omitted]

N-((5-(2-((6-cyclopropyl-1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

7

[Image Omitted]

N-((5-(2-((2-methylpyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

8

[Image Omitted]

N-((5-(2-((7-chloro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

9

[Image Omitted]

N-((5-(2-((6-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

10

[Image Omitted]

N-((5-(2-((7-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

11

[Image Omitted]

N-((5-(2-((2,7-dimethylquinazolin- 4-yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

12

[Image Omitted]

N-((5-(2-((7-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

13

[Image Omitted]

N-((5-(2-((2-ethylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

14

[Image Omitted]

N-((5-(2-((2-cyclobutylquinazolin- 4-yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

15

[Image Omitted]

N-((5-(2-((8-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

16

[Image Omitted]

N-((5-(2-((2- (dimethylamino)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

17

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

18

[Image Omitted]

N-((5-(2-((2-methylpyrido[3,2- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

19

[Image Omitted]

N-((5-(2-((2- (difluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

20

[Image Omitted]

N-((5-(2-((1-methyl-6- (trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

21

[Image Omitted]

N-((5-(2-((6-(difluoromethyl)-1- methyl-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

22

[Image Omitted]

N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

23

[Image Omitted]

N-((5-(2-((5-methyloxazolo[4,5- b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

24

[Image Omitted]

3-methyl-1-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

25

[Image Omitted]

1-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

26

[Image Omitted]

1-(2-(5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)pyrrolidin-2-one

27

[Image Omitted]

N-((2-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiazol-5- yl)methyl)pivalamide

28

[Image Omitted]

N-((3-fluoro-5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

29

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)pivalamide

30

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)benzamide

31

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanecarboxamide

32

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-phenylacetamide

33

[Image Omitted]

N-methyl-N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

34

[Image Omitted]

N-methyl-N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanecarboxamide

35

[Image Omitted]

N-((5-(2-((2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanecarboxamide

36

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)cyclopropanecarboxamide

37

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)benzamide

38

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

39

[Image Omitted]

2,2-difluoro-N-((5-(2-((6-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

40

[Image Omitted]

2,2,3,3,3-pentafluoro-N-((5-(2-((6- methoxy-2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

41

[Image Omitted]

N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanecarboxamide

42

[Image Omitted]

3,3,3-trifluoro-2-hydroxy-N-((5-(2- ((1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

43

[Image Omitted]

N-((5-(2-((2-cyclopropyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2,2- difluorocyclopropane-1- carboxamide

44

[Image Omitted]

N-((5-(2-((2-cyclopropyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2,2,3,3,3- pentafluoropropanamide

45

[Image Omitted]

1-hydroxy-N-((5-(2-((5- (trifluoromethyl)oxazolo[4,5- b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

46

[Image Omitted]

3,3,3-trifluoro-2-hydroxy-N-((5-(2- ((2-methyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

47

[Image Omitted]

1-hydroxy-N-((5-(2-((6- morpholino-2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

48

[Image Omitted]

2-hydroxy-2-methyl-N-((5-(2-((2- methyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

49

[Image Omitted]

1-hydroxy-N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

50

[Image Omitted]

1-hydroxy-N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

51

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanecarboxamide

52

[Image Omitted]

2-hydroxy-2-methyl-N-((5-(2-((1- methyl-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

55

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-(pyridin-2- yl)acetamide

56

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-(pyridin-3- yl)acetamide

57

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-(pyridin-4- yl)acetamide

58

[Image Omitted]

2-methoxy-N-((5-(2-((1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

59

[Image Omitted]

2-hydroxy-N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

60

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

61

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

62

[Image Omitted]

N-((5-(2-((2-ethylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

63

[Image Omitted]

2-hydroxy-N-((5-(2-((6- morpholino-2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

64

[Image Omitted]

2-hydroxy-N-((5-(2-((2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

65

[Image Omitted]

N-((5-(2-((2,6-dimethyl-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

66

[Image Omitted]

2-hydroxy-N-((5-(2-((2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

67

[Image Omitted]

N-((5-(2-((6-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

68

[Image Omitted]

N-((5-(2-((7-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

69

[Image Omitted]

N-((5-(2-((6-(difluoromethyl)-2- methyl-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

70

[Image Omitted]

2-hydroxy-N-((5-(2-((7-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

71

[Image Omitted]

2-hydroxy-N-((5-(2-((6- (trifluoromethyl)oxazolo[5,4- c]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

72

[Image Omitted]

2-hydroxy-N-((5-(2-((5- (trifluoromethyl)oxazolo[4,5- b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

73

[Image Omitted]

N-((5-(2-((6-chloro-7-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

74

[Image Omitted]

2-hydroxy-N-((5-(2-((1-methyl-6- (trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

75

[Image Omitted]

N-((5-(2-((7-fluoro-6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

76

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

77

[Image Omitted]

N-((5-(2-((6-cyclopropoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

78

[Image Omitted]

N-((5-(2-((6- ((cyclopropylmethyl)amino)-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

79

[Image Omitted]

N-((5-(2-((2-cyclopropyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

80

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy-2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

81

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- morpholinoquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

82

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (piperidin-1-yl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

83

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (1,4-oxazepan-4-yl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

84

[Image Omitted]

N-((5-(2-((6-(3,3- difluoropyrrolidin-1-yl)-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

85

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (4-methylpiperazin-1- yl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

86

[Image Omitted]

2-hydroxy-1-(3-(5-(2-((1-methyl- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)pyrrolidin-1-yl)ethan-1-one

87

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)methanesulfonamide

88

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)benzenesulfonamide

89

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanesulfonamide

90

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-1- phenylmethanesulfonamide

91

[Image Omitted]

N-methyl-N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanesulfonamide

92

[Image Omitted]

N-methyl-N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-1-(pyridin-4- yl)methanesulfonamide

93

[Image Omitted]

1-cyclopropyl-N-((5-(2-((2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)methanesulfonamide

94

[Image Omitted]

N-(2-(5-(2-((2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)methanesulfonamide

95

[Image Omitted]

1-(5-(1-(methylsulfonyl)pyrrolidin- 3-yl)thiophen-2-yl)-2-((2- (trifluoromethyl)quinazolin-4- yl)thio)ethan-1-one

96

[Image Omitted]

3-(5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)pyrrolidine-1-sulfonamide

97

[Image Omitted]

N-((5-(2-((2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)methanesulfonamide

98

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)methanesulfonamide

105

[Image Omitted]

2-hydroxy-N-((5-(2-((5- (trifluoromethyl)benzo[d]oxazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

106

[Image Omitted]

N-((5-(2-((6-cyclopropyl-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

107

[Image Omitted]

2-hydroxy-N-((5-(2-((7-methyl-2- (trifluoromethyl)pyrazolo[1,5- a][1,3,5]triazin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

108

[Image Omitted]

N-((5-(2-((8-fluoro-6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

109

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-N-methylacetamide

110

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

111

[Image Omitted]

2,2-difluoro-N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

112

[Image Omitted]

N-((5-(2-((7-cyclopropyl-2- (trifluoromethyl)pyrazolo[1,5- a][1,3,5]triazin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

113

[Image Omitted]

2-hydroxy-N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

114

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

115

[Image Omitted]

3-hydroxy-1-(2-(5-(2-((6-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)pyrrolidin-2-one

116

[Image Omitted]

2-hydroxy-N-methyl-N-((5-(2-((2- methyl-6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

117

[Image Omitted]

2-hydroxy-N-((5-(2-((5- (trifluoromethyl)oxazolo[5,4- b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

118

[Image Omitted]

2-hydroxy-N-((5-(2-((6- (trifluoromethyl)oxazolo[4,5- b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

119

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

120

[Image Omitted]

2,2-difluoro-N-((5-(2-((2-methyl-6- (trifluoromethoxy)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

121

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-methylpyrido[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

122

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropanesulfonamide

123

[Image Omitted]

2,2,2-trifluoro-N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)ethane-1-sulfonamide

124

[Image Omitted]

N-((5-(2-((6-fluoro-2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

125

[Image Omitted]

2-hydroxy-N-((5-(2-((1-(2- methoxyethyl)-6-(trifluoromethyl)- 1H-pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

126

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-6- (trifluoromethoxy)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

127

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)ethanesulfonamide

128

[Image Omitted]

(S)-2-hydroxy-N-(1-(5-(2-((6- methoxy-2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)acetamide

129

[Image Omitted]

(S)-2-hydroxy-N-(1-(5-(2-((6- (trifluoromethyl)oxazolo[4,5- c]pyridin-2- yl)thio)acetyl)thiophen-2- yl)ethyl)acetamide

130

[Image Omitted]

(S)-2-hydroxy-N-(1-(5-(2-((1- methyl-6-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)ethyl)acetamide

131

[Image Omitted]

2-hydroxy-N-methyl-N-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

132

[Image Omitted]

2-hydroxy-N-((5-(2-((2-(2- methoxyethyl)-6-(trifluoromethyl)- 2H-pyrazolo[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

133

[Image Omitted]

N-((5-(2-((1-cyclopropyl-6- (trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

134

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-(trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-methylpropanamide

135

[Image Omitted]

N-((5-(2-((2-ethyl-6- (trifluoromethyl)-2H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

136

[Image Omitted]

N-((5-(2-((1-ethyl-6- (trifluoromethyl)-1H-pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

137

[Image Omitted]

4-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)morpholin-3-one

138

[Image Omitted]

4-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)morpholin-3-one

139

[Image Omitted]

N-((5-(2-((2-(difluoromethyl)-6- methoxyquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

140

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

141

[Image Omitted]

3-hydroxy-1-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

142

[Image Omitted]

N-((5-(2-((6-chloro-8-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

143

[Image Omitted]

2-hydroxy-N-((5-(2-((5-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

144

[Image Omitted]

N-((5-(2-((6-ethoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

145

[Image Omitted]

N-((5-(2-((6-ethoxy-2- methylpyrido[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

146

[Image Omitted]

N-((5-(2-((6-chloro-5-fluoro-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

147

[Image Omitted]

N-((5-(2-((6-(2-oxa-5- azabicyclo[2.2.2]octan-5-yl)-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

148

[Image Omitted]

2-hydroxy-N-((5-(2-((8-methoxy- 2-methyl-6- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

149

[Image Omitted]

N-((5-(2-((6-(dimethylamino)-2- methylpyrido[3,4-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

150

[Image Omitted]

N-((5-(2-((8-(dimethylamino)-2- methyl-6- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

151

[Image Omitted]

2-hydroxy-N-((5-(2-((2-methyl-8- (methylamino)-6- (trifluoromethyl)quinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

152

[Image Omitted]

2-hydroxy-N-((5-(2-((2- (trifluoromethyl)pyrido[3,2- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

153

[Image Omitted]

2-hydroxy-N-((5-(2-((2- methylpyrido[3,2-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

154

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

155

[Image Omitted]

(S)-3-hydroxy-1-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

156

[Image Omitted]

(R)-3-hydroxy-1-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

157

[Image Omitted]

1-((5-(2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidin-2-one

158

[Image Omitted]

N-((5-(2-((5-fluoro-6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

159

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-N-methylacetamide

160

[Image Omitted]

N-((5-(2-((6-ethoxy-2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

161

[Image Omitted]

4-((5-(2-((6-methoxy-2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)morpholin-3-one

162

[Image Omitted]

2-hydroxy-N-((5-(2-((6-methoxy- 2-methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-N-methylacetamide

163

[Image Omitted]

2-methoxy-N-((5-(2-((6-methoxy- 2-methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

164

[Image Omitted]

N-((5-(2-((2-(difluoromethyl)-6- methoxypyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

165

[Image Omitted]

N-((5-(2-((1,7-naphthyridin-8- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

166

[Image Omitted]

N-((5-(2-((6-chloro-3H- imidazo[4,5-b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

167

[Image Omitted]

2-hydroxy-N-((5-(2-((5- methoxybenzo[d]oxazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

168

[Image Omitted]

2-hydroxy-N-((5-(2-((4- methoxybenzo[d]oxazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

169

[Image Omitted]

2-hydroxy-N-((5-(2-((1-methyl- 1H-benzo[d]imidazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

170

[Image Omitted]

2-hydroxy-N-((5-(2-((5- methylbenzo[d]oxazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

171

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)tetrahydrofuran-2- carboxamide

172

[Image Omitted]

2,2-difluoro-N-((5-(2-((6-methoxy- 2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

173

[Image Omitted]

2-hydroxy-N-((5-(2-((5-methoxy- 3H-imidazo[4,5-b]pyridin-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

174

[Image Omitted]

N-((5-(2-((5-chlorobenzo[d]oxazol- 2-yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

176

[Image Omitted]

2-hydroxy-N-((5-(2-(imidazo[1,2- a]pyrazin-8-ylthio)acetyl)thiophen- 2-yl)methyl)acetamide

177

[Image Omitted]

2-amino-N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

178

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-1-methylazetidine-3- carboxamide

179

[Image Omitted]

N-((5-(2-((1,6-naphthyridin-5- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

180

[Image Omitted]

N-((5-(2-((2,7-naphthyridin-1- yl)thio)acetyl)thiophen-2- yl)methyl)-2-hydroxyacetamide

181

[Image Omitted]

2-hydroxy-N-((5-(2-(imidazo[1,5- a]pyrazin-8-ylthio)acetyl)thiophen- 2-yl)methyl)acetamide

182

[Image Omitted]

2-hydroxy-N-((5-(2-(pyrazolo[1,5- a]pyrazin-4-ylthio)acetyl)thiophen- 2-yl)methyl)acetamide

183

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-2- (methylamino)acetamide

184

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)pyrrolidine-2- carboxamide

185

[Image Omitted]

(S)-2-hydroxy-N-((5-(2-((6- methoxy-2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

186

[Image Omitted]

(R)-2-hydroxy-N-((5-(2-((6- methoxy-2-methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)propanamide

189

[Image Omitted]

3-((5-(2-((6-methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)-1,1-dimethylurea

190

[Image Omitted]

tert-butyl ((5-(2-((6-methoxy-2- methylpyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen-2- yl)methyl)carbamate

191

[Image Omitted]

N-((5-(2-((3- (trifluoromethyl)isoquinolin-1- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

192

[Image Omitted]

N-((5-(2-(1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- ylthio)acetyl)-1,3,4-thiadiazol-2- yl)methyl)pivalamide

193

[Image Omitted]

N-((5-(2-(phthalazin-1- ylthio)acetyl)thiophen-2- yl)methyl)pivalamide

194

[Image Omitted]

N-((5-(2-((4-methylphthalazin-1- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide

195

[Image Omitted]

N-((5-(2-((4- (trifluoromethyl)phthalazin-1- yl)thio)acetyl)thiophen-2- yl)methyl)pivalamide)

196

[Image Omitted]

2-hydroxy-N-((5-(2-((4- (trifluoromethyl)benzo[d]oxazol-2- yl)thio)acetyl)thiophen-2- yl)methyl)acetamide

According to one embodiment, the compound of formula (I) is selected from the

TABLE 2

Cpd

#
CAS#
Structure
Name

99
1287068-38-5

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl) quinazolin-4- yl)thio)acetyl)thiophen- 2-yl)methyl)acetamide

100
1147354-39-9

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl) quinazolin-4- yl)thio)acetyl)thiophen- 2-yl)ethyl)acetamide

101
1010596-81-2

[Image Omitted]

N-(2-(5-(2-((2- cyclopropylquinazolin- 4- yl)thio)acetyl)thiophen- 2-yl)ethyl)acetamide

102
1210761-93-5

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen- 2-yl)methyl)pivalamide

103
1011002-97-3

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4- d]pyrimidin-4- yl)thio)acetyl)thiophen- 2-yl)methyl)acetamide

104
2419446-18-5

[Image Omitted]

N-(2-(5-(2-((5- methyloxazolo[4,5- b]pyridin-2- yl)thio)acetyl)thiophen- 2-yl)ethyl)acetamide

The compounds of Table 1 and Table 2 were named using ChemDraw® Professional 15.0 (PerkinElmer).

According to one embodiment, the compound of formula (I) is selected from the compounds of Table 1 or Table 2 herein.

Alternative Compounds

All references herein to a compound of the invention (e.g., a “compound of formula (I)”) include references to salts—preferably pharmaceutically acceptable salts, solvates, multi component complexes and liquid crystals thereof. All references herein to a compound of the invention include references to polymorphs and crystal habits thereof. All references to a compound of the invention include references to pharmaceutically acceptable prodrugs thereof. All references to a compound of the invention include references to isotopically-labelled compounds, including deuterated compounds.

A compound of the invention (e.g., a “compound of formula (I)”) and subformulae thereof may contain at least one asymmetric centre(s) and thus may exist as different stereoisomeric forms. Accordingly, all references to a compound of the invention include references to all possible stereoisomers and includes not only the racemic compounds but the individual enantiomers and their non-racemic mixtures as well. When a compound is desired as a single enantiomer, such single enantiomer may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as each are known in the art. Resolution of the final product, an intermediate, or a starting material may be carried out by any suitable method known in the art.

The compounds of the invention (e.g., a “compound of formula (I)”) may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, 2-(diethylamino)ethanol, diolamine, ethanolamine, glycine, 4-(2-hydroxyethyl)-morpholine, lysine, magnesium, meglumine, morpholine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. When a compound contains an acidic group as well as a basic group the compound may also form internal salts, and such compounds are within the scope of the invention. When a compound contains a hydrogen-donating heteroatom (e.g., NH), the invention also covers salts and/or isomers formed by transfer of said hydrogen atom to a basic group or atom within the molecule. Pharmaceutically acceptable salts of compounds of the invention may be prepared by one or more of these methods: (i) by reacting the compound with the desired acid; (ii) by reacting the compound with the desired base; (iii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using the desired acid; and/or (iv) by converting one salt of the compound to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

Further Compound Definitions

According to one embodiment, the compound of formula (I) is not CAS #1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide) or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

- CAS #2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,
- CAS #1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,
- CAS #871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,
- CAS #1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,
- CAS #1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,
- CAS #1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,
- CAS #1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide,
- CAS #1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and
- pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compound of formula (I) is not selected from:

- CAS #1287068-38-5: N-((5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #2182075-55-2: N-((5-(2-((2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1147354-39-9: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1010596-74-3: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #871674-28-1: N-((5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1147537-22-1: N-((5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1009199-55-6: N-(2-(5-(2-((2-(thiophen-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #1010596-81-2: N-(2-(5-(2-((2-cyclopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1089547-51-2: N-(2-(5-(2-((2-(furan-2-yl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1321173-73-2: N-((5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1320446-60-3: N-(2-(5-(2-((2-(morpholinomethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and pharmaceutically acceptable salts and solvates thereof.

According to one embodiment, when Y¹is optionally substituted quinazolinyl (e.g., quinazolin-4-yl), then R²is not an optionally substituted (C₁-C₆) alkyl, such as, for example, methyl or trifluoromethyl. In one embodiment, when Y¹is optionally substituted quinazolinyl (e.g., quinazolin-4-yl), then R²is not an optionally substituted (C₃-C₇) cycloalkyl such as, for example, cyclopropyl. In one embodiment, when Y¹is optionally substituted quinazolinyl (e.g., quinazolin-4-yl), then R²is not an optionally substituted heteroaryl such as, for example, furanyl or thiophenyl. In one embodiment, when Y¹is optionally substituted quinazolinyl such as quinazolin-4-yl, then R²is not an optionally substituted —(C₁-C₆) alkylene-(C₃-C₇) heterocycloalkyl, such as, for example, —CH₂-morpholinyl.

In one embodiment, Y¹is not optionally substituted quinazolin-4-yl. In one particular embodiment, Y¹is not optionally substituted quinazolinyl.

According to one embodiment, when Y¹is optionally substituted quinazolinyl (e.g., quinazolin-4-yl) and R¹is hydrogen, then Z¹is not an optionally substituted —C(O)—(C₁-C₆) alkyl such as, for example, —C(O)-methyl.

According to one embodiment, when Y¹is optionally substituted quinazolinyl (e.g., quinazolin-4-yl) and R¹is hydrogen, then Z¹is not an optionally substituted —S(O)₂—(C₁-C₆) alkyl such as, for example, —S(O)₂-methyl.

According to one embodiment, the compound of formula (I) is not CAS #1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide [CAS #1326255-51-9] or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide and or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

- CAS #1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,
- CAS #1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,
- CAS #1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,
- CAS #920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide,
- CAS #1324562-11-9; N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide,
- CAS #1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and
- pharmaceutically acceptable salts and solvates thereof.

In one embodiment, the compound of formula (I) is not selected from:

- CAS #1210761-93-5: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide
- CAS #1011056-89-5: N-(2-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1060780-01-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1326255-51-9: N-(2-(5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #920953-29-3: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1324562-11-9: N-(2-(5-(2-((1-(4-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #1011002-97-3: N-((5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1030737-65-5: N-((5-(2-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide, and
- pharmaceutically acceptable salts and solvates thereof.

According to one embodiment, when Y¹is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl), then R⁵is not an optionally substituted (C₁-C₆) alkyl, such as, for example, methyl. In one embodiment, when Y¹is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl), then R⁵is not an optionally substituted aryl, such as, for example, phenyl or fluorophenyl (e.g., 4-fluorophenyl).

In one embodiment, Y¹not optionally substituted 1H-pyrazolo[3,4-d]pyrimidin-4-yl. In one particular embodiment, Y¹not optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl.

According to one embodiment, when Y¹is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl) and R¹is hydrogen, then Z¹is not an optionally substituted —C(O)—(C₁-C₆) alkyl such as, for example, —C(O)-methyl and —C(O)-t-butyl.

According to one embodiment, when Y¹is optionally substituted 1H-pyrazolo[3,4-d]pyrimidinyl (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl) and R¹is hydrogen, then Z¹is not an optionally substituted —S(O)₂—(C₁-C₆) alkyl such as, for example, —SO₂-methyl.

According to one embodiment, the compound of formula (I) is not CAS #1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide or a pharmaceutically acceptable salt or solvate thereof. According to one embodiment, the compound of formula (I) is not CAS #1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the compound of formula (I) is not selected from:

- CAS #1325066-46-3: N-((5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1324658-47-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #1325082-97-0: N-(2-(5-(2-(imidazo[1,5-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #949826-51-1: 2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)acetamide
- CAS #1099735-84-8: N-((5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1009471-75-3: N-(2-(5-(2-((2,4-dimethyl-5-phenylimidazo[1,5-b]pyridazin-7-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1118826-22-4: N-(2-(5-(2-((6,8-dichloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #1299961-73-1: N-((5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #1302276-01-2: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)methanesulfonamide
- CAS #1293687-72-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #878598-17-5: N-((5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide
- CAS #2184821-90-5: N-(2-(5-(2-((8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1297565-13-9: N-(2-(5-(2-((6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #919869-52-6: N-(2-(5-(2-((5,7-dimethyl-[1,2,4]triazolo[4,3-a]pyrimidin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide
- CAS #1001791-67-8: 2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-1-(5-(2-morpholino-2-oxoethyl)thiophen-2-yl)ethan-1-one CAS #874609-73-1: N-((5-(2-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)acetyl)thiophen-2-yl)methyl)pivalamide
- CAS #1010352-07-4: N-(2-(5-(2-((6-(N,N-diethylsulfamoyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide, and
- pharmaceutically acceptable salts and solvates thereof.

In one embodiment, Y¹is not an optionally substituted imidazo[1,5-a]pyridin-3-yl. In one particular embodiment, Y¹is not an optionally substituted imidazo[1,5-a]pyridinyl. In one embodiment, Y¹is not an optionally substituted imidazo[1,5-b]pyridazin-7-yl. In one particular embodiment, Y¹is not an optionally substituted imidazo[1,5-b]pyridazinyl. In one embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In one particular embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl. In one embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyrimidin-3-yl. In one particular embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyrimidinyl. In one embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyridin-3-yl. In one particular embodiment, Y¹is not an optionally substituted [1,2,4]triazolo[4,3-a]pyridinyl.

In one particular embodiment, Y¹is not the group of formula (Sc7)

[Image Omitted]

- wherein A¹-A⁴and G¹are independently as defined hereinabove.

According to one embodiment, the compound of formula (I) is not CAS #2419446-18-5: N-(2-(5-(2-((5-methyloxazolo[4,5-b]pyridin-2-yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide [named using ChemDraw® Professional 15.0 (PerkinElmer)]

[Image Omitted]

- nor a pharmaceutically acceptable salt and/or solvate thereof.

According to one embodiment, Y¹is not an optionally substituted oxazolo[4,5-b]pyridin-2-yl such as, for example, 5-methyloxazolo[4,5-b]pyridin-2-yl. In one particular embodiment, Y¹is not an optionally substituted oxazolo[4,5-b]pyridinyl such as, for example, 5-methyloxazolo[4,5-b]pyridinyl.

According to one embodiment, when Y¹is an optionally substituted oxazolo[4,5-b]pyridin-2-yl (e.g., 5-methyloxazolo[4,5-b]pyridin-2-yl) and R¹is hydrogen, then Z¹is not an optionally substituted —C(O)—(C₁-C₆) alkyl such as, for example, —C(O)-methyl and —C(O)-t-butyl

Manufacturing Process

This invention also relates to process for manufacturing a compound of the invention as described herein. According to one embodiment, the process comprises a step of reacting: (i) a linear or cyclic amine with an acyl chloride, a carboxylic acid or sulfonyl chloride; or (ii) a halo-ketone with a thiol.

Pharmaceutical Compositions

This invention also relates to a pharmaceutical composition comprising a compound of the invention as described herein and at least one pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition does not comprise any therapeutic agent other than the compound of the invention. According to another embodiment, the pharmaceutical composition further comprises at least another therapeutic agent. In one embodiment, the at least another therapeutic agent is selected from therapeutic agent known in the art for treating inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and/or idiopathic diseases.

The compound of the invention may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.

Medical Uses and Methods of Treatment

This invention also relates to a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, for use as a medicament.

According to one particular embodiment, the compound or pharmaceutical composition of the invention is for use in the treatment and/or prevention of an HDAC6-associated disease as defined herein.

This invention also relates to a method of inhibiting an HDAC6 enzyme. According to one embodiment, the inhibition of an HDAC6 enzyme treats and/or prevents an HDAC6-associated disease. According to one embodiment, the method comprises a step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein.

This invention also relates to a method for treating and/or preventing a HDAC6-associated disease comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention as described herein, or of a pharmaceutical composition of the invention as described herein. This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the manufacture of a medicament for the treatment and/or prevention of an HDAC6-associated disease. This invention also relates to the use of a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, in the treatment and/or prevention of an HDAC6-associated disease.

Advantageously, the compound of the invention shows a superior inhibitory activity against an HDAC enzyme (e.g., class II HDAC enzyme, preferably HDAC6 enzyme) compared to state-of-the art compounds for treating and/or preventing an HDAC-associated disease. Advantageously, the compound of the invention shows a low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, hematotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) against an HDAC enzyme (e.g., class II HDAC enzyme, preferably HDAC6 enzyme) compared to state-of-the art compounds for treating and/or preventing an HDAC-associated disease. In particular, the compound of the invention shows a low genetic toxicity.

According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders, cardiovascular diseases, addiction-related disorders, gastrointestinal diseases, pulmonary diseases, metabolic or hormonal disorders, immune disorders, age-related diseases, and idiopathic diseases. According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of inflammatory diseases, autoimmune diseases, proliferative diseases (such as cancers), neurodegenerative diseases, pains, neuropathies, psychiatric diseases, neurodevelopmental disorders, sleep disorders and cardiovascular diseases. According to one embodiment, the HDAC6-associated disease is selected from the group comprising or consisting of proliferative diseases (such as cancers), neurodegenerative diseases, neuropathies and cardiovascular diseases.

A selection of references evidencing that inhibition of HDAC6 has the effect of treating and/or preventing a given class of diseases are listed on Table 3 below.

TABLE 3

Diseases
References

Inflam-
Ran J and Zhou J.: “Targeted inhibition of histone

matory
deacetylase 6 in inflammatory diseases.” Thorac.

diseases
Cancer. 2019; 10(3): 405-412.

Lee J W et al.: “Histone Deacetylase 6 Inhibitor CKD-

506 Inhibits NF-κB Signaling in Intestinal Epithelial

Cells and Macrophages and Ameliorates Acute and

Chronic Murine” Colitis. Inflamm. Bowel Dis. 2020;

26(6): 852-862.

Zhang Q et al. “Role of HDAC6 inhibition in sepsis-

induced acute respiratory distress syndrome.” Exp Ther

Med. 2021; 21(5): 422.

Autoimmune
Park J K et al.: “Therapeutic potential of CKD-506, a

diseases
novel selective histone deacetylase 6 inhibitor, in a

murine model of rheumatoid arthritis.” Arthritis Res

Ther. 2020; 22(1): 176.

Choi E W et al. “CKD-506, a novel HDAC6-selective

inhibitor, improves renal outcomes and survival in a

mouse model of systemic lupus erythematosus.” Sci

Rep. 2018 Nov. 23; 8(1): 17297.

Proliferative
Yussuf K M et al. “Overcome the tumor immunotherapy

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According to one embodiment, the HDAC6-associated disease is an inflammatory disease such as, for example, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and the like. In one embodiment, the inflammatory disease is selected from the group comprising or consisting of acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic inflammatory response syndrome (SIRS), postoperative or posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, diabetic nephropathy, uveitis, suppurative hidradenitis, cerebrospinal meningitis, inflammatory bowel disease, ulcerative colitis and Crohn's disease.

According to one embodiment, the HDAC6-associated disease is an autoimmune disease, such as, for example, arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjogren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylopoietic spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft versus host disease, dermatitis, radiodermatitis, primary biliary cirrhosis, and the like. In one embodiment, the autoimmune disease is selected from the group comprising or consisting of arthritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis), Sjogren's syndrome, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, discoid lupus erythematosus, Castleman's disease, ankylopoietic spondylarthritis, polymyositis, dermatomyositis (DM), polyarteritis nodosa (PN), mixed connective tissue disease (MCTD), scleroderma, lupus erythematosus profundus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, pemphigus, chronic active hepatitis, myasthenia gravis, graft versus host disease, dermatitis, radiodermatitis and primary biliary cirrhosis.

According to one embodiment, the HDAC6-associated disease is a proliferative disease, e.g., cancer, such as, for example, malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastasis melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney or transitional cell carcinoma in urinary duct), uterine cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, chorionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine, tumor fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary, leukemia (such as acute leukemia (e.g., acute lymphatic leukemia or acute myelocytic leukemia), chronic leukemia (e.g., chronic lymphatic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor), myelofibrosis, and the like. In one embodiment, the proliferative disease, e.g., cancer is selected from the group comprising or consisting of malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, chronic sarcoma, metastasis melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer or gastrointestinal stromal tumor), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer or malignant mesothelioma), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma or adenosquamous carcinoma), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ or inflammatory breast cancer), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor or ovarian low malignant potential tumor), prostate cancer (e.g., hormone-dependent prostate cancer or non-hormone dependent prostate cancer), liver cancer (e.g., primary liver cancer or extrahepatic bile duct cancer), thyroid cancer (e.g., medullary thyroid carcinoma), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney or transitional cell carcinoma in urinary duct), uterine cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma or anaplastic astrocytoma), melanoma, sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic neurinoma, retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer, penile cancer, urinary duct cancer, testis tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, chorionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine, tumor fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary, leukemia (such as acute leukemia (e.g., acute lymphatic leukemia or acute myelocytic leukemia), chronic leukemia (e.g., chronic lymphatic leukemia or chronic myelocytic leukemia)), myelodysplastic syndrome, uterine sarcoma (e.g., mixed mesodermal tumor, uterine leiomyosarcoma or endometrial stromal tumor) and myelofibrosis. In one particular embodiment, the proliferative disease is cancer. In one embodiment, the cancer is selected from the group comprising or consisting of malignant melanoma, multiple myeloma, leukemia, lymphoma, breast cancer and Hodgkin's disease.

According to one embodiment, the HDAC6-associated disease is a neurodegenerative disease, such as, for example, Alzheimer's disease, dementia of Alzheimer type, Alzheimer-type senile dementia, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognition memory disorders, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's type dementia, Niemann-Pick syndrome, Down's disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt, and the like. In one embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer's disease, dementia of Alzheimer type, Alzheimer-type senile dementia, Parkinson's disease, muscular dystrophy, Parkinson's disease associated with dementia, senile dementia, age-related cognition memory disorders, Huntington's disease, multi-infarct dementia, frontotemporal lobar degeneration, frontotemporal dementia, Pick's disease, Parkinson's type dementia, Niemann-Pick syndrome, Down's disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, Rubinstein-Taybi syndrome, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND) and Creutzfeldt. In one particular embodiment, the neurodegenerative disease is selected from the group comprising or consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, Niemann-Pick syndrome, Down's disease, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), and multiple sclerosis.

According to one embodiment, the HDAC6-associated disease is a pain (including central or peripheral pain), such as, for example, pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (e.g., incision pain, deep pain, visceral pain or chronic pain after operation), muscular pain (e.g., muscular pain associated with chronic pain disease or stiff shoulder), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, catatonic headache, headache associated with fever or headache associated with hypertension), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, renal pain, urinary tract pain or bladder pain), obstetric and gynecologic pain (mittelschmerz, dysmenorrhea, labor pain), neuropathic pain (e.g., hernia of intervertebral disk, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia or lumbago), migraine, stress headache, catatonic headache, muscular spasm, irritable bowel syndrome, and the like. In one embodiment, the pain is selected from the group comprising or consisting of pain, cancer pain, acute pain caused by inflammation, pain associated with chronic inflammation, postoperative pain (e.g., incision pain, deep pain, visceral pain or chronic pain after operation), muscular pain (e.g., muscular pain associated with chronic pain disease or stiff shoulder), arthralgia, toothache, temporomandibular joint pain, headache (e.g., migraine, catatonic headache, headache associated with fever or headache associated with hypertension), visceral pain (e.g., cardiac pain, angina pain, abdominal pain, renal pain, urinary tract pain or bladder pain), obstetric and gynecologic pain (e.g., mittelschmerz, dysmenorrhea, or labor pain), neuropathic pain (e.g., hernia of intervertebral disk, nerve root pain, neuralgia after herpes zoster, trigeminal neuralgia or lumbago), migraine, stress headache, catatonic headache, muscular spasm and irritable bowel syndrome.

According to one embodiment, the HDAC6-associated disease is a neuropathy (including central or peripheral neuropathy), such as, for example, demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloidotic polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia, injury-related neuropathy (e.g., traumatic brain injury or cerebral apoplexy), and the like. Anticancer drugs susceptible to cause neuropathy include taxanes (e.g., paclitaxel (Taxol)), vinca alkaloids (e.g., vincristine), platinum-based agents (e.g., cisplatin, carboplatin or oxaliplatin), or other molecularly targeted drugs (e.g., bortezomib). In one embodiment, the neuropathy is selected from the group comprising or consisting of demyelinating diseases and neuropathy (e.g., multiple sclerosis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy or familial amyloidotic polyneuropathy), peripheral neuropathy (CIPN) derived from anticancer drugs and neurological symptoms associated therewith (e.g., chemotherapy-induced neuropathic pain (CINP)), diabetic neuropathy, autonomic ataxia and injury-related neuropathy (e.g., traumatic brain injury or cerebral apoplexy).

In one particular embodiment, the neuropathy is selected from the group comprising or consisting of Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), Charcot-Marie-Tooth disease, hereditary sensory and autonomic neuropathy, familial amyloidotic polyneuropathy, chemotherapy-induced peripheral neuropathy (CIPN) using chemotherapeutic anticancer agents, diabetic peripheral neuropathy (DPN), neuralgia, pain and neuropathic pain.

