CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 61/595,239 filed Feb. 6, 2012.

BACKGROUND OF THE INVENTION

The disclosure generally relates to the novel compounds of formula I including pharmaceutically acceptable salts, which have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV. The disclosure also relates to compositions and methods of using these compounds.

Hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide, with 3 to 4 million infected individuals in the United States alone (Boyer, N. and Marcellin, P. J. Hepatology. 2000, 32:98-112; Alter, M. J., et al. Engl. J. Med. 1999, 341:556-562). Prior to the mid 1990s, transfusion with infected blood products was the main route of HCV transmission. Following the introduction of blood screening methods, transmission via injection drug use became the primary risk factor. Chronic infection often leads to the development of severe liver complications, including fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection is also the leading cause of orthotopic liver transplantation in the United States. The degree to which disease progression is related to viral and cellular factors is not completely understood.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence of the HCV genome (Simmonds, P. J. Gen. Virology. 2004, 85:3173-3188). Based on this sequence diversity, six major genotypes and multiple associated subtypes have been described. The genotypes of HCV differ in their worldwide distribution, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

Medical treatment for HCV is limited by the lack of a vaccine or approved therapies that specifically target the virus. Currently, patients undergo treatment with a combination of parenterally administered pegylated alpha-interferon and oral ribavirin. Genotype 1 HCV is the most difficult to treat and elimination of the virus (sustained virologic response) is achieved for only approximately 50% of patients (Fried, M. W. et al. N. Engl. J. Med. 2002, 347:975-982; Zeumzem, S, Nature Clinical Practice. 2008, 5:610-622). This poor treatment response, combined with often severe side effects induced by therapy, highlight a need for improved antiviral drugs with better efficacy and safety profiles.

HCV is a member of the Flaviviridae family of viruses with a single-stranded positive-sense RNA genome. Following infection of host cells, the 9.6 Kb genome is translated into a polyprotein precursor of approximately 3,000 amino acids (reviewed in Lindenbach, B. D. and Rice, C. M. Nature. 2005, 436:933-938; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). Post-translational processing by both cellular and viral proteases results in the generation of at least 10 separate viral proteins. The structural proteins (which by definition are found in mature virions) include core, E1, E2, and possibly p7, and originate from the amino-terminal region of the polyprotein. The core protein assembles into the viral nucleocapsid. The E1 and E2 glycoproteins form heterodimers that are found within the lipid envelope surrounding the viral particles, and mediate host cell receptor binding and entry of the virus into cells. It is unclear if p7 is a structural protein, and its role in replication has yet to be defined. However p7 is believed to form an ion channel in cellular membranes, preventing acidification of intracellular compartments in which virions are assembled, and it has been shown to be essential for viral replication and assembly. The nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B are produced through maturational cleavages of the carboxy-terminal region of the polyprotein. NS2 along with the amino terminus of NS3 form the NS2-3 metalloprotease which cleaves at the NS2-NS3 junction. Additionally, NS2 is involved in assembly and egress of nascent virions. The NS3 protein contains both a serine protease in its amino-terminal region, and a nucleotide-dependent RNA helicase in its carboxy-terminal region. NS3 forms a heterodimer with the NS4A protein, constituting the active protease which mediates cleavages of the polyprotein downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The NS4B protein has been shown to be important for localization of HCV proteins into replication complexes in altered membranous structures within the cell. NS5B encodes an RNA-dependent RNA polymerase that is involved in the replication of HCV.

Subgenomic HCV replicons, containing the untranslated regions 5â€² and 3â€² to the coding sequence fused to the nonstructural proteins or the full-length polyprotein, are competent for translation, viral protein expression, and replication within cultured cells (Lohmann, V. et al. Science. 1999, 285:110-113; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). The replicon system has proven valuable for the identification of inhibitors targeting the nonstructural proteins associated with these functions. However, only limited subsets of HCV genotypes have been used to generate functional replicons.

Other systems have been used to study the biology of the HCV structural proteins that mediate the entry into host cells. For example, virus-like-particles made in recombinant baculovirus-infected cells with the HCV core, E1 and E2 proteins have also been used to study the function of the HCV E1 and E2 proteins (Barth, H., et al. J. Biol. Chem. 2003, 278:41003-41012). In addition, pseudotyping systems where the E1 and E2 glycoproteins are used to functionally replace the glycoproteins of retroviruses have been developed (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642; Hsu, M. et al. Proc. Natl. Acad. Sci. USA. 2003, 100:7271-7276). These systems yield HCV pseudoparticles that bind to and enter host cells in a manner which is believed to be analogous to the natural virus, thus making them a convenient tool to study the viral entry steps as well as to identify inhibitors block this process.

Recently, a full-length genotype 2a HCV clone, JFH1, was isolated and demonstrated the ability to replicate in vitro. Through repeated passage and adaptation in cell culture increased titers of infectious virus were produced (Lindenbach, B. D., et al. Science. 2005, 309:623-626; Wakita, T. et al. Nature Med. 2005, 11:791-796). In contrast to the HCV replicon or pseudotyping systems, the infectious virus is useful for studying the complete HCV replication cycle, including identifying inhibitors of not only the replication proteins, but those involved in early steps in virus infection (entry and uncoating) and production of progeny viruses (genome packaging, nucleocapsid assembly, virion envelopment and egress).