According to one embodiment, the HDAC6-associated disease is a psychiatric disease, such as, for example, depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depression symptom, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptom, negative symptom or cognitive symptom), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, emotional disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, neurotic anorexia, eating disorder, anorexia nervosa, hyperorexia or other eating disorder, pharmacophilia, pharmacophobia, pharmacomania, and the like. In one embodiment, the psychiatric disease is selected from the group comprising or consisting of depression, major depression, bipolar depression, psychotic major depression, refractory major depression, treatment-resistant depression, depression symptom, postpartum depression, bipolar disorder, schizophrenia (e.g., positive symptom, negative symptom or cognitive symptom), cognitive dysfunction associated with schizophrenia, stress disorder, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, social anxiety disorder, obsessive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, dysthymic disorder, emotional disorder (e.g., seasonal affective disorder), phobia, social phobia, neurosis, chronic fatigue syndrome, epilepsy, cyclothymia, addiction, neurotic anorexia, eating disorder, anorexia nervosa, hyperorexia or other eating disorder, pharmacophilia, pharmacophobia, and pharmacomania.

According to one embodiment, the HDAC6-associated disease is a neurodevelopmental disorder, such as, for example, Tourette syndrome, autism, autistic spectrum syndrome, fragile X syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD), and the like. In one embodiment, the neurodevelopmental disorder is selected from the group comprising or consisting of Tourette syndrome, autism, autistic spectrum syndrome, fragile X syndrome, Rett syndrome, and attention deficit hyperactivity disorder (ADHD).

According to one embodiment, the HDAC6-associated disease is a sleep disorder, such as, for example, intrinsic sleep disorders (e.g., psychophysiological insomnia), extrinsic sleep disorder, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome or non-24-hour sleep-wake), parasomnia, sleep disorders associated with internal medical or psychiatric disorder (e.g., chronic obstructive pulmonary diseases, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomniac neurosis, sleep apnea syndrome, and the like. In one embodiment, the sleep disorder is selected from the group comprising or consisting of intrinsic sleep disorders (e.g., psychophysiological insomnia), extrinsic sleep disorder, circadian rhythm disorders (e.g., time zone change syndrome (jet lag), shift work sleep disorder, irregular sleep-wake pattern, delayed sleep phase syndrome, advanced sleep phase syndrome or non-24-hour sleep-wake), parasomnia, sleep disorders associated with internal medical or psychiatric disorder (e.g., chronic obstructive pulmonary diseases, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression or anxiety neurosis), stress, insomnia, insomnia, insomniac neurosis and sleep apnea syndrome.

According to one embodiment, the HDAC6-associated disease is a cardiovascular disease, such as, for example, chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, cardiac disease, tachycardia, congestive cardiac failure, and the like. In one embodiment, the cardiovascular disease is selected from the group comprising or consisting of chronic heart failure or acute heart failure, acute decompensated heart failure, ischemic heart disease, cardiomyopathy, myocarditis, valvular disease, hypertension, cardiac disease, tachycardia and congestive cardiac failure. In one particular embodiment, the heart-related disease is selected from the group comprising or consisting of heart failure, cardiomyopathy and myocarditis.

According to one embodiment, the HDAC6-associated disease is an addiction-related disorder, such as, for example, alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcoholic insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic insanity, drug withdrawal, and the like. In one embodiment, the addiction related disorder is selected from the group comprising or consisting of alcohol dependence, alcohol abuse, alcoholic amnesia, alcohol paranoia, alcohol preference, alcohol withdrawal, alcoholic insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent psychiatric disorder, alcoholic insanity and drug withdrawal.

According to one embodiment, the HDAC6-associated disease is a gastrointestinal disease, such as, for example, peptic ulcer, stress gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation or postoperative ileus, and the like. In one embodiment, the gastrointestinal disease is selected from the group comprising or consisting of peptic ulcer, stress gastrointestinal disorder, stress vomiting, peptic ulcer, diarrhea, constipation ileus and postoperative ileus.

According to one embodiment, the HDAC6-associated disease is a pulmonary disease, such as, for example, hyperventilation, bronchial asthma, apnea, and the like. In one embodiment, the pulmonary disease is selected from the group comprising or consisting of hyperventilation, bronchial asthma and apnea.

According to one embodiment, the HDAC6-associated disease is a metabolic or hormonal disorder, such as, for example, obesity, diabetes, acromegaly, infertility, metabolic syndrome, and the like. In one embodiment, the metabolic or hormonal disorder is selected from the group comprising or consisting of obesity, diabetes, acromegaly, infertility and metabolic syndrome.

According to one embodiment, the HDAC6-associated disease is an immune disorder, such as, for example, allergic disease, immunodeficiency syndrome caused by HIV infection, immunodeficiency syndrome caused by stress, and the like. In one embodiment, the immune disorder is selected from the group comprising or consisting of immunodeficiency syndrome caused by HIV infection and immunodeficiency syndrome caused by stress.

According to one embodiment, the HDAC6-associated disease is an age-related disease, such as, for example, alopecia, glaucoma, impotence, climacteric disorder, incontinence, osteoporosis, and the like. In one embodiment, the age-related disease is selected from the group comprising or consisting of alopecia, glaucoma, impotence, climacteric disorder, incontinence and osteoporosis.

According to one embodiment, the HDAC6 associated disease is an idiopathic disease, such as, for example, Meniere's disease, sudden infant death syndrome, and the like. In one embodiment, the idiopathic disease is Meniere's disease or sudden infant death syndrome.

The compound or pharmaceutical composition of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, intracerebroventricular (ICV), intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration. In the treatment and/or prevention of an infectious disease an appropriate dosage level may be from about 0.01 to 500 mg per kg patient body weight per day (mg/kg/day), which can be administered in single or multiple doses. Typically, the dosage level will be from about 0.1 to about 250 mg/kg/day, preferably from about 0.5 to about 100 mg/kg/day, more preferably from about 2.5 to about 20 mg/kg/day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular diseases and the host undergoing therapy.

Advantageously, the compound of the invention is selective over at least one HDAC other than HDAC6, preferably over at least one class II HDAC other than HDAC6, more preferably over any class II HDAC other than HDAC6, furthermore preferably over HDAC other than HDAC6. Particularly advantageously, the compound of the invention is selective over HDAC1. Particularly advantageously, the compound of the invention is selective over HDAC10. Selectivity is strongly associated with the avoidance of side-effects of HDAC inhibitors.

Kit

This invention also relates to a kit comprising a compound of the invention as described herein, or a pharmaceutical composition of the invention as described herein, and means to administer said compound or pharmaceutical composition.

Means for administering a compound or a pharmaceutical composition are well-known in the art and may be identified by a person skilled in the art depending of the desired administration route.

EXAMPLES

The present invention is further illustrated by the following examples.

Example 1: Synthesis of the Compounds

The compounds of formula (I) (1)-(196) represented on Table 1 and/or Table 2 hereinabove were prepared as described hereinafter. Compounds 99 (CAS 1287068-38-5), 100 (CAS 1147354-39-9), 102 (CAS 1210761-93-5) and 104 (CAS 2419446-18-5) were commercially purchased. However, they may have been prepared by using similar methods.

General Synthetic Methods

The compounds according to the invention, in particular the compounds according to the formula (I), may be prepared by methods known to the person skilled in the art of organic synthesis or by using the following synthesis schemes. In all of the schemes described below it is understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with the general principles of organic chemistry. Protecting groups are manipulated according to standard methods (T.W. Green and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 1991, John Wiley & Sons, Inc.). These groups are then removed at a convenient stage of the synthesis using methods that are readily apparent to those skilled in the art. Many of the heterocyclic compounds of formula (I) where Y¹or Y²is a heteroaryl may be prepared using synthetic routes well known in the art (A. R. Katrizky and C. W. Rees, 1984, Comprehensive Heterocyclic Chemistry, Pergamon Press).

The synthesis of the HDAC6 inhibitors disclosed in the present invention have been prepared using the following synthetic schemes. Specific conditions for carrying out these reactions are provided in the detailed examples. The synthetic schemes described below show exemplified approaches to compounds of the present invention, but these routes should not be taken as the only possible synthetic routes to compounds of the present invention.

Compounds of formula (I) may be obtained according to Scheme 1 below:

[Image Omitted]

Amines T-1 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Intermediates T-2 may be prepared by protecting the amine group of T-1 (Step 1) by, for example using Boc₂O in the presence of a base (e.g., Et₃N or NaHCO₃) and in a solvent (e.g. DCM or THF) at the appropriate temperature. Protected amine intermediate T-2 can be engaged into a halogenation step to provide a T-3 in which X is a halo such as, for instance, bromo (Br) using, for example NBS or Br₂in a solvent (e.g., DCM) at the appropriate temperature (Step 2). Halide T-3 can next be transformed into the corresponding ketone T-4 in a single or multiple step-sequence, for example: (Option 1) a 2-step sequence such as (i) metal-catalyzed cross coupling sequence using tributyl(1-ethoxyvinyl)tin, in the presence of a catalyst/ligand system (e.g., Pd(PPh₃)₄, a base (e.g., t-BuOK), in a solvent (e.g., dioxane)), at the appropriate temperature to provide the enol ether intermediate, which is turn transformed into the desired ketone T-4 using acidic media such as aqueous HCl or formic acid at the appropriate temperature (Step 3); or (Option 2) in a 3-step sequence such as (i) a metal-halide exchange, using for example n-BuLi, under inert atmosphere like nitrogen atmosphere, at controlled temperature like −78° C., in a non protic solvent like dry THF, followed by the introduction of dimethylformaldehyde, or equivalent reagent, to provide the corresponding aldehyde intermediate T-5 (Step 4). Intermediate T-5 can be treated with a methylating agent such as, for instance, MeMgBr, in a non-protic solvent (e.g., THF) at the appropriate temperature to provide the resulting alcohol T-6 (Step 5). Alcohol T-6 can be transformed into the corresponding ketone T-4 by the use of an oxidizing agent for example DMP or PCC in a solvent (e.g., DCM) at the appropriate temperature (Step 6). Ketone T-4 can be further engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at the appropriate temperature to provide halo-ketone T-7 (Step 7). Halo-ketone T-7 is then reacted with thiol hetero-aryl derivatives of Formula Y¹—SH in the presence of a base (e.g., MeONa or K₂CO₃) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide heteroaryl intermediate T-8 (Step 8). Heteroaryl Y¹—SH are commercially available or may be prepared by methods known to the person skilled in the art, for example from the corresponding heteroaryl Y¹—OH derivatives using Lawesson's reagent or P₂S₅reagent in a solvent (e.g., toluene) at the appropriate temperature. Heteroaryl Y¹—OH are commercially available or may be prepared by methods known to the person skilled in the art. The protected amine T-8 can then be deprotected in acidic or basic media depending of the choice of the protecting group, for example in acidic media such as, for example, formic acid or aqueous HCl, to remove of a BoC-protecting group, or upon hydrogenolysis using H₂in the presence a of catalyst (e.g., Pd(OH)₂) in a protic solvent (e.g., MeOH) to remove a benzyl-type protecting group such as, for example, Cbz, to finally provide the corresponding amine intermediate T-9 (Step 9).

Final compounds of formula (I) wherein Z¹is CO—R⁹may be obtained by the reaction of amine T-9 with either an acyl chloride of Formula R⁹—COCl in the presence of a base (e.g., Et₃N), a suitable solvent (e.g., DCM or THF) at the appropriate temperature (Step 10a). Alternatively, final compounds of formula (I) wherein Z¹is CO—R⁹may be obtained by the reaction of amine T-9 or with a carboxylic acid of Formula R⁹—CO₂H acid in the presence of a coupling agent (e.g., HOBt or HATU), a base (e.g., Et₃N) in a solvent (e.g., DMF) at the appropriate temperature (Step 10b). Final compounds of formula (I) wherein Z¹is CO—R⁹and R⁹is —CH₂—OH, may be obtained by the reaction of amine T-9 and with a carboxylic acid of Formula HO₂C—CH₂—OSiR₃, wherein SiR₃is, for example, tert-butyldiphenylsilyl (TBDPS-) in the presence of a coupling agent (e.g., EDCI/HOBt or HATU), a base (e.g., Et₃N)) in a solvent (e.g., DMF) at the appropriate temperature, followed by the deprotection of the silyl ether function —OSiR₃using a fluoride-based agent (e.g., TBAF) in a non-protic solvent (e.g., THF) at the appropriate temperature (Step 10c). Final compounds of formula (I) wherein Z¹is SO₂—R⁹are obtained by the reaction of amine T-9 with either sulfonyl chloride of Formula R⁹—SO₂Cl in the presence of a base (e.g., Et₃N), a solvent (e.g., DCM or THF) at the appropriate temperature (Step 10b).

Compounds of formula (I) may be obtained also according to Scheme 2 (Method 2) below:

[Image Omitted]

Amines T-10 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. Intermediate compounds T-11, wherein Z¹is CO—R⁹, may be prepared from the reaction of amines T-10 with either an acyl chloride of Formula R⁹—COCl in the presence of a base (e.g., Et₃N), a solvent (e.g., DCM or THF) at the appropriate temperature; or with a carboxylic acid of Formula R⁹—CO₂H acid in the presence of a coupling agent (e.g., EDCI/HOBt or HATU), a base (e.g., Et₃N) in a solvent (e.g., DMF) at the appropriate temperature (Step 1a). Intermediate compounds T-11, wherein Z¹is SO₂—R⁹, can be obtained by the reaction of amine T-10 with either a sulfonyl chloride of Formula R⁹—SO₂Cl in the presence of a base (e.g., Et₃N), a solvent (e.g., DCM or THF) at the appropriate temperature (Step 1b). Heteroaryl intermediate T-11 are then reacted with an acylating agent for example acetyl chloride in the presence of a suitable catalyst such as, for example, AlCl₃, in a suitable solvent (e.g., DCM) at the appropriate temperature to provide intermediate ketone T-12, (Step 2). Alternative methods to prepare ketone T-12 can be used such as the method described in Scheme 1 (Method 1), either using from Scheme 1 the Step 2 and Step 3, or Step 2 to Step 6 synthesis sequence of reactions. Ketone T-12 can be engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at the appropriate temperature to provide halo-ketone T-13 (Step 3). Halo-ketone T-13 can be reacted with heteroaryl thiol derivatives of Formula Y¹—SH in the presence of a base (e.g., MeONa or K₂CO₃) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide the compound of Formula (I) (Step 4).

In some cases, Z¹might carry a protective group such as, for example, tert-butyldiphenylsilyl (TBDPS). This protective group may be removed during one of the reactions steps such as, for instance, Step 3. Alternatively, this protective group may be removed in a separate deprotection step using an appropriate deprotection reagent such as, for instance, pyridinium fluoride (HF.Py) in a suitable solvent such as, for instance, ACN at a suitable temperature such as, for example, 30° C.

Compounds of formula (I) wherein L and R¹are linked together to form a cyclic amine, may be obtained also according to Scheme 3 (Method 3) below:

[Image Omitted]

Protected cyclic amines T-14 are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature, for example using the Step 1 described in Scheme 1, Method 1 from the corresponding free cyclic amine. Compound T-14 can be reacted with phenyltriflimide, N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-trifluoromethylsulfonyl)methanesulfonamide or trifluoromethanesulfonic anhydride in the presence of a suitable base (e.g., LiHMDS) and solvent (e.g., THF) at the appropriate temperature to provide the triflate enol ether T-15 in which X is an OSO₂CF₃group (Step 1). A Suzuki cross coupling-type reaction of triflate T-15 with a boronic acid or boronic ester of Formula T-15A in the presence of a catalyst (e.g., Pd(dppf)Cl₂), a base (e.g., Cs₂CO₃), in a solvent (e.g., DMF) at the appropriate temperature may provide intermediate ketone T-16 (Step 2). Boronic acid or boronic ester of Formula T-15A may be commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature. The double-bond of the cycle amine intermediate T-16 can then be reduced upon hydrogenation using H₂in the presence a of catalyst (e.g., Pd/C or Pd(OH)₂) in a solvent (e.g., MeOH) to provide the corresponding saturated amine intermediate T-17 (Step 3). Ketone T-17 can be engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., DCM or THF) at the appropriate temperature to provide halo-ketone T-18 (Step 4). Halo-ketone T-18 can then be reacted with thiol hetero-aryl derivatives of Formula Y¹—SH in the presence of a base (e.g., MeONa or K₂CO₃) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide heteroaryl intermediate T-19 (Step 5). The protected amine T-19 can be deprotected in acidic, neutral or basic media depending of the choice of the protecting group, for example in acidic media to remove of a BoC-protecting group using formic acid or aqueous HCl solution, to provide the corresponding amine intermediate T-20 (Step 6).

Final compounds of formula (I) wherein Z¹is CO—R⁹can be obtained by the reaction of cyclic amine T-20 with either an acyl chloride of Formula R⁹—COCl in the presence of a base (e.g., Et₃N), a solvent (e.g., DCM or THF) at the appropriate temperature; or with a carboxylic acid of Formula R⁹—CO₂H acid in the presence of a coupling agent (e.g., EDCI/HOBt or HATU), a base (e.g., Et₃N)) in a solvent (e.g., DMF) at the appropriate temperature (Step 7a). Final compounds of formula (I) wherein Z¹is SO₂—R⁹can be obtained by the reaction of cyclic amine T-20 with either sulfonyl chloride of Formula R⁹—SO₂Cl in the presence of a base (e.g., Et₃N), a solvent (e.g., DCM or THF) at the appropriate temperature (Step 7b).

Compounds of Formula (I) wherein L and R⁹of the Z¹group are linked together to form a cyclic heterocycle, for example cyclic amide, may also be obtained according to Scheme 4 (Method 4) below:

[Image Omitted]

Intermediate T-21, wherein X is a halide, are commercially available or may be synthesized by a person skilled in the art of organic chemistry using multiple ways described in the literature, for example from the corresponding alcohol (X═OH) using a halogenating agent (e.g., SOCl₂) in a solvent (e.g., THF) at the appropriate temperature. Halide T-21 may be reacted with a heterocyclic amide Formula T-21A, in the presence of a base (e.g., NaH), in a solvent (e.g., THF) at the appropriate temperature to provide the corresponding intermediate T-22 (Step 1). Alternatively, compound T-22 can be prepared in 2-step sequence from intermediate T-1 aforementioned wherein R¹is H (Step 5, Method 4a), that may react with chloro alkyl acyl chloride such as, for example, 3-chloropropionyl chloride, in the presence of a base (e.g., Et₃N), in a solvent (e.g., DCM) at the appropriate temperature (Step 1), followed by an intramolecular cyclization in the presence of a base (e.g., NaH), in a solvent (e.g., DMF) at the appropriate temperature (Step 2). Introduction of the ketone group on T-22 may be performed using the methods described previously in Scheme 1 (Step 2 and Step 3; or Step 2 to Step 6) or in Scheme 2 (Step 2) to provide ketone derivatives T-23 (Step 2). Ketone intermediate T-23 can be engaged into a halogenation reaction, using for example NBS or phenyltrimethylammonium tribromide in a solvent (e.g., ACN or DCM or THF) at the appropriate temperature to provide halo-ketone T-24 (Step 3).

Halo-ketone T-24 is then reacted with thiol hetero-aryl derivatives of Formula Y¹—SH in the presence of a base (e.g., MeONa or K₂CO₃) in a solvent (e.g., DMF or ACN) at the appropriate temperature to provide the final compounds of formula (I) (Step 4).

Synthesis of the Compounds—Experimental Results

Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification.

Materials and Analytical Methods

All reactions were monitored by TLC with 0.25 mm E. Merck precoated silica gel plates (60 F254) and Waters liquid chromatography-mass spectroscopy (LCMS).

LCMS (Method 1): LC-MS spectra were recorded on a Waters Acquity I class UPLC system using the following system. Formic acid and acetonitrile used as HPLC grade. For analytical RP-HPLC analysis the following gradient conditions were used:

Column
ECLIPS XBD C18 (4.6 × 150 mm, 3.5 μm)

Column temperature
ambient temperature

Mobile phase A
0.01% FA in water

(MPA)

Mobile phase B
MeCN

(MPB)

Flow rate
0.8 mL/min

Injection volume
10 μL

Time(min)

Gradient Ratio

0.01
2
20
30

A (%)
90
90
10
10

B (%)
10
10
90
90

Detection
225 nm and 254 nm

MS Mode
Positive

MS Range
100-1000

LCMS (Method 2): LCMS were recorded on an Agilent 1200 & 6120B apparatus. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters in order to obtain ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW) and/or exact mass monoisotopic molecular weight. Data acquisition was performed with appropriate software. An ES MS detector was used, acquiring in positive or negative ionization modes. Compounds can be described by their molecular ion corresponding to the [M+H⁺](protonated molecule) or [M−H⁺](deprotonated molecule). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used. The gradient conditions used are described below:

Column:
Xbridge C18 2.1 * 50 mm, 5 μm

Column temperature:
40° C.

Mobile phase A (MPA)
H₂O + 10 mM NH₄HCO₃

Mobile phase B (MPB)
Acetonitrile

Flow rate:
0.8 mL/min

Gradient Ratio:
Time (min)
0.00
0.40
3.40
3.85
3.86
4.50

A (%)
95
95
5
5
95
95

B (%)
5
5
95
95
5
5

Detection:
220 nm

MS Mode:
Positive

MS Range:
100-1000

LCMS (method 3): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:

Column
Method 3: Kinetex EVO C18 (2.1 × 50 mm, 1.7 μm)

Column
40° C.

temperature

Mobile phase A
0.01% FA in water

(MPA)

Mobile phase B
0.01% FA in ACN

(MPB)

Flow rate:
0.8 mL/min

Gradient Ratio:
Time (min)
0.01
0.2
1.5
3

A (%)
90
90
10
10

B (%)
10
10
90
90

Detection:
220 nm and 254 nm

MS Mode:
Positive and negative

MS Range:
100-1000

LCMS (method 4): Liquid chromatography-mass spectroscopy (LCMS) spectra were recorded on a Waters Acquity I class UPLC system. The gradient conditions used are described below:

Column
LUNA 5μ C18 (4.6 × 100 mm)

Column temperature
40° C.

Mobile phase A (MPA)
0.01% FA in water

Mobile phase B (MPB)
ACN

Flow rate:
0.8 mL/min

Gradient Ratio:
Time (min)
0.01
2
20
30

A (%)
90
90
10
10

B (%)
10
10
90
90

Detection:
220 nm and 254 nm

MS Mode:
Positive and negative

MS Range:
100-1000

LCMS (Method 5): LCMS spectra were recorded on a Waters Acquity I class UPLC system using the following system. Formic acid and ammonia or TFA was used as HPLC grade. The following gradient conditions were used:

Column
Interchim Acquity BEH C18 (2.1 × 100 mm, 1.7 μm)

Column
ambient temperature

temperature

Mobile phase A
0.01% FA in water

(MPA)

Mobile phase B
0.01% FA in ACN

(MPB

Flow rate
0.4 mL/min

Injection volume
10 μL

Gradient Ratio
Time(min)
0.01
0.5
4
7

A (%)
90
90
10
10

B (%)
10
10
90
90

Detection
220 nm and 254 nm

MS Mode
Positive

MS Range
100-1000

LCMS (Method 6): LCMS were recorded on an Agilent 1200 apparatus. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. The following gradient conditions were used:

Column
Waters, Xbridge C18 50 * 2.1 mm, 5 um

Mobile Phase
A: water (4 L) + TFA (1.5 mL)

B: acetonitrile (4 L) + TFA (0.75 mL)

TIME (min)
B %

0
1

0.4
1

3.4
90

3.85
100

3.86
1

Flow Rate
0.8 mL/min

wavelength
UV 220 nm

Oven Temp
40° C.

MS ionization
ESI

LCMS (Method 7): LCMS were recorded on an Agilent 1200 apparatus. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. The following gradient conditions were used:

Column
Waters, Xbridge C18 50 * 2.1 mm, 5 um

Mobile Phase
A: water (4 L) + TFA (1.5 mL)

B: acetonitrile (4 L) + TFA (0.75 mL)

TIME (min)
B %

0
10

0.4
10

3.4
100

3.85
100

3.86
10

Flow Rate
0.8 mL/min

wavelength
UV 220 nm

MS Mode:
Positive

MS Range:
100-1350

LCMS (Method 8): LCMS were recorded on a Agilent 1200. The High-Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array or a UV detector. The following gradient conditions were used:

Column
Waters, Xbridge C18 50 * 2.1 mm, 5 um

Mobile Phase
A: water (4 L) + NH₃/H₂O (1.5 mL)

B: Acetonitrile

TIME (min)
B %

0
15

0.5
15

3.4
100

3.9
100

3.91
15

4
15

Flow Rate
0.8 mL/min

wavelength
UV 220 nm

MS Mode:
Positive

MS Range:
100-1350

RP-HPLC: Reversed phase HPLC was performed on a Waters HPLC system using following system [solvent A: acetonitrile, solvent B: 0.1% NH₃in water] or [solvent A: acetonitrile, solvent B: 0.1% TFA in water]. Ammonia was used as HPLC grade. All the separations were performed at ambient temperatures.

Flash column chromatography: Purification of reaction products was carried out by column chromatography using commercially available silica or flash chromatography using Combiflash Rf with Teledyne Isco RediSep Rf High Performance Gold or Silicycle SiliaSep High Performance columns (40, 80, or 120 g). The purity of all final compounds was over 95% and was analysed with a Waters LCMS system.

¹H NMR: ¹H NMR spectra were recorded on Varian 400 MHz spectrometers and are reported in ppm with the solvent resonance employed as the internal standard [CDCl₃at 7.26 ppm, DMSO-d₆at 2.50 ppm]. Peaks are reported as (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet or unresolved, br s=broad signal, coupling constant(s) in Hz, integration).

DSC: Melting points were determined using differential scanning calorimetry. The following instrument, parameters and procedure was used:

Instrument
Differential Scanning Calorimeter

Instrument Model
DSC 214

Manufacturers
NETZSCH

Crucible Type
High-voltage gold-plated crucible

Gas
Nitrogen

Flow rate
100 mL/min

Temperature program:

Starting Temp/° C.
Heating Rate/(K/min)
Final Temp/° C.

30
10
400

Operation procedure:

Weigh 1-8 mg of sample into a high-pressure crucible; seal with the matching tool, place the prepared sample into the corresponding position of instrument, call the parameters in the software, and start the sequence run.

Abbreviations

Abbreviations are used as follows.

Abbreviation
Name

aq.
aqueous

AMC
7-amino-4-methylcoumarin

1-BuOH
1-butanol

ACN
acetonitrile

AIBN
azobisisobutyronitrile

BRET
Bioluminescence Resonance Energy Transfer

BSA
Bovine serum albumin

(Boc)₂O
di-tert-butyl dicarbonate

cHex
cyclohexane

Cpd
compound

d
days

DBU
1,8-diazabicyclo[5.4.0]undec-7-ene

DCM
dichloromethane

DEAD
diethyl azodicarboxylate

DIBAL-H
diisobutylaluminium hydride

DIPEA or
N,N-diethylisopropylamine

DIEA

DMAP
4-dimethylaminopyridine

DMF
N,N-dimethylformamide

DMSO
dimethyl sulfoxide

DPPA
diphenylphosphorylazide

DTT
dithiothreitol

EDCI
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide

EDTA
ethylenediaminetetra-acetic acid

Et₂O
diethyl ether

EtOAc
ethyl atetate

eq. or equiv.
equivalents

FA
Formic Acid

g
gram

GST
Glutathione-S-transferase

h
hours

H
proton

HCl
hydrochloric acid

HATU
Hexafluorophosphate Azabenzotriazole Tetramethyl

Uronium

HDAC
histone deacetylase

HOBt
1-hydroxy-benzotriazol

Hz
Hertz

IPA
iso-propanol

J
scalar ¹H-¹H coupling constant

K₂CO₃
potassium carbonate

KOH
potassium hydroxide

LCMS
liquid chromatography - mass spectrometry

LiHMDS
lithium bis(trimethylsilyl)amide

M
molar

Me
methyl

MeOH
methanol

MeONa
sodium methoxide

mg
milligram

MHz
megahertz

μw
microwave

N₂
nitrogen

NaH
sodium hydride

Na₂CO₃
sodium carbonate

NaHCO₃
sodium bicarbonate

NaOH
sodium hydroxide

Na₂SO₄
sodium sulfate

NBS
N-bromosuccinimide

NMP
N-methylpyrrolidone

NMR
nuclear magnetic resonance

PBS
Phosphate-buffered saline

P₂S₅
Phosphorus pentasulfide

PCC
Pyridinium chlorochromate

Pd/C
Palladium on charcoal

PdCl₂(dppf)
[1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium

(II)

Pd(PPh₃)₄
Tetrakis(triphenylphosphine) palladium

Pd(OH)₂
Palladium hydroxide

quant.
quantitative

R_for Rt
retention factor or retention time

RP
Reversed Phase

rt
room temperature

SAHA
suberoylanilide hydroxamic acid

Sat.
saturated

SFC
Supercritical fluid chromatography

SiO₂
silica

SOCl₂
thionyl chloride

TBAF
Tetrabutylammonium fluoride

TBATB
Tetrabutylammonium tribromide

TBDPS
tert-Butyldiphenylsilyl

TBS
tert-Butyldimethylsilyl

TEA
triethylamine

TFA
Trifluoroacetic acid

THF
Tetrahydrofuran

TLC
thin layer chromatography

TMSCF₃
Trifluoromethyltrimethylsilane

TSA
Trichostatin A

Preparation of Synthetic Intermediates

Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-1), According to Method 1 (Scheme 1):

[Image Omitted]

Synthesis of tert-butyl (thiophen-2-ylmethyl)carbamate (I-1a) To a solution mixture of thiophen-2-ylmethanamine (50.0 g, 441.770 mmol) in THF (500 mL) was added NaHCO₃(37.1 g, 485.947 mmol) and (Boc)₂O (111.5 mL, 441.770 mmol) slowly. The resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with 30% EtOAc in hexane and passed through silica get to afford compound (I-1a) (100 g, quantitative) as a white gummy solid. Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-1b) To a solution mixture of compound I-1a (50 g, 234.741 mmol) in DMF (500.0 mL) was added NBS (45.9 g, 258.215 mmol) at 0° C. The reaction mixture was stirred for 2 h at rt. Cold water was added to reaction mixture and it was extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and compound was eluted using 10% EtOAc in hexane to afford compound (I-1b) (60.5 g, Yield: 87%) as a brown gummy liquid. Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)carbamate (I-1c) To a solution mixture of compound I-1b (30.0 g, 102.739 mmol) in Dry THF (600.0 mL) was added n-BuLi (1.6 M in hexane) (321 mL, 513.698 mmol) at −78° C. and stirring for 30 min at same temperature. DMF (39 mL, 513.698 mmol) was added dropwise at −78° C. and stirring was continued for 2 h. After completion of reaction, the reaction mixture was quenched with sat. NH₄Cl solution (200 mL) and extracted with EtOAc (2×500 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and compound was eluted using 12% EtOAc in hexane to afford compound I-1c (12.0 g, Yield: 49%) as a brown gummy liquid. ¹H NMR [400 MHz, CDCl₃]: 9.83 (s, 1H), 7.63 (d, J=3.6 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 5.0 (s, 1H) 4.52 (d, J=6 Hz, 2H) 1.41 (s, 9H). Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)carbamate (I-1d) To a solution of compound I-c (18.5 g, 76.7 mmol) in dry THF (400.0 mL) was added methyl magnesium bromide (1.0 M in THF) (767 mL, 767.0 mmol) at 0° C., after which it was stirred for 2 h at rt. The reaction mixture was quenched with sat. NH₄Cl solution (500 mL) and washed with EtOAc (2×500 mL). Combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and compound was eluted using 20% EtOAc in hexane to afford compound I-1d (13.0 g, Yield: 66%) as a brown gummy liquid. ¹H NMR [400 MHz, DMSO-d₆]: 8.13 (s, 1H), 7.43 (s, 1H), 7.00 (s, 1H), 4.85 (d, J=5.6 Hz, 2H), 4.19 (d, J=2.0 Hz, 1H) 1.38-1.23 (m, 12H). Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)carbamate (I-1e) To a solution mixture of compound I-1d (6.5 g, 25.26 mmol) in DCM (65.0 mL) was added PCC (13.6 g, 63.15 mmol) at rt. The reaction mixture was stirred for 2 h at rt. After completion of reaction, mixture was filtered in vacuo and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) and the compound was eluted using 20% EtOAc in hexane to afford compound I-1e (4.9 g, Yield: 75%) as a brown gummy liquid. Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)carbamate (I-1) To a solution mixture of compound-6 (4.8 g, 18.8 mmol) in THF (50 mL) was added phenyltrimethylammonium tribromide (4.95 g, 13.1 mmol) at 0° C. The reaction mixture was stirred for 16 h at rt. After completion of reaction, mixture was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using combi-flash C-18 purification to afford compound I-1 (1.5 g, Yield: 24%) as pale brown solid.

¹H NMR [400 MHz, DMSO-d₆]: 7.91 (d, J=4 Hz, 1H), 7.65 (t, J=6 Hz, 1H), 7.06 (d, J=3.6 Hz, 1H), 4.77 (s, 2H), 4.31 (d, J=6 Hz, 2H), 1.39 (s, 9H).

Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (1-2), according to Method 1 (Scheme 1):

[Image Omitted]

Synthesis of tert-butyl (2-(thiophen-2-yl)ethyl)carbamate (I-2a) To a stirred solution of 2-(thiophen-2-yl)ethan-1-amine (20.0 g, 157.22 mmol) in dichloromethane (200 mL) cooled to 0° C. was added (Boc)₂O (41.1 g, 188.66 mmol) followed by Et₃N (24.6 g, 243.10 mmol). The resulting mixture was stirred for 16 h at rt, after which it was concentrated under reduced pressure. The crude residue was diluted with water (100 mL), extracted with DCM (2×100 mL), and the combined organic layers dried over Na₂SO₄, and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 10% EtOAc in hexane, and the pure fractions were evaporated to afford compound I-2a (28 g, Yield: 74%) as a brown gummy liquid. Synthesis of tert-butyl (2-(5-bromothiophen-2-yl)ethyl)carbamate (I-2b) To a solution of compound I-2a (28 g, 123.172 mmol) in DMF (400 mL) cooled to 0° C. was added portion wise NBS (21.9 g, 123.172 mmol). The mixture was then stirred for 2 h at rt before it was poured to mixture of ice water (100 mL) and EtOAc (200 mL). The organic layer was separated, washed with brine solution (100 mL), dried over Na₂SO₄and then concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 10% EtOAc in hexane to afford compound I-2b (37.08 g, Yield: 98%) as an off-white solid. Synthesis of tert-butyl (2-(5-formylthiophen-2-yl)ethyl)carbamate (I-2c) To a solution of compound I-2b (20.0 g, 65.312 mmol) in dry THF (200 mL) cooled to −78° C. was added dropwise n-BuLi (1.6 M solution in hexanes) (204.0 mL, 326.563 mmol) and the resulting mixture was stirred for 15 min, after which dry DMF (35.9 g, 491.80 mmol) was added and stirring was continued for 30 min at same temperature. After completion of reaction, the reaction mixture was quenched with sat. aq. NH₄Cl solution (150 mL) and extracted with EtOAc (2×200 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 15% EtOAc in hexane to afford compound I-2c (10.0 g, Yield: 57%) as gummy liquid. Synthesis of tert-butyl (2-(5-(1-hydroxyethyl)thiophen-2-yl)ethyl)carbamate (I-2d) To a solution of compound I-2c (18.0 g, 70.496 mmol) in dry THF (180 mL) cooled to 0° C. was added dropwise of methyl magnesium bromide (1.0 M solution in THF) (705.0 mL, 70.496 mmol), after which it was slowly warmed to rt and stirred for 2 h. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (2×300 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 20% EtOAc in hexane to afford compound I-2d (15.0 g, Yield: 78%) as gummy solid. Synthesis of tert-butyl (2-(5-acetylthiophen-2-yl)ethyl)carbamate (I-2e) To a solution of compound I-2d (10 g, 36.849 mmol) in dry DCM (100 mL) cooled to 0° C. was added Dess-Martin periodinane (46.8 g, 110.547 mmol) after which it was slowly warmed to rt and stirred for 16 h. The reaction mixture was filtered through a celite pad and washed with dichloromethane before the solvent was evaporated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 15% EtOAc in hexane to afford compound I-2e (7.1 g, Yield: 72%) as gummy solid. Synthesis of tert-butyl (2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)carbamate (I-2) To a solution of compound I-2e (7.0 g, 25.987 mmol) in dry THF (70.0 mL) was added trimethylphenylammonium tribromide (7.8 g, 20.789 mmol), and mixture was then stirred at room temperature for 16 h. The solvent was then evaporated, and the crude was purified by Combi-flash reversed phase chromatography to afford I-2 (2.05 g, Yield: 23%) as an off-white solid.

Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3), According to Method 1 (Scheme 1):

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Synthesis of tert-butyl ((5-bromothiophen-2-yl)methyl)(methyl)carbamate (I-3a) To a solution mixture of tert-butyl ((5-bromothiophen-2-yl)methyl)carbamate (I-1b) (40 g, 136.986 mmol) in DMF (400.0 mL) was added NaH (6.56 g, 273.0 mmol) followed by methyl iodide (12.8 mL, 205.479 mmol) at 0° C. The reaction mixture was stirred for 3 h at rt. The reaction mixture was quenched with ice water (150 mL) and extracted with EtOAc (2×500 mL) and dried over Na₂SO₄, concentrated in vacuo gave crude 43 g of compound I-3a, which was taken to the next step without further purification. Synthesis of tert-butyl ((5-formylthiophen-2-yl)methyl)(methyl)carbamate (I-3b) To a solution mixture of compound (I-3a) (22.0 g, 71.89 mmol) in dry THF (400.0 mL) and added n-BuLi (1.6 M in hexane) (224 mL, 359.47 mmol) at −78° C. and stirring for 30 min at −78° C. After DMF (27.9 mL, 359.47 mmol) was added at −78° C. and stirring for 2 h, reaction mixture was quenched with Sat. NH₄Cl solution (200.0 mL) and extracted with EtOAc (2×500 mL) and the combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 12% EtOAc in hexane to afford compound I-3b (6.5 g, Yield: 35%) as gummy liquid, used without further purification. Synthesis of tert-butyl ((5-(1-hydroxyethyl)thiophen-2-yl)methyl)(methyl)carbamate (I-3c) To a solution mixture of compound I-3b (13.0 g, 50.9 mmol) in dry THF (250.0 mL) was added methyl magnesium bromide (1.0M in THF) (509 mL, 509.0 mmol) at 0° C. and stirred the reaction for 2 h at rt. The reaction mixture was quenched with sat. NH₄Cl solution (500 mL) and washed with EtOAc (2×500 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 20% EtOAc in hexane to afford compound I-3c (10 g, Yield: 72%) as gummy liquid, used without further purification. Synthesis of tert-butyl ((5-acetylthiophen-2-yl)methyl)(methyl)carbamate (I-3d) To a solution mixture of compound I-3c (10.0 g, 36.9 mmol) in DCM (100.0 mL) was added PCC (19.8 g, 92.2 mmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture after which it was filtered and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) compound was eluted using 20% EtOAc in hexane to afford compound I-3d (7.6 g, Yield: 77%) as gummy liquid, which was used without further purification. Synthesis of tert-butyl ((5-(2-bromoacetyl)thiophen-2-yl)methyl)(methyl)-carbamate (I-3) To a solution mixture of compound I-3d (4.3 g, 15.9 mmol) in THF (50 mL) and added phenyltrimethylammonium tribromide (4.20 g, 11.1 mmol) at 0° C. The reaction mixture was stirred for 16 h at rt. The reaction mixture was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using combi-flash reverse phase purification (using an ACN and 0.001% TFA in Water) to afford compound I-3 (1.5 g, Yield: 27%) as pale brown solid.

Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pivalamide (I-4), according to Method 2 (Scheme 2):

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Synthesis of N-(thiophen-2-ylmethyl)pivalamide (I-4a) To a solution mixture of thiophen-2-ylmethanamine (30 g, 265.062 mmol) in DCM (300.0 mL) and added Et₃N (55.7 mL, 398.230 mmol) at 0° C. The resultant reaction mixture was stirred for 10 min at 0° C., after which pivaloyl chloride (39.14 mL, 318.584 mmol) was added. The reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with DCM (500.0 mL) and washed with water (2×100 mL) and organic layer was dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 10% EtOAc in hexane to afford compound I-4a (40 g, Yield: 77%) as a gummy liquid, which was used without further purification. Synthesis of N-((5-acetylthiophen-2-yl)methyl)pivalamide (I-4b) To a solution mixture of AlCl₃(14.05 g, 105.30 mmol) in DCM (166.0 mL) at 0° C., acetyl chloride (3.60 mL, 50.5 mmol) was added drop by drop. After 5 min, compound-I-4a (8.3 g, 42.1 mmol) was added at 0° C. The reaction mixture was stirred for 2 h at 0° C. The reaction mixture after which it was quenched with cold water (100 mL) and extracted with DCM (2×300 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 20% EtOAc in hexane to afford compound I-4b (8.0 g, Yield: 80%) as a white solid. Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pivalamide (I-4) To a solution mixture of compound I-4b (25 g, 104.6 mmol) in THF (460 mL) and added phenyltrimethyl ammonium tribromide (27.53 g, 73.2 mmol) at 0° C. The reaction mixture was stirred for 16 h at rt. The reaction mixture was filtered through celite bed and concentrated in vacuo. The crude compound was purified using combi-flash reverse phase purification (using an ACN and 0.001% TFA in water) to afford I-4 (6.2 g, Yield: 19%) as an off-white solid. ¹H NMR [400 MHz, DMSO-d₆]: 8.37-8.32 (m, 1H), 7.91-7.86 (m, 1H), 7.13-7.06 (m, 1H), 4.76 (s, 2H), 4.44 (d, J=5.6 Hz, 2H), 1.11 (s, 9H).

Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1-carboxylate (I-5), according to Method 3 (Scheme 3):

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Synthesis of tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5a) To a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (1 g, 5.398 mmol) in dry THF (10 mL) cooled to −78° C. was added dropwise LiHMDS (1.0 M soln. in THF) (6.0 mL, 5.934 mmol), and the resulting mixture was stirred for 60 min. N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide in THF (2.33 g, 5.934 mmol) was added to the solution and stirred for 30 min at the same temperature. Next, the reaction mixture was warmed to rt, quenched with sat. aq. NaHCO₃(10 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (60-120 mesh) eluting with 10% EtOAc in hexane to afford compound I-5a (0.63 g, 37% yield) as gummy liquid. Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (I-5b) To a stirred solution of (5-acetylthiophen-2-yl) boronic acid (1.6 g, 9.463 mmol) and tert-butyl 3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate 2 (3 g, 9.463 mmol) in dioxane:H₂O (30 mL, 3:1), K₂CO₃(3.9 g, 28.389 mmol) and Pd(dppf)Cl₂(1.0 g, 0.9463 mmol) was added. The reaction was purged with N₂for 15 min, then heated to 100° C. for 16 h. Next, the mixture was quenched with sat. aq. NaHCO₃(20 mL), and then extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na₂SO₄, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography using a silica gel (60-120 mesh, eluent: 50% EtOAc in hexane) to afford the title compound I-5b (2.7 g, 75% yield) as a gummy liquid. Synthesis of tert-butyl 3-(5-acetylthiophen-2-yl)pyrrolidine-1-carboxylate (I-5c) To a stirred solution of tert-butyl 3-(5-acetylthiophen-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate I-5b (2 g, 6.825 mmol) in MeOH (20 mL) was added 10% Pd—C(2.0 g), then H₂gas was inserted for 5 h at 60 psi. The reaction mixture was filtered through a celite bed under vacuo. The solvent was evaporated under reduced pressure and the residue purified by column chromatography over silica gel (60-120 mesh, eluent: 50% EtOAc in hexane) to afford the title compound I-5c (1.5 g, 74% yield) as yellow liquid. Synthesis of tert-butyl 3-(5-(2-bromoacetyl)thiophen-2-yl)pyrrolidine-1-carboxylate (I-5) To a solution of compound I-5c (0.2 g, 0.680 mmol) in dry THF (5 mL) tetrabutylammonium tribromide (0.8 g, 1.360 mmol) added then stirred at room temperature for 16 h. The reaction mixture was concentrated to get crude compound, which was purified by Combi-flash reversed phase chromatography to afford I-5 (0.07 g, 27% yield) as a white solid. ¹H NMR [400 MHz, DMSO-d₆]: 7.95 (d, J=3.6 Hz, 1H), 7.15 (d, J=4 Hz, 1H), 4.78 (s, 2H), 3.73-3.69 (m, 2H), 3.40-3.23 (m, 4H), 2.33-2.29 (m, 1H), 1.40 (s, 9H).

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6), according to Method 4 (Scheme 4)

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Synthesis of 2-(chloromethyl)thiophene (I-6a) according to Method 4, Step 1: To a solution of thiophen-2-ylmethanol (2.0 g, 17.518 mmol) in THF (20 mL) was added SOCl₂(2.5 g, 21.021 mmol) at 0° C. The reaction mixture was stirred at 50° C. for 3 h. The progress of the reaction was monitored by TLC. After complete consumption of starting material, the reaction mixture was concentrated. The crude residue was taken to the next step without further purification. Synthesis of 3-methyl-1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-6b) To a solution of compound I-6a (0.5 g, 5.043 mmol) in dry THF (5.0 mL) was added NaH (60% in oil) (0.3 g, 7.575 mmol) at 0° C. 3-Methylpyrrolidin-2-one (0.66 g, 5.043 mmol) was added at same temperature and the mixture stirred for 30 min. The reaction mixture before it was brought to rt and stirred for another 16 h. After completion of reaction, the reaction mixture was concentrated and purified by column chromatography over silica gel (60-120 mesh, eluent: 10% EtOAc in hexane) to afford compound I-6b (0.45 g, 50% yield) as a yellow gummy liquid. Synthesis of 1-((5-bromothiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6c) To a solution of compound I-6b (0.45 g, 2.304 mmol) in acetonitrile (5.0 mL) was added NBS (0.4 g, 2.304 mmol) at 0° C. and the reaction mixture was stirred for 2 h at rt. After completion of reaction, the reaction mixture was concentrated, diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The organic layer was separated, dried over Na₂SO₄, and the solvent concentrated under reduced pressure. The crude was purified by combi-flash reversed phase chromatography to afford compound I-6c (0.5 g, 79% yield) as a yellow gummy liquid. Synthesis of 1-((5-acetylthiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6d) A stirred solution of compound I-6c (0.5 g, 1.824 mmol) in toluene was purged with N₂followed by addition of tributyl(1-ethoxyvinyl)stannane (0.78 g, 2.160 mmol) and Pd (PPh₃)₄(0.2 g, 0.182 mmol). The reaction mixture was stirred at 110° C. for 16 h. Saturated KF solution was added to the reaction mixture and stirring continued for 30 min at rt. The organic layer was separated and concentrated under reduced pressure to get the crude compound. THF (20 mL) and conc. HCl were added to the crude reaction mixture. After stirring for 30 min, solid Na₂CO₃was added until pH ˜7. The mixture was diluted with water (20 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by column chromatography column chromatography over silica gel (60-120 mesh, eluent 20% EtOAc in hexane) to afford compound I-6d (0.3 g, 70% yield) as a white solid. Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-methylpyrrolidin-2-one (I-6) To a solution of compound I-6d (0.3 g, 1.265 mmol) in dry THF (5 mL) was added tetrabutylammonium tribromide (0.6 g, 1.265 mmol) and the reaction mixture was stirred at room temperature for 16 h. Next, the reaction mixture was concentrated and the residue was purified by Combi-flash reversed phase chromatography to afford I-6 (0.07 g, 16% yield) as a white solid.

Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophen-2-yl)methyl)pivalamide (I-7), according to Method 2 (Scheme 2)

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Synthesis of (3-fluorothiophen-2-yl)methanol (I-7a) To a stirred solution of methyl 3-fluorothiophene-2-carboxylate (5.0 g, 31.25 mmol) in dry THF (50 mL) was added lithium aluminium hydride (1 M solution in THF, 30 mL) dropwise at 0° C. and reaction mixture was stirred for 1 h at 0° C. under nitrogen. After completion of reaction, mixture was quenched with 10 mL water, 15% NaOH solution (10 mL) and stirred for 1 h. The reaction mixture was filtered over celite and the celite pad washed with EtOAc and THF. The aqueous layer was extracted, and combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluting with 8% EtOAc/hexane to get pure yellowish liquid compound I-7a (3.0 g, Yield: 73%). ¹H NMR [400 MHz, DMSO-d₆]: 7.464-7.440 (m, 1H), 6.936-6.920 (m, 1H), 5.46 (t, J=5.6 Hz, 1H), 4.54 (dd, J=6.0, 1.6 Hz, 2H). Synthesis of 2-(azidomethyl)-3-fluorothiophene (I-7b) To a stirred solution of compound I-7a (3 g, 22.7 mmol) in toluene (30 mL) was added DPPA (5.8 mL, 27.2 mmol) followed by DBU (4 mL, 27.2 mmol) at 0° C. and resulting mixture was stirred at rt for 1 h under N₂. After completion of reaction (TLC monitoring), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 2% EtOAc/hexane to afford compound I-7b (2.5 g, Yield: 71%) colourless oil. ¹H NMR [400 MHz, CDCl₃]: 7.22-7.19 (m, 1H), 6.83-6.61 (m, 1H), 4.44 (s, 2H). Synthesis of (3-fluorothiophen-2-yl)methanamine (I-7c) To a stirred solution of compound I-7b (2.6 g, 16.5 mmol) in dry THF (40 mL) was added solution of LAH in THF (1.2 g, 33.1 mmol) at 0° C. Then reaction mixture was stirred at 0° C. for 30 min. The reaction was monitored by TLC. After completion of reaction, mixture was quenched with water and 10% NaOH solution. The reaction mixture was washed with EtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel eluting with 2% MeOH/DCM to get yellowish oily compound I-7c (2 g, Yield: 95%). ¹H NMR [400 MHz, DMSO-d₆]: 7.37-7.35 (m, 1H), 6.92-6.89 (m, 1H), 3.83 (s, 2H). Synthesis of N-((3-fluorothiophen-2-yl)methyl)pivalamide (I-7d) According to Method 2 (Step 1): to a stirred solution of compound I-7c (2.5 g, 19.08 mmol) in DCM (25 mL) was added TEA (6.7 mL, 47.7 mmol) followed by pivaloyl chloride (3.5 mL, 28.6 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction was monitored by TLC and after completion, the mixture was quenched in water and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified using column chromatography using 10% to 30% ethyl acetate:petroleum ether as an eluent providing compound I-7d (2.5 g, Yield: 61%). Synthesis of N-((5-bromo-3-fluorothiophen-2-yl)methyl)pivalamide (I-7e) According to Method 2 (Step 2): to a stirred solution of compound I-7d (1.2 g, 5.6 mmol) in ACN (12 mL) was added NBS (1 g, 5.6 mmol) and the resulting mixture was stirred at rt for 1 h. After completion of reaction, the crude compound was purified using RP combi-flash column chromatography using 10% acetonitrile:H₂O (0.01% FA) as an eluent to afford compound I-7e (400 mg, Yield: 25%). Synthesis of N-((5-acetyl-3-fluorothiophen-2-yl)methyl)pivalamide (I-7f) According to Method 2 (Step 3): To a stirred solution of compound I-7e (770 mg, 2.6 mmol) in dioxane (10 mL) was added tributyl(1-ethoxyvinyl)tin (1.2 g, 3.4 mmol) followed by Pd (PPh₃)₄(0.3 g, 2.6 mmol) and resulting mixture was stirred at 110° C. for 16 h under N₂. After completion of reaction, mixture was cooled to rt. Saturated KF solution was added and the mixture stirred for 30 minutes before EtOAc (20 mL) was added. The aqueous layer was extracted, and the combined organic layers were dried over Na₂SO₄and concentrated. The solid residue was dissolved in 2 N HCl and the mixture stirred for 30 minutes. Solid Na₂CO₃was next added to the mixture until pH >7 and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by column chromatography using 20% ethyl acetate: petroleum ether as an eluent to get pure compound I-7f (290 mg, Yield: 43%). Synthesis of N-((5-(2-bromoacetyl)-3-fluorothiophen-2-yl)methyl)pivalamide (I-7) According to Method 2 (Step 4): To a stirred solution of compound 7 (290 mg, 1.1 mmol) in dry THF (4 mL) was added tetrabutylammonium tribromide (1 g, 2.2 mmol) at 0° C. and resulting mixture was stirred at 50° C. for 16 h. After completion of reaction, solvent was concentrated under reduced pressure to get crude compound which was purified using combi-flash to afford compound I-7 (130 mg, Yield: 34%) as gummy solid.

Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8), According to Method 2 (Scheme 2).

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Synthesis of (2-bromothiazol-5-yl)methanol (I-8a) To a solution of methyl 2-bromothiazole-5-carboxylate (24.0 g, 101.69 mmol) in dry THF (200 mL) was added DIBAL-H (1.0 M in toluene) (203.0 mL, 203.38 mmol) at 0° C. The resulting mixture was stirred for 15 min, then slowly warmed to rt for 2 h. Next, the reaction mixture was quenched with sat. aq. NH₄Cl (200 mL) and extracted with EtOAc (2×200 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (60-120 mesh, eluent: 10% EtOAc in hexane) to afford compound I-8a (11.1 g, 56% yield) as a gummy solid. Synthesis of 2-((2-bromothiazol-5-yl)methyl)isoindoline-1,3-dione (I-8b) To a stirred solution of triphenylphosphine (16.2 g, 61.8 mmol.) in dry THF (100 mL) was added DEAD (9.8 g, 56.6 mmol) dropwise at 0° C. and the reaction mixture was stirred for 15 min at this temperature. Compound I-8a (10.0 g, 51.5 mmol) in THF (20 mL) was added to the reaction mixture followed by isoindoline-1,3-dione (8.3 g, 56.6 mmol) at 0° C. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (150 mL) extracted with DCM (2×100 mL), the organic layer separated, dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel (60-120 mesh, eluent: 30% EtOAc in hexane) to afford compound-I-8b (8.0 g, 50% yield) as a white solid. Synthesis of (2-bromothiazol-5-yl)methanamine (I-8c) To a stirred solution of compound I-8b (8.0 g, 24.76 mmol) in EtOH (80 mL) was added hydrazine hydrate (3.9 g, 123.8 mmol) dropwise at 0° C. The mixture was stirred for 15 min at 0° C., and then stirred at 75° C. for 2 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was diluted with water (100 mL) extracted with DCM (2×100 mL). The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure to get crude compound I-8c (4.0 g crude, 46% pure by LCMS). The crude was taken next step without further purification. Synthesis of N-((2-bromothiazol-5-yl)methyl)pivalamide (I-8d) According to Method 2 (Step 1): To a stirred solution of compound I-8c (1.0 g, 5.177 mmol) in DCM (10 mL) was added Et₃N (1.0 g, 10.354 mmol) followed by pivaloyl chloride (0.92 g, 7.765 mmol) at 0° C. and. The reaction mixture was stirred for 2 h at rt, and then concentrated under reduced pressure. The crude residue was diluted with water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel (60-120 mesh, eluent: 20% EtOAc in hexane) to afford the crude compound I-8d (0.7 g) as a white solid. Synthesis of N-((2-acetylthiazol-5-yl)methyl)pivalamide (I-8e) According to Method 1 (Step 2 and Step 3): To a stirred solution of compound I-8d (2.0 g, 7.220 mmol) and tributyl(1-ethoxyvinyl)stannane (3.3 g, 9.386 mmol) in toluene (20 mL) was added Pd(PPh₃)₄(0.8 g, 0.72 mmol) under N₂and the reaction mixture was stirred to 110° C. for 16 h. To the reaction mixture saturated potassium fluoride solution was added and stirring was continued for 30 min at rt. The organic layer was separated and concentrated under reduced pressure. THF followed by conc. HCl was added to the residue and the biphasic mixture was stirred for 30 min. The reaction mixture pH was adjusted to >7 by slow addition of solid Na₂CO₃. Next, the mixture was diluted with water (80 mL) and extracted with DCM (2×100 mL). The combined organic layers were dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel (60-120 mesh) using 10% ethyl acetate:petroleum ether as an eluent to afford the crude compound I-8e (0.5 g, 36% product by LCMS) as a gummy solid, which was used as such. Synthesis of N-((2-(2-bromoacetyl)thiazol-5-yl)methyl)pivalamide (I-8) According to Method 2 (Step 3): To a solution of compound I-8e (0.450 g, 1.87 mmol) in dry THF (4.0 mL) was added tetrabutylammoniumtribromide (0.9 g, 1.8 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated, and the crude residue was purified by Combi-flash reversed phase chromatography to afford I-8 (0.15 g, 68% yield) as a white solid.

Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9), according to Method 2 (Scheme 2):

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Synthesis of (S,E)-N-((5-bromothiophen-2-yl)methylene)-2-methylpropane-2-sulfinamide (I-9a) To a solution of 5-bromothiophene-2-carbaldehyde (12.0 g, 62.8 mmol, 7.45 mL) in THF (150 mL) was added Ti(OEt)₄(28.7 g, 126 mmol, 26.1 mL) and (S)-2-methylpropane-2-sulfinamide (9.14 g, 75.4 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was quenched by addition H₂O (50.0 mL) at 25° C., and then extracted with EtOAc (30.0 mL×4). The combined organic layers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give compound I-9a (17.0 g, 90% yield, 98.1% purity) as a light yellow solid. Synthesis of (S)—N—((S)-1-(5-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide (I-9b) To a solution of compound I-9a (17.0 g, 57.8 mmol) in THF (119 mL) was added dropwise MeMgBr (3 M, 57.8 mL) at 0° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was then quenched by addition NH₄Cl (50.0 mL) at 25° C., and then extracted with DCM (50.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give compound I-9b (13.4 g, 62% yield, 83.5% purity) as a light yellow solid. Synthesis of (S)-1-(5-bromothiophen-2-yl)ethan-1-amine (I-9c) To a solution of compound I-9b (3.00 g, 9.67 mmol) in MeOH (21.0 mL) was added dropwise acetyl chloride (2.28 g, 29.0 mmol, 2.07 mL) at 25° C. After addition, the mixture was stirred at this temperature for 1 h. The solvent was removed in vacuo and then TEA (10.3 g, 102 mmol, 14.1 mL) and THF (30.0 mL) was added dropwise at 25° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give compound I-9c (7.40 g, 60.2% yield) as a light yellow oil. Synthesis of (S)—N-(1-(5-bromothiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9d) To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetic acid (12.4 g, 39.5 mmol) in DCM (66.6 mL) and DMF (7.40 mL) was added HOBt (7.28 g, 53.9 mmol), EDCI (10.3 g, 53.9 mmol) and DIPEA (13.9 g, 108 mmol, 18.8 mL) at 25° C. And then compound I-9c (7.40 g, 35.9 mmol) was added at 25° C. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by addition H₂O (30.0 mL) at 25° C., and then extracted with EtOAc (13.0 mL×3). The combined organic layers were washed with brine (20.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=I/O to 0/1) to give compound I-9d (9.60 g, 52% yield, 96.7% purity) as a light yellow oil. Synthesis of N-(1-(5-acetylthiophen-2-yl)ethyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-9e) To a solution of compound I-9d (9.50 g, 18.9 mmol) in toluene (66.5 mL) was added dropwise tributyl(1-ethoxyvinyl)stannane (13.7 g, 37.8 mmol, 12.8 mL) at 25° C., and then Pd(PPh₃)₄(1.09 g, 945 umol) was added at 25° C. The resulting mixture was stirred at 120° C. for 2 h. Saturated potassium fluoride solution (50.0 ml) was added to the reaction mixture and stirred for 30 min at rt. The organic layer was separated and concentrated under reduced pressure to get the crude compound. THF (50.0 mL) and 1 M HCl (20.0 mL) was added to the crude reaction mixture and stirred for 30 min and solid Na₂CO₃was added until pH-7. The reaction mixture diluted with water (50.0 mL) extracted with DCM (50.0 mL×3). Organic layer is separated, dried over Na₂SO₄, concentrate under reduced pressure to get crude compound. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=3/1) to give compound I-9e (6.40 g, 71% yield, 98.0% purity) as a yellow oil. Synthesis of N-(1-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-2-hydroxyacetamide (I-9) To a solution of compound I-9e (6.30 g, 13.5 mmol) in DCM (37.8 mL) and MeOH (94.5 mL) was added TBATB (6.85 g, 14.2 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by addition H₂O (20.0 mL) at 25° C., and then extracted with EtOAc (40.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=I/O to 0/1) to give compound I-9 (3.00 g, 61% yield, 83.8% purity) as a light yellow oil.

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10), According to Method 4a (Scheme 4).

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Synthesis of 4-chloro-N-(thiophen-2-ylmethyl)butanamide (I-10a) According to Method 4a (Step 1): To a solution mixture of thiophen-2-ylmethanamine (5.0 g, 44.1 mmol) and Et₃N (19.8 mL, 141.0 mmol) in DCM (130.0 mL) was added drop wise a solution of 4-chlorobutanoyl chloride (6.57 mL, 58.3 mmol) in DCM (20.0 mL) at 0° C. The reaction mixture was stirred for 1 h at 0° C. before it was quenched with cold water (100 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was taken to next step without further purification, to afford compound I-10a (7.0 g, Yield: 73%) as gummy liquid. Synthesis of 1-(thiophen-2-ylmethyl)pyrrolidin-2-one (I-10b) According to Method 4a (Step 2): To a solution mixture of compound I-10a (3.0 g, 13.7 mmol) in DMF (30.0 mL) was added NaH (826 mg, 20.6 mmol (60% in mineral oil)) at rt, and the mixture was stirred for 3 h. Next, the reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by column chromatography over silica gel (100-200 mesh) eluting with 12% EtOAc in hexane to afford compound I-10b (1.8 g, Yield: 72%) as a gummy liquid. Synthesis of 1-((5-acetylthiophen-2-yl)methyl)pyrrolidin-2-one (I-10c) According to Method 2 (Step 3): To a solution of AlCl₃(1.95 g, 14.91 mmol) in DCM (50.0 mL) was added acetyl chloride (0.80 mL, 11.93 mmol) drop wise at 0° C. After 5 min, compound I-10b (1.8 g, 9.94 mmol) was added stirring was continued for 1 h at 0° C. The reaction mixture was then quenched with cold water (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) eluting with 30% EtOAc in hexane to afford compound I-10c (0.99 g, Yield: 45%) as a gummy liquid. Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)pyrrolidin-2-one (I-10) According to Method 2 (Step 4): To a solution mixture of compound I-10c (500 mg, 2.242 mmol) in THF (10 mL) and added phenyltrimethyl ammonium tribromide (576.0 mg, 1.569 mmol) at 0° C. The reaction mixture was stirred for 16 h at rt after which it was filtered through a celite bed and concentrated in vacuo. The crude compound was purified using Combi-flash reversed phase purification (using ACN and 0.001% TFA in water as eluent) to afford compound I-10 (0.25 g, Yield: 36%) as an off-white solid.

Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11), According to Method 4a (Scheme 4).

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Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12): The synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)pyrrolidin-2-one (I-11) was performed in similar experimental conditions than intermediate I-10, starting from 2-(thiophen-2-yl)ethan-1-amine and reacting with chlorobutanoyl chloride to afford compound I-11 (0.45 g, Yield: 26%) as an off-white solid.

Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12), According to Method 2 (Scheme 2):

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Synthesis of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole (I-12a) To a stirred solution of 2-bromo-5-methyl-1,3,4-thiadiazole (4.5 g, 25.1 mmol) in CCl₄(100 mL) cooled to 0° C. was added N-bromosuccinimide (4.4 g, 25.1 mmol) followed by AIBN (0.4 g, 2.51 mmol). Then, the reaction mixture was stirred at 80° C. for 16 h after which it was diluted with water (100 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over Na₂SO₄, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (60-120 mesh) eluting with 50% EtOAc in hexane to afford compound I-12a (2.0 g, 31% yield) as a white solid. Synthesis of (5-bromo-1,3,4-thiadiazol-2-yl)methanamine (I-12b): To a stirred solution of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole I-12a (2.0 g, 7.81 mmol) in MeOH (20 mL) cooled to 0° C. was added 7 N methanolic ammonia (40 mL). The reaction mixture was then stirred at rt for 16 h after which it was concentrated in vacuo. The residue was purified by column chromatography using silica gel (60-120 mesh) eluting with 30% EtOAc in hexane to afford compound I-12b (1.5 g) as a gummy solid. Synthesis of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12c) To a stirred solution of (5-bromothiazol-2-yl)methanamine I-12b (1.6 g, 8.24 mmol) was dissolved in DCM (20 mL) cooled to 0° C. added Et₃N (1.6 g, 16.2 mmol) followed by pivaloyl chloride (1.4 g, 12.3 mmol) was added then slowly warmed to rt and stirred for 2 h at rt. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and extracted with DCM (2×80 mL). The combined organic layers were dried over Na₂SO₄, and the solvent evaporated under reduced pressure. The crude was purified by column chromatography over silica gel (60-120 mesh) eluting with 30% EtOAc in hexane to afford compound I-12c (1.0 g, 45% yield) as a gummy solid. Synthesis of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12d): To a stirred solution of N-((5-bromo-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12c (1.0 g, 3.597 mmol) and tributyl(1-ethoxyvinyl)stannane (1.6 g, 4.676 mmol) in toluene (10 mL) was added Pd(PPh₃)₄(0.4 g, 0.346 mmol). Next, the mixture was slowly heated to 110° C. for 16 h. After cooling to rt, saturated KF solution was added stirring was continued for 30 min at rt. The organic layer was separated, dried over Na₂SO₄, and concentrated under reduced pressure. To the residue was added THF and then conc. HCl, and the resulting biphasic mixture was stirred for 30 min. Next, the pH of the mixture was adjusted to >7 by slow addition of solid Na₂CO₃. The mixture was then diluted with water (50 mL), extracted with DCM (2×100 mL). The combined organic layers were dried over Na₂SO₄, and the solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (60-120 mesh) eluting with 30% EtOAc in hexane to afford compound I-12d (0.7 g, 81% yield) as a pale-yellow solid. Synthesis of N-((5-(2-bromoacetyl)-1,3,4-thiadiazol-2-yl)methyl)pivalamide (I-12) To a solution of N-((5-acetyl-1,3,4-thiadiazol-2-yl)methyl)pivalamide I-12d (0.4 g, 1.659 mmol) in dry THF (5 mL) tetrabutylammonium tribromide (0.8 g, 1.659 mmol) was added, and the resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated to get crude compound. The crude was purified by Combi-flash reversed phase chromatography to afford compound I-12 (0.2 g, Yield: 38%, 70% pure by LCMS) as a white solid.

Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13), according to Method 2 (Scheme 2):

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Synthesis of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (I-13a) To a solution of glycolic acid (110 g, 1.45 mol) in THE (770 mL) was added TEA (293 g, 2.89 mol, 403 mL), DMAP (17.7 g, 145 mmol) and TBDPSCl (477 g, 1.74 mol, 446 mL) at 0° C., and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was acidified with aqueous HCl (1 M) until pH=1 was reached and extracted with EtOAc (300 mL×3). The organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by SiO₂column chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give compound I-13a (283 g, 57% yield, 91.0% purity) as light red oil. ¹H NMR: (400 MHz, CDCl₃) δ 7.70-7.68 (m, 4H), 7.45-7.43 (m, 6H), 4.28 (s, 2H), 1.13 (s, 9H). Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-(thiophen-2-ylmethyl)acetamide (I-13b) To a solution of I-13a (281 g, 894 mmol) in DMF (644 mL) was added DIEA (420 g, 3.25 mol, 566 mL), EDCI (233 g, 1.22 mol) and HOBt (165 g, 1.22 mol) at 15° C. and this mixture was stirred at 15° C. for 30 min. To this mixture was added thiophen-2-ylmethanamine (92.0 g, 813 mmol, 83.6 mL). This mixture was stirred at 15° C. for 2 h. The reaction mixture was then diluted with H₂O (1.50 L) and extracted with EtOAc (500 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, ethyl acetate/petroleum ether=100/1 to 0/1; TLC: ethyl acetate/petroleum ether=5/1, compound I-13b R_f=0.60) to give compound I-13b (246 g, 70% yield, 94.2% purity) as light yellow oil. ¹H NMR: ET45071-646-P1B (400 MHz, CDCl₃) δ 7.53-7.50 (m, 4H), 7.38-7.27 (m, 6H), 7.17-7.16 (m, 1H), 7.69 (s, 1H), 6.92-6.88 (m, 2H), 4.62 (d, J=5.6 Hz, 2H), 4.09 (s, 2H), 0.98 (s, 9H). Synthesis of N-((5-bromothiophen-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13c) Two reactions were carried out in parallel on the same scale. To the solution of compound I-13b (82.0 g, 200 mmol) in DMF (574 mL) was added NBS (39.2 g, 220 mmol). The mixture was stirred at 20° C. for 1 hr. The two reactions were combined for work up. The reaction mixture was diluted with H₂O (3.40 L) and extracted with EtOAc (1.50 L×3). The combined organic layers were washed with H₂O (500 mL×8) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give compound I-13c (199 g, 85% yield, 83.1% purity) as a light yellow solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.61-7.59 (m, 4H), 7.48-7.37 (m, 6H), 7.20 (s, 1H), 6.92 (d, J=3.6 Hz, 1H), 6.74 (d, J=3.6 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.18 (s, 2H), 1.08 (s, 9H). Synthesis of N-((5-acetylthiophen-2-yl)methyl)-2-((tert-butyldiphenylsilyl)oxy)acetamide (I-13d) To a solution of compound I-13c (94.0 g, 192 mmol) in toluene (658 mL) was added tributyl(1-ethoxyvinyl)tin (90.4 g, 250 mmol, 84.5 mL) and Pd(PPh₃)₄(22.2 g, 19.2 mmol). The mixture was degassed and purged with N₂for 3 times and then it was stirred at 110° C. for 16 h under N₂atmosphere. The same reaction was performed in parallel with 105 g of I-13c, and both mixtures were combined for work-up. Saturated KF solution (2.00 L) was added to the reaction mixture and the mixture was stirred for 30 min at 20° C. The organic layer was separated and HCl (0.5 M, 2.0 L) was added to the crude reaction mixture and the mixture was stirred for 30 min. The organic layer was separated and extracted with EtOAc (500 mL×2). The combined organic layers were dried over Na₂SO₄, concentrated in vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=3/1 to 1/1) to give compound I-13d (124 g, 63% yield, 93.6% purity) as a yellow solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.62-7.58 (m, 5H), 7.48-7.38 (m, 6H), 7.30 (s, 1H), 7.01 (d, J=3.6 Hz, 1H), 4.72 (d, J=3.6 Hz, 1H), 4.20 (s, 2H), 2.55 (s, 3H), 1.09 (s, 9H). Synthesis of N-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide (I-13) To the solution of compound I-13d (119 g, 263 mmol) in DCM (714 mL) and MeOH (1.78 L) was added TBATB (133 g, 276 mmol) and the mixture was stirred at 15° C. for 12 h. The reaction mixture was concentrated in vacuum and the residue was diluted with DCM (100 mL) and washed with H₂O (40.0 mL×3). The organic layer was concentrated in vacuum. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=0/1 to 1/0) to give compound I-13 (46.0 g, 55% yield, 91.3% purity) as colorless oil. ¹H NMR: (400 MHz, DMSO-d₆) δ 8.55 (t, J=6.0 Hz, 1H), 7.91 (d, J=4.0 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H), 4.75 (s, 2H), 4.49 (d, J=6.0 Hz, 2H), 3.86 (s, 2H).

4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14), according to Method 4 (Scheme 4):

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Synthesis of 2-(chloromethyl)thiophene (I-14a) To the solution of 2-thienylmethanol (2.00 g, 17.5 mmol, 1.65 mL) in DCM (14.0 mL) was added SOCl₂(4.17 g, 35.0 mmol, 2.54 mL) dropwise at 0° C. under N₂atmosphere. The mixture was stirred at 0° C. for 30 min, after which the mixture was stirred at 25° C. for 30 min. The reaction mixture was quenched by NaHCO₃(110 mL) and extracted with EtOAc (80.0 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give compound I-14a (1.50 g, 65% yield) as a brown oil. Synthesis of 4-(thiophen-2-ylmethyl)morpholin-3-one (I-14b) To a solution of morpholin-3-one (2.29 g, 22.6 mmol) in THF (10.0 mL) was added dropwise LiHMDS (1 M, 17.0 mL) at 0° C. After addition, the mixture was stirred at this temperature for 30 min, and then compound I-14a (1.50 g, 11.3 mmol) in THF (8.00 mL) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 7 h. The reaction was quenched by addition of 10.0 mL of NH₄Cl at 0° C. and then diluted with H₂O (10.0 mL) and extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give compound I-14b (1.10 g, 42% yield, 85.4% purity) as a brown oil. ¹H NMR [400 MHz, CDCl₃]: 7.26 (t, J=1.2 Hz, 1H), 7.00 (d, J=2.4 Hz, 1H), 4.76 (s, 2H), 4.20 (s, 2H) 3.86-3.83 (m, 2H) 3.36 (t, J=5.2 Hz, 2H). Synthesis of 4-((5-bromothiophen-2-yl)methyl)morpholin-3-one (I-14c) To a solution of compound I-14b (1.10 g, 5.58 mmol) in DMF (7.70 mL) was added NBS (993 mg, 5.58 mmol). The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with H₂O (10.0 mL) and washed with EtOAc (10.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=1/1) to give compound I-14c (crude) (2.00 g, 88.8% purity) as a light yellow solid. ¹H NMR [400 MHz, CDCl₃]: 6.89 (d, J=3.6 Hz, 1H), 6.75 (d, J=3.6 Hz, 1H), 4.64 (s, 2H), 4.19 (s, 2H), 3.85 (t, J=4.8 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 2.73 (s, 3H). Synthesis of 4-((5-acetylthiophen-2-yl)methyl)morpholin-3-one (I-14d) To a solution of compound I-14c (2.00 g, 7.24 mmol) in toluene (14.0 mL) was added tributyl(1-ethoxyvinyl)stannane (3.22 g, 8.91 mmol, 3.01 mL) and Pd(PPh₃)₄(837 mg, 724 umol). The mixture was stirred at 110° C. for 16 h. Saturated KF solution (20.0 mL) was added to the reaction mixture and the mixture was stirred for 30 min at 20° C. The organic layer was separated and HCl (0.5 M, 20.0 mL) was added to the crude reaction mixture and the mixture was stirred for 30 mins. The organic layer was separated and extracted with EtOAc (20.0 mL×2). The combined organic layers were dried over Na₂SO₄, concentrated in vacuum. The residue was purified by column chromatography (SiO₂, DCM/Ethyl acetate=50/1 to 0/1) to give compound I-14d (1.00 g, 58% yield) as a black solid. Synthesis of 4-((5-(2-bromoacetyl)thiophen-2-yl)methyl)morpholin-3-one (I-14) To a solution of compound I-14d (1.00 g, 4.18 mmol) in DCM (2.00 mL) and IPA (5.00 mL) was added TBATB (2.32 g, 4.81 mmol). And the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with H₂O (25.0 mL) and washed with EtOAc (25.0 mL×3). The combined organic layers were washed with brine (25.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give compound I-14 (1.00 g, 3.14 mmol, 75% yield) as a brown oil.

Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-hydroxypyrrolidin-2-one (I-15), According to Method 4 (Scheme 4):

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Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(thiophen-2-ylmethyl) pyrrolidin-2-one (I-15a) To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (25.0 g, 73.6 mmol) in THF (170 mL) was added dropwise LiHMDS (1 M, 110 mL) at 0° C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-(chloromethyl)thiophene (19.5 g, 147 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 7 h. LCMS showed the 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one was consumed completely and 27% desired compound detected. The reaction mixture was quenched by addition H₂O (100 mL) at 25° C., and then extracted with EtOAc 300 mL (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, petroleum ether/ethyl acetate=3/1) to give compound I-15a (9.00 g, 28.0% yield) as a yellow oil. Synthesis of 1-((5-bromothiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl) oxy)pyrrolidin-2-one (I-15b) To a solution of compound I-15a (9.00 g, 20.7 mmol) in DMF (50.0 mL) was added NBS (4.04 g, 22.7 mmol). The mixture was stirred at 20° C. for 2 h after which it was quenched by addition H₂O (100 mL) at 25° C., and then extracted with EtOAc 150 mL (50.0 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-15b (6.70 g, 63% yield) as a brown oil. Synthesis of 1-((5-acetylthiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl) oxy)pyrrolidin-2-one (I-15c) To the solution of compound I-15b (6.70 g, 13.0 mmol) in Tol (42.0 mL) was added tributyl(1-ethoxyvinyl)stannane (6.58 g, 18.2 mmol, 6.15 mL) and Pd(PPh₃)₄(1.50 g, 1.30 mmol). The mixture was degassed and purged with N₂for three times, and then the mixture was stirred at 110° C. for 16 h under N₂atmosphere. Saturated potassium fluoride solution was added to the reaction mixture and stirred for 30 min at 15° C. The organic layer was separated and concentrated under reduced pressure to get the crude compound. HCl (0.5 M, 90.0 mL) was added to the crude and the mixture was stirred for 30 min and solid Na₂CO₃(˜5 g) was added until pH=−7. The reaction mixture was diluted with water (50.0 mL) extracted with ethyl acetate (50.0 mL×2). The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-15c (5.50 g, 88% yield) as a yellow solid. Synthesis of 1-((5-(2-bromoacetyl)thiophen-2-yl)methyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-15) To a solution of compound I-15c (0.50 g, 1.05 mmol) in DCM (3.00 mL) and IPA (7.50 mL) was added trimethylphenylammonium tribromide (413 mg, 1.10 mmol). The mixture was stirred at 50° C. for 2 h. The reaction mixture was quenched by H₂O 10.0 mL at 25° C., and then extracted with EtOAc 15.0 mL (5.00 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give compound I-15 (0.90 g, 46% yield, 30% purity) as a white solid.

Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-hydroxypyrrolidin-2-one (I-16), According to Method 4 (Scheme 4):

[Image Omitted]

Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-1-(2-(thiophen-2-yl)ethyl)pyrrolidin-2-one (I-16a) To a solution of 3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (10.8 g, 31.8 mmol) in THF (70.0 mL) was added dropwise LiHMDS (1 M, 47.7 mL) at 0° C. After addition, the mixture was stirred at this temperature for 30 min, and then 2-(2-thienyl)ethyl 4-methylbenzenesulfonate (10.8 g, 38.2 mmol) in THF (30.0 mL) was added dropwise at 0° C. The resulting mixture was stirred at 60° C. for 7 h. The reaction mixture was quenched by addition H₂O (100 mL) at 25° C., and then extracted with EtOAc 150 mL (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-16a (7.00 g, 49% yield) as a white solid. Synthesis of (S)-1-(2-(5-bromothiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16b) To a solution of compound I-16a (7.00 g, 15.6 mmol) in DMF (56.0 mL) was added NBS (3.05 g, 17.1 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by addition H₂O (50.0 mL) at 25° C., and then extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-16b (4.60 g, 56% yield) as a colorless oil. Synthesis of 1-(2-(5-acetylthiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16c) To the solution of compound I-16b (4.60 g, 8.70 mmol) in Tol. (32.0 mL) was added tributyl(1-ethoxyvinyl)stannane (4.40 g, 12.1 mmol, 4.11 mL) and Pd(PPh₃)₄(1.01 g, 870 umol). The mixture was degassed and purged with N₂for three times, and then the mixture was stirred at 110° C. for 16 h under N₂atmosphere. Saturated potassium fluoride solution was added to the reaction mixture and stirred for 30 min at 15° C. The organic layer was separated and concentrated under reduced pressure to get the crude compound. HCl (0.5 M, 90.0 mL) was added to the crude reaction mixture and stirred for 30 min and solid Na₂CO₃(˜15.0 g) was added until pH=−7. The reaction mixture diluted with water (50.0 mL) extracted with Ethyl acetate (10.0 mL×2). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure to get crude compound. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-16c (3.49 g, 82% yield) as a yellow oil. Synthesis of 1-(2-(5-(2-bromoacetyl)thiophen-2-yl)ethyl)-3-((tert-butyldiphenylsilyl)oxy)pyrrolidin-2-one (I-16) To a solution of compound I-16c (1.00 g, 2.03 mmol) in MeOH (5.00 mL) and DCM (1.50 mL) was added TBATB (1.03 g, 2.14 mmol). The mixture was stirred at 20° C. for 2 h. The reaction mixture was quenched by addition H₂O (10.0 mL) at 25° C., and then extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) to give compound I-16 (0.80 g, 69% yield) as a yellow oil.

Preparation of Intermediate Compounds of Formula Y¹—SH, Wherein R²=H:

Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1)

[Image Omitted]

Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ol (J-1-1) A solution mixture of ethyl 5-amino-1-methyl-1H-pyrazole-4-carboxylate (10 g, 59.1 mmol) in formamide (40 mL) was stirred at 180° C. for 4 h. The reaction mixture was cooled to rt, after which a precipitate formed. The resulting precipitate was filtered in vacuo, washed with hexane and dried in vacuo to afford J-1-1 (7.2 g, Yield: 79%) as an off-white solid. Synthesis of 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-thiol (J-1) To a solution of compound J-1-1 (3.4 g, 22.6 mmol) in toluene (50.0 mL) was added Lawesson's reagent (5.4 g, 13.5 mmol) at 0° C. The reaction mixture was stirred for 2 h at 120° C. Next, the mixture was concentrated in vacuo, and the residue was purified by column chromatography over silica gel (60-120 mesh) eluting with 10% EtOAc in hexane to afford J-1 (3.0 g, Yield: 81%) as a pale-yellow solid.

Synthesis of 1,7-naphthyridine-8-thiol (J-5)

[Image Omitted]

Synthesis of 1,7-naphthyridine-8-thiol (J-5) To a solution of 8-chloro-1,7-naphthyridine (500 mg, 3.04 mmol) in DMF (3.00 mL) was added NaSH (681 mg, 12.2 mmol). The mixture was stirred at 80° C. for 2 h. The reaction mixture was used into the next step directly without work-up.

The following compounds have been prepared using the experimental conditions described above from commercially available or art known hydroxy-substituted heteroaryls of formula Y¹—OH by thionation using P₂S₅reagent or Lawesson's reagent or, alternatively, from chloro-substituted heteroaryls of formula Y—C₁by thiol substitution using NaSH or Na₂S. Alternatively, some of the following compounds could be obtained commercially:

Cpd

number
Structure
Name

J-2

[Image Omitted]

quinazoline-4-thiol

J-3

[Image Omitted]

1,6-naphthyridine-5-thiol

J-4

[Image Omitted]

2,7-naphthyridine-1-thiol

J-6

[Image Omitted]

imidazo[1,2-a]pyrazine-8-thiol

J-7

[Image Omitted]

imidazo[1,5-a]pyrazine-8-thiol

J-8

[Image Omitted]

pyrazolo[1,5-a]pyrazine-4-thiol

Preparation of Intermediate Compounds of Formula Y¹—SH, Wherein R²=Haloalkyl, CF₃or CHF₂:

Synthesis of 2-(trifluoromethyl)quinazoline-4-thiol (K-1)

[Image Omitted]

Synthesis of 2-(trifluoromethyl)quinazolin-4-ol (K-1-1) To a stirred solution of 2-aminobenzamide (1.0 g, 7.344 mmol) in dry DCM was added trifluoroacetic anhydride (1.7 g, 8.022 mmol), pyridine (1.0 mL) and DMAP (0.018 mg, 0.147 mmol) at room temperature. The reaction mixture was stirred at rt for 16 h. The progress of the reaction was monitored by TLC consumption of starting material. After consumption of starting material, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na₂SO₄, and the solvent concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (100:200 mesh, solvents: 10% EtOAc in hexane) to obtain K-1-1 (1.0 g, 63% yield). Synthesis of 2-(trifluoromethyl)quinazoline-4-thiol (K-1) To a stirred solution of 2-(trifluoromethyl)quinazolin-4 (1H)-one (K-1-1) (0.5 g, 7.344 mmol) in dry toluene was added Lawesson's reagent (1.01 g, 7.344 mmol) under an atmosphere of dry argon, the reaction was then heated under reflux for 16 h until no more starting material could be detected by TLC. Next, a solution of 3 N NaOH was added to the mixture. After neutralizing with 1 N HCl, the formed solid was filtered and dried under vacuum to afford K-1 (0.28 g, 52% yield) as an off-white solid.

Synthesis of 3-(trifluoromethyl)isoquinoline-1-thiol (K-22)

[Image Omitted]

Synthesis of 3-(trifluoromethyl)-1H-isochromen-1-one (K-22-1) To a stirred solution of 2-(carboxymethyl)benzoic acid (2.0 g, 11.10 mmol) was added trifluroacetic anhydride (2.1 mL) at room temperature and the reaction mixture was stirred at 100° C. for 48 h. The reaction mixture was concentrated under reduced pressure to get K-22-1 (2.5 g, Crude) was taken to next step without any further purification. Synthesis of 3-(trifluoromethyl)isoquinolin-1 (2H)-one (K-22-2): 3-(trifluoromethyl)-1H-isochromen-1-one K-22-1 (2.5 g (crude), 11.62 mmol) was added to NH₄OH (37.0 mL) at rt. The resulting mixture was stirred at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure to give crude compound K-22-2 (160 mg, Yield: 7%) as a white solid. Synthesis of 3-(trifluoromethyl)isoquinoline-1-thiol (K-22): To a stirred solution of 3-(trifluoromethyl)isoquinolin-1 (2H)-one K-22-2 (160 mg, 0.751 mmol) in dry toluene (6.0 mL) was added Lawesson's reagent (303 g, 0.751 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 4 h, then concentrated under vacuum. The residue was purified using combi-flash reversed phase purification (eluent: ACN and 0.001% TFA in water) to afford compound K-22 (50 mg, Yield 29%) as an off-white solid.

The following intermediate compounds (K-2) to (K-21) have been prepared using the experimental conditions described above from the reaction of substituted amino carboxamide aryl and heteroaryl, and trifluoroacetic anhydride or CHF₂-based reagents. Alternatively, they were prepared from art known or commercial hydroxy-substituted heteroaryls of formula Y¹—OH by thionation using P₂S₅reagent or Lawesson's reagent. Alternatively, some of the following compounds could be obtained commercially:

Cpd

number
Structure
Name

K-2

[Image Omitted]

2-(difluoromethyl)quinazoline-4- thiol

K-3

[Image Omitted]

6-methoxy-2- (trifluoromethyl)quinazoline-4- thiol

K-4

[Image Omitted]

6-morpholino-2- (trifluoromethyl)quinazoline- 4-thiol

K-5

[Image Omitted]

2-methyl-6-(trifluoromethyl)- 2H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-6

[Image Omitted]

6-(difluoromethyl)-1-methyl- 1H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-7

[Image Omitted]

1-methyl-6-(trifluoromethyl)- 1H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-8

[Image Omitted]

6-(difluoromethyl)-2-methyl- 2H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-9

[Image Omitted]

2-cyclopropyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidine- 4-thiol

K-10

[Image Omitted]

2-(difluoromethyl)-6- methoxyquinazoline-4-thiol

K-11

[Image Omitted]

2-(trifluoromethyl)pyrido[2,3- d]pyrimidine-4-thiol

K-12

[Image Omitted]

1-ethyl-6-(trifluoromethyl)- 1H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-13

[Image Omitted]

2-ethyl-6-(trifluoromethyl)- 2H-pyrazolo[3,4- d]pyrimidine-4-thiol

K-14

[Image Omitted]

1-cyclopropyl-6- (trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine- 4-thiol

K-15

[Image Omitted]

7-methyl-2- (trifluoromethyl)pyrazolo[1,5- a][1,3,5]triazine-4-thiol

K-16

[Image Omitted]

2-(difluoromethyl)-6- methoxypyrido[2,3- d]pyrimidine- 4-thiol

K-17

[Image Omitted]

7-cyclopropyl-2- (trifluoromethyl)pyrazolo[1,5- a][1,3,5]triazine-4-thiol

K-18

[Image Omitted]

6-methoxy-2- (trifluoromethyl)pyrido[3,4- d]pyrimidine-4-thiol

K-19

[Image Omitted]

2-(2-methoxyethyl)-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidine- 4-thiol

K-20

[Image Omitted]

1-(2-methoxyethyl)-6- (trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidine- 4-thiol

K-21

[Image Omitted]

2-(trifluoromethyl)pyrido[3,2- d]pyrimidine-4-thiol

Preparation of Intermediate Compounds of Formula Y¹—SH, Wherein R²=Alkyl and the Like:

Synthesis of 7-chloro-2-methylquinazoline-4-thiol (M-1)

[Image Omitted]

Synthesis of 7-chloro-2-methylquinazolin-4-ol (M-1-1) To a solution of 2-amino-4-chlorobenzamide (1.5 g, 8.823 mmol) in dioxane (10 mL) was added DIPEA (1.61 mL, 9.264 mmol) followed by acetyl chloride (0.63 mL, 8.823 mmol) at 0° C. and the reaction mixture was stirred for 15 min at 0° C. The reaction mixture was heated to reflux for 16 h after which it was concentrated in vacuo. The residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo. The crude 7-chloro-2-methylquinazolin-4-ol (M-1-1) was taken to next step without further purification. Synthesis of 7-chloro-2-methylquinazoline-4-thiol (M-1) To a solution of compound M-1-1 (400 mg, 2.061 mmol) in toluene (6.0 mL) was added P₂S₅(457.7 mg, 2.061 mmol) at 0° C. The reaction mixture was stirred for 2 h at 120° C. after which it was concentrated in vacuo. The residue was diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue compound was washed with hexane and dried in vacuo to afford 7-chloro-2-methylquinazoline-4-thiol (M-1) (190 mg, crude).

Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11)

[Image Omitted]

Synthesis of 6-methoxy-2-methylquinazolin-4-ol (M-11-1) To EtOH (500 mL) was added NaH (42.1 g, 1.05 mol, 60% purity) in portions at 0° C. and then 2-amino-5-methoxybenzamide (25.0 g, 150 mmol) was added followed by EtOAc (53.0 g, 601 mmol, 58.91 mL). The resulting mixture was stirred at 90° C. for 12 h. The reaction mixture was quenched by 1 M HCl (500 mL) and filtered. The filter cake was collected. The collected filter cake was dissolved in EtOAc/MeOH (V/V=1/1, 200 mL) and filtered. The filtrate was concentrated in vacuum to give compound M-11-1 (34.0 g, crude) as an off-white solid. ¹H NMR: (400 MHz, DMSO-d₆) δ 12.2 (s, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.45 (d, J=2.8 Hz), 7.36 (dd, J=8.8 Hz, 1H), 3.84 (s, 1H), 2.32 (s, 3H). Synthesis of 6-methoxy-2-methylquinazoline-4-thiol (M-11) To a solution of compound M-11-1 (20.0 g, 105 mmol) in toluene (140 mL) was added Lawesson's reagent (46.8 g, 115 mmol) and the mixture was stirred at 120° C. for 12 h under N₂atmosphere. Two additional runs were done of this reaction on 18.0 g scale and 7.20 g scale of M-11-1, and the crude mixtures of all three runs were combined for work-up. The reaction mixture was concentrated in vacuum to remove solvent. The residue was triturated with EtOAc/MeOH (V/V=10/1, 10 V, 3 times) at 25° C. for 6 h to give compound M-11 (25.5 g, 72% yield, 85.3% purity) as a yellow solid. ¹H NMR: (400 MHz, DMSO-d₆) δ 13.9 (s, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.51 (dd, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.48 (s, 3H).

The following intermediate compounds M-2 to M-48 have been prepared using the experimental conditions described above from the reaction of substituted amino carboxamide aryl and heteroaryl, and trifluoroacetic anhydride or CHF₂-based reagents. Alternatively, they were prepared from art known or commercial hydroxy-substituted heteroaryls of formula Y¹—OH by thionation using P₂S₅reagent or Lawesson's reagent. Alternatively, some of the following compounds could be obtained commercially:

Cpd

number

M
Structure
Name

M-2

[Image Omitted]

2,7-dimethyl- quinazoline-4- thiol

M-3

[Image Omitted]

2-isopropyl- quinazoline-4- thiol

M-4

[Image Omitted]

2-methyl- quinazoline-4- thiol

M-5

[Image Omitted]

2-cyclobutyl- quinazoline-4- thiol

M-6

[Image Omitted]

2-cyclopropyl- quinazoline-4- thiol

M-7

[Image Omitted]

6-fluoro-2- methyl- quinazoline-4- thiol

M-8

[Image Omitted]

2-methylpyrido [2,3-d] pyrimidine-4- thiol

M-9

[Image Omitted]

7-fluoro-2- methyl- quinazoline-4- thiol

M-10

[Image Omitted]

7-methoxy-2- methyl- quinazoline-4- thiol

M-12

[Image Omitted]

2-ethyl- quinazoline-4- thiol

M-13

[Image Omitted]

2-methylpyrido [3,2-d] pyrimidine-4- thiol

M-14

[Image Omitted]

2-(methoxy- methyl) quinazoline-4- thiol

M-15

[Image Omitted]

6-chloro-7- fluoro-2- methyl- quinazoline-4- thiol

M-16

[Image Omitted]

7-fluoro-6- methoxy-2- methyl- quinazoline-4- thiol

M-17

[Image Omitted]

2-methyl-6- (trifluoro- methyl) quinazoline-4- thiol

M-18

[Image Omitted]

6- cyclopropoxy- 2-methyl- quinazoline-4- thiol

M-19

[Image Omitted]

6- ((cyclopropyl- methyl) amino)-2- methyl- quinazoline-4- thiol

M-20

[Image Omitted]

2-methyl-6- morpholino- quinazoline-4- thiol

M-21

[Image Omitted]

2-methyl-6- (piperidin-1-yl) quinazoline-4- thiol

M-22

[Image Omitted]

2-methyl-6- (1,4-oxazepan- 4-yl) quinazoline-4- thiol

M-23

[Image Omitted]

6-(3,3- difluoro- pyrrolidin-1- yl)-2-methyl- quinazoline- 4-thiol

M-24

[Image Omitted]

2-methyl-6-(4- methyl- piperazin-1-yl) quinazoline-4- thiol

M-25

[Image Omitted]

2,6-dimethyl- 2H-pyrazolo [3,4-d] pyrimidine-4- thiol

M-26

[Image Omitted]

6-cyclopropyl- 1-methyl-1H- pyrazolo[3,4-d] pyrimidine-4- thiol

M-27

[Image Omitted]

1,6-dimethyl- 1H-pyrazolo [3,4-d] pyrimidine-4- thiol

M-28

[Image Omitted]

2-methyl- quinazoline-4- thiol

M-29

[Image Omitted]

6-chloro-8- fluoro-2- methyl- quinazoline-4- thiol

M-30

[Image Omitted]

8-fluoro-2- methyl- quinazoline-4- thiol

M-31

[Image Omitted]

2-methyl-8- (methylamino)- 6-(trifluoro- methyl) quinazoline-4- thiol

M-32

[Image Omitted]

8-(dimethyl- amino)-2- methyl-6- (trifluoro- methyl) quinazoline-4- thiol

M-33

[Image Omitted]

6-(dimethyl- amino)-2- methylpyrido [3,4-d] pyrimidine-4- thiol

M-34

[Image Omitted]

8-methoxy-2- methyl-6- (trifluoro- methyl) quinazoline-4- thiol

M-35

[Image Omitted]

6-fluoro-2- methylpyrido [2,3-d] pyrimidine-4- thiol

M-36

[Image Omitted]

6-methoxy-2- methylpyrido [3,4-d] pyrimidine-4- thiol

M-37

[Image Omitted]

2-methyl-6- (trifluoro- methoxy) quinazoline-4- thiol

M-38

[Image Omitted]

2-methyl-6- (trifluoro- methyl)pyrido [2,3-d] pyrimidine-4- thiol

M-39

[Image Omitted]

6-methoxy-2- methylpyrido [2,3-d] pyrimidine-4- thiol

M-40

[Image Omitted]

6-ethoxy-2- methylpyrido [2,3-d] pyrimidine-4- thiol

M-41

[Image Omitted]

5-fluoro-6- methoxy-2- methyl- quinazoline-4- thiol

M-42

[Image Omitted]

8-fluoro-6- methoxy-2- methyl- quinazoline-4- thiol

M-43

[Image Omitted]

6-cyclopropyl- 2-methyl- quinazoline-4- thiol

M-44

[Image Omitted]

6-(2-oxa-5- azabicyclo [2.2.2]octan-5- yl)-2-methyl- quinazoline-4- thiol

M-45

[Image Omitted]

6-chloro-5- fluoro-2- methyl- quinazoline-4- thiol

M-46

[Image Omitted]

6-ethoxy-2- methylpyrido [3,4-d] pyrimidine-4- thiol

M-47

[Image Omitted]

6-ethoxy-2- methyl- quinazoline-4- thiol

M-48

[Image Omitted]

5-methoxy-2- methyl- quinazoline-4- thiol

Preparation of Intermediate Compounds of Formula Y¹—SH, Wherein R²—═NR²:

Synthesis of 2-(dimethylamino)quinazoline-4-thiol (N-1)

[Image Omitted]

Synthesis of 2-(dimethylamino)quinazolin-4-ol (N-1-1) To a solution mixture of 2-iodobenzoic acid (1.0 g, 4.00 mmol) and compound-2 (743 mg, 6.0 mmol) in ACN (10 mL) was added K₂CO₃(2.2 g, 16.1 mmol) and copper chloride hydrate (13 mg, 0.08 mmol) at rt. The reaction mixture was heated at 90° C. for 16 h. After cooling to rt, water (100 mL) was added, and the mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over Na₂SO₄and concentrated in vacuo affording compound N-1-1 (700 mg, Yield: 91%) as an off-white solid, which was taken to the next step without further purification. Synthesis of 2-(dimethylamino)quinazoline-4-thiol (N-1) To a stirred solution of compound N-1-1 (300 mg, 1.67 mmol) in dry toluene (4.0 mL) was added Lawesson's reagent (677 g, 1.675 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80° C. for 4 h, then concentrated under vacuum. The crude compound was purified by column chromatography over silica gel (100-200 mesh) to afford compound N-1 (150 mg, Yield: 46%) as a yellow solid.

Preparation of Intermediate Compounds of Formula Y¹—SH, Wherein G¹=N:

Synthesis of 4-methylphthalazine-1-thiol (0-1)

[Image Omitted]

To a solution mixture of 4-methylphthalazin-1 (2H)-one (300 mg, 1.875 mmol) in toluene (5.0 mL) was added Lawesson's reagent (757.5 mg, 1.875 mmol) at 0° C. The reaction mixture was stirred for 2 h at 110° C. after which it was concentrated in vacuo. The residue (0-1) was taken to next step without further purification.

Synthesis of 4-(trifluoromethyl)phthalazine-1-thiol (0-2)

[Image Omitted]

Synthesis of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1 (3H)-one (0-2-1): To a stirred solution of isobenzofuran-1,3-dione (0.5 g, 3.378 mmol) in THF were added cuprous iodide (0.062 g, 0.337 mmol), PPh₃(0.086 g, 0.338 mmol) and anhydrous KF (0.38 g, 6.551 mmol) under argon atmosphere. TMSCF₃(0.5 g, 3.378 mmol) was added to the reaction mixture and stirring was continued for 6 h at 50° C. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure. The residue was purified by column chromatography by using silica gel affording O-2-1 (0.25 g, 35% yield) as an off-white solid. Synthesis of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2): To a stirred solution of 3-hydroxy-3-(trifluoromethyl)isobenzofuran-1 (3H)-one (O-2-1) (0.2 g, 0.917 mmol) in NMP was added bromoethane (0.1 g, 0.929 mmol) and K₂CO₃(0.15 g, 1.086 mmol) at 0° C., and the resulting mixture was stirred at 70° C. for 6 h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by column chromatography by using silica gel affording O-2-2 (0.18 g, 48% pure by LCMS) as a white solid. Synthesis 4-(trifluoromethyl)phthalazine-1 (2H)-one (O-2-3): To a stirred solution of ethyl 2-(2,2,2-trifluoroacetyl)benzoate (O-2-2) (0.2 g, 0.81 mmol) in EtOH (2.0 mL) was added hydrazine hydrate (0.052 g, 1.60 mmol) at 0° C. slowly warmed to 90° C. for 16 h. The reaction was monitored by TLC. After consumption of the starting material, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄and the solvent concentrated under reduced pressure. The residue was purified by column chromatography by using silica gel afford O-2-3 (0.18 g, 78% yield) as a white solid. Synthesis of 4-(trifluoromethyl)phthalazine-1-thiol (0-2) To a stirred solution of 4-(trifluoromethyl)phthalazin-1 (2H)-one (O-2-3) (0.2 g, 0.934 mmol, 1.0 eq.) in dry toluene was added Lawesson's reagent (0.37 g, 0.936 mmol, 1.0 eq) under an atmosphere of dry argon. The reaction mixture was then heated under pw conditions for 1 h at 110° C. The crude was purified by column chromatography on silica gel to afford compound (0-2) (0.07 g, 10% pure by LCMS) as a yellow solid.

The following intermediate compound 0-3 has been prepared using the experimental conditions described above from a commercial hydroxy-substituted heteroaryl of formula Y¹—OH by thionation using P₂S₅reagent or Lawesson's reagent:

Cpd number
Structure
Name

O-3

[Image Omitted]

phthalazine-1(2H)-thione

Preparation of Intermediate Compounds of Formula Y¹—SH with [5,6] Bicyclic Heteroaryl, Wherein G²=O or N—R⁴:

Synthesis of 5-(trifluoromethyl)oxazolo[5,4-b]pyridine-2-thiol (P-1)

[Image Omitted]

Synthesis of 3-amino-6-(trifluoromethyl)pyridin-2-ol (P-1-1) To a stirred solution of 3-nitro-6-(trifluoromethyl)pyridin-2-ol (200 mg, 0.961 mmol) in MeOH (1 mL) was added 15% Pd—C(30 mg). Then H₂gas was inserted for 3 h at 60 psi., after which the mixture was heated to 50° C. for 3 h. The reaction mixture was filtered through a celite bed under vacuum. The solvent was evaporated under reduced pressure to get title compound P-1-1 (142 mg, 75% yield). Synthesis of 5-(trifluoromethyl)oxazole[5,4-b]pyridine-2-thiol (P-1) To a solution of 3-amino-6-(trifluoromethyl)pyridin-2-ol P-1-1 (1.8 g, 0.010 mol) in EtOH (18 mL) was added KOH (1.13 g, 0.0202 mol) followed by CS₂(1.13 mL, 0.0202 mol) at 0° C. The resultant reaction mixture was stirred at 80° C. for 16 h. After completion of the reaction, the solvent was evaporated under reduced pressure and purified by C18-reversed phase combi-flash chromatography (eluent: 0.1% formic acid in ACN) to get title compound P-1 (1.8 g, 81% yield) as an off-white solid.

Synthesis of 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6)

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Synthesis of 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1) To a solution of 2-(trifluoromethyl)pyridin-4-ol (7.50 g, 45.9 mmol) in H₂SO₄(40.0 mL) was added fuming nitric acid (68.6 g, 980 mmol) and H₂SO₄(82.8 g, 844 mmol) at 0° C. The mixture was stirred at 120° C. for 8 h. The reaction mixture was quenched by addition ice-cold water (300 mL) at 0° C. and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give 5-nitro-2-(trifluoromethyl)pyridin-4-ol (P-6-1) (3.62 g, 38% yield) as a yellow solid. Synthesis of 5-amino-2-(trifluoromethyl)pyridin-4-ol (P-6-2) To a solution of Pd/C (2.00 g, 64.8 mmol, 10% purity) in MeOH (100 mL) was added compound P-6-1 (13.5 g, 64.8 mmol) under Ar. The suspension was degassed under vacuum and purged with H₂several times after which the mixture was stirred under H₂(15 psi) at 25° C. for 5 h. The suspension was filtered, and the filter cake was washed with MeOH (100 mL×3). The combined filtrates were concentrated to dryness. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give 5-amino-2-(trifluoromethyl) pyridin-4-ol (P-6-2) (9.10 g, 67% yield) as a brown solid. Synthesis of 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6) To a solution of compound P-6-2 (1.00 g, 5.61 mmol) in Py (10.0 mL) was added dropwise potassium ethylxanthate (1.08 g, 6.74 mmol) at 25° C. The resulting mixture was stirred at 110° C. for 12 h. The reaction mixture was poured into 1 N HCl to pH=4-5, and then extracted with EtOAc (30.0 mL×3), The combined organic layers were washed with brine (30.0 mL×2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1, petroleum ether/ethyl acetate=2/1, R_f=0.2) to give 6-(trifluoromethyl)oxazolo[4,5-c]pyridine-2-thiol (P-6) (400 mg, 32% yield) as a brown solid.

Synthesis of 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7)

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Synthesis of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (P-7-1) To a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (8.00 g, 33.2 mmol) in dioxane (40.0 mL) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.27 g, 36.5 mmol), KOAc (9.77 g, 99.6 mmol) and Pd(dppf)Cl₂(729 mg, 996 umol). The mixture was stirred at 90° C. for 6 h. The reaction mixture was quenched by addition H₂O (20.0 mL) at 25° C., and then extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=100/1 to 0/1) to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine P-7-1 (9.00 g, 94% yield) as a white solid. Synthesis of 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2) To a solution of compound P-7-1 (9.00 g, 31.2 mmol) in THF (90.0 mL) was added H₂O₂(43.4 g, 383 mmol, 36.8 mL, 30% purity). The mixture was stirred at 25° C. for 2 h. The reaction mixture was quenched by addition aq. sat. NH₄Cl (80.0 mL) at 5° C., and then extracted with EtOAc (40.0 mL×3). The combined organic layers were washed with brine (30.0 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (40.0 mL), and then extracted with 1 M HCl (40 mL). The aqueous phase was adjusted to pH=8 with NaHCO₃, and then extracted with EtOAc (40.0 mL×3) to give 2-amino-5-(trifluoromethyl)pyridin-3-ol (P-7-2) (5.00 g, 79% yield, 87.5% purity) as a light yellow solid. Synthesis of 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7) To a solution of compound P-7-2 (3.00 g, 16.8 mmol) in EtOH (30.0 mL) was added CS₂(3.85 g, 50.5 mmol, 3.05 mL) and KOH (2.84 g, 50.5 mmol). The mixture was stirred at 80° C. for 16 h. The reaction mixture was quenched by addition 2 M HCl (30.0 mL) at 25° C., and then extracted with EtOAc (30.0 mL×3). The combined organic layers were washed with 2 M HCl (30.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give 6-(trifluoromethyl)oxazolo[4,5-b]pyridine-2-thiol (P-7) (2.47 g, 67% yield) as a yellow solid.

The following intermediate thiols (P-2) to (P-15) have been prepared using the experimental conditions described above for K-1, from the reaction of substituted bicyclic oxazole 2-hydroxyl and Lawesson's reagent. Alternatively, some of the following compounds could be obtained commercially:

Cpd

number
Structure
Name

P-2

[Image Omitted]

6-(trifluoromethyl) oxazolo[5,4-c] pyridine-2-thiol

P-3

[Image Omitted]

5-(trifluoromethyl) oxazolo[4,5-b] pyridine-2-thiol

P-4

[Image Omitted]

5-(trifluoromethyl) benzo[d]oxazole-2- thiol

P-5

[Image Omitted]

4-(trifluoromethyl) benzo[d]oxazole-2- thiol

P-8

[Image Omitted]

5-methyloxazolo [4,5-b]pyridine-2- thiol

P-9

[Image Omitted]

6-chloro-3H- imidazo[4,5-b] pyridine-2-thiol

P-10

[Image Omitted]

5-methoxybenzo [d]oxazole-2-thiol

P-11

[Image Omitted]

4-methoxybenzo [d]oxazole-2-thiol

P-12

[Image Omitted]

1-methyl-1H-benzo [d]imidazole-2- thiol

P-13

[Image Omitted]

5-methylbenzo [d]oxazole-2-thiol

P-14

[Image Omitted]

5-methoxy-3H- imidazo[4,5-b] pyridine-2-thiol

P-15

[Image Omitted]

5-chlorobenzo [d]oxazole-2-thiol

Preparation of Example Compounds
Example 1: N-((5-(2-((2-isopropylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

[Image Omitted]

According to Method 2 (Scheme 2), Step 4: To a solution mixture of intermediate M-3 (100 mg, 0.49 mmol, 1 eq.) in DMF (3.0 mL) and added NaOMe (29.12 mg, 0.539 mmol) at 0° C. The resultant reaction mixture was stirred for 30 min at 0° C. and was added compound I-4 (171 mg, 0.539 mmol). The reaction mixture was stirred for 16 h at rt. After completion of reaction, cold water was added to reaction mixture was extracted using EtOAc (2×50 mL), total organic layer was dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by Combi-Flash chromatography to afford example 1 (70 mg, 30% yield).