Triazines have been disclosed. See WO 2009/091388 and US 2009/0286778.

The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

[Image Omitted]

where

R1 is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, or benzyl wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxy, cyano, haloalkyl, alkoxy, and haloalkoxy;

R²is alkyl, cycloalkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, or (((Ar²)alkyl)cycloalkyl)alkyl;

R³is hydrogen, alkyl or cycloalkyl;

R⁴is hydrogen, alkyl or cycloalkyl;

R⁵is

[Image Omitted]

where ring A is a 4 to 7 membered alkylene ring;

R^5ais alkyl or benzyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, and alkoxy;

R⁶is hydrogen, alkyl or cycloalkyl; R⁷is hydroxy, alkyloxy, phenoxy, SO₂R⁹, SO₂N(R¹⁰)(R¹¹), CN, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ether, cyclicether, benzocyclicether, bicyclicether, CO₂R⁹, NR⁹CO₂R¹¹, N(R¹⁰)(R¹¹), CON(R¹⁰(R¹¹), NR⁹CON(R¹⁰)(R¹¹), SO₂N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;

or R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar⁴;

R⁸is hydrogen, alkyl, or cycloalkyl, and alkyl or cycloalkyl is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, fused bicyclic alkyl, bridged bicyclic alkyl, spiro bicyclic alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;

or R⁸is substituted with biotin, flurescein or rhosamin;

or R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl;

R⁹is hydrogen, Ar³, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy;

R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶;

R¹¹is hydrogen, alkyl, cycloalkyl, or Ar⁶;

or R¹⁰and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl;

R¹²is hydrogen, alkyl, cycloalkyl, or Ar⁶;

R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹⁵)(R¹⁶), and alkylCO;

R¹⁴is hydrogen, alkyl, cycloalkyl, or Ar⁶;

or R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl;

R¹⁵is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl;

R¹⁶is hydrogen, alkyl, or cycloalkyl;

or R¹⁵and R¹⁶taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl;

L is alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, or alkyl(cycloalkyl)alkyl, and is substituted with 0-2 substituents selected from alkyl, alkoxy, hydroxy, CO₂R¹²and CONR¹³R¹⁴;

Ar¹is phenyl substituted with 1 CON(R⁵)(R⁶) and with 0-3 substituents selected from Ar³, hydroxy, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar²is phenyl substituted with 0-3 substituents selected from halo, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, and haloalkoxy;

Ar³is phenyl, biphenyl, terphenyl, naphthalenyl, furanyl, benzofuranyl, fluorenyl, fluorenonyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzoisothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, indolinyl, chromenonyl, or dibenzofuranyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, Ar⁵, OAr⁵, NR¹³Ar⁵, N(R¹³)COAr⁵, N(R¹³)SO₂Ar⁵, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, and PhCONHSO₂; and said alkyl, alkenyl, cycloalkyl, alkynyl or Ar⁵is further substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, aryoxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, PhCONHSO₂and Ar⁶;

or Ar^ais phenyl substituted with 1 substituents selected from benzyl, phenoxy, pyridyloxy, pyrimidyloxy, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, dimethoxypyrimdinyl, indolyl, indolinyl, and isoindolinyl;

Ar⁴is phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹³)(R¹⁴), and alkylCO;

Ar⁵is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, OAr⁶, NR¹³Ar⁶, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone and sulfamide;

or Ar⁵is substituted with biotin, flurescein or rhosamin;

Ar⁶is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, phenyl, hydroxy, alkoxy, aryloxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, ester, ketone, amidine, urea, ketone, sulfone and sulfamide;

or Ar⁶is substituted with biotin, flurescein or rhosamin;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where:

R¹is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, or benzyl wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

R²is alkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, or (((Ar²)alkyl)cycloalkyl)alkyl;

R⁴is hydrogen or alkyl;

[Image Omitted]

R⁵is where ring A is a 4 to 7 membered alkylene ring substituted with L;

R⁶is hydrogen or alkyl;

R⁷is alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, and Ar⁴;

or R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar³;

R⁸is hydrogen or alkyl;

or R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;

R⁹is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy;

R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl;

R¹¹is hydrogen, alkyl;

or R¹⁶and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;

R¹²is hydrogen or alkyl;

R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl;

R¹⁴is hydrogen or alkyl;

or R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl;

L is alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, or alkyl(cycloalkyl)alkyl, and is substituted with 0-1 CO₂R¹²or CONR¹³R¹⁴;

Ar¹is phenyl substituted with 1 CON(R⁵)(R⁶) and with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar²is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;

Ar³is phenyl, indanyl, fluorenyl, biphenyl, terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, benzoxazolyl, indolinyl, or dibenzofuranyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkenyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴)))alkyl, phenyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, CO₂R¹², CON(R¹³)(R¹⁴), or PhCONHSO₂;

or Ar³is phenyl substituted with 1 substituents selected from benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, dimethoxypyrimdinyl; and

Ar⁴is phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, or imidazolyl, triazolyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹³)(R¹⁴), and alkylCO;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, or benzyl.

Another aspect of the invention is a compound of formula I where R¹is alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, benzyl, indanyl, or alkylcarbonyl.

Another aspect of the invention is a compound of formula I where R²is alkyl, cycloalkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, or (((Ar²)alkyl)cycloalkyl)alkyl.

Another aspect of the invention is a compound of formula I where R²is alkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, or (((Ar²)alkyl)cycloalkyl)alkyl.

Another aspect of the invention is a compound of formula I where R³is hydrogen, alkyl or cycloalkyl.

Another aspect of the invention is a compound of formula I where R³is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R³is hydrogen.

Another aspect of the invention is a compound of formula I where R⁴is hydrogen, alkyl or cycloalkyl.

Another aspect of the invention is a compound of formula I where R⁴is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R⁴is hydrogen.

Another aspect of the invention is a compound of formula I where R⁵is

[Image Omitted]

where ring A is a 4 to 7 membered alkylene ring substituted with L.

Another aspect of the invention is a compound of formula I where R⁵is

[Image Omitted]

where ring A is a 4 to 7 membered alkylene ring substituted with L.

Another aspect of the invention is a compound of formula I where R^5ais alkyl or benzyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, and alkoxy.

Another aspect of the invention is a compound of formula I where R⁶is hydrogen, alkyl or cycloalkyl.

Another aspect of the invention is a compound of formula I where R⁶is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R⁷is hydroxy, alkyloxy, phenoxy, SO₂R⁹, SO₂N(R¹⁰)(R¹¹), CN, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ether, cyclicether, benzocyclicether, bicyclicether, CO₂R⁹, NR⁹CO₂R¹¹, N(R¹⁰)(R¹¹), CON(R¹⁰)(R¹¹), NR⁹CON(R¹⁰)(R¹¹), SO₂N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;

Another aspect of the invention is a compound of formula I where R⁷is alkyl, cycloalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, and Ar⁴.

Another aspect of the invention is a compound of formula I where R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar⁴.

Another aspect of the invention is a compound of formula I where R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar³.

Another aspect of the invention is a compound of formula I where R⁸is hydrogen, alkyl or cycloalkyl, and said alkyl or cycloalkyl is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, fused bicyclic alkyl, bridged bicyclic alkyl, spiro bicyclic alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³.

Another aspect of the invention is a compound of formula I where R⁸is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R⁸is substituted with biotin, flurescein or rhosamin.

Another aspect of the invention is a compound of formula I where R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R⁹is hydrogen, Ar³, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy.

Another aspect of the invention is a compound of formula I where R⁹is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy.

Another aspect of the invention is a compound of formula I where R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶.

Another aspect of the invention is a compound of formula I where R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹¹is hydrogen, alkyl, cycloalkyl, or Ar⁶.

Another aspect of the invention is a compound of formula I where R¹¹is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R¹⁰and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹⁰and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹²is hydrogen, alkyl, cycloalkyl, or Ar⁶.

Another aspect of the invention is a compound of formula I where R¹²is hydrogen or alkyl.

Another aspect of the invention is a compound of formula I where R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, haloalkoxy, N(R¹⁵)(R¹⁶), and alkylCO.

Another aspect of the invention is a compound of formula I where R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹⁴is hydrogen, alkyl, cycloalkyl, or Ar⁶.

Another aspect of the invention is a compound of formula I where R¹⁴is hydrogen or alkyl;

Another aspect of the invention is a compound of formula I where R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-2 substituents selected from alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹⁵is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where R¹⁶is hydrogen, alkyl or cycloalkyl.

Another aspect of the invention is a compound of formula I where R¹⁵and R¹⁶taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)alkyl, alkylcarbonyl, and alkoxycarbonyl.

Another aspect of the invention is a compound of formula I where L is alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, or alkyl(cycloalkyl)alkyl, and is substituted with 0-2 substituents selected from alkyl, alkoxy, hydroxy, CO₂R¹²or CONR¹³R¹⁴.

Another aspect of the invention is a compound of formula I where L is alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, or alkyl(cycloalkyl)alkyl, and is substituted with 0-1 CO₂R¹²or CONR¹³R¹⁴.

Another aspect of the invention is a compound of formula I where Ar¹is phenyl substituted with 1 CON(R⁵)(R⁶) and with 0-3 substituents selected from Ar³, hydroxy, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar²is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar¹is fluorophenyl substituted with 1 CON(R⁵)(R⁶) and with 0-3 substituents selected from Ar³, hydroxy, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar²is phenyl substituted with 0-3 substituents selected from halo, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar²is phenyl substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar³is phenyl, biphenyl, terphenyl, naphthalenyl, furanyl, benzofuranyl, fluorenyl, fluorenonyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzoisothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, indolinyl, chromenonyl, or dibenzofuranyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, Ar⁵, OAr⁵, NR¹³, Ar⁵, N(R¹³)COAr⁵, N(R¹³)SO₂Ar⁵, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, and PhCONHSO₂; and said alkyl, alkenyl, cycloalkyl, alkynyl or Ar⁵is further substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, aryoxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, PhCONHSO₂and Ar⁶.