Example 60: 2-Hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

[Image Omitted]

To a solution of M-11 (10.0 g, 48.5 mmol) in DMF (108 mL) was added NaOMe (2.62 g, 48.5 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 min. Then compound I-13 was added to the mixture (15.6 g, 53.3 mmol) and the mixture was stirred at 25° C. for 2 h. Three additional runs were done of this reaction on 5.0 g scale, 10 g scale and 10 g scale of M-11, and the crude mixtures of all four runs were combined for work-up. The combined reaction mixture was poured into H₂O (651 mL) and filtered to collect the solid. The solid was triturated with MTBE (10 V×2) at 25° C. for 2 h to give example 60 (16.25 g, 31.7% yield, 98.9% purity) as a light-yellow solid. 1H NMR: (400 MHz, DMSO-d₆) δ 8.55 (t, J=12.0 Hz, 1H), 8.09 (d, J=4.00 Hz, 1H), 7.80 (d, J=9.20 Hz, 1H), 7.57-7.60 (m, 1H), 7.28 (d, J=4.00 Hz, 1H), 5.55-5.58 (m, 1H), 4.84 (s, 2H), 4.52 (d, J=6.40 Hz, 2H), 3.94 (s, 3H), 3.87 (d, J=6.00 Hz, 2H), 2.41 (s, 4H). LCMS: [M+H]⁺ 418.1. M.P. (DSC): 185.65° C.

The following Examples have been prepared using similar experimental conditions described above for the synthesis of Example 1 (General Method 2, Scheme 2, Step 4), obtained from the reaction of intermediate of Formula Y¹—SH M, N, O or P with compound I-4:

Cpd

Ex
Y¹—SH
Name

2
M-6
N-((5-(2-((2-cyclopropylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

3
M-4
N-((5-(2-((2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

4
M-14
N-((5-(2-((2-(methoxymethyl)quinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

5
M-27
N-((5-(2-((1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

6
M-26
N-((5-(2-((6-cyclopropyl-1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pivalamide

7
M-8
N-((5-(2-((2-methylpyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

8
M-1
N-((5-(2-((7-chloro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

9
M-7
N-((5-(2-((6-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

10
M-9
N-((5-(2-((7-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

11
M-2
N-((5-(2-((2,7-dimethylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

12
M-10
N-((5-(2-((7-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

13
M-12
N-((5-(2-((2-ethylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

14
M-5
N-((5-(2-((2-cyclobutylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

15
M-30
N-((5-(2-((8-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

16
N-1
N-((5-(2-((2-(dimethylamino)quinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

17
M-11
N-((5-(2-((6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

18
M-13
N-((5-(2-((2-methylpyrido[3,2-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

23
P-8
N-((5-(2-((5-methyloxazolo[4,5-b]pyridine-2-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

194
O-1
N-((5-(2-((4-methylphthalazin-1-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

195
O-2
N-((5-(2-((4-(trifluoromethyl)phthalazin-1-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide)

The following Examples have been prepared using similar experimental conditions described above for the synthesis of Example 1 (Method 2, Scheme 2, Step 4), obtained from the reaction of intermediate of Formula Y¹—SH K with compound I-4:

Cpd

Ex.
Y¹—SH
Name

19
K-2
N-((5-(2-((2-(difluoromethyl)quinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

20
K-7
N-((5-(2-((1-methyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pivalamide

21
K-6
N-((5-(2-((6-(difluoromethyl)-1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pivalamide

22
K-5
N-((5-(2-((2-methyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pivalamide

38
K-1
N-((5-(2-((2-(trifluoromethyl)quinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

191
K-22
N-((5-(2-((3-(trifluoromethyl)isoquinolin-1-

yl)thio)acetyl)thiophen-2-yl)methyl)pivalamide

The following Examples have been prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 4, Scheme 4, Step 4), obtained from the reaction of intermediate compound of Formula Y¹—SH J, M or K with intermediate compound I-n, where applicable:

Cpd
Cpd

Ex.
Y¹—SH
I
NAME

24
J-1
I-6
3-methyl-1-((5-(2-((1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

25
J-1
I-10
1-((5-(2-((1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

26
K-1
I-11
1-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-

yl)thio)acetyl)thiophen-2-yl)ethyl)pyrrolidin-

2-one

115
M-11
I-16
3-hydroxy-1-(2-(5-(2-((6-methoxy-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-

yl)ethyl)pyrrolidin-2-one

137
M-11
I-14
4-((5-(2-((6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)morpholin-

3-one

138
K-11
I-14
4-((5-(2-((2-(trifluoromethyl)pyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)morpholin-3-one

157
K-11
I-10
1-((5-(2-((2-(trifluoromethyl)pyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

161
M-39
I-14
4-((5-(2-((6-methoxy-2-methylpyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)morpholin-3-one

The following Examples have been prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 2, Scheme 2, Step 4), obtained from the reaction of intermediate compound of Formula Y¹—SH J, M or K with intermediate compound I-n, where applicable:

Cpd
Cpd

Ex.
Y¹—SH
I
NAME

27
J-1
I-8
N-((2-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiazol-5-yl)methyl)pivalamide

28
J-1
I-7
N-((3-fluoro-5-(2-((1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pivalamide

128
M-11
I-9
(S)-2-hydroxy-N-(1-(5-(2-((6-methoxy-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-

yl)ethyl)acetamide

129
P-6
I-9
(S)-2-hydroxy-N-(1-(5-(2-((6-

(trifluoromethyl)oxazolo[4,5-c]pyridin-2-

yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

130
K-7
I-9
(S)-2-hydroxy-N-(1-(5-(2-((1-methyl-6-

(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)ethyl)acetamide

115
M-11
I-16
3-hydroxy-1-(2-(5-(2-((6-methoxy-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-

yl)ethyl)pyrrolidin-2-one

141
M-11
I-15
3-hydroxy-1-((5-(2-((6-methoxy-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

165
J-5
I-13
N-((5-(2-((1,7-naphthyridin-8-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

166
P-9
I-13
N-((5-(2-((6-chloro-3H-imidazo[4,5-b]pyridin-2-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

167
P-10
I-13
2-hydroxy-N-((5-(2-((5-methoxybenzo[d]oxazol-

2-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

168
P-11
I-13
2-hydroxy-N-((5-(2-((4-methoxybenzo[d]oxazol-

2-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

169
P-12
I-13
2-hydroxy-N-((5-(2-((1-methyl-1H-

benzo[d]imidazol-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

170
P-13
I-13
2-hydroxy-N-((5-(2-((5-methylbenzo[d]oxazol-2-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

173
P-14
I-13
2-hydroxy-N-((5-(2-((5-methoxy-3H-imidazo[4,5-

b]pyridin-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

174
P-15
I-13
N-((5-(2-((5-chlorobenzo[d]oxazol-2-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

176
J-6
I-13
2-hydroxy-N-((5-(2-(imidazo[1,2-a]pyrazin-8-

ylthio)acetyl)thiophen-2-yl)methyl)acetamide

179
J-3
I-13
N-((5-(2-((1,6-naphthyridin-5-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

180
J-4
I-13
N-((5-(2-((2,7-naphthyridin-1-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

181
J-7
I-13
2-hydroxy-N-((5-(2-(imidazo[1,5-a]pyrazin-8-

ylthio)acetyl)thiophen-2-yl)methyl)acetamide

182
J-8
I-13
2-hydroxy-N-((5-(2-(pyrazolo[1,5-a]pyrazin-4-

ylthio)acetyl)thiophen-2-yl)methyl)acetamide

192
J-1
I-12
N-((5-(2-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-

4-ylthio)acetyl)-1,3,4-thiadiazol-2-

yl)methyl)pivalamide

193
O-3
I-4
N-((5-(2-(phthalazin-1-ylthio)acetyl)thiophen-2-

yl)methyl)pivalamide

The following Examples have been prepared using the experimental conditions described above for the synthesis of compound (1) (according to Method 2, Scheme 2, Step 4), obtained from the reaction of intermediate compound of Formula Y¹—SH K-11 with intermediate compound 1-15, followed by a separation of enantiomers using chiral SFC (Waters SFC80 preparative SFC; Column: DAICEL CHIRALPAK JH (250 mm*30 mm, 10 um); Mobile phase: A for CO₂and B for MeOH; Gradient: B %=40% isocratic elution mode; Flow rate: 70 g/min; Wavelength: 220 nm; Column temperature: 40° C. System back pressure: 100 bar):

Ex.
NAME

155
(S)-3-hydroxy-1-((5-(2-((2-(trifluoromethyl)pyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

156
(R)-3-hydroxy-1-((5-(2-((2-(trifluoromethyl)pyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)pyrrolidin-2-one

Synthesis of 1-(5-(2-aminoethyl)thiophen-2-yl)-2-((2-(trifluoromethyl)quinazolin-4-yl)thio)ethan-1-one (Q-1)

[Image Omitted]

To a solution mixture of compound K-1 (390 mg, 130 mmol) in DMF (5 mL) is added NaOMe (77 mg, 1.43 mmol) at 0° C. The resultant reaction mixture was stirred for 30 min at 0° C. and was added compound I-2 (549 mg, 156 mmol). The reaction mixture was stirred for 2 h at rt. The reaction mixture was quenched with cold water and extracted with EtOAc (2×50 mL). Organic layer was dried over Na₂SO₄and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (60-120 mesh). The compound was eluted using 30% EtOAc in hexane to afford compound (Q-1-1). To a solution mixture of compound (Q-1-1) in dioxane (3.0 mL) was added 4 M HCl in dioxane (6.0 mL) at 0° C. The reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated in vacuo. The crude compound was washed with n-pentane and dried in vacuo to afford the hydrochloride salt of compound (Q-1) as a white solid.

The following intermediate compounds Q have been prepared using the experimental conditions described above (General Method 1) from the reaction of compounds J, K and M of Formula Y¹—SH with bromo-ketone I-1, I-2, I-3 or I-5, followed by deprotection of the Boc protecting group to provide a terminal amino group.

Cpd Q
Structure
Cpd Y¹-SH
Cpd I
IUPAC name

Q-2

[Image Omitted]

J-1
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethanone hydrochloride

Q-3

[Image Omitted]

K-5
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethanone hydrochloride

Q-4

[Image Omitted]

M-4
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methylquinazolin- 4-yl)thio)ethanone hydrochloride

Q-5

[Image Omitted]

J-1
I-3
2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)-1-(5- ((methylamino)methyl) thiophen-2-yl)ethanone hydrochloride

Q-6

[Image Omitted]

K-1
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2- (trifluoromethyl)quinazolin- 4-yl)thio)ethanone hydrochloride

Q-7

[Image Omitted]

K-1
I-2
1-(5-(2- aminoethyl)thiophen-2-yl)- 2-((2- (trifluoromethyl)quinazolin- 4-yl)thio)ethanone hydrochloride

Q-8

[Image Omitted]

M-6
I-2
1-(5-(2- aminoethyl)thiophen-2-yl)- 2-((2- cyclopropylquinazolin-4- yl)thio)ethanone hydrochloride

Q-9

[Image Omitted]

K-1
I-5
1-(5-(pyrrolidin-3- yl)thiophen-2-yl)-2-((2- (trifluoromethyl)quinazolin- 4-yl)thio)ethanone

Q-10

[Image Omitted]

M-28
I-2
1-(5-(2- aminoethyl)thiophen-2-yl)- 2-((2-methylquinazolin-4- yl)thio)ethanone hydrochloride

Q-11

[Image Omitted]

M-11
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-methoxy-2- methylquinazolin-4- yl)thio)ethanone hydrochloride

Q-12

[Image Omitted]

M-12
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-ethylquinazolin-4- yl)thio)ethanone hydrochloride

Q-13

[Image Omitted]

M-8
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methylpyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-14

[Image Omitted]

M-25
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2,6-dimethyl-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-15

[Image Omitted]

M-7
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-fluoro-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-16

[Image Omitted]

M-9
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((7-fluoro-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-17

[Image Omitted]

K-8
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-(difluoromethyl)- 2-methyl-2H-pyrazolo[3,4- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-18

[Image Omitted]

M-10
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((7-methoxy-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-19

[Image Omitted]

P-2
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6- (trifluoromethyl)oxazolo[5, 4-c]pyridin-2-yl)thio)ethan- 1-one hydrochloride

Q-20

[Image Omitted]

P-3
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((5- (trifluoromethyl)oxazolo[4, 5-b]pyridin-2-yl)thio)ethan- 1-one hydrochloride

Q-21

[Image Omitted]

M-15
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-chloro-7-fluoro-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-22

[Image Omitted]

J-1
I-5
2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)-1-(5-(pyrrolidin-3- yl)thiophen-2-yl)ethan-1- one hydrochloride

Q-23

[Image Omitted]

P-5
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((4- (trifluoromethyl)benzo[d] oxazol-2-yl)thio)ethan-1-one hydrochloride

Q-24

[Image Omitted]

K-7
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((1-methyl-6- (trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-25

[Image Omitted]

M-16
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((7-fluoro-6-methoxy- 2-methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-26

[Image Omitted]

M-17
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-27

[Image Omitted]

M-18
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-cyclopropoxy-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-28

[Image Omitted]

K-16
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-(difluoromethyl)- 6-methoxypyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-29

[Image Omitted]

M-19
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6- ((cyclopropylmethyl)amino)- 2-methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-30

[Image Omitted]

K-9
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-cyclopropyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-31

[Image Omitted]

K-3
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-methoxy-2- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-32

[Image Omitted]

M-20
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- morpholinoquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-33

[Image Omitted]

M-21
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- (piperidin-1-yl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-34

[Image Omitted]

M-22
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6-(1,4- oxazepan-4-yl)quinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-35

[Image Omitted]

M-23
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-(3,3- difluoropyrrolidin-1-yl)-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-36

[Image Omitted]

M-24
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6-(4- methylpiperazin-1- yl)quinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-37

[Image Omitted]

K-4
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-morpholino-2- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-38

[Image Omitted]

J-2
I-2
1-(5-(2- aminoethyl)thiophen-2-yl)- 2-(quinazolin-4- ylthio)ethan-1-one

Q-39

[Image Omitted]

M-39
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-methoxy-2- methylpyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-40

[Image Omitted]

M-39
I-3
2-((6-methoxy-2- methylpyrido[2,3- d]pyrimidin-4-yl)thio)-1-(5- ((methylamino)methyl) thiophen-2-yl)ethan-1-one hydrochloride

Q-41

[Image Omitted]

M-40
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-ethoxy-2- methylpyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-42

[Image Omitted]

K-18
I-3
2-((6-methoxy-2- (trifluoromethyl)pyrido[3,4- d]pyrimidin-4-yl)thio)-1-(5- ((methylamino)methyl) thiophen-2-yl)ethan-1-one hydrochloride

Q-43

[Image Omitted]

M-41
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((5-fluoro-6-methoxy- 2-methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-44

[Image Omitted]

K-18
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-methoxy-2- (trifluoromethyl)pyrido[3,4- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-45

[Image Omitted]

M-13
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methylpyrido[3,2- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-46

[Image Omitted]

K-21
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2- (trifluoromethyl)pyrido[3,2- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-47

[Image Omitted]

M-31
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-8- (methylamino)-6- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-48

[Image Omitted]

M-32
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((8-(dimethylamino)- 2-methyl-6- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-49

[Image Omitted]

M-33
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-(dimethylamino)- 2-methylpyrido[3,4- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-50

[Image Omitted]

M-34
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((8-methoxy-2- methyl-6- (trifluoromethyl)quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-51

[Image Omitted]

M-44
I-1
2-((6-(2-oxa-5- azabicyclo[2.2.2]octan-5- yl)-2-methylquinazolin-4- yl)thio)-1-(5- (aminomethyl)thiophen-2- yl)ethan-1-one hydrochloride

Q-52

[Image Omitted]

M-45
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-chloro-5-fluoro-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-53

[Image Omitted]

M-46
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-ethoxy-2- methylpyrido[3,4- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-54

[Image Omitted]

M-47
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-ethoxy-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-55

[Image Omitted]

M-48
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((5-methoxy-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-56

[Image Omitted]

M-29
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-chloro-8-fluoro-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-57

[Image Omitted]

K-10
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-(difluoromethyl)- 6-methoxyquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-58

[Image Omitted]

K-12
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((1-ethyl-6- (trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-59

[Image Omitted]

K-13
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-ethyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-60

[Image Omitted]

K-14
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((1-cyclopropyl-6- (trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-61

[Image Omitted]

K-19
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-(2-methoxyethyl)- 6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-62

[Image Omitted]

K-11
I-3
1-(5- ((methylamino)methyl) thiophen-2-yl)-2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-63

[Image Omitted]

K-11
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-64

[Image Omitted]

M-37
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- (trifluoromethoxy) quinazolin- 4-yl)thio)ethan-1-one hydrochloride

Q-65

[Image Omitted]

K-20
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((1-(2-methoxyethyl)- 6-(trifluoromethyl)-1H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)ethan-1-one hydrochloride

Q-66

[Image Omitted]

M-35
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-fluoro-2- methylpyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-67

[Image Omitted]

M-36
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-methoxy-2- methylpyrido[3,4- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-68

[Image Omitted]

M-38
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((2-methyl-6- (trifluoromethyl)pyrido[2,3- d]pyrimidin-4-yl)thio)ethan- 1-one hydrochloride

Q-69

[Image Omitted]

P-7
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6- (trifluoromethyl)oxazolo[4, 5-b]pyridin-2-yl)thio)ethan- 1-one hydrochloride

Q-70

[Image Omitted]

P-1
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((5- (trifluoromethyl)oxazolo[5, 4-b]pyridin-2-yl)thio)ethan- 1-one hydrochloride

Q-71

[Image Omitted]

K-5
I-3
2-((2-methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin-4- yl)thio)-1-(5- ((methylamino)methyl) thiophen-2-yl)ethan-1-one hydrochloride

Q-72

[Image Omitted]

K-17
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((7-cyclopropyl-2- (trifluoromethyl)pyrazolo[1, 5-a][1,3,5]triazin-4- yl)thio)ethan-1-one hydrochloride

Q-73

[Image Omitted]

M-11
I-3
2-((6-methoxy-2- methylquinazolin-4-yl)thio)- 1-(5- ((methylamino)methyl) thiophen-2-yl)ethan-1-one hydrochloride

Q-74

[Image Omitted]

M-42
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((8-fluoro-6-methoxy- 2-methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-75

[Image Omitted]

K-15
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((7-methyl-2- (trifluoromethyl)pyrazolo[1, 5-a][1,3,5]triazin-4- yl)thio)ethan-1-one hydrochloride

Q-76

[Image Omitted]

M-43
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((6-cyclopropyl-2- methylquinazolin-4- yl)thio)ethan-1-one hydrochloride

Q-77

[Image Omitted]

P-4
I-1
1-(5- (aminomethyl)thiophen-2- yl)-2-((5- (trifluoromethyl)benzo[d] oxazol-2-yl)thio)ethan-1-one hydrochloride

Example 190: tert-butyl ((5-(2-((6-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)carbamate

[Image Omitted]

Example 190 has been prepared using the experimental conditions described above for intermediate Q-1-1 from the reaction of intermediate M-39 with intermediate I-1.

Example 189: Synthesis of 3-((5-(2-((6-methoxy-2-methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-1,1-dimethylurea

[Image Omitted]

To a solution of compound Q-11 (100 mg, 278 mol) in THE (2.00 mL) was added DIEA (108 mg, 835 mol, 145 μL) and dimethylcarbamic chloride (32.9 mg, 306 mol, 28.1 μL). The mixture was stirred at 50° C. for 2 h. The reaction mixture was concentrated to dryness. The residue was purified by prep-HPLC (column: waters Xbridge BEH C18 100×30 mm×10 um; mobile phase: [water (NH₄HCO₃)-ACN]; gradient:30%-60% B over 8 min) to give example 189 (32 mg, 27% yield, 100% purity) as a light yellow solid.

Example 29: N-(2-(5-(2-((2-(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-yl)ethyl)pivalamide

[Image Omitted]

To a solution mixture of compound Q-1 (190 mg, 25 mmol) in DCM (2.0 mL) was added Et₃N (2 eq) and (CH₃)₃CCOCl (29 mg, 1.5 equiv.) at 0° C. The resultant reaction mixture was stirred for 1 h at rt. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (2×20 mL) and the combined organic layers dried over Na₂SO₄, and concentrated in vacuo. The residue compound was purified using column chromatography to afford example compound (29) as a white solid (60 mg, 50% yield).

The following Examples have been prepared using the experimental conditions described above in Example 29 from the reaction of compounds Q with an acyl chloride of formula R⁹—COCl:

Cpd

Ex.
Q
R⁹-COCl
IUPAC name

30
Q-2
PhCOCl
N-((5-(2-((1-methyl-1H-

pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiophen-

2-yl)methyl)benzamide

31
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl) cyclopropanecarboxamide

32
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d] pyrimidin-4-yl)thio)acetyl) thiophen-2-yl)methyl)-2- phenylacetamide

33
Q-5
tBuCOCl
N-methyl-N-((5-(2-((1-

methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)

acetyl)thiophen-2-yl)

methyl)pivalamide

34
Q-5

[Image Omitted]

N-methyl-N-((5-(2-((1- methyl-1H-pyrazolo[3,4-d] pyrimidin-4-yl)thio)acetyl) thiophen-2-yl)methyl) cyclopropanecarboxamide

35
Q-4

[Image Omitted]

N-((5-(2-((2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl) cyclopropanecarboxamide

36
Q-1

[Image Omitted]

N-(2-(5-(2-((2- (trifluoromethyl) quinazolin-4-yl)thio) acetyl)thiophen-2-yl)ethyl) cyclopropanecarboxamide

37
Q-1
PhCOCl
N-(2-(5-(2-((2-

(trifluoromethyl)

quinazolin-4-yl)thio)

acetyl)thiophen-2-yl)ethyl)

benzamide

39
Q-11

[Image Omitted]

2,2-difluoro-N-((5-(2-((6- methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

40
Q-11

[Image Omitted]

2,2,3,3,3-pentafluoro-N- ((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)propanamide

41
Q-3

[Image Omitted]

N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl) cyclopropanecarboxamide

43
Q-30

[Image Omitted]

N-((5-(2-((2-cyclopropyl- 6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)-2,2- difluorocyclopropane-1- carboxamide

44
Q-30

[Image Omitted]

N-((5-(2-((2-cyclopropyl- 6-(trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)-2,2,3,3,3- pentafluoropropanamide

51
Q-11

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl) cyclopropanecarboxamide

101
Q-8
CH₃COCl
N-(2-(5-(2-((2-

cyclopropylquinazolin-4-

yl)thio)acetyl)thiophen-2-

yl)ethyl)acetamide

103
Q-2
CH₃COCl
N-((5-(2-((1-methyl-1H-

pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiophen-

2-yl)methyl)acetamide

Example 63: 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

[Image Omitted]

Synthesis of 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholino-quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1) To a solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid I-13a (699 mg, 2.22 mmol) in DMF (4.00 mL) was added HATU (699 mg, 2.02 mmol) at 0° C. After addition, the mixture was stirred at 0° C., and a mixture of compound Q-37 (837 mg, 2.02 mmol) and DIEA (1.41 mL, 8.08 mmol) in DMF (4.00 mL) was added dropwise to the above mixture at 0° C. The resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL×3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to yield 2-((tert-butyldiphenylsilyl)oxy)-N-((5-(2-((2-methyl-6-morpholino-quinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (R-1-1) which was used without further purification. Synthesis of 2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)acetamide (63) To a solution of compound R-1-1 (0.60 g, 862 umol) in THF (6.00 mL) was added TBAF (1 M, 905 uL). The mixture was stirred at 20° C. for 1 h. The reaction mixture was quenched by addition H₂O (10.0 mL) at 25° C., and then extracted with EtOAc (5.00 mL×3). The combined organic layers were washed with brine (5.00 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=50/1 to 5/1) TLC (petroleum ether/ethyl acetate 1/1, product RT=0.2) to give compound 63 (200 mg, 57.4% yield).

The following Examples have been prepared using the experimental conditions described above in Example 63 from the reaction of compounds Q with protected hydroxy-acid derivatives of formula HO₂C—CH₂—OTBDPS and HO₂C—CH₂—OTBS:

Ex.
Cpd Q
IUPAC name

60
Q-11
2-hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

64
Q-13
2-hydroxy-N-((5-(2-((2-methylpyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

65
Q-14
N-((5-(2-((2,6-dimethyl-2H-pyrazolo[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

66
Q-4
2-hydroxy-N-((5-(2-((2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

67
Q-15
N-((5-(2-((6-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

68
Q-16
N-((5-(2-((7-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

69
Q-17
N-((5-(2-((6-(difluoromethyl)-2-methyl-2H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

70
Q-18
2-hydroxy-N-((5-(2-((7-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

71
Q-19
2-hydroxy-N-((5-(2-((6-(trifluoromethyl)oxazolo[5,4-

c]156yrrolid-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

72
Q-20
2-hydroxy-N-((5-(2-((5-(trifluoromethyl)oxazolo[4,5-

b]156yrrolid-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

73
Q-21
N-((5-(2-((6-chloro-7-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

74
Q-24
2-hydroxy-N-((5-(2-((1-methyl-6-(trifluoromethyl)-1H-

pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

75
Q-25
N-((5-(2-((7-fluoro-6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

76
Q-26
2-hydroxy-N-((5-(2-((2-methyl-6-

(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

77
Q-27
N-((5-(2-((6-cyclopropoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

78
Q-29
N-((5-(2-((6-((cyclopropylmethyl)amino)-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

79
Q-30
N-((5-(2-((2-cyclopropyl-6-(trifluoromethyl)-2H-

pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)-2-hydroxyacetamide

80
Q-31
2-hydroxy-N-((5-(2-((6-methoxy-2-

(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

81
Q-32
2-hydroxy-N-((5-(2-((2-methyl-6-morpholinoquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

82
Q-33
2-hydroxy-N-((5-(2-((2-methyl-6-(piperidin-1-

yl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

83
Q-34
2-hydroxy-N-((5-(2-((2-methyl-6-(1,4-oxazepan-4-

yl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

84
Q-35
N-((5-(2-((6-(3,3-difluoropyrrolidin-1-yl)-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

85
Q-36
2-hydroxy-N-((5-(2-((2-methyl-6-(4-methylpiperazin-1-

yl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

86
Q-2
2-hydroxy-1-(3-(5-(2-((1-methyl-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)157yrrolidine-

1-yl)ethan-1-one

105
Q-77
2-hydroxy-N-((5-(2-((5-(trifluoromethyl)benzo[d]oxazol-2-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

106
Q-76
N-((5-(2-((6-cyclopropyl-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

107
Q-75
2-hydroxy-N-((5-(2-((7-methyl-2-

(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

108
Q-74
N-((5-(2-((8-fluoro-6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

109
Q-73
2-hydroxy-N-((5-(2-((6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-N-methylacetamide

112
Q-72
N-((5-(2-((7-cyclopropyl-2-(trifluoromethyl)pyrazolo[1,5-

a][1,3,5]triazin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

113
Q-63
2-hydroxy-N-((5-(2-((2-(trifluoromethyl)pyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

116
Q-71
2-hydroxy-N-methyl-N-((5-(2-((2-methyl-6-

(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

117
Q-70
2-hydroxy-N-((5-(2-((5-(trifluoromethyl)oxazolo[5,4-

b]157yrrolid-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

118
Q-69
2-hydroxy-N-((5-(2-((6-(trifluoromethyl)oxazolo[4,5-

b]157yrrolid-2-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

119
Q-68
2-hydroxy-N-((5-(2-((2-methyl-6-

(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

121
Q-67
2-hydroxy-N-((5-(2-((6-methoxy-2-methylpyrido[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

124
Q-66
N-((5-(2-((6-fluoro-2-methylpyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

125
Q-65
2-hydroxy-N-((5-(2-((1-(2-methoxyethyl)-6-

(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

126
Q-64
2-hydroxy-N-((5-(2-((2-methyl-6-

(trifluoromethoxy)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

131
Q-63
2-hydroxy-N-methyl-N-((5-(2-((2-

(trifluoromethyl)pyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

132
Q-61
2-hydroxy-N-((5-(2-((2-(2-methoxyethyl)-6-

(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

133
Q-60
N-((5-(2-((1-cyclopropyl-6-(trifluoromethyl)-1H-

pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)-2-hydroxyacetamide

135
Q-59
N-((5-(2-((2-ethyl-6-(trifluoromethyl)-2H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

136
Q-58
N-((5-(2-((1-ethyl-6-(trifluoromethyl)-1H-pyrazolo[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

139
Q-57
N-((5-(2-((2-(difluoromethyl)-6-methoxyquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

140
Q-39
2-hydroxy-N-((5-(2-((6-methoxy-2-methylpyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

142
Q-56
N-((5-(2-((6-chloro-8-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

143
Q-55
2-hydroxy-N-((5-(2-((5-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

144
Q-54
N-((5-(2-((6-ethoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

145
Q-53
N-((5-(2-((6-ethoxy-2-methylpyrido[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

146
Q-52
N-((5-(2-((6-chloro-5-fluoro-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

147
Q-51
N-((5-(2-((6-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-2-

methylquinazolin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

148
Q-50
2-hydroxy-N-((5-(2-((8-methoxy-2-methyl-6-

(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

149
Q-49
N-((5-(2-((6-(dimethylamino)-2-methylpyrido[3,4-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

150
Q-48
N-((5-(2-((8-(dimethylamino)-2-methyl-6-

(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)-2-hydroxyacetamide

151
Q-47
2-hydroxy-N-((5-(2-((2-methyl-8-(methylamino)-6-

(trifluoromethyl)quinazolin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

152
Q-46
2-hydroxy-N-((5-(2-((2-(trifluoromethyl)pyrido[3,2-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-

yl)methyl)acetamide

153
Q-45
2-hydroxy-N-((5-(2-((2-methylpyrido[3,2-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

154
Q-44
2-hydroxy-N-((5-(2-((6-methoxy-2-

(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

158
Q-43
N-((5-(2-((5-fluoro-6-methoxy-2-methylquinazolin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

159
Q-42
2-hydroxy-N-((5-(2-((6-methoxy-2-

(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-N-methylacetamide

160
Q-41
N-((5-(2-((6-ethoxy-2-methylpyrido[2,3-d]pyrimidin-4-

yl)thio)acetyl)thiophen-2-yl)methyl)-2-hydroxyacetamide

162
Q-40
2-hydroxy-N-((5-(2-((6-methoxy-2-methylpyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-N-

methylacetamide

164
Q-28
N-((5-(2-((2-(difluoromethyl)-6-methoxypyrido[2,3-

d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)-2-

hydroxyacetamide

196
Q-23
2-hydroxy-N-((5-(2-((4-(trifluoromethyl)benzo[d]oxazol-2-

yl)thio)acetyl)thiophen-2-yl)methyl)acetamide

The following Examples have been prepared using the experimental conditions described above from the reaction of compounds Q with carboxylic acids R⁹—CO₂H. In some cases, the R⁹group contained an alcohol group, which was protected with a suitable protective group such as TBS or TBDPS, and later removed similarly as described herein for the conversion of R-1-1 to example compound 63. In other cases, the R⁹group contained an amino group, which was protected with a suitable protective group known in the art such as Boc, and later removed using conditions known in the art, such as TFA/DCM.

Cpd

Ex.
Q
R⁹-CO₂H
IUPAC name

42
Q-2

[Image Omitted]

3,3,3-trifluoro-2-hydroxy- N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)propanamide

45
Q-20

[Image Omitted]

1-hydroxy-N-((5-(2-((5- (trifluoromethyl)oxazolo [4,5-b]157yrrolid-2-yl) thio)acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

46
Q-3

[Image Omitted]

3,3,3-trifluoro-2-hydroxy- N-((5-(2-((2-methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)propanamide

47
Q-37

[Image Omitted]

1-hydroxy-N-((5-(2-((6- morpholino-2- (trifluoromethyl) quinazolin-4-yl)thio) acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

48
Q-3

[Image Omitted]

2-hydroxy-2-methyl-N-((5- (2-((2-methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)propanamide

49
Q-3

[Image Omitted]

1-hydroxy-N-((5-(2-((2- methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)cyclopropane- 1-carboxamide

50
Q-11

[Image Omitted]

1-hydroxy-N-((5-(2-((6- methoxy-2- methylquinazolin-4- yl)thio)acetyl)thiophen-2- yl)methyl)cyclopropane-1- carboxamide

52
Q-2

[Image Omitted]

2-hydroxy-2-methyl-N- ((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)propanamide

55
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d] pyrimidin-4-yl)thio)acetyl) thiophen-2-yl)methyl)-2- (158yrrolid-2-yl)acetamide

56
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)-2- (158yrrolid-3-yl)acetamide

57
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)-2- (158yrrolid-4-yl)acetamide

58
Q-2

[Image Omitted]

2-methoxy-N-((5-(2-((1- methyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl)acetamide

59
Q-2

[Image Omitted]

2-hydroxy-N-((5-(2-((1- methyl-1H-pyrazolo[3,4- d]pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl)acetamide

60
Q-11

[Image Omitted]

2-hydroxy-N-((5-(2-((6- methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)acetamide

61
Q-3

[Image Omitted]

2-hydroxy-N-((5-(2-((2- methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)acetamide

62
Q-12

[Image Omitted]

N-((5-(2-((2- ethylquinazolin-4-yl)thio) acetyl)thiophen-2-yl) methyl)-2- hydroxyacetamide

110
Q-13

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- methylpyrido[2,3-d] pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

111
Q-3

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- methyl-6- (trifluoromethyl)-2H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)cyclopropane- 1-carboxamide

114
Q-63

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- (trifluoromethyl)pyrido [2,3-d]pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

120
Q-64

[Image Omitted]

2,2-difluoro-N-((5-(2-((2- methyl-6- (trifluoromethoxy) quinazolin-4-yl)thio) acetyl)thiophen-2-yl) methyl)cyclopropane-1- carboxamide

134
Q-31

[Image Omitted]

2-hydroxy-N-((5-(2-((6- methoxy-2- (trifluoromethyl) quinazolin-4-yl)thio) acetyl)thiophen-2-yl) methyl)-2- methylpropanamide

163
Q-39

[Image Omitted]

2-methoxy-N-((5-(2-((6- methoxy-2-methylpyrido [2,3-d]pyrimidin-4-yl) thio)acetyl)thiophen-2-yl) methyl)acetamide

171
Q-11

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)tetrahydrofuran-2- carboxamide

172
Q-11

[Image Omitted]

2,2-difluoro-N-((5-(2-((6- methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)acetamide

177
Q-11

[Image Omitted]

2-amino-N-((5-(2-((6- methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)acetamide

178
Q-11

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)-1- methylazetidine-3- carboxamide

183
Q-11

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)-2-(methylamino) acetamide

184
Q-11

[Image Omitted]

N-((5-(2-((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)pyrrolidine-2- carboxamide

185
Q-11

[Image Omitted]

(S)-2-hydroxy-N-((5-(2- ((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)propanamide

186
Q-11

[Image Omitted]

(R)-2-hydroxy-N-((5-(2- ((6-methoxy-2- methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl)propanamide

Example 87: N-(5-(2-((1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)thio)acetyl)thiophen-2-yl)methyl)methanesulfonamide

[Image Omitted]

To a solution mixture of compound Q-2 (100 mg, 0.281 mmol, 1 eq.) in DCM (3.0 mL) was added E_t3N (0.075 mL, 2 eq.) at 0° C. The resultant reaction mixture was stirred for 10 min at 0° C. and methane sulfonyl chloride (0.032 mL, 0.422 mmol) was added. The reaction mixture was stirred for 3 h at rt. The reaction mixture was concentrated in vacuo. Cold water (10 mL) was added to crude compound and extracted with EtOAc to afford crude compounds which after final purification gave compound (87) as a white solid (40 mg, 31% yield) solid.

The following Examples have been prepared using the experimental conditions described above in Example 87 from the reaction of compounds Q with sulfonyl chloride derivatives of Formula R⁹—SO₂Cl:

Cpd

Ex.
Q
R⁹-SO₂Cl
IUPAC name

88
Q-2
PhSO₂Cl
N-((5-(2-((1-methyl-1H-

pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiophen-

2-yl)methyl)

benzenesulfonamide

89
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl) cyclopropanesulfonamide

90
Q-2

[Image Omitted]

N-((5-(2-((1-methyl-1H- pyrazolo[3,4-d]pyrimidin- 4-yl)thio)acetyl)thiophen- 2-yl)methyl)-1- phenylmethanesulfonamide

91
Q-5

[Image Omitted]

N-methyl-N-((5-(2-((1- methyl-1H-pyrazolo[3,4-d] pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl) cyclopropanesulfonamide

92
Q-5

[Image Omitted]

N-methyl-N-((5-(2-((1- methyl-1H-pyrazolo[3,4-d] pyrimidin-4-yl)thio) acetyl)thiophen-2-yl) methyl)-1-(160yrrolid-4- yl)methanesulfonamide

93
Q-4

[Image Omitted]

1-cyclopropyl-N-((5-(2- ((2-methylquinazolin-4-yl) thio)acetyl)thiophen-2-yl) methyl) methanesulfonamide

94
Q-10
CH₃SO₂Cl
N-(2-(5-(2-((2-

methylquinazolin-4-yl)

thio)acetyl)thiophen-2-yl)

ethyl)methanesulfonamide

95
Q-9
CH₃SO₂Cl
1-(5-(1-(methylsulfonyl)

161yrrolidine-3-yl)

thiophen-2-yl)-2-((2-

(trifluoromethyl)

quinazolin-4-yl)thio)

ethanone

96
Q-9
Cl—SO₂—NH₂
3-(5-(2-((1-methyl-1H-

pyrazolo[3,4-d]pyrimidin-

4-yl)thio)acetyl)thiophen-

2-yl)pyrrolidine-1-

sulfonamide

97
Q-4
CH₃SO₂Cl
N-((5-(2-((2-

methylquinazolin-4-

yl)thio)acetyl)thiophen-2-

yl)methyl)

methanesulfonamide

98
Q-1
CH₃SO₂Cl
N-(2-(5-(2-((2-

(trifluoromethyl)

quinazolin-4-yl)thio)

acetyl)thiophen-2-yl)

ethyl)methanesulfonamide

122
Q-63

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl)pyrido [2,3-d]pyrimidin-4-yl) thio)acetyl)thiophen-2- yl)methyl) cyclopropanesulfonamide

123
Q-63

[Image Omitted]

2,2,2-trifluoro-N-((5-(2- ((2-(trifluoromethyl) pyrido[2,3-d]pyrimidin-4- yl)thio)acetyl)thiophen- 2-yl)methyl)ethane-1- sulfonamide

127
Q-63

[Image Omitted]

N-((5-(2-((2- (trifluoromethyl)pyrido [2,3-d]pyrimidin-4-yl) thio)acetyl)thiophen-2-yl) methyl) ethanesulfonamide

Properties of Examples Compounds

The properties of synthetized example compounds are shown on Table 4 below.

TABLE 4

LCMS

Ex.
Form
m/z (Rt)
Method
¹H-NMR [400 MHz]

1
Yellow
442.32
1
δ (DMSO-d₆): 8.33 (t, J = 6.0 Hz, 1H), 8.13-8.10

solid
[M + H]^+,

(m, 2H), 7.97-7.92 (m, 1H), 7.88-7.86 (m, 1H),

(16.27 min)

7.69-7.65 (m, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.87

(s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 2.96-2.89 (m,

1H), 1.11 (s, 9H), 1.01 (m, 6H).

2
White
440.29
4
δ (DMSO-d₆): 8.36-8.32 (m, 1H), 8.10-8.07 (m,

solid
[M + H]^+,

2H), 7.92 (t, J = 8.4 Hz, 1H), 7.83-7.79 (m, 1H),

(16.19 min)

7.61 (t, J = 8.0 Hz, 1H) 7.11 (d, J = 3.6 Hz, 1H),

4.84 (s, 2H), 4.48-4.42 (m, 2H), 2.07-1.99 (m,

1H), 1.11 (s, 9H), 0.81 (t, J = 3.2 Hz, 4H).

3
Yellow
414.28
4
δ (DMSO-d₆): 8.33 (br s, 1H), 8.12-8.08 (m, 2H),

solid
[M + H]⁺,

7.95-7.92 (m, 1H), 7.85(d, J = 8.0 Hz, 1H), 7.69-

(13.87 min)

7.66 (m, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.84 (s,

2H), 4.46 (d, J = 5.6 Hz, 2H), 2.42 (s, 3H), 1.11

(s, 9H).

4
Light
444.28
4
δ (DMSO-d₆): 8.35 (t, J = 6.0 Hz, 1H), 8.18-

yellow
[M + H]⁺,

8.16(m, 1H), 8.09 (d, J = 4.0 Hz, 1H), 8.02-7.83

solid
(15.16 min)

(m, 2H), 7.76-7.71 (m, 1H), 7.11 (d, J = 4.0 Hz,

1H), 4.89 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.38

(s, 2H), 3.23 (s, 3H), 1.11 (s, 9H).

5
White
418.31
4
δ (DMSO-d₆): 8.34 (t, J = 5.6 Hz, 1H), 8.29 (s,

solid
[M + H]⁺,

1H), 8.06 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 3.6 Hz,

(14.73 min)

1H), 4.85 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 3.95

(s, 3H), 2.42 (s, 3H), 1.11 (s, 9H).

6
Yellow
444.28
4
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.24 (s,

solid
[M + H]⁺,

1H), 8.07 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 4.0 Hz,

(15.77 min)

1H), 4.84 (s, 2H), 4.46 (d, J = 5.6 Hz, 2H), 3.94

(s, 3H), 2.00-1.98 (m, 1H), 1.11 (s, 9H), 0.82 (q,

J = 7.6 Hz, 4H).

7
Pale
415.28
4
δ (DMSO-d₆): 9.19 (q, J = 6.0 Hz, 1H), 8.61 (q, J =

Yellow
[M + H]⁺,

8.4 Hz, 1H), 8.35 (t, J = 6.0 Hz, 1H), 8.10 (d, J =

solid
(11.32 min)

4.0 Hz, 1H), 7.67 (q, J = 8.4 Hz, 1H), 7.12 (d, J =

3.6 Hz, 1H), 4.89 (s, 2H), 4.47 (d, J = 6.0 Hz,

2H), 2.47 (s, 3H) 1.11 (s, 9H).

8
Yellow
448.24
4
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.15 (d, J =

solid
[M + H]⁺,

8.8 Hz, 1H), 8.09 (d, J = 3.6 Hz, 1H), 7.94 (s,

(16.45 min)

1H), 7.69 (dd, J = 8.8 Hz, J = 8.8 Hz, 1H), 7.11

(d, J = 4.0 Hz, 1H), 4.85 (s, 2H), 4.46 (d, J = 6.0

Hz, 2H), 2.41 (s, 3H), 1.11 (s, 9H).

9
Yellow
432.24
1
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.97-7.85 (m, 3H), 7.11 (d, J = 4.0

(15.02 min)

Hz, 1H), 4.85 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H),

2.41 (s, 3H), 1.11 (s, 9H).

10
Light
432.31
1
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.24-8.21

yellow
[M + H]⁺,

(m, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.65-7.55 (m,

solid
(15.19 min)

2H), 7.11 (d, J = 4.0 Hz, 1H), 4.85 (s, 2H), 4.46

(d, J = 6.0 Hz, 2H), 2.41 (s, 3H), 1.11 (s, 9H).

11
Light
428.17
1
δ (DMSO-d₆): 8.33 (t, J = 6.0 Hz, 1H), 8.08 (d, J =

yellow
[M + H]⁺,

3.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.64 (s,

solid
(15.04 min)

1H), 7.50 (dd, J = 8.4 Hz, J = 8.4 Hz, 1H), 7.10

(d, J = 3.6 Hz, 1H), 4.82 (s, 2H), 4.46 (d, J = 6.0

Hz, 2H), 2.51-2.49 (m, 3H), 2.39 (s, 3H), 1.11 (s,

9H).

12
Off
444.14
1
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.08 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.26-7.23

solid
(14.59 min)

(m, 2H), 7.10 (d, J = 4.0 Hz, 1H), 4.80 (s, 2H),

4.46 (d, J = 6.0 Hz, 2H), 3.92 (s, 3H), 2.37 (s,

3H), 1.11 (s, 9H).

13
Off
428.15
3
δ (DMSO-d₆): 8.31 (t, J = 6.0 Hz, 1H), 8.10-8.06

white
[M + H]⁺,

(m, 2H), 7.95-7.83 (m, 2H), 7.67-7.63 (m, 1H),

solid
(13.02 min)

7.08 (d, J = 3.6 Hz, 1H), 4.83 (s, 2H), 4.44 (d, J =

5.6 Hz, 2H), 2.66 (q, J = 8.0 Hz, 2H), 1.12-1.03

(m, 12H).

14
Off
454.16
3
δ (DMSO-d₆): 8.32 (t, J = 6.0 Hz, 1H), 8.14-8.11

white
[M + H]⁺,

(m, 2H), 7.96-7.85 (m, 2H), 7.69-7.65 (m, 1H),

solid
(14.08 min)

7.12 (d, J = 3.6 Hz, 1H), 4.90 (s, 2H), 4.45 (d, J =

6.0 Hz, 2H), 3.56-3.52 (m, 1H), 2.20-2.15 (m,

2H), 2.07-2.01 (m, 2H), 1.82-1.80 (m, 1H), 1.44-

1.40 (m, 1H), 1.11 (s, 9H).

15
Off
432.07
1
δ (DMSO-d₆): 8.34 (t, J = 6.0 Hz, 1H), 8.10 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.83-7.78

solid
(14.63 min)

(m, 1H), 7.68-7.62 (m, 1H), 7.11 (d, J = 3.6 Hz,

1H), 4.86 (s, 2H), 4.47 (d, J = 6.0 Hz, 2H), 2.44

(s, 3H), 1.11 (s, 9H).

16
Off
443.28
4
δ (DMSO-d₆): 8.33 (t, J = 6.0 Hz, 1H), 8.07 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 7.87 (dd, J₁= 8.4 Hz, , J₂= 8.0 Hz,

solid
(12.13 min)

1H), 7.69-7.65 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H),

7.23-7.19 (m, 1H), 7.08 (d, J = 3.6 Hz, 1H), 4.86

(s, 2H), 4.45 (d, J = 6.0 Hz, 2H), 2.95 (br s, 6H),

1.12 (s, 9H).

17
Pale
444.11
4
δ (DMSO-d₆): 8.32 (t, J = 6.0 Hz, 1H), 8.08 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.60-7.57

solid
(14.07 min)

(m, 1H), 7.27 (d, J = 3.0 Hz, 1H), 7.10 (d, J = 4.0

Hz, 1H), 4.83 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H),

3.94 (s, 3H), 2.39 (s, 3H), 1.11 (s, 9H).

18
Off
415.11
3
δ (DMSO-d₆): 8.95 (q, J = 4.4 Hz, 1H), 8.34-8.26

white
[M + H]⁺,

(m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 7.98-7.95 (m,

solid
(10.48 min)

1H), 7.11 (d, J = 4.0 Hz, 1H), 4.76 (s, 2H), 4.45

(d, J = 4.4 Hz, 2H), 2.47 (s, 3H), 1.10 (m, 9H).

19
Off
450.27
1
δ (DMSO-d₆): 8.35-8.28 (m, 2H), 8.14-8.07 (m,

white
[M + H]⁺,

3H), 7.90-7.86 (m, 1H), 7.10 (d, J = 4.0 Hz, 1H),

solid
(15.45 min)

6.90-6.63(m, 1H), 4.97 (s, 2H), 4.46 (d, J = 6.0

Hz, 2H), 1.11 (s, 9H).

20
Off
472.25
4
δ (DMSO-d₆): 8.62 (s, 1H), 8.33 (t, J = 5.6 Hz,

white
[M + H]⁺,

1H), 8.04 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 3.6 Hz,

solid
(16.67 min)

1H), 4.97 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.06(s,

3H), 1.11 (s, 9H).

21
Light
454.26
4
δ (DMSO-d₆): 8.53 (s, 1H), 8.34 (t, J = 6.0 Hz,

yellow
[M + H]⁺,

1H), 8.05 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 4.0 Hz,

solid
(15.72 min)

1H), 6.90-6.63 (m, 1H), 4.98 (s, 2H), 4.45 (d, J =

6.0 Hz, 2H), 4.05 (s, 3H), 1.11 (s, 9H).

22
White
472.12
4
δ (DMSO-d₆): 9.05 (s, 1H), 8.32 (t, J = 6.0 Hz,

solid
[M + H]⁺,

1H), 8.03 (d, J = 4.0 Hz, 1H), 7.09 (d, J = 4.0 Hz,

(13.19 min)

1H), 4.93 (s, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.25

(s, 3H), 1.11 (s, 9H).

23
Off
404.27
4
δ (DMSO-d₆): 8.35 (t, J = 6.0 Hz, 1H), 8.05 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.19 (d, J =

solid
(14.91 min)

8.4 Hz, 1H), 7.12 (d, J = 4.0 Hz, 1H), 5.03 (s,

2H), 4.46 (d, J = 5.6 Hz, 2H), 2.50 (s, 3H), 1.12

(s, 9H).

24
White
402.27
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.40 (s, 1H), 8.09 (d,

solid
[M + H]⁺,

J = 4.0 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 4.99 (s,

(12.35 min)

2H), 4.61 (s, 2H), 4.02 (s, 3H), 3.29-3.26 (m, 2H),

2.45-2.38 (m, 1H), 2.25-2.15 (m, 1H), 1.60-1.51

(m, 1H), 1.07 (d, J = 7.2 Hz, 3H).

25
White
388.26
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.40 (s, 1H), 8.08 (d,

solid
[M + H]⁺,

J = 3.6 Hz, 1H), 7.19 (d, J = 3.6 Hz, 1H), 4.90 (d,

(11.45 min)

J = 8.8 Hz, 2H), 4.60 (s, 2H), 4.09 (s, 3H), 3.42

(d, J = 8.8 Hz, 1H), 3.33 (t, J = 8.2 Hz, 2H), 2.28

(t, J = 8.0 Hz, 2H), 1.95 (t, J = 7.6 Hz, 2H)

26
White
466.23
1
δ (DMSO-d₆): 8.40 (d, J = 8.0 Hz, 1H), 8.19-8.13

solid
[M + H]⁺,

(m, 2H), 8.09 (d, J = 4.0 Hz, 1H), 7.96-7.92 (m,

(15.42 min)

1H), 7.12 (d, J = 3.6 Hz, 1H), 4.97 (s, 2H), 3.48

(t, J = 7.2 Hz, 2H), 3.30 (t, J = 6.8 Hz, 2H), 3.09

(t, J = 6.8 Hz, 2H), 2.19 (t, J = 8.0 Hz, 2H), 1.92-

1.85 (m, 2H)

27
Off
405.27
1
δ (DMSO-d₆): 8.62 (s, 1H), 8.40 (s, 1H), 8.37 (br

white
[M + H]⁺,

t, J = 5.6 Hz, 1H), 8.02 (s, 1H), 5.08 (s, 2H), 4.52

solid
(12.85 min)

(d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 1.10 (s, 9H).

28
Off
422.26
1
δ (DMSO-d₆): 8.66 (s, 1H), 8.41 (s, 1H), 8.34 (t,

white
[M + H]⁺,

J = 6.0 Hz, 1H), 8.12 (s, 1H), 4.95 (s, 2H), 4.39

solid
(13.74 min)

(d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 1.09 (s, 9H).

29
White
482.26
1
δ (DMSO-d₆): 8.34 (d, J = 8.0 Hz, 1H), 8.19-8.13

solid
[M + H]⁺,

(m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 7.96-7.92 (m,

(16.88 min)

1H), 7.62 (t, J = 6.0 Hz, 1H), 7.07 (d, J = 3.6 Hz,

1H), 4.92 (s, 2H), 3.36-3.32 (m, 2H), 3.03 (t, J =

6.8 Hz, 2H), 1.06 (s, 9H).

30
White
424.23
1
δ (DMSO-d₆): 9.32 (t, d, J = 5.6 Hz, 1H), 8.67 (s,

solid
[M + H]⁺,

1H), 8.40 (s, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.88

(13.27 min)

(d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.49

(t, J = 7.6 Hz, 2H), 7.20 (d, J = 4.0 Hz, 1H), 4.98

(s, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.01 (s, 3H)

31
White
388.22
1
δ (DMSO-d₆): 8.81 (brs, 1H), 8.67 (s, 1H), 8.39

solid
[M + H]⁺,

(s, 1H), 8.05 (d, J = 3.2 Hz, 1H), 7.12 (d, J = 3.6

(11.49 min)

Hz, 1H), 4.99 (s, 2H), 4.49 (d, J = 5.6 Hz, 2H),

4.01 (s, 3H), 1.58 (br s, 1H), 0.70-0.68 (s, 4H)

32
White
438.23
1
δ (DMSO-d₆): 8.80 (t, J = 5.6 Hz, 1H), 8.66 (s,

solid
[M + H]⁺,

1H), 8.39 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.31-

(13.20 min)

7.20 (m, 5H), 7.10 (d, J = 4.0 Hz, 1H), 4.97 (s,

2H), 4.48 (d, J = 5.6 Hz, 2H), 4.01 (s, 3H), 3.47

(s, 2H).

33
Light
418.27
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.39 (s, 1H), 8.06 (d,

yellow
[M + H]⁺,

J = 4.0 Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H), 4.99 (s,

solid
(14.59 min)

2H), 4.69 (s, 2H), 4.02 (s, 3H), 3.07 (s, 3H), 1.22

(s, 9H).

34
Off
402.24
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.39 (s, 1H), 8.06 (d,

white
[M + H]⁺,

J = 4.0 Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H), 4.99 (s,

solid
(12.70 min)

2H), 4.69 (s, 2H), 4.02 (s, 3H), 3.07 (s, 3H), 1.22

(s, 9H).

35
Pale
398.25
4
δ (DMSO-d₆): 8.83 (t, J = 5.6 Hz, 1H), 8.13-8.10

Yellow
[M + H]⁺,

(m, 2H), 7.97-7.93 (m, 1H), 7.85 (d, J = 8.0 Hz,

solid
(12.23 min)

1H), 7.69-7.65 (m, 1H), 7.14 (d, J = 4.0 Hz, 1H),

4.85 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 2.43 (s, 3H),

1.60-1.57 (m, 1H), 0.71-0.67 (m, 4H)

36
Off
466.20
1
δ (DMSO-d₆): 8.31 (d, J = 8.4 Hz, 1H), 8.23 (t, J =

white
[M + H]⁺,

5.6 Hz, 1H), 8.19 (d, J = 3.6 Hz, 1H), 7.97-7.92

solid
(18.68 min)

(m, 1H), 7.45 (s, 1H), 7.12 (d, J = 3.6 Hz, 1H),

6.90 (d, J = 3.6 Hz, 1H), 3.34-3.29 (m, 2H), 2.95

(t, J = 6.8 Hz, 2H), 2.07-1.98 (m, 1H), 1.56-1.51

(m, 1H), 1.23-1.09 (m, 2H), 0.70-0.61 (m, 2H).

37
White
502.20
1
δ (DMSO-d₆): 8.66 (t, J = 5.2 Hz, 1H), 8.34 (d, J =

solid
[M + H]⁺,

8.0 Hz, 1H), 8.16-8.09 (m, 3H), 7.96-7.92 (m,

(16.84 min)

1H), 7.83-7.81 (m, 2H), 7.54-7.44 (m, 3H), 7.14

(d, J = 4.0 Hz, 1H), 4.97 (s, 2H), 3.57 (q, J = 4.0

Hz, 2H), 3.17 (t, J = 6.8 Hz, 2H).

38
White
468.23
1
δ (DMSO-d₆): 8.35-8.33 (m, 2H), 8.16-8.13 (m,

solid
[M + H]⁺,

2H), 8.06 (d, J = 4.0 Hz, 1H), 7.96-7.92 (m, 1H),

(16.57 min)

7.11 (d, J = 3.6 Hz, 1H), 4.99 (s, 2H), 4.47 (d, J =

6.0 Hz, 2H), 1.11 (s, 9H)

39
Yellow
464.1
2
δ (CDCl₃): 7.79 (d, J = 4.0 Hz, 1H), 7.73 (d, J =

solid
[M + H]⁺,

8.4 Hz, 1H), 7.39 (dd, J = 9.2, 2.8 Hz, 1H), 7.17

(2.837 min)

(d, J = 2.4 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.15

(s, 1H), 4.54-4.71 (m, 4H), 3.87 (s, 3H), 2.52 (s,

3H), 2.27-2.21 (m, 1H), 2.00-2.15 (m, 1H), 1.58-

1.72 (m, 1H)

40
Yellow
506.1
2
δ (DMSO-d₆): 8.13 (d, J = 3.6 Hz, 1H), 7.79 (d, J =

solid
[M + H]^+,

9.2 Hz, 1H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 7.20

(3.166 min)

(d, J = 3.6 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 4.84

(s, 2H), 4.66 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.36

(s, 3H)

41
White
456.0
2
δ (CDCl₃): 8.18 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H),

solid
[M + H]⁺,

7.06 (d, J = 4.0, 1H), 6.07 (s, 1H), 4.18 (s, 2H),

(2.663 min)

4.68 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 1.42-1.36

(m, 1H), 1.06-1.02 (m, 2H), 0.83-0.78 (2H)

42
White
446.1
2
δ (DMSO-d₆): 8.06 (m, 1H), 8.67 (s, 1H), 8.40 (s,

solid
[M + H]⁺,

1H), 7.31 (d, J = 6.8 Hz, 1H), 7.12 (d, J = 4.0 Hz,

(2.481 min)

1H), 4.98 (s, 2H), 4.62 (m, 3H), , 4.02 (s, 1H), ,

2.67 (m, 1H), 2.33 (m, 1H)

43
Light
518.1
2
δ (DMSO-d₆): 9.20 (s, 1H), 9.06 (t, J = 6.0 Hz,

yellow
[M + H]⁺,

1H), 8.05 (d, J = 3.6 Hz, 1H), 7.14 (d, J = 3.6 Hz,

solid
(2.894 min)

1H), 4.94 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.29-

4.24 (m, 1H), 1.98-1.88 (m, 3H), 1.40-1.37 (m,

2H), 1.23-1.20 (m, 2H).

44
Light
560.1
2
δ (DMSO-d₆): 10.3 (t, J = 6.0 Hz, 1H), 9.19 (s,

yellow
[M + H]⁺,

1H), 8.07 (d, J = 4.0 Hz, 1H), 7.18 (d, J = 3.6 Hz,

solid
(3.145 min)

1H), 4.94 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 4.29-

4.24 (m, 1H), 1.41-1.37 (m, 2H), 1.23-1.20 (m,

2H).

45
Light
458.1
2
δ (DMSO-d₆): 8.72 (t, J = 6.0 Hz, 1H), 8.33 (d, J =

yellow
[M + H]⁺,

8.4 Hz, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.88 (d, J =

solid
(2.703 min)

8.4 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 5.10 (s,

2H), 4.51 (d, J = 6.0 Hz, 2H), 0.98-1.08 (m, 2H),

0.79-0.90 (m, 2H)

46
White
514.1
2
δ (CDCl₃): 8.19 (s, 1H), 7.87 (d, J = 4.0 Hz, 1H),

solid
[M + H]⁺,

7.09 (d, J = 4.0 Hz, 1H), 6.70 (s, 1H), 4.79-4.76

(2.852 min)

(m, 4H), 4.53-4.41 (m, 1H), 4.15 (s, 3H), 3.92 (d,

J = 5.6 Hz, 1H)

47
Yellow
553.2
2
δ (DMSO-d₆): 8.71 (m, 1H), 8.05 (d, J = 4.0 Hz,

solid
[M + H]⁺,

1H), 7.98 (s, 2H), 7.17 (s, 1H), 7.12 (d, J = 4.0

(2.812 min)

Hz, 1H), 6.29 (s, 1H), 4.93 (s, 2H), 4.52 (d, J =

6.0 Hz, 2H)

48
Yellow
474.1
2
δ (CDCl₃): 8.18 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H),

solid
[M + H]⁺,

7.25 (s, 1H), 7.06 (d, J = 4.0 Hz, 1H), 4.78 (s, 2H),

(2.713 min)

4.67 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 2.07 (s, 1H),

1.50 (s, 6H)

49
Light
472.1
2
δ (CDCl₃): 8.18 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H),

yellow
[M + H]⁺,

7.39-7.31 (m, 1H), 7.08 (d, J = 4.0 Hz, 1H), 4.78

solid
(2.689 min)

(s, 2H), 4.15 (s, 3H), 2.54 (s, 1H), 1.43 (q, J = 2.8

Hz, 2H), 1.10 (q, J = 2.8 Hz, 2H)

50
Light
444.2
2
δ (DMSO-d₆): 8.73 (m, 1H), 8.09 (d, J = 4.0 Hz,

yellow
[M + H]⁺,

1H), 7.80 (d, J = 9.2 Hz, 1H), 7.60 (m, 1H), 7.27

solid
(2.568 min)

(d, J = 2.4 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 6.30

(s, 1H), 4.84 (s, 2H), 4.52 (d, J = 6.4 Hz, 2H), 3.94

(s, 3H), 2.41 (s, 3H), 1.04 (m, 2H), 0.87 (m, 2H)

51
Yellow
428.1
2
δ (CDCl₃): 7.79 (d, J = 9.2 Hz, 1H), 7.75 (d, J =

solid
[M + H]⁺,

2.8 Hz, 1H), 7.48 (m, 1H), 7.48 (m, 1H), 7.10 (m,

(2.733 min)

1H), 7.07 (m, 1H), 6.10 (s, 1H), 4.73 (m, 2H),

4.68 (m, 2H), 3.95 (s, 3H), 2.60 (s, 1H), 1.40 (m,

1H), 1.05 (m, 2H), 0.80 (m, 2H)

52
White
406
2
δ (CDCl3): 8.65 (s, 1H), 8.08 (s, 1H), 7.83 (s, 1H),

solid
[M + H]⁺,

7.04 (t, J = 3.6 Hz, 1H), 4.79 (s, 2H), 4.66 (d, J =

(2.016 min)

6.4 Hz, 2H), 4.09 (s, 3H), 1.49 (s, 6H)

55
Off
439.29
1
δ (DMSO-d₆): 8.87 (t, J = 6.0 Hz, 1H), 8.67 (s,

white
[M + H]⁺,

1H), 8.49-8.47 (m, 1H), 8.40 (s, 1H), 8.05 (d, J = 4.0

solid
(10.44 min)

Hz, 1H), 7.75-7.71 (m, 1H), 7.34 (d, J = 7.6 Hz,

1H), 7.27-7.23 (m, 1H), 7.13 (d, J = 4.0 Hz, 1H),

4.97 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.02 (s, 3H),

3.68 (s, 2H).

56
Off
439.23
1
δ (DMSO-d₆): 8.95 (d, J = 6.0 Hz, 1H), 8.66-8.62

white
[M + H]⁺,

(m, 3H), 8.40 (s, 1H), 8.06 (d, J = 4.0 Hz,

solid
(9.11 min)

2H), 7.66 (t, J = 8.0 Hz, 1H), 7.14(d, J = 3.6 Hz,

1H), 4.98 (s, 2H), 4.58 (d, J = 6.0 Hz, 2H), 4.02

(s, 3H), 3.68 (s, 2H).

57
Light
439.23
1
δ (DMSO-d₆): 8.91 (t, J = 6.0 Hz, 1H), 8.66 (s,

yellow
[M + H]⁺,

1H), 8.48 (d, J = 5.6 Hz, 2H), 8.39 (s, 1H), 8.04 (d, J =

solid
(8.55 min)

3.6 Hz, 1H), 7.28 (d, J = 6.0 Hz, 2H), 7.12 (d,

J = 4.0 Hz, 1H), 4.97 (s, 2H), 4.50 (d, J = 5.6 Hz,

2H), 4.02 (s, 3H), 3.54 (s, 2H).

58
Off
392.26
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.56 (t, J = 6.0 Hz,

white
[M + H]⁺,

1H), 8.39 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12

solid
(10.83 min)

(d, J = 4.0 Hz, 1H), 4.97 (s, 2H), 4.50 (d, J = 6.4

Hz, 2H), 4.01 (s, 3H), 3.86 (s, 2H), 3.33 (s, 3H).

59
Off
378.23
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.56 (t, J = 6.0 Hz,

white
[M + H]⁺,

1H), 8.39 (s, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12

solid
(9.46 min)

(d, J = 4.0 Hz, 1H), 5.57 (t, J = 5.6 Hz, 1H), 4.97

(s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 4.01 (s, 3H), 3.86

(d, J = 5.6 Hz, 2H).

60
White
418.1
2
δ (DMSO-d₆): 8.56 (m, 1H), 8.09 (m, 1H), 7.80

solid
[M + H]⁺,

(m, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.14 (d, J = 3.6

(2.466 min)

Hz, 1H), 5.57 (m, 1H), 4.84 (s, 2H), 4.52 (d, J =

6.0 Hz, 2H), 3.94 (s, 3H), 3.85 (d, J = 4 Hz, 2H),

2.41 (s, 3H)

61
White
446.07
4
δ (DMSO-d₆): 9.06 (s, 1H), 8.56 (t, J = 6.4 Hz,

solid
[M + H]⁺,

1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 4.0 Hz,

(9.74 min)

1H), 5.57 (t, J = 6.0 Hz, 1H), 4.94 (s, 2H), 4.50

(d, J = 6.4 Hz, 2H), 4.25 (s, 3H), 3.86 (d, J = 6.0

Hz, 2H)

62
Off
402.07
1
δ (DMSO-d₆): 8.53 (t, J = 6.4 Hz, 1H), 8.13-8.09

white
[M + H]⁺,

(m, 2H), 7.95-7.86 (m, 2H), 7.69-7.67 (m, 1H),

solid
(11.38 min)

7.13 (d, J = 3.6 Hz, 1H), 5.57 (t, J = 5.6 Hz, 1H),

4.86 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86 (d, J =

6.0 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.09 (t, J =

7.6 Hz, 3H).

63
Yellow
527.1
2
δ (DMSO-d₆): 8.56 (m, 1H), 8.05 (d, J = 4.0 Hz,

solid
[M + H]⁺,

1H), 7.95 (s, 2H), 7.17 (s, 1H), 7.13 (d, J = 4.0

(2.697 min)

Hz, 1H), 5.57 (m, 1H), 4.93 (s, 2H), 4.52 (d, J =

6.4 Hz, 2H), 3.87 (d, J = 5.6 Hz, 2H), 3.82 (m,

4H), 3.43 (m, 4H), 3.29 (s, 1H)

64
Yellow
389.1
2
δ (DMSO-d₆): 9.20-9.18 (m, 1H), 8.62-8.59 (m,

solid
[M + H]⁺,

1H), 8.57 (t, J = 6.4 Hz, 1H), 8.10 (d, J = 4.0 Hz,

(2.023 min)

1H), 7.70-7.67 (m, 1H), 5.59 (t, J = 5.6 Hz, 1H),

4.91 (s, 2H), 4.52 (d, J = 6.0 Hz, 2H), 3.87 (d, J =

5.6 Hz, 2H), 3.32 (s, 3H).

65
White
392.1
2
δ (CDCl₃): 8.00 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H),

solid
[M + H]⁺,

7.08 (d, J = 3.9 Hz, 1H), 4.78-4.69 (m, 4H), 4.21

(2.225 min)

(s, 2H), 4.05 (s, 3H), 2.58 (s, 3H).

66
Yellow
388.1
2
δ (MeOD): 8.15 (d, J = 8.4 Hz, 1H), 8.03 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.95-7.89 (m, 1H), 7.85-7.80 (m,

(2.406 min)

1H), 7.64 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 4.0 Hz,

1H), 4.66 (s, 2H), 4.03 (s, 2H), 2.49 (s, 3H)

67
Yellow
406.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.0 Hz, 1H), 8.08 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.89-7.84 (m,

(2.477 min)

2H), 7.14 (d, J = 3.6 Hz, 1H), 5.56 (s, 1H), 4.86

(s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86 (s, 2H), 2.43

(s, 3H).

68
Yellow
406.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.4 Hz, 1H), 8.25-8.23

solid
[M + H]⁺,

(m, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.65-7.56 (m,

(2.493 min)

2H), 7.14 (d, J = 3.6 Hz, 1H), 5.56 (t, J = 5.6 Hz,

1H), 4.86 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86

(d, J = 6.0 Hz, 2H), 2.43 (s, 3H)

69
White
428.1
2
δ (DMSO-d₆): 8.56-8.52 (m, 2H), 8.05 (d, J = 4.0

solid
[M + H]⁺,

Hz, 1H), 7.12 (d, J = 4.0 Hz, 1H), 6.79 (t, J = 54

(2.428 min)

Hz, 1H), 5.61 (t, J = 5.6 Hz, 1H), 4.99 (s, 2H),

4.50 (d, J = 6.0 Hz, 2H), 4.05 (s, 3H), 3.86 (d, J =

5.6 Hz, 2H).

70
Yellow
418.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.07 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.27-7.23

(2.495 min)

(m, 2H), 7.13 (d, J = 4.0 Hz, 1H), 5.58-5.55 (m,

1H), 4.81 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.93

(s, 3H), 3.86 (d, J = 5.2 Hz, 2H), 2.40 (s, 3H).

71
White
432.0
2
δ (CDCl₃): 8.91 (s, 1H), 7.95 (s, 1H), 7.84 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 7.08 (s, 1H),

(2.258 min)

4.86 (s, 2H), 4.78 (d, J = 6.0 Hz, 2H), 4.26 (s, 2H)

72
Off-
431.9
2
δ (DMSO-d₆): 8.56 (t, J = 6.4 Hz, 1H), 8.33 (d, J =

white
[M + H]⁺,

8.4 Hz, 1H), 8.07 (t, J = 7.2 Hz, 1H), 7.88 (d, J =

solid
(2.599 min)

8.4 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 5.56 (s,

1H), 5.10 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86

(s, 2H).

73
Yellow
440.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.36 (d, J =

solid
[M + H]⁺,

7.6 Hz, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.89 (d, J =

(2.746 min)

10.4 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 5.56 (t,

J = 6.0 Hz, 1H), 4.87 (s, 2H), 4.51 (d, J = 6.0 Hz,

2H), 3.86 (d, J = 5.6 Hz, 2H), 2.43 (s, 3H).