Another aspect of the invention is a compound of formula I where Ar³is phenyl, indanyl, fluorenyl, biphenyl, terphenyl, pyridinyl, pyrazolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, benzoxazolyl, indolinyl, or dibenzofuranyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkenyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl, CO₂R¹², CON(R¹³)(R¹⁴), or PhCONHSO₂.

Another aspect of the invention is a compound of formula I where Ar³is phenyl substituted with 1 substituents selected from benzyl, phenoxy, pyridyloxy, pyrimidyloxy, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, dimethoxypyrimdinyl, indolyl, indolinyl, and isoindolinyl.

Another aspect of the invention is a compound of formula I where Ar³is phenyl substituted with 1 substituents selected from benzyl, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, and dimethoxypyrimdinyl.

Another aspect of the invention is a compound of formula I where Ar⁴is phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹³)(R¹⁴), and alkylCO.

Another aspect of the invention is a compound of formula I where Ar⁵is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, OAr⁶, NR¹³Ar⁶, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone and sulfamide.

Another aspect of the invention is a compound of formula I where Ar⁵is substituted with biotin, flurescein, or rhosamin.

Another aspect of the invention is a compound of formula I where Ar⁶is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, phenyl, hydroxy, alkoxy, aryloxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, ester, ketone, amidine, urea, ketone, sulfone and sulfamide

Another aspect of the invention is a compound of formula I where Ar⁶is substituted with biotin, flurescein, or rhosamin;

Another aspect of the invention is a compound of formula I where R¹is haloalkyl or a pharmaceutically acceptable salt thereof

Another aspect of the invention is a compound of formula I where R¹is trifluoroethyl or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹is alkyl or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹is phenylalkyl substituted with 0-5 halo, alkyl, alkenyl, haloalkyl, alkoxy or haloalkoxy or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹is benzyl substituted with 0-5 halo, alkyl, alkenyl, haloalkyl, alkoxy or haloalkoxy or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R²is (Ar²)alkyl or (Ar²)cycloalkyl, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R²is (Ar²)alkyl or (Ar²)cycloalkyl, or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R⁷is hydroxy, alkyloxy, phenoxy, SO₂R⁹, SO₂N(R¹⁰)(R¹¹), CN, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or a bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ether, cyclicether, benzocyclicether, bicyclicether, CO₂R⁹, NR⁹CO₂R¹¹, N(R¹⁰)(R¹¹), CON(R¹⁰)(R¹¹), NR⁹CON(R¹⁰)(R¹¹), SO₂N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³.

Another aspect of the invention is a compound of formula I where R⁷is Ar⁴or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where L is

[Image Omitted]

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where Ar¹is phenyl para-substituted with 1 CON(R⁵)(R⁶), or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where Ar¹is fluoro phenyl para-substituted with 1 CON(R⁵)(R⁶), or a pharmaceutically acceptable salt thereof.

Any scope of any variable, including R¹, R², R³, R⁴, R⁵, R^5a, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, L, Ar¹, Ar², Ar³, Ar⁴, Ar⁵, and Ar⁶can be used independently with the scope of any other instance of a variable.

Unless specified otherwise, these terms have the following meanings. â€œHaloâ€ means fluoro, chloro, bromo, or iodo. â€œAlkylâ€ means a straight or branched alkyl group composed of 1 to 6 carbons. â€œAlkenylâ€ means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. â€œAlkynylâ€ means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. â€œCycloalkylâ€ means a monocyclic ring system composed of 3 to 8 carbons. â€œBenzocycloalkylâ€ means a monocyclic ring system composed of 3 to 8 carbons fused to a benzene ring system. â€œBicycloalkylâ€ means a fused bicyclic ring system wherein each ring is composed of 3 to 7 carbons, that is a [(3-7).0.(3-7)] system. â€œBridged bicycloalkylâ€ means a [(3-7).(1-3).(3-7)] ring system. â€œSpirocycloalkylâ€ means a spirocyclic ring system wherein each ring is composed of 3 to 7 carbons. â€œAlkyleneâ€ means a straight or branched divalent alkyl group. â€œAlkenyleneâ€ means a straight or branched divalent alkyl group with at least one double bond. â€œCycloalkyleneâ€ means a divalent cycloalkane moiety composed of 3 to 7 carbons and includes gem-divalency (for example 1,1-cyclopropanediyl) as well as non-gem-divalency (for example, 1,4-cyclohexanediyl). â€œAlkylidinylâ€ means a divalent alkene substituent where the divalency occurs on the same carbon of the alkene. â€œHydroxyalkyl,â€ â€œalkoxyâ€ and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. â€œHaloalkylâ€ and â€œhaloalkoxyâ€ include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. â€œArylâ€ includes carbocyclic and heterocyclic aromatic substituents. Phenylene is a divalent benzene ring. â€œ1,4-Phenyleneâ€ means 1,4-benzenediyl with respect to regiochemistry for the divalent moiety. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The substituents described above may be attached at any suitable point of attachment unless otherwise specified. However, it is understood that the compounds encompassed by the present invention are those that are chemically stable as understood by those skilled in the art. Additionally, the compounds encompassed by the present disclosure are those that are suitably stable for use as a pharmaceutical agent.