74
Off-
446.1
2
δ (DMSO-d₆): 8.61 (s, 1H), 8.57 (t, J = 6.4 Hz,

white
[M + H]⁺,

1H), 8.05 (d, J = 4.0, 1H), 7.12 (d, J = 4.4 Hz,

solid
(2.560 min)

1H), 4.98 (s, 2H), 4.50 (d, J = 6.4 Hz, 2H), 4.06

(s, 3H), 3.86 (s, 2H)

75
Yellow
436.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.4 Hz, 1H), 8.08 (d, J =

soild
[M + H]⁺,

3.6 Hz, 1H), 7.69 (d, J = 12 Hz, 1H), 7.44 (d, J =

(2.548 min)

9.2 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 5.57-5.54

(m, 1H), 4.85 (s, 1H), 4.51 ((d, J = 6.0 Hz, 2H),

4.04 (s, 3H), 3.86 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H)

76
Yellow
456.1
2
δ (DMSO-d₆): 8.59-8.56 (m, 1H), 8.39 (s, 1H),

solid
[M + H]⁺,

8.24-8.22 (m, 1H), 8.11-8.05 (m, 2H), 7.14 (d, J =

(2.753 min)

3.6 Hz, 1H), 5.58 (t, J = 6.0 Hz, 1H), 4.91 (s,

2H), 4.51 (6.0 Hz, 2H), 3.86 (d, J = 6.0 Hz, 2H),

3.33 (s, 3H).

77
yellow
444.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

solid
[M + H]⁺,

3.6 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.60-7.57

(2.672 min)

(m, 2H), 7.14 (d, J = 3.6 Hz, 1H), 5.57 (t, J = 6.0

Hz, 1H), 4.84 (s, 2H), 4.51 (d, J = 6.4 Hz, 2H),

4.10-4.07 (m, 1H), 3.86 (d, J = 5.6 Hz, 2H), 2.41

(s, 3H), 0.92-0.74 (m, 4H).

78
Yellow
457.1
2
δ (DMSO-d₆): 8.53 (t, J = 6.4 Hz, 1H), 8.06 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.38-7.41

(2.653 min)

(m, 1H), 7.13(d, J = 3.6 Hz, 1H), 6.64 (d, J = 2.4

Hz, 1H), 6.58 (t, J = 3.2 Hz, 1H), 5.55 (t, J = 6.0

Hz, 1H), 4.77 (s, 2H), 4.51(d, J = 6.4 Hz, 2H),

3.87 (d, J = 6.0 Hz, 2H), 3.00 (t, J = 6.0 Hz, 2H),

2.34 (s, 3H), 1.09-1.15 (m, 1H), 0.51-0.55 (m,

2H), 0.27-0.31 (m, 2H).

79
Yellow
472.1
2
δ (DMSO-d6): 9.19 (s, 1H), 8.53 (t, J = 6.8 Hz,

solid
[M + H]⁺,

1H), 8.03 (d, J = 4.0 Hz, 1H), 7.11 (d, J = 3.6 Hz,

(2.503 min)

1H), 5.55 (t, J = 6.0 Hz, 1H), 4.94 (s, 2H), 4.50

(d, J = 6.4 Hz, 2H), 4.29-4.24 (m, 1H), 3.86 (d, J =

6.0 Hz, 2H), 1.41-1.38 (m, 2H), 1.24-1.20 (m, 2H).

80
White
471.9
2
δ (CDCl3): 8.01-7.99 (m, 2H), 7.72-7.69 (m, 1H),

solid
[M + H]⁺,

7.47 (d, J = 2.8 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H),

(2.502 min)

4.90 (s, 2H), 4.66 (s, 2H), 4.04 (s, 2H), 4.03 (s,

3H).

81
Yellow
473.2
2
δ (DMSO-d6): 8.53 (t, J = 6.0 Hz, 1H), 8.07 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.81-7.78 (m, 1H), 7.72 (d, J = 9.6

(2.397 min)

Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.07 (d, J = 2.4

Hz, 1H), 5.52 (t, J = 5.6 Hz, 1H), 4.81 (s, 2H),

4.51 (d, J = 6.0 Hz, 2H), 3.86 (d, J = 6.0 Hz, 2H),

3.79 (t, J = 4.4 Hz, 4H), 3.28 (t, J = 4.0 Hz, 4H),

2.39 (s, 3H)

82
Yellow
471.2
2
δ (DMSO-d6): 8.54 (t, J = 6.4 Hz, 1H), 8.07 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.76-7.79 (m, 1H), 7.67 (d, J = 9.6

(2.828 min)

Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 7.04 (d, J = 2.4

Hz, 1H), 5.55 (t, J = 5.6 Hz, 1H), 4.80 (s, 2H),

4.51 (d, J = 6.4 Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H),

3.32 (s, 4H), 2.38 (s, 3H), 1.66-1.67 (m, 4H),

1.56-1.60 (m, 2H).

83
Yellow
487.2
2
δ (DMSO-d₆): 8.54 (t, J = 6.0 Hz, 1H), 8.07 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.13 (d, J = 4.0

(2.458 min)

Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 5.57-5.53 (m,

1H), 4.79 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86

(d, J = 5.6 Hz, 2H), 3.78-3.71 (m, 7H), 3.62-3.32

(m, 2H), 2.36 (s, 3H), 1.97-1.94 (m, 2H)

84
Yellow
493.1
2
δ (DMSO-d6): 8.56 (t, J = 6.4 Hz, 1H), 8.08 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.47-7.44

(2.691 min)

(d, 1H), 7.13 (d, J = 4.0 Hz, 1H), 6.72 (d, J = 2.4

Hz, 1H), 5.58 (t, J = 5.6 Hz, 1H), 4.80 (s, 2H),

4.50 (d, J = 6.0 Hz, 2H), 3.87 (t, J = 7.6 Hz, 4H),

3.64 (t, J = 7.2 Hz, 2H), 2.64-2.56 (m, 2H), 2.36

(s, 3H).

85
Yellow
486.2
2
δ (DMSO-d₆): 8.51-8.61 (m, 1H), 8.09 (d, J = 4.0

solid
[M + H]⁺,

Hz, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.67-7.76 (m,

(2.337 min)

1H), 6.97-7.20 (m, 2H), 5.57 (t, J = 6.0 Hz, 1H),

4.82 (s, 2H), 4.53 (d, J = 6.4 Hz, 2H), 3.88 (d, J =

6.0 Hz, 2H), 3.32 (s, 4H), 2.49-2.51 (m, 4H), 2.40

(s, 3H), 2.26 (s, 3H)

86
Yellow
418.0
2
δ (CD₃CN): 8.60 (s, 1H), 8.17 (s, 1H), 7.93-

solid
[M + H]⁺,

7.92(d, J = 3.6 Hz, 1H), 7.19-7.09 (t, J = 2.8 Hz,

(2.088 min)

1H), 4.84 (s, 2H), 4.01-3.98 (m, 5H), 3.78-3.69

(m, 2H), 3.51-3.46 (m, 2H), 3.44-3.32 (m, 1H),

2.46-2.39 (m, 1H), 2.05-2.04 (m, 1H)

87
White
398.18
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.40 (s, 1H), 8.08 (d,

solid
[M + H]⁺,

J = 3.6 Hz, 1H), 7.88 (t, J = 6.4 Hz, 1H), 7.20 (d,

(11.05 min)

J = 3.6 Hz, 1H), 4.99 (s, 2H), 4.42 (d, J = 6.0 Hz,

2H), 4.01 (s, 3H), 2.94 (s, 3H).

88
White
460.15
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.48 (t, J = 6.4 Hz,

solid
[M + H]⁺,

1H), 8.40 (s, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.80

(13.93 min)

(d, J = 7.2 Hz, 2H), 7.66-7.57 (m, 3H), 7.08 (d, J =

4.0 Hz, 1H), 4.96 (s, 2H), 4.26 (d, J = 6.0 Hz,

2H), 4.02 (s, 3H).

89
Light
424.19
1
δ (DMSO-d₆): 8.66 (s, 1H), 8.40 (s, 1H), 8.07 (d,

yellow
[M + H]⁺,

J = 4.0 Hz, 1H), 7.95 (t, J = 6.4 Hz, 1H), 7.21 (d,

solid
(12.16 min)

J = 4.0 Hz, 1H), 4.99 (s, 2H), 4.44 (d, J = 6.0 Hz,

2H), 4.01 (s, 3H), 2.57-2.50 (m, 1H), 0.92 (d, J =

8.0 Hz, 4H).

90
White
474.21
1
δ (DMSO-d₆): 8.66 (s, 1H), 8.39 (s, 1H), 8.06 (d,

solid
[M + H]⁺,

J = 4.0 Hz, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.37 (s,

(14.16 min)

5H), 7.15 (d, J = 4.0 Hz, 1H), 4.99 (s, 2H), 4.39

(s, 2H), 4.33 (d, J = 6.0 Hz, 2H), 4.01 (s, 3H).

91
Off
438.23
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.40 (s, 1H), 8.10 (d,

white
[M + H]⁺,

J = 4.0 Hz, 1H), 7.26 (d, J = 3.6 Hz, 1H), 5.00 (s,

solid
(13.74 min

2H), 4.59 (s, 2H), 4.02 (s, 3H), 2.82 (s, 3H), 2.69

(t, J = 6.4 Hz, 1H), 1.00 (d, J = 6.0 Hz, 4H).

92
Off
489.21
1
δ (DMSO-d₆): 8.66 (s, 1H), 8.61 (q, J = 6.0 Hz,

white
[M + H]⁺,

2H), 8.39 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.44

solid
(12.25 min)

(q, J = 6.0 Hz, 2H), 7.21 (d, J = 4.0 Hz, 1H), 4.99

(s, 2H), 4.63(s, 2H), 4.47(s, 2H), 4.01 (s, 3H),

2.76 (s, 3H).

93
White
448.14
1
δ (DMSO-d₆): 8.13-8.11 (m, 2H), 7.98-7.91 (m,

solid
[M + H]⁺,

2H), 7.85 (d, J = 8.0 Hz, 1H), 7.70-7.66 (m,

(14.18 min

1H), 7.21 (d, J = 4.0 Hz, 1H), 4.86 (s, 2H), 4.43 (d,

J = 6.0 Hz, 2H), 2.99 (d, J = 7.2 Hz, 2H), 2.43 (s,

3H), 1.03-0.98 (m, 1H), 0.60-0.55 (m, 2H), 0.34-

0.30 (m, 2H).

94
Light
422.23
1
δ (DMSO-d₆): 8.14-8.11 (m, 2H), 7.97-7.93 (m,

brown
[M + H]⁺,

1H), 7.85 (d, J = 8.4 Hz, 1H), 7.69-7.65 (m, 1H),

solid
(13.26 min)

7.24 (t, J = 5.6 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H),

4.85 (s, 2H), 3.34-3.23 (m, 2H), 3.07 (t, J = 7.2

Hz, 2H), 2.90 (s, 3H), 2.43 (s, 3H).

95
Off
502.22
4
δ (DMSO-d₆): 8.35 (d, J = 8.0 Hz, 1H), 8.17-8.13

white
[M + H]⁺,

(m, 3H), 7.97-7.93 (m, 1H), 7.24 (d, J = 3.6 Hz,

solid
(17.22 min)

1H), 4.98 (s, 2H), 3.81-3.75 (m, 2H), 3.48-3.43 (m,

1H), 3.40-3.34 (m, 1H), 3.24-3.22 (m, 1H), 2.97

(s, 3H), 2.41-2.38 (m, 1H), 2.07-2.01 (m, 1H).

96
Yellow
439.1
2
δ (CD₃CN): 8.59 (s, 1H), 8.16 (s, 1H), 7.92 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.10 (d, J = 4.0 Hz, 1H), 5.27 (br

(2.485 min)

s, 2 H), 4.84 (s, 2H), 4.01 (s, 3H), 3.73-3.83 (m,

1H), 3.69 (dd, J = 9.6, 7.2 Hz, 1H), 3.40-3.48 (m,

1H), 3.35-3.32 (m, 1H), 3.24-3.20 (m, 1H), 247-

2.39 (m, 1H), 2.07-2.04 (m, 1H)

97
Off
408.09
1
δ (DMSO-d₆): 8.14-8.12 (m, 2H), 7.98-7.94 (m,

white
[M + H]⁺,

1H), 7.91-7.84 (m, 2H), 7.70-7.66 (m, 1H), 7.23-

solid
(12.45 min)

7.21 (m, 1H), 4.87 (s, 2H), 4.43 (d, J = 6.4 Hz,

2H), 2.92 (s, 3H), 2.42 (s, 3H).

98
White
476.10
1
δ (DMSO-d₆): 8.35 (d, J = 8.0 Hz, 1H), 8.19-8.13

solid
[M + H]⁺,

(m, 2H), 8.08 (d, J = 4.0 Hz, 1H), 8.06-7.999 (m,

(15.28 min)

1H), 7.96-7.92 (m, 1H), 7.09 (d, J = 4.0 Hz, 1H),

4.98 (s, 2H), 3.35-3.30 (m, 2H), 3.01 (t, J = 6.8

Hz, 2H), 1.80 (s, 3H)

101
Off
412.28
1
δ (DMSO-d₆): 8.12-8.07 (m, 2H), 8.02 (t, J = 5.2

white
[M + H]+

Hz, 1H), 7.93-7.89 (m, 1H), 7.80 (d, J = 8.4 Hz,

solid
(12.67 min)

1H), 7.63-7.59 (m, 1H), 7.11 (d, J = 3.6 Hz, 1H),

4.84 (s, 2H), 3.34 (d, J = 6.8 Hz, 2H), 3.01 (t, J =

6.8 Hz, 2H), 2.03-2.01 (m, 1H), 1.80 (s, 3H), 0.82

(t, J = 5.6 Hz, 4H).

103
White
362.19
1
δ (DMSO-d₆): 8.67 (s, 1H), 8.62 (t, d, J = 6 Hz,

solid
[M + H]+

1H), 8.40 (s, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.12

(10.12 min)

(d, J = 4.0 Hz, 1H), 4.98 (s, 2H), 4.46 (d, J = 6.0

Hz, 2H), 4.01 (s, 3H), 1.87 (s, 3H)

105
White
431.1
2
δ (DMSO-d₆): 7.77-7.89 (m, 2H), 7.54 (d, J = 0.8

solid
[M + H]⁺,

Hz, 2H), 7.10 (d, J = 4.0 Hz, 1H), 6.96-7.04 (m,

(0.988 min)

1H), 4.79 (s, 2H), 4.73 (d, J = 6.0 Hz, 2H), 4.22

(d, J = 4.8 Hz, 2H), 2.38 (t, J = 5.2 Hz, 1H)

106
Yellow
428.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.4 Hz, 1H), 8.08 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.76-7.73 (m, 2H), 7.61-7.58 (m,

(2.710)

1H), 7.14 (d, J = 3.6 Hz, 1H), 5.56 (t, J = 6.0 Hz,

1H), 4.83 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H), 3.86

(d, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.24-2.20 (m,

1H), 1.09-1.06 (m, 2H), 0.86-0.83 (m, 2H)

107
Yellow
446.1
2
δ (DMSO-d₆): 7.98 (d, J = 3.6 Hz, 1H), 7.16 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 6.71 (s, 1H), 4.66 (s, 2H), 4.03 (s,

(2.594 min)

2H), 2.57 (s, 3H)

108
Yellow
436.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.14 (d, J = 2.8

(2.531 min)

Hz, 2H), 5.56 (t, J = 5.6 Hz, 1H), 4.86 (s, 2H),

4.51 (d, J = 6.4 Hz, 2H), 3.96 (s, 3H), 3.87 (d, J =

6.0 Hz, 2H), 2.43 (s, 3H)

109
Yellow
432.2
2
δ (DMSO-d₆): 8.27 (t, J = 3.6 Hz, 1H), 8.22 (s,

solid
[M + H]⁺,

1H), 7.90 (d, J = 9.2 Hz, 1H), 7.72-7.69 (m, 1H),

(2.586 min)

7.38 (d, J = 2.8 Hz, 1H), 7.33 (d, J = 4.0 Hz, 1H),

4.97 (d, J = 11.2 Hz, 2H), 4.86 (d, J = 13.2 Hz,

2H), 4.77 (t, J = 6.0 Hz, 1H), 4.29 (d, J = 5.6 Hz,

1H), 4.24 (d, J = 5.6 Hz, 2H), 3.00 (d, J = 17.2

Hz, 3H), 2.49 (d, J = 4.4 Hz, 3H)

110
Yellow
435.1
2
δ (DMSO-d₆): 9.20-9.18 (m, 1H), 9.07 (t, J = 6.0

solid
[M + H]⁺,

Hz, 1H), 8.62-8.59 (m, 1H), 8.11 (d, J = 3.6 Hz,

(2.412 min)

1H), 7.69-7.66 (m, 1H), 7.17 (d, J = 3.6 Hz, 1H),

4.90 (s, 2H), 4.56 (d, J = 6.0 Hz, 2H), 2.68-2.61

(m, 1H), 1.95-1.86 (m, 2H)

111
Off
492.1
2
δ (DMSO-d₆): 9.08 (t, J = 6.0 Hz, 1H), 8.61 (s,

white
[M + H]⁺,

1H), 8.06 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 4.0 Hz,

solid
(2.946 min)

1H), 4.98 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.07

(s, 3H), 2.67-2.59 (m, 1H), 1.95-1.86 (m, 2H)

112
Off
472.1
2
δ (DMSO-d₆): 7.97 (d, J = 4.0 Hz, 1H), 7.15 (d, J =

white
[M + H]⁺,

4.0 Hz, 1H), 6.60 (s, 1H), 4.86 (s, 2H), 4.66 (s,

solid
(2.772 min)

2H), 4.03 (s, 2H), 2.26-2.19 (m, 1H), 1.18-1.16

(m, 2H), 1.04-1.02 (m, 2H)

113
White
442.9
2
δ (DMSO-d₆): 9.38 (dd, J = 1.6, 2.0 Hz, 1H), 8.82

solid
[M + H]⁺,

(d, J = 6.4 Hz, 1H), 8.82 (t, J = 6.4 Hz, 1H), 8.07

(2.025 min)

(d, J = 4.0 Hz, 1H), 7.93-7.90 (m, 1H), 7.13 (d, J =

4.0 Hz, 1H), 5.01 (m, 2H), 4.51 (d, J = 6.0 Hz,

2H), 3.86 (m, 2H)

114
Brown
488.9
2
δ (DMSO-d₆): 9.38 (dd, J = 1.6, 2.0 Hz, 1H), 9.07

solid
[M + H]⁺,

(t, J = 5.6 Hz, 1H), 8.82 (dd, J = 1.6, 2.0 Hz, 1H),

(2.375 min)

8.08 (d, J = 4.0 Hz, 1H), 7.93-7.91 (m, 1H), 7.15

(d, J = 4.0 Hz, 1H), 5.01 (m, 2H), 4.56 (d, J = 6.0

Hz, 2H), 2.67-2.61 (m, 1H), 1.95-1.86 (m, 2H)

115
Yellow
458.2
2
δ (DMSO-d₆): 8.12 (d, J = 4.0 Hz, 1H), 7.80 (d, J =

solid
[M + H]⁺,

9.2 Hz, 1H), 7.59 (dd, J = 9.2, 2.8 Hz, 1H), 7.28

(2.567 min)

(d, J = 2.8 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 5.52

(d, J = 5.6 Hz, 1H), 4.84 (s, 2H), 4.06 (d, J = 5.6

Hz, 1H), 3.95 (s, 3H), 3.40-3.58 (m, 2H), 3.09-

3.30 (m, 4H), 2.40 (s, 3H), 2.19-2.30 (m, 1H),

1.60-1.73 (m, 1H)

116
Yellow
460.1
2
δ (DMSO-d₆): 8.61 (s, 1H), 8.12-8.06 (m, 1H),

solid
[M + H]⁺,

7.30-7.20 (m, 1H), 4.97 (s, 2H), 4.75-4.64 (m,

(2.674 min)

3H), 4.17-4.12 (m, 2H), 4.11 (s, 3H), 2.90-2.85

(m, 3H)

117
White
432.0
2
δ (DMSO-d₆): 8.56 (t, J = 6.4 Hz, 1H), 8.29 (d, J =

solid
[M + H]⁺,

8.0 Hz, 1H), 8.05 (d, J = 3.6 Hz, 1H), 7.94 (d, J =

(2.689 min)

8.0 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 5.10 (s,

2H), 4.51 (d, J = 6.4 Hz, 2H), 3.86 (s, 2H).

118
Light
432.1
2
δ (DMSO-d₆): 8.83 (d, J = 1.2 Hz, 1H), 8.65 (d, J =

yellow
[M + H]⁺,

2.0 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.06 (d, J =

solid
(2.590 min)

4.0 Hz, 1H), 7.16 (d, J = 4.0 Hz, 1H), 5.74-5.36

(m, 1H), 5.13 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H),

3.86 s, 2H)

119
Yellow
457.1
2
δ (DMSO-d₆): 9.53 (d, J = 2.4 Hz, 1H), 8.93 (d, J =

solid
[M + H]⁺,

1.6 Hz, 1H), 8.57 (t, J = 6.0 Hz, 1H), 8.12 (d, J =

(2.454 min)

4.0 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 5.58 (t, J =

5.8 Hz, 1H), 4.97 (s, 2H), 4.54 (d, J = 6.0 Hz,

2H), 3.88 (d, J = 6.0 Hz, 2H), 3.31 (s, 3H)

120
Light
518.1
2
δ (DMSO-d₆): 9.06 (t, J = 6.0 Hz, 1H), 8.11 (d, J =

yellow
[M + H]⁺,

4.0 Hz, 1H), 8.07-7.92 (m, 3H), 7.17 (d, J = 4.0

solid
(3.133 min)

Hz, 1H), 4.89 (s, 2H), 4.56 (d, J = 6.0 Hz, 2H),

2.65-2.59 (m, 1H), 2.45 (s, 3H), 2.01-1.80 (m,

2H)

121
Yellow
419.1
2
δ (MeOD): 8.93 (s, 1H), 8.01 (d, J = 3.6 Hz, 1H),

solid
[M + H]⁺,

7.23 (s, 1H), 7.20 (s, 1H), 4.85 (s, 2H), 4.66 (s,

(2.322 min)

2H), 4.05 (s, 3H), 4.03 (s, 2H), 2.48 (s, 3H)

δ (CDCl₃): 9.03 (s, 1H), 8.85 (d, J = 3.6 Hz, 1H),

7.16 (s, 1H), 7.10 (d, J = 3.6 Hz, 1H), 6.96 (s, 1H),

4.73 (d, J = 6.0 Hz, 2H), 4.67 (s, 2H), 4.22 (s, 2H),

4.06 (s, 3H), 2.60 (s, 3H)

122
Yellow
489.0
2
δ (DMSO-d₆): 9.53-9.36 (m, 1H), 9.36-9.30 (m,

solid
[M + H]⁺,

1H), 8.84 (dd, J = 8.3, 1.5 Hz, 1H), 8.11 (d, J =

(2.621 min)

3.8 Hz, 1H), 7.83-8.02 (m, 2H), 7.23 (d, J = 3.8

Hz, 1H), 5.03 (s, 2H), 4.46 (d, J = 6.3 Hz, 2H),

1.01-0.81 (m, 4H)

123
Light
531.0
2
δ (DMSO-d₆): 9.57-9.27 (m, 1H), 8.83 (br d, J =

yellow
[M + H]⁺,

8.4 Hz, 1H), 8.67 (br t, J = 6.0 Hz, 1H), 8.11 (d, J =

solid
(2.770 min)

3.6 Hz, 1H), 7.93 (dd, J = 8.4, 4.4 Hz, 1H), 7.23

(d, J = 3.6 Hz, 1H), 5.03 (s, 2H), 4.67-4.35 (m, 4H)

124
Light
407.1
2
δ (DMSO-d₆): 9.24 (d, J = 2.4 Hz, 1H), 8.55 (t, J =

yellow
[M + H]⁺,

6.4 Hz, 1H), 8.51-8.48 (m, 1H), 8.09 (d, J = 3.6

solid
(2.128 min)

Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 5.55 (t, J = 6.0

Hz, 1H), 4.90 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H),

3.86 (d, J = 6.0 Hz, 2H), 2.50 (s, 3H).

125
Light
490.1
2
δ (DMSO-d₆): 8.64 (s, 1H), 8.54 (t, J = 6.2 Hz,

yellow
[M + H]⁺,

1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 4.0 Hz,

solid
(2.564 min)

1H), 5.55 (t, J = 5.8 Hz, 1H), 4.98 (s, 2H), 4.61 (t,

J = 5.2 Hz, 2H), 4.51 (d, J = 6.2 Hz, 2H), 3.86 (d,

J = 5.8 Hz, 2H), 3.81 (t, J = 5.3 Hz, 2H), 3.17 (s,

3H)

126
Light
472.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

yellow
[M + H]⁺,

4.0 Hz, 1H), 8.05-7.95 (m, 3H), 7.14 (d, J = 4.0

solid
(2.774 min)

Hz, 1H), 5.56 (t, J = 5.6 Hz, 1H), 4.89 (s, 2H),

4.52 (d, J = 6.0 Hz, 2H), 3.87 (d, J = 6.0 Hz, 2H),

2.48-2.44 (m, 3H)

127
Yellow
477.1
2
δ (DMSO-d₆): 9.38 (q, J = 2.4 Hz, 1H), 8.83 (q, J =

solid
[M + H]⁺,

6.4 Hz, 1H), 8.10 (d, J = 4.0 Hz, 1H), 7.94-7.91

(2.552 min)

(m, 2H), 7.21 (d, J = 4.0 Hz, 1H), 5.02 (s, 1H),

4.41 (d, J = 6.4 Hz, 2H), 3.02-2.96 (m, 2H), 1.18

(d, J = 7.2 Hz, 2H).

128
Light
432.1
2
δ (DMSO-d₆): 8.34 (d, J = 8.4 Hz, 1H), 8.10 (d, J =

yellow
[M + H]⁺,

3.9 Hz, 1H), 7.79 (d, J = 9.3 Hz, 1H), 7.59 (dd,

solid
(2.548 min)

J = 9.1, 2.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.17

(d, J = 3.9 Hz, 1H), 5.48 (t, J = 5.9 Hz, 1H), 5.28

(quin, J = 7.3 Hz, 1H), 4.85 (s, 2H), 3.94 (s, 3H),

3.86 (d, J = 5.9 Hz, 2H), 2.42 (s, 3H), 1.53 (d, J =

7.2 Hz, 3H)

129
White
446.1
2
δ (DMSO-d₆): 9.07 (s, 1H), 8.42 (d, J = 0.8 Hz,

solid
[M + H]⁺,

1H), 8.37 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 4.0 Hz,

(2.670 min)

1H), 7.18 (d, J = 4.0 Hz, 1H), 5.49 (t, J = 5.2 Hz,

1H), 5.27 (t, J = 7.6 Hz, 1H), 5.12 (s, 3H), 3.86

(d, J = 4.4 Hz, 3H), 1.53 (d, J = 7.2 Hz, 4H)

130
Light
460.1
2
δ (DMSO-d₆): 8.61 (s, 1H), 8.34 (d, J = 8.4 Hz,

yellow
[M + H]⁺,

1H), 8.05 (d, J = 4.0 Hz, 1H), 7.16 (d, J = 4.0 Hz,

solid
(2.640 min)

1H), 5.47 (t, J = 6.0 Hz, 1H), 5.27 (t, J = 7.2 Hz,

1H), 4.99 (s, 2H), 4.07 (s, 3H), 3.86 (d, J = 6.0

Hz, 2H), 1.52 (d, J = 7.2 Hz, 3H)

131
Yellow
457.1
2
δ (DMSO-d₆): 9.40 (dd, J = 4.4, 1.6 Hz, 1H), 8.84

solid
[M + H]⁺,

(dd, J = 8.4, 1.6 Hz, 1H), 8.07-8.18 (m, 1H), 7.93

(2.367 min)

(dd, J = 8.4, 4.4 Hz, 1H), 7.17-7.30 (m, 1H), 5.02

(s, 2H), 4.72-4.80 (m, 2H), 4.68 (d, J = 7.6 Hz,

1H), 4.10-4.22 (m, 2H), 2.83-2.95 ppm (m, 3H)

132
Yellow
490.1
2
δ (DMSO-d₆): 9.09 (s, 1H), 8.56 (t, J = 6.4 Hz,

solid
[M + H]⁺,

1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 4.0 Hz,

(2.326 min)

1H), 5.57 (t, J = 5.8 Hz, 1H), 4.96 (s, 2H), 4.68 (t,

J = 5.2 Hz, 2H), 4.50 (d, J = 6.2 Hz, 2H), 3.82-

3.91 (m, 4H), 3.23 (s, 3H)

133
Light
472.3
2
δ (DMSO-d₆): 8.55-8.52 (m, 2H), 8.04 (d, J = 3.6

yellow
[M + H]⁺,

Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 5.55 (br t, J =

solid
(2.717 min)

5.6 Hz, 1H), 4.97 (s, 2H), 4.51 (br d, J = 6.0 Hz,

2H), 4.06-3.90 (m, 1H), 3.86 (br d, J = 5.6 Hz,

2H), 1.08-1.28 (m, 4H)

134
Light
500.1
2
δ (DMSO-d₆): 8.49 (s, 1H), 8.11-8.02 (m, 2H),

yellow
[M + H]⁺,

7.83-7.76 (m, 1H), 7.45 (s, 1H), 7.13-7.08 (m,

solid
(2.906 min)

1H), 5.43 (s, 1H), 4.96 (s, 2H), 4.47 (d, J = 6.0

Hz, 2H), 4.02 (s, 3H), 1.25 (s, 6H)

135
Yellow
459.9
2
δ (DMSO-d₆): 9.11 (s, 1H), 8.54 (t, J = 6.4 Hz,

solid
[M + H]⁺,

1H), 8.04 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 3.6 Hz,

(2.373 min)

1H), 5.55 (t, J = 5.6 Hz, 1H), 4.95 (s, 2H), 4.58-

4.44 (m, 5H), 3.86 (d, J = 5.6 Hz, 2H), 1.54 (t, J =

7.2 Hz, 3H)

136
Light
459.9
2
δ (DMSO-d₆): 8.62 (s, 1H), 8.55 (br t, J = 6.4 Hz,

yellow
[M + H]⁺,

1H), 8.05 (d, J = 4.0 Hz, 1H), 7.13 (d, J = 4.0 Hz,

solid
(2.700 min)

1H), 5.56 (t, J = 5.6 Hz, 1H), 4.98 (s, 2H), 4.58-

4.41 (m, 4H), 3.87 (d, J = 6.0 Hz, 2H), 1.44 (t, J =

7.2 Hz, 3H)

137
Light
444.1
2
δ (DMSO-d₆): 7.90 (d, J = 4.0 Hz, 1H), 7.78 (d, J =

yellow
[M + H]⁺,

9.2 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.25 (d, J =

solid
(2.631 min)

2.8 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 4.81 (s,

2H), 4.70 (s, 2H), 4.25 (s, 2H), 3.95 (s, 3H), 3.90

(t, J = 5.2 Hz, 2H), 3.44 (t, J = 4.8 Hz, 2H), 2.59

(s, 3H)

138
Yellow
469.1
2
δ (DMSO-d₆): 9.34 (d, J = 2.4 Hz, 1H), 8.60 (d, J =

solid
[M + H]⁺,

8.4 Hz, 1H), 7.89 (t, J = 4.0 Hz, 1H), 7.73-7.69

(2.438 min)

(m, 1H), 7.13 (d, J = 3.6 Hz, 1H), 4.81 (d, J = 10.0

Hz, 4H), 4.25 (s, 2H), 3.91 (t, J = 5.6 Hz, 2H),

3.44 (t, J = 5.2 Hz, 2H)

139
Light
454.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.4 Hz, 1H), 8.07 (d, J =

yellow
[M + H]⁺,

3.6 Hz, 1H), 8.02 (t, J = 9.2 Hz, 1H), 7.76-7.73

solid
(2.615 min)

(m, 1H), 7.40 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 3.6

Hz, 1H), 6.77 (t, J = 54.8 Hz, 1H), 5.56 (t, J = 5.6

Hz, 1H), 4.98 (s, 2H), 4.51 (d, J = 6.0 Hz, 2H),

4.01 (s, 3H), 3.86 (d, J = 5.6 Hz, 2H)

140
Yellow
418.9
2
δ (DMSO-d₆): 8.94 (d, J = 3.2 Hz, 1H), 8.55 (t, J =

solid
[M + H]⁺,

6.0 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.70 (d, J =

(2.137 min)

3.2 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 5.56 (t, J =

5.6 Hz, 1H), 4.89 (s, 2H), 4.52 (d, J = 6.0 Hz,

2H), 4.01 (s, 3H), 3.87 (d, J = 5.6 Hz, 2H), 2.46

(s, 4H)

141
Yellow
458.2
2
δ (DMSO-d₆): 8.12 (d, J = 4.0 Hz, 1H), 7.80 (d, J =

solid
[M + H]⁺,

9.2 Hz, 1H), 7.60-7.57 (m, 1H), 7.28 (d, J = 2.4

(2.567 min)

Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 5.52 (d, J = 5.6

Hz, 1H), 4.84 (s, 2H), 4.08-4.03 (m, 1H), 3.95 (s,

3H), 3.41-3.59 (m, 2H), 3.05-3.30 (m, 4H), 2.40

(s, 3H), 2.19-2.30 (m, 1H), 1.57-1.75 (m, 1H)

142
Yellow
440.1
2
δ (DMSO-d₆): 8.54 (t, J = 6.4 Hz, 1H), 8.09-8.06

solid
[M + H]⁺,

(m, 2H), 8.03-7.98 (m, 1H), 7.14 (d, J = 4.0 Hz,

(2.669 min)

1H), 5.55 (t, J = 6.0 Hz, 1H), 4.88 (s, 2H), 4.51

(d, J = 6.0 Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H), 2.45

(s, 3H).

143
Yellow
418.1
2
δ (DMSO-d₆): 8.53 (t, J = 6.4 Hz, 1H), 8.06 (d, J =

solid
[M + H]⁺,

3.6 Hz, 1H), 7.79 (t, J = 8.4 Hz, 1H), 7.35 (d, J =

(2.391 min)

8.0 Hz, 1H), 7.12 (t, J = 3.6 Hz, 2H), 5.56-5.53

(m, 1H), 4.57 (s, 2H), 4.51 (t, J = 6.4 Hz, 2H),

4.03 (s, 3H), 3.86 (s, 2H), 2.07 (s, 3H)

144
Yellow
432.1
2
δ (DMSO-d₆): 8.56 (t, J = 6.0 Hz, 1H), 8.10 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.59 (dd,

(2.621 min)

J = 9.2, 2.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.15

(d, J = 4.0 Hz, 1H), 5.57 (t, J = 6.0 Hz, 1H), 4.85

(s, 2H), 4.53 (d, J = 6.2 Hz, 2H), 4.23 (q, J = 6.8

Hz, 2H), 3.88 (d, J = 5.6 Hz, 2H), 2.42 (s, 3H),

1.43 (t, J = 6.8 Hz, 3H)

145
Light
433.1
2
δ (DMSO-d₆): 9.03 (s, 1H), 8.55 (s, 1H), 8.08 (d,

yellow
[M + H]⁺,

J = 3.6 Hz, 1H), 7.17 (s, 1H), 7.15 (t, J = 4.0 Hz,

solid
(2.524 min)

1H), 5.56 (t, J = 6.0 Hz, 1H), 4.87 (s, 2H), 4.51 (t,

J = 6.4 Hz, 2H), 4.45-4.40 (m, 2H), 3.86 (d, J =

6.5 Hz, 2H), 2.49 (s, 3H), 1.38 (t, J = 7.2 Hz, 3)

146
Light
440.0
2
δ (DMSO-d₆): 8.55 (t, J = 6.4 Hz, 1H), 8.12-8.03

yellow
[M + H]⁺,

(m, 2H), 7.72 (dd, J = 8.8, 1.1 Hz, 1H), 7.14 (d, J =

solid
(2.672 min)

3.6 Hz, 1H), 5.56 (t, J = 6.0 Hz, 1H), 4.78 (s,

2H), 4.52 (d, J = 6.0 Hz, 2H), 3.87 (d, J = 6.0 Hz,

2H), 3.31-3.29 (m, 2H), 2.34 (s, 3H)

147
Yellow
499.2
2
δ (DMSO-d₆): 8.54 (s, 1H), 8.07 (d, J = 4.0 Hz,

solid
[M + H]⁺,

1H), 7.68 (d, J = 4.0 Hz, 1H), 7.69-7.55 (m, 1H),

(2.468 min)

7.13 (d, J = 3.6 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H),

5.55 (t, J = 6.0 Hz, 1H), 4.79 (s, 2H), 4.51 (d, J =

6.4 Hz, 2H), 4.21 (s, 1H), 4.07-4.00 (m, 3H), 3.86

(d, J = 6.0 Hz, 2H), 3.76 (d, J = 10.4 Hz, 1H), 3.45

(d, J = 10.8 Hz, 1H), 2.37 (s, 3H), 2.15-2.00 (m,

1H), 1.98-1.94 (m, 2H), 1.78-1.60 (m, 1H)

148
Light
486.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

yellow
[M + H]⁺,

4.0 Hz, 1H), 7.87 (s, 1H), 7.56 (s, 1H), 7.14 (d,

solid
(2.692 min)

J = 3.6 Hz, 1H), 5.56 (t, J = 5.6 Hz, 1H), 4.89 (s,

2H), 4.52 (d, J = 6.4 Hz, 2H), 4.04 (s, 3H), 3.87

(d, J = 6.0 Hz, 2H), 2.47-2.48 (m, 3H)

149
Yellow
431.9
2
δ (DMSO-d₆): 8.92 (s, 1H), 8.53 (d, J = 6.4 Hz,

solid
[M + H]⁺,

1H), 8.07 (d, J = 4.0 Hz, 1H), 7.12 (d, J = 4.0 Hz,

(2.443 min)

1H), 5.55 (t, J = 6.0 Hz, 1H), 4.83 (s, 2H), 4.51

(d, J = 6.0 Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H), 3.17

(s, 6H), 2.32 (s, 3H).

150
Light
499.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.09 (d, J =

yellow
[M + H]⁺,

3.6 Hz, 1H), 7.69 (s, 1H), 7.21 (s, 1H), 7.14 (d,

solid
(3.066 min)

J = 3.6 Hz, 1H), 5.56 (t, J = 5.6 Hz, 1H), 4.86 (s,

2H), 4.52 (d, J = 6.4 Hz, 2H), 3.87 (d, J = 5.6 Hz,

2H), 3.14 (s, 6H), 2.47 (s, 3H)

151
Light
485.1
2
δ (DMSO-d₆): 8.55 (t, J = 6.4 Hz, 1H), 8.08 (d, J =

yellow
[M + H]⁺,

4.0 Hz, 1H), 7.33 (s, 1H), 7.14 (d, J = 3.6 Hz,

solid
(3.086 min)

1H), 6.99 (q, J = 4.8 Hz, 1H), 6.80 (d, J = 1.2 Hz,

1H), 5.57 (s, 1H), 4.86 (s, 2H), 4.51 (d, J = 6.4

Hz, 2H), 3.87 (s, 2H), 2.91 (d, J = 5.2 Hz, 3H),

2.60-2.41 (m, 16H)

152
White
443.1
2
δ (DMSO-d₆): 9.19 (dd, J = 4.4, 1.6 Hz, 1H), 8.51-

solid
[M + H]⁺,

8.62 (m, 2H), 8.16 (dd, J = 8.4, 4.4 Hz, 1H), 8.06

(2.451 min)

(d, J = 4.0 Hz, 1H), 7.13 (d, J = 4.0 Hz, 1H), 5.55

(t, J = 5.6 Hz, 1H), 4.89 (s, 2H), 4.51 (d, J = 6.0

Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H)

153
White
389.0
2
δ (DMSO-d₆): 8.96 (dd, J = 4.0, 1.6 Hz, 1H), 8.54

solid
[M + H]⁺,

(t, J = 6.4 Hz, 1H), 8.27 (dd, J = 8.4, 1.6 Hz, 1H),

(2.084 min)

8.08 (d, J = 3.6 Hz, 1H), 7.97 (dd, J = 8.4, 4.0 Hz,

1H), 7.14 (d, J = 3.6 Hz, 1H), 5.56 (t, J = 5.6 Hz,

1H), 4.77 (s, 2H), 4.51 (d, J = 6.4 Hz, 2H), 3.87

(d, J = 6.0 Hz, 2H), 2.49-2.48 (m, 4H)

154
Light
473.1
2
δ (DMSO-d₆): 9.33 (s, 1H), 8.55 (t, J = 6.4 Hz,

yellow
[M + H]]⁺,

1H), 8.06 (d, J = 4.0 Hz, 1H), 7.40 (s, 1H), 7.13

solid
(2.700 min)

(d, J = 4.0 Hz, 1H), 5.56 (t, J = 5.6 Hz, 1H), 4.99

(s, 3H), 4.51 (d, J = 6.0 Hz, 3H), 4.07 (s, 4H), 3.87

(d, J = 6.0 Hz, 3H)

155
Yellow
453.0
2
δ (DMSO-d₆): 9.39 (dd, J = 4.4, 1.6 Hz, 1H), 8.83

solid
[M + H]⁺,

(dd, J = 8.4, 1.6 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H),

(1.500 min)

7.92 (dd, J = 8.4, 4.4 Hz, 1H), 7.21 (d, J = 3.6 Hz,

1H), 5.01 (s, 2H), 4.62 (s, 2H), 2.28 (t, J = 8.0 Hz,

2H), 2.05-1.81 (m, 2H)

156
Yellow
469.1
2
δ (DMSO-d₆): 9.34-9.45 (m, 1H), 8.84 (dd, J =

solid
[M + H]⁺,

8.4, 1.2 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.93

(2.329 min)

(dd, J = 8.4, 4.4 Hz, 1H), 7.21 (d, J = 3.6 Hz, 1H),

5.63 (d, J = 5.6 Hz, 1H), 5.02 (s, 2H), 4.64 (s, 2H),

4.08-4.24 (m, 1H), 3.15-3.27 (m, 2H), 2.23-2.33

(m, 1H), 1.77-1.69 (m, 1H)

157
Yellow
453.0
2
δ (DMSO-d₆): 9.39 (dd, J = 4.4, 1.6 Hz, 1H), 8.83

solid
[M + H]⁺,

(dd, J = 8.4, 1.6 Hz, 1H), 8.11 (d, J = 3.6 Hz, 1H),

(1.500 min)

7.92 (dd, J = 8.4, 4.4 Hz, 1H), 7.21 (d, J = 3.6 Hz,

1H), 5.01 (s, 2H), 4.62 (s, 2H), 2.28 (t, J = 8.0 Hz,

2H), 2.05-1.81 (m, 2H)

158
Yellow
436.1
2
δ (CD₃CN): 7.97-7.87 (m, 1H), 7.79-7.72 (m,

solid
[M + H]⁺,

1H), 7.68-7.63 (m, 1H), 7.61-7.50 (m, 1H), 7.11

(2.450 min)

(d, J = 4.0 Hz, 1H), 4.62 (s, 4H), 4.00 (s, 3H), 3.96

(d, J = 6.0 Hz, 2H), 3.56 (t, J = 6.0 Hz, 1H), 2.35

(s, 3H)

159
Yellow
487.1
2
δ (DMSO-d₆): 9.34 (s, 1H), 8.10 (d, J = 3.8 Hz,

solid
[M + H]⁺,

1H), 7.41 (s, 1H), 7.22 (d, J = 3.8 Hz, 1H), 4.99

(2.814 min)

(s, 2H), 4.71-4.80 (m, 3H), 4.67 (t, J = 5.6 Hz,

1H), 4.13 (d, J = 5.6 Hz, 2H), 4.08 (s, 3H), 2.91

(s, 3H)

160
Light
433.1
2
δ (DMSO-d₆): 8.93 (d, J = 3.2 Hz, 1H), 8.55 (t, J =

yellow
[M + H]⁺,

6.0 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.68 (d, J =

solid
(2.305 min)

3.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 5.56 (t, J =

5.6 Hz, 1H), 4.88 (s, 2H), 4.51 (d, J = 6.4 Hz,

2H), 4.29 (q, J = 7.2 Hz, 2H), 3.87 (d, J = 5.6 Hz,

2H), 2.46 (s, 4H), 1.43 (t, J = 6.8 Hz, 3H)

161
Yellow
445.1
2
δ (DMSO-d₆): 8.95 (d, J = 3.2 Hz, 1H), 8.14 (d, J =

solid
[M + H]⁺,

3.6 Hz, 1H), 7.71 (d, J = 3.2 Hz, 1H), 7.26 (d, J =

(2.305 min)

4.0 Hz, 1H), 4.90 (s, 2H), 4.77 (s, 2H), 4.11 (s,

3H), 4.02 (s, 3H), 3.92-3.75 (m, 3H), 3.42-3.35

(m, 3H), 2.47-2.41 (m, 5H)

162
Yellow
433.1
2
δ (DMSO-d₆): 8.94 (d, J = 3.2 Hz, 1H), 8.12 (d, J =

solid
[M + H]⁺,

3.6 Hz, 1H), 7.70 (d, J = 3.2 Hz, 1H), 7.22 (d, J =

(2.264 min)

3.6 Hz, 1H), 4.89 (s, 2H), 4.60-4.79 (m, 3H),

4.07-4.19 (m, 2H), 4.01 (s, 3H), 2.86-2.95 (m,

3H), 2.44 (s, 3H)

163
White
431.1
2
δ (DMSO-d₆): 8.94 (d, J = 3.2 Hz, 1H), 8.62 (t, J =

solid
[M − H]⁻,

6.0 Hz, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.70 (d, J =

(2.363 min)

3.2 Hz, 1H), 7.15 (d, J = 3.6 Hz, 1H), 4.89 (s,

2H), 4.52 (d, J = 6.0 Hz, 3H), 4.01 (s, 4H), 3.87

(s, 3H), 3.31-3.30 (m, 3H), 2.46 (s, 3H)

164
Yellow
455.1
2
δ (DMSO-d₆): 9.11 (d, J = 3.2 Hz, 1H), 8.57 (t, J =

solid
[M + H]⁺,

6.4 Hz, 1H), 8.08 (d, J = 3.8 Hz, 1H), 7.83 (d, J =

(2.286 min)

3.2 Hz, 1H), 7.14 (d, J = 4.0 Hz, 1H), 6.66-7.00

(m, 1H), 5.58 (t, J = 5.8 Hz, 1H), 5.03 (s, 2H),

4.52 (d, J = 6.2 Hz, 2H), 4.08 (s, 3H), 3.87 (d, J =

6.0 Hz, 2H)

165
Light
374.1
2
δ (DMSO-d₆): 9.00 (dd, J = 4.0, 1.6 Hz, 1H), 8.54

yellow
[M + H]⁺,

(t, J = 6.0 Hz, 1H), 8.41 (dd, J = 8.4, 1.6 Hz, 1H),

solid
(2.267 min)

8.28 (d, J = 5.6 Hz, 1H), 8.03 (d, J = 3.8 Hz, 1H),

7.83 (dd, J = 8.4, 4.4 Hz, 1H), 7.58 (d, J = 5.6 Hz,

1H), 7.11 (d, J = 4.0 Hz, 1H), 5.56 (t, J = 5.6 Hz,

1H), 4.76 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 3.86

(d, J = 5.6 Hz, 2H)

166
Yellow
397.0
6
¹H NMR (DMSO-d₆, 400 MHz) 8 13.30 (br s, 1H),

solid
[M + H]⁺,

8.56 (brt, 1H, J = 6.3 Hz), 8.20 (d, 1H, J = 1.8 Hz), 7.9-

(2.310 min)

8.0 (m, 2H), 7.12 (d, 1H, J = 3.7 Hz), 5.57 (t, 1H, J = 5.7

Hz), 4.95 (s, 2H), 4.49 (d, 2H, J = 6.2 Hz), 3.85 (d, 2H,

J = 5.7 Hz), 2.07 (s, 1H)

167
Brown
393.0
6
N/A

solid
[M + H]⁺,

(2.692 min)

168
Yellow
393.0
6
N/A

solid
[M + H]⁺,

(2.706 min)

169
White
376.1
6
N/A

solid
[M + H]⁺,

(2.206 min)

170
Yellow
377.0
6
N/A

solid
[M + H]⁺,

(2.815 min)

171
Yellow
458.1
2
δ (DMSO-d₆): 8.68-8.55 (m, 1H), 8.09 (d, J = 3.6

solid
[M + H]⁺,

Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2

(2.674 min)

Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.12 (d, J = 3.6

Hz, 1H), 4.84 (s, 2H), 4.35-4.59 (m, 2H), 4.26 (d,

J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.93-3.86 (m, 1H),

3.83-3.65 (m, 1H), 2.40 (s, 3H), 2.19-2.02 (m,

1H), 1.95-1.63 (m, 3H)

172
Yellow
438.1
2
δ (DMSO-d₆): 9.57 (t, J = 5.6 Hz, 1H), 8.12 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.59 (dd,

(2.741 min)

J = 9.1, 2.8 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.19

(d, J = 3.9 Hz, 1H), 6.12-6.47 (m, 1H), 4.85 (s,

2H), 4.58 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.39

ppm (s, 3H)

173
Brown
393.1
6
N/A

solid
[M + H]⁺,

(2.153 min)

174
Yellow
397.0
6
N/A

solid
[M + H]+

(2.772 min)

176
Light
362.9
2
δ (DMSO-d₆): 8.55 (t, J = 6.0 Hz, 1H), 8.34 (d, J =

yellow
[M + H]⁺,

4.8 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 8.02 (d, J =

solid
(1.928 min)

4.0 Hz, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.63 (d, J =

4.8 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 5.56 (s,

1H), 4.82 (s, 2H), 4.55 (d, J = 3.2 Hz, 2H), 3.86

(s, 2H).

177
Yellow
417.0
2
δ (DMSO-d₆): 8.65-8.50 (m, 1H), 8.09 (d, J = 4.0

solid
[M + H]⁺,

Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.59 (d, J = 9.2

(2.369 min)

Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.15 (d, J = 4.0

Hz, 1H), 4.84 (s, 2H), 4.52 (s, 2H), 3.94 (s, 3H),

3.14 (s, 2H), 2.41 (s, 3H)

178
Yellow
457.0
2
δ (DMSO-d₆): 8.60 (d, J = 9.2 Hz, 1H), 8.09(d, J =

solid
[M + H]]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.603-

(2.512 min)

7.537 (m, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.126 (s,

1H), 4.84 (s, 2H), 4.48 (d, J = 6.4 Hz, 2H), 3.944

(s, 3H), 3.33(s, 3H), 3.09(d, J = 6.4 Hz, 3H),

2.399 (s, 3H), 2.216 (s, 3H).

179
Yellow
373.9
2
δ (DMSO-d₆): 9.16-9.14 (m, 1H), 8.63 (d, J = 8.0

solid
[M + H]⁺,

Hz, 1H), 8.55 (t, J = 6.2 Hz, 1H), 8.43 (d, J = 6.0

(2.209 min)

Hz, 1H), 8.05 (d, J = 3.9 Hz, 1H), 7.73-7.70 (m,

1H), 7.61 (d, J = 6.0 Hz, 1H), 7.13 (d, J = 4.0 Hz,

1H), 5.57 (t, J = 5.6 Hz, 1H), 4.92 (s, 2H), 4.51

(d, J = 6.0 Hz, 2H), 3.87 (d, J = 6.0 Hz, 2H)

180
Yellow
406.1
2
δ (DMSO-d₆): 9.58 (s, 1H), 8.79 (d, J = 5.6 Hz,

solid
[M + H]⁺,

1H), 8.548 (t, J = 6.4 Hz, 1H), 8.40 (d, J = 5.6 Hz,

(2.477 min)

1H), 8.05 (d, J = 3.6 Hz, 1H), 7.87 (d, J = 5.6 Hz,

1H), 7.57 (d, J = 5.6 Hz, 1H), 7.12 (d, J = 4.0 Hz,

1H), 5.563 (t, J = 5.6 Hz, 1H), 4.93 (s, 2H), 4.50

(d, J = 6.4 Hz, 2H), 3.87 (d, J = 6.0 Hz, 2H).

181
Yellow
362.9
2
δ (DMSO-d₆): 8.54 (s, 2H), 8.12 (d, J = 4.8 Hz,

solid
[M + H]⁺,

1H), 8.00 (d, J = 4.0 Hz, 1H), 7.79 (s, 1H), 7.33

(2.000 min)

(d, J = 4.8, 1H), 7.11 (d, J = 4.0, 1H), 5.56 (s, 1H),

4.85 (s, 2H), 4.49 (d, J = 6.4, 2H), 3.86 (d, J = 5.2,

2H)

182
Yellow
362.9
2
δ (DMSO-d₆): 8.53 (t, J = 6.0 Hz, 2H), 8.14 (d, J =

solid
[M + H]⁺,

2.4 Hz, 1H), 8.02 (d, J = 3.6 Hz, 1H), 7.66 (d, J =

(2.215 min)

4.4 Hz, 1H), 7.12 (d, J = 4.0 Hz, 1H), 6.99 (d, J =

1.6 Hz, 1H), 5.56 (s, 1H), 4.90 (s, 2H), 4.50 (d,

J = 6.4 Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H)

183
Yellow
431.1
2
δ (DMSO-d₆): 8.55 (d, J = 6.0 Hz, 1H), 8.09 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.59 (d, J =

(2.452 min)

9.2 Hz, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.14 (d, J =

4.0 Hz, 1H), 6.08 (s, 1H), 4.84 (s, 2H), 4.52 (d,

J = 4.8 Hz, 2H), 3.94 (s, 3H), 3.09 (s, 2H), 2.40

(s, 3H), 2.25 (s, 3H)

184
Light
229.0
2
δ (DMSO-d₆): 8.06 (d, J = 3.2 Hz, 1H), 7.70-7.80

yellow
[M + H]⁺,

(m, 1H), 7.51-7.60 (m, 1H), 7.18-7.27 (m, 1H),

solid
(2.482 min)

7.10 (s, 1H), 4.81 (s, 2H), 4.45 (s, 2H), 3.91 (s,

3H), 3.48-3.56 (m, 1H), 2.67-2.88 (m, 2H), 2.36

(d, J = 1.6 Hz, 3H), 1.75-2.08 (m, 2H), 1.55-1.73

(m, 2H)

185
Light
432.0
2
δ (DMSO-d₆): 8.543-8.511 (m, 1H), 8.09 (d, J =

yellow
[M + H]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.60-7.57

solid
(2.513 min)

(m, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 3.6

Hz, 1H), 5.59 (d, J = 5.2 Hz, 1H), 4.84 (s, 2H),

4.48 (d, J = 6.0 Hz, 2H), 4.03-4.0 (m, 1H), 3.94

(s, 3H), 2.45 (s, 3H), 1.22 (d, J = 6.4 Hz, 3H).

186
White
432.0
2
δ (DMSO-d₆): 8.546-8.512 (m, 1H), 8.09 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.79 (d, J = 9.2 Hz, 1H), 7.60-7.57

(2.514 min)

(m, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.12 (d, J = 3.6

Hz, 1H), 5.59 (d, J = 5.2 Hz, 1H), 4.84 (s, 2H),

4.48 (d, J = 6.0 Hz, 2H), 4.03-4.0 (m, 1H), 3.94

(s, 3H), 2.45 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H).

189
Light
431.1
2
δ (DMSO-d₆): 8.08 (d, J = 4.0 Hz, 1H), 7.80 (d, J =

yellow
[M + H]⁺,

9.2 Hz, 1H), 7.60 (d, J = 9.2, Hz, 1H), 7.28 (d,

solid
(2.598 min)

J = 2.8 Hz, 1H), 7.08-7.16 (m, 2H), 4.85 (s, 2H),

4.43 (d, J = 6.0 Hz, 2H), 3.95 (s, 3H), 2.82 (s, 6H),

2.43 (s, 3H)

190
Yellow
461.2
2
δ (CDCl₃): δ = 8.91 (d, J = 3.2 Hz, 1H), 7.86 (d, J =

solid
[M + H]⁺,

4.0 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.06 (d, J =

(2.835 min)

4.0 Hz, 1H), 5.05 (s, 1H), 4.75 (s, 2H), 4.54 (d,

J = 5.6 Hz, 2H), 3.99 (s, 3H), 2.68 (s, 3H), 1.48

(s, 9H)

191
White
467.19
5
1H NMR [400 MHz, DMSO-d6]: δ1.11 (s, 9H),

solid
[M + H]⁺,

4.46 (d, J = 6.0 Hz, 2H), 4.85 (s, 2H), 7.07 (d, J =

(4.23 min)

4.0 Hz, 1H), 7.88-7.99 (m, 2H), 8.04 (d, J = 4.0

Hz, 1H), 8.16-8.34 (m, 4H).

192
Yellow
420.23
1
1H NMR [400 MHz, DMSO-d6]: δ1.11 (s, 9H),

solid
[M + H]⁺,

4.02 (s, 3H), 4.71 (d, J = 5.6 Hz, 2H), 5.15 (s, 2H),

(14.76 min).

8.43 (s, 1H), 8.60 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H).

193
Off-
400.28
4
1H NMR [400 MHz, DMSO-d6]: δ1.13 (s, 9H),

white
[M + H]⁺,

4.46 (d, J = 5.6 Hz, 2H), 5.00 (s, 2H), 7.11 (d, J =

solid
(14.66 min)

3.6 Hz, 1H), 8.04-8.20 (m, 5H), 8.34 (t, J = 6.0

Hz, 1H), 9.42 (s, 1H).

194
Off-
414.28
4
1H NMR [400 MHz, DMSO-d6]: δ1.12 (s, 9H),

white
[M + H]⁺,

2.81(s, 3H), 4.46 (d, J = 5.6 Hz, 2H), 4.94 (s, 2H),

solid
(14.38 min)

7.10 (d, J = 3.6 Hz, 1H), 8.02-8.23 (m, 5H), 8.34

(t, J = 6.0 Hz, 1H).

195
Off-
468.29
4
1H NMR [400 MHz, DMSO-d6]: δ1.12 (s, 9H),

white
[M + H]⁺,

4.47 (d, J = 6.0 Hz, 2H), 5.09 (s, 2H), 7.13 (d, J =

solid
(17.36 min)

4.0 Hz, 1H), 8.23 (bs, 3H), 8.34 (t, J = 6.0 Hz,

1H), 8.43 (t, J = 4.4 Hz, 1H).

196
Light
430.9
2
δ (DMSO-d₆): 7.98 (d, J = 4.0 Hz, 1H), 7.77 (d, J =

yellow
[M + H]⁺,

8.4 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.43 (t, J =

solid
(2.440 min)

8.0 Hz, 1H), 7.14 (d, J = 3.6 Hz, 1H), 4.94 (s,

2H), 4.65 (s, 2H), 4.03 (s, 2H)

Example 2: Cellular Target Engagement Assay—NanoBRET
Materials and Methods

NanoBRET target engagement was performed against the catalytic domain 2 (CD2) of HDAC6, with minor modifications of kit manufacturer protocol (Promega). Expression of exogenous NanoLuc-HDAC6(CD2) fusion and in HEK293T was achieved following transient transfection with FuGENE HD Transfection Reagent (Promega). The intracellular target engagement assay on HDAC6(CD2) was performed in a 384-well plate format with 8,000 cells per well and a tracer concentration of 0.125 μM or 0.600 μM for HDAC6(CD2). Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were added either manually by diluting them in culture medium at 8× final assay concentration and then adding 5 μL to assay plate or in an automated way by adding 160 nL compound to 5 μL OptiMEM without phenol red (Gibco) using the Echo650 (Labcyte). Tracer solution was added to the cells before seeding 35 μL cell/tracer mixture in the assay plate. The final reaction volume was 40 μL, final DMSO concentration was 1.4% (manual compound addition) or 1.25% (automated compound addition). Assay plates were incubated at 37° C. in a humidified atmosphere containing 5% CO₂for 2 hours. The NanoBRET Nano-glo Substrate/Inhibitor was prepared by diluting NanoBRET Nano-Glo Substrate (1:332) and Extracellular Inhibitor (1:1000) in assay medium (Promega). The NanoBRET TE Nano-glo Substrate/Inhibitor was added to cells and measurement of NanoBRET donor and acceptor signal (460-80 and 647-75, respectively) was performed at room temperature with either the EnVision Xcite (PerkinElmer) or the CLARIOstar (BMG Labtech) plate reader 1-2 minutes after NanoLuc substrate addition. BRET ratios were calculated from acceptor/donor signal ratio (mBRET=acceptor/donor*1000) and normalized for each plate. Percentage inhibition was calculated by setting the mBRET obtained with cells without tracer to 100%, while the mBRET obtained with uninhibited cells with tracer was set to 0%. IC50-values were calculated from the percentage inhibition with the log(inhibitor) vs. response—Variable slope (four parameters) nonlinear regression in GraphPad Prism software.

Results

The results of this assays are presented on Table 5 below, wherein “+” means: 1000 nM<IC₅₀≤10000 nM, “++” means: 500 nM<IC₅₀≤1000 nM, “+++” means: 100 nM<IC₅₀≤500 nM and “++++” means: IC₅₀≤100 nM.

TABLE 5

IC₅₀

Cpd #
(HDAC6(CD2) interaction)

1
+++

2
+++

3
++++

4
++

5
++

6
+++

7
++++

8
+++

9
+++

10
+++

11
+++

12
+++

13
+++

14
+++

15
+++

16
+++

17
+++

18
+++

19
+++

20
+++

21
++

22
++++

23
+++

24
+++

25
+++

26
+++

27
+++

28
++

29
+++

30
++++

31
+

33
+++

34
+++

35
+++

36
++++

37
+

38
++++

39
++

40
+

41
++++

42
++

43
+++

44
+++

45
++++

46
++++

47
+++

48
++++

49
++++

50
+++

51
+++

52
++

55
++

56
++++

57
+++

58
+

59
+++

60
++++

61
++++

62
++++

63
+++

64
++++

65
++

66
++++

67
+++

68
+++

69
+++

70
+++

71
++++

72
++++

73
++++

74
++++

75
+++

76
++++

77
++++

78
++++

79
++++

80
++++

81
++++

82
++++

83
++++

84
++++

85
++++

86
+

87
+++

88
+

89
+

90
+

91
+++

92
+++

93
+++

94
+++

95
+++

96
++

97
+++

98
++++

99
++++

100
+++

101
+++

102
+++

103
++

104
+++

105
+

106
++++

107
+++

108
+++

109
++

110
+++

111
+++

112
++++

113
++++

114
++++

115
++

116
+++

117
++++

118
++++

119
++++

120
+++

121
++++

122
++++

123
++++

124
++++

125
++++

126
++++

127
++++

128
+++

129
++++

130
+++

131
++++

132
++++

133
++++

134
+++

135
++++

136
++++

137
+++

138
++++

139
+++

140
++++

141
+++

142
++++

143
+++

144
++++

145
++++

146
++++

147
++++

148
++++

149
++++

150
++++

151
+++

152
++++

153
++++

154
++++

155
++++

156
++++

157
++++

158
++++

159
++++

160
++++

161
+++

162
+++

163
++++

164
++++

165
+++

166
+

167
+

168
+

169
+

170
+

171
+++

172
+++

173
+

174
+

176
+

177
+++

178
++++

179
+++

180
+++

181
+++

182
+

183
+++

184
+++

185
++++

186
+++

189
+++

190
+++

193
+++

194
+++

196
+

The results clearly evidence that the compounds of formula (I), effectively inhibit the interaction between HDAC6 catalytic domain 2 and its substrate, thereby inhibiting its deacetylation activity. Thus, this assay shows that the compounds of formula (I) may be used in the treatment and/or prevention of HDAC6-associated diseases.

Example 3: Acetylated α-Tubulin Measurement In Vitro
Materials and Methods

HeLa cells were cultured in UltraCulture serum-free medium (Lonza) supplemented with 2 mM glutamine (Lonza). Assays were performed at 96-well or 384-well format, differences in assay protocols are detailed in Table 6. Cells per well were plated and incubated overnight at 37° C. overnight in a humidified atmosphere containing 5% CO₂. Cell density and seeding volumes are detailed in Table 6. Compounds (dissolved in 100% DMSO) or DMSO (vehicle) were added manually by diluting them in culture medium at 10× final assay concentration and adding 10 μL to cells (96-well protocol). Alternatively, 50 nL compound was added directly to the cell culture using the Echo650 (Labcyte) (384-well protocol). In this assay, the final assay concentration of DMSO is 0.1%-0.4%. Trichostatin A (TSA) was used as a positive control. Cells were incubated with compounds at 37° C. in a humidified atmosphere containing 5% CO₂for 6 hours. Levels of acetylated tubulin (Lys40) were assessed by immunocytochemistry using target-specific antibodies. Cells were fixed with 4% PFA at RT as detailed in Table 6. After 2-3 wash steps with PBS, cells were permeabilized with 0.5% Triton in PBS at RT for 10 minutes followed by 1-2 washes with PBS. To avoid non-specific antibody staining, cells were blocked with 3% BSA in PBS at room temperature for 1 hour. Then, cells were incubated for 1 h at RT with 1:3000 anti-acetylated tubulin (mouse monoclonal antibody, acetylated tubulin Lys40, clone 6-11B, Sigma) and 1:1000 anti-α-tubulin (rabbit monoclonal, abcam) diluted in 1% BSA. Cells were washed 2-3 times with PBS and labelled for 1 h at RT with goat anti-mouse conjugated with Alexa 647 (Thermofisher) and goat anti-rabbit conjugated with Alexa 555 (Thermofisher) secondary antibodies, diluted in 1% BSA to a final concentration of 1:1000. Simultaneously, nuclei were stained with 1:10000-1:15000 Hoechst (Thermofisher). Incubation time and temperature of the primary antibodies are detailed in Table 6. Cells were washed 2-3 times with PBS and they were imaged with the Operetta CLS or Opera Phenix (PerkinElmer). Imaging is further detailed in Table 6. For imaging analysis, the Harmony analysis software (PerkinElmer) was used. Cytoplasmic (defined by total α-tubulin staining) intensities per well were used for α-tubulin (acetylated and total) quantification. Intensities were measured per cell and then averaged per well. Mean intensity levels of acetylated tubulin were normalized to the mean intensity levels of total tubulin. The changes in acetylated tubulin were normalized for each plate using GraphPad Prism software: tubulin acetylation in vehicle (DMSO)-treated cells were set to 0% while tubulin acetylation in TSA-treated cells were set to 100%. EC50 values were calculated using the log(inhibitor) vs. response—Variable slope (four parameters) nonlinear regression in GraphPad Prism software.

TABLE 6

Protocol 1
Protocol 2

Plate format
96-well
384-well

#cells/well
5000
2000

Cell seeding
90 μL
50 μL

volume

Fixation
1-step
2-step

10% PFA added
4% PFA added directly to

directly to the
the medium in 1:1 ratio, 10

medium, 15 min
min at RT

at RT
4% PFA added directly to

the cells, 10 min at RT

Antibody
α-tubulin (acetylated
α-tubulin (acetylated

incubation
& total): ON, 4° C.
& total): 1 h, RT

Imaging
Operetta CLS
Opera Phenix

40x water
10x objective and spinning

NA1.1 objective
disc confocality

16 fields
1 field, 3 focal planes,

maximal intensity projection

Results

The results of this assay are presented on Table 7 below, wherein “+” means: 1000 nM<IC₅₀≤3333 nM, “C++” means: 500 nM<IC₅₀≤1000 nM, “+++” means: 100 nM<IC₅₀≤500 nM, “++++” means: IC₅₀≤100 nM, and “−” means: IC₅₀>3333 nM.

TABLE 7

Cpd #
IC₅₀(Tubulin deacetylation)

5
−

7
+++

8
−

9
+

10
+

12
+

16
+

17
++

18
+

19
+

20
+++

21
+

22
+++

23
++

25
−

27
+

28
+

30
+

31
+

34
+

36
−

38
++

39
++

40
++

41
+

43
+++

44
+++

45
++++

46
+++

47
+++

48
+++

49
+++

50
+++

51
+

59
+++

60
+++

61
++++

62
+++

63
+++

64
++++

65
+

66
+++

67
+++

68
+++

69
+++

70
+++

71
++++

72
++++

73
+++

74
+++

75
+++

76
++++

77
+++

78
+++

79
++++

80
+++

81
+++

82
++++

83
++++

84
++++

85
++++

86
+

87
+

91
−

95
++

97
+

98
+

106
+++

107
+++

108
+++

109
+++

110
++++

111
+++

112
+++

113
++++

114
++++

115
++

116
+++

117
++++

118
+++

119
++++

120
+++

121
++++

122
+++

123
+++

124
++++

125
++++

126
++++

127
+++

128
+++

129
+++

130
+++

131
+++

132
++++

133
+++

134
+++

135
++++

136
+++

137
+++

138
+++

139
+++

140
+++

141
+++

142
++++

143
+++

144
++++

145
++++

146
+++

147
++++

148
++++

149
++++

150
+++

151
+

152
++++

153
++++

154
++++

155
++++

156
++++

157
++++

158
+++

159
++++

160
++++

161
+++

162
+++

163
+++

164
++++

171
+++

172
+++

177
++++

178
++++

179
++++

180
+++

181
+++

182
++

183
+++

184
+++

185
++++

186
++++

189
+++

190
+++

194
++

The results clearly evidence that the compounds of formula (I), increase acetylated α-tubulin over total α-tubulin ratio in HeLa cells, indicating HDAC6 inhibition, HDAC6 being the only HDAC enzyme enabling α-tubulin deacetylation. Thus, this assay shows that the compounds of formula (I) may be used in the treatment and/or prevention of HDAC6-associated diseases.

Example 4: HDAC6 Enzymatic Activity Assay
Materials and Methods

Dose response testing of HDAC6 and HDAC 1 were run at Reaction Biology Corporation (RBC). Inhibition of HDAC enzymes was performed using N-terminal GST tagged human full-length recombinant HDAC6 (H88-30G, SignalChem) and C-terminal FLAG His tag human full-length recombinant HDAC1 produced in insect cells (KDA-21-365, RBC). Enzyme reactions were run in 50 mM Tris-HCl, pH8.0, 137 mM NaCl, 2.7 mM KCl, and 1 mM MgCl2 with 1 mg/ml BSA, 1% DMSO freshly added. 2× enzyme was delivered in the wells of the reaction plate except for the “no enzyme” control wells. In the latter, buffer was added. Compounds in 100% DMSO were delved into the enzyme mixture by acoustic technology (Echo550). Plates are spun down and compounds were incubation with the enzyme for 10 min at room temperature. 2× Fluorogenic peptide from p53 residues 379-382 (RHKKAc, 10 μM final concentration) was added in all wells to initiate the reaction, followed by 1 h incubation at 30° C. Developer containing Trichostatin A was added to stop the reaction and generate fluorescent color. A kinetic measurement was carried out for 20 min with 5 min interval on the Envision plate reader (Perkin Elmer, Ex/Em=360/460). End point reading i.e., plateau of the development reaction was used for analysis. Data was reported by RBC as percentage enzyme activity. Percentage inhibition was calculated by subtracting percentage enzyme activity from 100. IC50 values were calculated using GraphPad Prism 9 based on the log(inhibitor) vs. response—Variable slope (four parameters) equation.

Results

The results of this assay are presented on Table 8 below, wherein “+” means: 1000 nM<IC₅₀≤10000 nM, “++” means: 500 nM<IC₅₀≤1000 nM, “+++” means: 100 nM<IC₅₀≤500 nM, “++++” means: IC₅₀≤100 nM, “−” means IC₅₀>10000 nM, and “NT” means “not tested”.

TABLE 8

HDAC6
HDAC1

Cpd #
biochem
biochem

31
++++
−

43
++++
−

44
++++
−

60
++++
−

61
++++
−

64
++++
−

69
++++
NT

71
++++
+

72
++++
++

73
++++
−

74
++++
−

75
++++
−

76
++++
−

79
++++
−

85
++++
−

108
++++
NT

109
++++
NT

113
++++
−

114
++++
−

116
++++
NT

117
++++
−

118
++++
++

119
++++
−

124
++++
−

125
++++
−

126
++++
−

132
++++
−

133
++++
−

135
++++
−

138
++++
−

140
++++
−

142
++++
−

147
++++
NT

148
++++
−

152
++++
−

153
++++
NT

154
++++
NT

158
++++
NT

159