The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, the structures below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.

The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

Biological Methods

Infection Assays.

HCV pseudoparticles, produced using standardized methodology (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642) were made via a liposome-based transfection procedure of 293T cells with plasmids expressing the murine leukemia virus capsid and polymerase proteins, an MLV genome encoding the luciferase reporter gene, and envelope glycoproteins from either HCV or vesicular stomatitis virus (VSV). The genotype 1a HCV E1 and E2 envelope coding sequences were derived from the H77C isolate (GenBank accession number AF009606). Media containing pseudoparticles was collected 3 days following transfection, filtered, and stored at âˆ’20Â° C. as a viral stock. Infections were performed in 384-well plates by mixing pseudovirus with 1Ã—10⁴Huh7 cells/well in the presence or absence of test inhibitors, followed by incubation at 37Â° C. Luciferase activity, reflecting the degree of entry of the pseudoparticles into host cells, was measured 2 days after infection. The specificity of the compounds for inhibiting HCV was determined by evaluating inhibition of VSV pseudoparticle infection.

Compounds and Data Analysis.

Test compounds were serially diluted 3-fold in dimethyl sulfoxide (DMSO) to give a final concentration range in the assay of 50.0 Î¼M to 0.04 Î¼M. Maximum activity (100% of control) and background were derived from control wells containing DMSO but no inhibitor or from uninfected wells, respectively. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. Assays were performed in duplicate and average EC₅₀values (reflecting the concentration at which 50% inhibition of virus replication was achieved) were calculated. Compound EC₅₀data is expressed as A=0.01â‰¦10 nM; B=10-1000 nM. Representative data for compounds are reported in Table 1.

Lengthy table referenced hereUS20130203758A1-20130808-T00001Please refer to the end of the specification for access instructions.

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon or a ribavirin. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5â€²-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon or a ribavirin.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5â€²-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

â€œTherapeutically effectiveâ€ means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.

â€œPatientâ€ means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

â€œTreatment,â€ â€œtherapy,â€ â€œregimen,â€ â€œHCV infection,â€ and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will be determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods are listed in Table 2.

TABLE 2Type of Inhibitor orBrand NamePhysiological ClassTargetSource CompanyNIM811Cyclophilin InhibitorNovartisZadaxinImmuno-modulatorScicloneSuvusMethylene blueBioenvisionActilonTLR9 agonistColey(CPG10101)Batabulin (T67)AnticancerÎ²-tubulin inhibitorTularik Inc., SouthSan Francisco, CAISIS 14803AntiviralantisenseISISPharmaceuticals Inc,Carlsbad, CA/ElanPhamaceuticals Inc.,New York, NYSummetrelAntiviralantiviralEndoPharmaceuticalsHoldings Inc.,Chadds Ford, PAGS-9132 (ACH-AntiviralHCV InhibitorAchillion/Gilead806)PyrazolopyrimidineAntiviralHCV InhibitorsArrow Therapeuticscompounds andLtd.saltsFrom WO-200504728826 May 2005LevovirinAntiviralIMPDH inhibitorRibapharm Inc.,Costa Mesa, CAMerimepodibAntiviralIMPDH inhibitorVertex(VX-497)PharmaceuticalsInc., Cambridge,MAXTL-6865 (XTL-Antiviralmonoclonal antibodyXTL002)BiopharmaceuticalsLtd., Rehovot, IsrealTelaprevirAntiviralNS3 serine proteaseVertex(VX-950, LY-inhibitorPharmaceuticals570310)Inc., Cambridge,MA/Eli Lilly andCo. Inc.,Indianapolis, INHCV-796AntiviralNS5B ReplicaseWyeth/ViropharmaInhibitorNM-283AntiviralNS5B ReplicaseIdenix/NovartisInhibitorGL-59728AntiviralNS5B ReplicaseGene Labs/InhibitorNovartisGL-60667AntiviralNS5B ReplicaseGene Labs/InhibitorNovartis2â€²C MeAAntiviralNS5B ReplicaseGileadInhibitorPSI 6130AntiviralNS5B ReplicaseRocheInhibitorR1626AntiviralNS5B ReplicaseRocheInhibitor2â€²C MethylAntiviralNS5B ReplicaseMerckadenosineInhibitorJTK-003AntiviralRdRp inhibitorJapan Tobacco Inc.,Tokyo, JapanLevovirinAntiviralribavirinICNPharmaceuticals,Costa Mesa, CARibavirinAntiviralribavirinSchering-PloughCorporation,Kenilworth, NJViramidineAntiviralRibavirin ProdrugRibapharm Inc.,Costa Mesa, CAHeptazymeAntiviralribozymeRibozymePharmaceuticalsInc., Boulder, COBILN-2061Antiviralserine proteaseBoehringerinhibitorIngelheim PharmaKG, Ingelheim,GermanySCH 503034Antiviralserine proteaseSchering PloughinhibitorZadazimImmune modulatorImmune modulatorSciClonePharmaceuticalsInc., San Mateo, CACepleneImmunomodulatorimmune modulatorMaximPharmaceuticalsInc., San Diego, CACellCeptImmunosuppressantHCV IgG immuno-F. Hoffmann-LasuppressantRoche LTD, Basel,SwitzerlandCivacirImmunosuppressantHCV IgG immuno-NabisuppressantBiopharmaceuticalsInc., Boca Raton, FLAlbuferon-Î±Interferonalbumin IFN-Î±2bHuman GenomeSciences Inc.,Rockville, MDInfergen AInterferonIFNInterMunealfacon-1PharmaceuticalsInc., Brisbane, CAOmega IFNInterferonIFN-Ï‰Intarcia TherapeuticsIFN-Î² and EMZ701InterferonIFN-Î² and EMZ701TransitionTherapeutics Inc.,Ontario, CanadaRebifInterferonIFN-Î²1aSerono, Geneva,SwitzerlandRoferon AInterferonIFN-Î±2aF. Hoffmann-LaRoche LTD, Basel,SwitzerlandIntron AInterferonIFN-Î±2bSchering-PloughCorporation,Kenilworth, NJIntron A andInterferonIFN-Î±2b/Î±1-thymosinRegeneRxZadaxinBiopharma. Inc.,Bethesda, MD/SciClonePharmaceuticals Inc,San Mateo, CARebetronInterferonIFN-Î±2b/ribavirinSchering-PloughCorporation,Kenilworth, NJActimmuneInterferonINF-Î³InterMune Inc.,Brisbane, CAInterferon-Î²InterferonInterferon-Î²-1aSeronoMultiferonInterferonLong lasting IFNViragen/ValentisWellferonInterferonLympho-blastoid IFN-GlaxoSmithKlineÎ±n1plc, Uxbridge, UKOmniferonInterferonnatural IFN-Î±Viragen Inc.,Plantation, FLPegasysInterferonPEGylated IFN-Î±2aF. Hoffmann-LaRoche LTD, Basel,SwitzerlandPegasys andInterferonPEGylated IFN-Î±2a/MaximCepleneimmune modulatorPharmaceuticalsInc., San Diego, CAPegasys andInterferonPEGylated IFN-F. Hoffmann-LaRibavirinÎ±2a/ribavirinRoche LTD, Basel,SwitzerlandPEG-IntronInterferonPEGylated IFN-Î±2bSchering-PloughCorporation,Kenilworth, NJPEG-Intron/InterferonPEGylated IFN-Schering-PloughRibavirinÎ±2b/ribavirinCorporation,Kenilworth, NJIP-501Liver protectionantifibroticIndevusPharmaceuticalsInc., Lexington, MAIDN-6556Liver protectioncaspase inhibitorIdunPharmaceuticalsInc., San Diego, CAITMN-191 (R-7227)Antiviralserine proteaseInterMuneinhibitorPharmaceuticalsInc., Brisbane, CAGL-59728AntiviralNS5B ReplicaseGenelabsInhibitorANA-971AntiviralTLR-7 agonistAnadysBoceprevirAntiviralserine proteaseSchering PloughinhibitorTMS-435Antiviralserine proteaseTibotec BVBA,inhibitorMechelen, BelgiumBI-201335Antiviralserine proteaseBoehringerinhibitorIngelheim PharmaKG, Ingelheim,GermanyMK-7009Antiviralserine proteaseMerckinhibitorPF-00868554Antiviralreplicase inhibitorPfizerANA598AntiviralNon-NucleosideAnadysNS5B PolymerasePharmaceuticals,InhibitorInc., San Diego, CA,USAIDX375AntiviralNon-NucleosideIdenixReplicase InhibitorPharmaceuticals,Cambridge, MA,USABILB 1941AntiviralNS5B PolymeraseBoehringerInhibitorIngelheim CanadaLtd R&D, Laval,QC, CanadaPSI-7851AntiviralNucleosidePharmasset,Polymerase InhibitorPrinceton, NJ, USAPSI-7977AntiviralNucleotide NS5BPharmasset,Polymerase InhibitorPrinceton, NJ, USAVCH-759AntiviralNS5B PolymeraseViroChem PharmaInhibitorVCH-916AntiviralNS5B PolymeraseViroChem PharmaInhibitorGS-9190AntiviralNS5B PolymeraseGileadInhibitorPeg-interferonAntiviralInterferonZymoGenetics/Bristol-lamdaMyers Squibb

Synthetic Methods

The compounds may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered â€œRâ€ substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: â€œNaHMDSâ€ for sodium bis(trimethylsilyl)amide; â€œDMFâ€ for N,N-dimethylformamide; â€œMeOHâ€ for methanol; â€œNBSâ€ for N-bromosuccinimide; â€œArâ€ for aryl; â€œTFAâ€ for trifluoroacetic acid; â€œLAHâ€ for lithium aluminum hydride; â€œBOCâ€ , â€œDMSOâ€ for dimethylsulfoxide; â€œhâ€ for hours; â€œrtâ€ for room temperature or retention time (context will dictate); â€œminâ€ for minutes; â€œEtOAcâ€ for ethyl acetate; â€œTHFâ€ for tetrahydrofuran; â€œEDTAâ€ for ethylenediaminetetraacetic acid; â€œEt₂Oâ€ for diethyl ether; â€œDMAPâ€ for 4-dimethylaminopyridine; â€œDCEâ€ for 1,2-dichloroethane; â€œACNâ€ for acetonitrile; â€œDMEâ€ for 1,2-dimethoxyethane; â€œHOBtâ€ for 1-hydroxybenzotriazole hydrate; â€œDIEAâ€ for diisopropylethylamine, â€œNfâ€ for CF₃(CF₂)₃SO₂â€”; and â€œTMOFâ€ for trimethylorthoformate.

Abbreviations are defined as follows: â€œ1Ã—â€ for once, â€œ2Ã—â€ for twice, â€œ3Ã—â€ for thrice, â€œÂ° C.â€ for degrees Celsius, â€œeqâ€ for equivalent or equivalents, â€œgâ€ for gram or grams, â€œmgâ€ for milligram or milligrams, â€œLâ€ for liter or liters, â€œmLâ€ for milliliter or milliliters, â€œÎ¼Lâ€ for microliter or microliters, â€œNâ€ for normal, â€œMâ€ for molar, â€œmmolâ€ for millimole or millimoles, â€œminâ€ for minute or minutes, â€œhâ€ for hour or hours, â€œrtâ€ for room temperature, â€œRTâ€ for retention time, â€œatmâ€ for atmosphere, â€œpsiâ€ for pounds per square inch, â€œconc.â€ for concentrate, â€œsatâ€ or â€œsat'dâ€ for saturated, â€œMWâ€ for molecular weight, â€œmpâ€ for melting point, â€œeeâ€ for enantiomeric excess, â€œMSâ€ or â€œMass Specâ€ for mass spectrometry, â€œESIâ€ for electrospray ionization mass spectroscopy, â€œHRâ€ for high resolution, â€œHRMSâ€ for high resolution mass spectrometry, â€œLCMSâ€ for liquid chromatography mass spectrometry, â€œHPLCâ€ for high pressure liquid chromatography, â€œRP HPLCâ€ for reverse phase HPLC, â€œTLCâ€ or â€œticâ€ for thin layer chromatography, â€œNMRâ€ for nuclear magnetic resonance spectroscopy, â€œ¹Hâ€ for proton, â€œÎ´â€ for delta, â€œsâ€ for singlet, â€œdâ€ for doublet, â€œtâ€ for triplet, â€œqâ€ for quartet, â€œmâ€ for multiplet, â€œbrâ€ for broad, â€œHzâ€ for hertz, and â€œÎ±â€ , â€œÎ²â€ , â€œRâ€ , â€œSâ€ , â€œEâ€ , and â€œZâ€ are stereochemical designations familiar to one skilled in the art.

LC/MS Method (i.e., Compound Identification).

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS or LC-20AS liquid chromotograph using a SPD-10AV or SPD-20A UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode.

HPLC Method (i.e., Compound Isolation).

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using a Shimadzu LC-8A or LC-10A or Dionex APS-3000 or Waters Acquityâ„¢ automated preparative HPLC system.

Syntheses of IntermediatesPreparation of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid, In-1001

[Image Omitted]

Step 1:

To a solution of 2,4,6-trichloro-1,3,5-triazine (15 g) in THF (300 mL) was added 2,2,2-trifluoroethanol (8.14 g) and Hunig'sBase (15.63 mL). The resulting mixture was stirred for 16 hours. After removal of most THF and precipitate through a plug washing with THF, the filtrate was concentrate to give a crude that will be used as it is.

Step 2:

To a solution of the product in Step 1 above (10 g) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g) and Hunig'sBase (7.04 mL). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with Et₂O, dried, then washed with water and dried to give 10.6 g of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoateMS (M + H)⁺ Calcd.405.1MS (M + H)⁺ Observ.405.0LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Step 3:

To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g) and 1-(4-chlorophenyl)cyclopropanamine (1.49 g) in THF (50 mL) was stirred for 5 hours at 80Â° C. The precipitate was filtrated through a plug washing with THF to give acrude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoateMS (M + H)⁺ Calcd.536.2MS (M + H)⁺ Observ.536.0LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Step 4:

A solution of above tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (4 g) and HCl in dioxane (7.46 ml, 4M) was stirred for 4 hours. Concentration gave 3.58 g of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid as a solid.

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid, In-1001MS (M + H)⁺ Calcd.480.1MS (M + H)⁺ Observ.480.1LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Preparation of (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate, In-1002

[Image Omitted]

Step 1:

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr₂NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.

(S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoateMS (M + H)⁺ Calcd.680.2MS (M + H)⁺ Observ.680.3Retention Time3.44 minLC ConditionSolvent A5% ACN:95% Water:10 mM Ammonium ActetateSolvent B95% ACN:5% Water:10 mM Ammonium ActetateStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex Luna C18, 50 Ã— 2, 3 u

Step 2:

To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (1 g) in CH₂Cl₂(10 mL) was added TFA (3 mL). The mixture was stirrred at room temperature for 16 hours. All the solvents were removed under vacuum to give (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (0.8 g).

(S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate, In-1002MS (M + H)⁺ Calcd. 580.2MS (M + H)⁺ Observ.580.0Retention Time1.35 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Preparation of (S)-methyl 4-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate, In-1003

[Image Omitted]

In-1003 was prepared by using the same procedure of synthesizing In-1002, using (S)-methyl 2-amino-4-(tert-butoxycarbonylamino)butanoate as a starting material.

(S)-methyl 4-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate:MS (M + H)⁺ Calcd.594.2MS (M + H)⁺ Observ.594.4Retention Time1.64 minLC ConditionSolvent A5% ACN:95% Water:10 mM Ammonium ActetateSolvent B95% ACN:5% Water:10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex LUNA C18, 30 Ã— 2, 3u

Preparation of (S)-methyl 5-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate

[Image Omitted]

In-1004 was prepared by using the same procedure of synthesizing In-1002, using (S)-methyl 2-amino-5-(tert-butoxycarbonylamino)pentanoate as a starting material.

(S)-methyl 5-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate, In-1004MS (M + H)⁺ Calcd.608.2MS (M + H)⁺ Observ.608.1Retention Time2.44LC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Preparation of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide, In-1005

[Image Omitted]

iPr₂NEt (0.266 g) and O-benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetra-methyluronium tetrafluoroborate (0.610 g) were added into a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.760 g) and tert-butyl 3-amino-2,2-dimethylpropylcarbamate (0.352 g) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 16 hrs before 200 mL of EtOAc was added. The organic phase was washed with water (2Ã—25 mL) and brine (20 mL), dried over MgSO4, and concentrated to give crude product tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamate (0.75 g) which was dissolved in CH₂Cl₂(3 mL) and TFA (1.3 mL). After being stirred at room temperature for 16 hours, the mixture was concentrated to give a crude product, N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (0.63 g).

tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamateMS (M + H)⁺ Calcd.664.3MS (M + H)⁺ Observ.664.4Retention Time3.75 minLC ConditionSolvent Aâ€‚5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: â€‚5% Water : 10 mM Ammonium ActetateStart % Bâ€ƒ0Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex LUNA C18, 50 Ã— 2, 3 u

N-(3-amino-2,2-dimethylpropy1)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide, In-1005MS (M + H)⁺ Calcd.564.2MS (M + H)⁺ Observ.564.3Retention Time3.02 minLC ConditionSolvent Aâ€‚5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: â€‚5% Water : 10 mM Ammonium ActetateStart % Bâ€ƒ0Final % B100Gradient Timeâ€ƒâ€‚4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex LUNA C18, 50 Ã— 2, 3 u

Preparation of N-(3-amino-2,2-dimethylpropyl)-4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamide, In-1006

Intermediate In-1006 was prepared by using the same synthetic route of synthesizing In-1005, using methyl 4-amino-2-fluorobenzoate as one of the starting materials.

In-1006

MS (M + H)⁺ Calcd.â€‰â€‚582.2MS (M + H)⁺ Observ.â€‰â€‚582.2Retention Time1.74minLC ConditionSolvent A90% Water - 10% Methanol - 0.l% TFASolvent B10% Water - 90% Methanol - 0.1% TFAStart % Bâ€‚30Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater - Methanol - TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Synthesis of Compound 1001, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-2-oxoacetamido)propanoate

[Image Omitted]

To a solution of In-1002 (25 mg) in CH₂Cl₂(5 mL) was added ethyl 2-chloro-2-oxoacetate (5.89 mg). The mixture was stirred at room temperature for 4 hours. The reaction was quenched with the MeOH and all the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1001 (5 mg).

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-2-oxoacetamido)propanoate, 1001MS (M + H)⁺ Calcd.680.2MS (M + H)⁺ Observ.680.1Retention Time3.16 minLC ConditionSolvent A90% Water -10% Methanol-0.1% TFASolvent B10% Water -90% Methanol-0.1% TFAStart % Bâ€‚50Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3um

Synthesis of Compound 1002, (S)-methyl 3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate

[Image Omitted]

To a solution of 2-amino-2-oxoacetic acid (11.52 mg) and TBTU (41.5 mg) in DMF (2 mL) was added In-1002 (50 mg). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 1002 (14 mg).

(S)-methyl 3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate, 1002MS (M + H)⁺ Calcd.651.2MS (M + H)⁺ Observ.651.0Retention Time3.61 minLC ConditionSolvent A90% Water -10% Methanol-0.1% TFASolvent B10% Water -90% Methanol-0.1% TFAStart % Bâ€‚40Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1003, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoate

[Image Omitted]

To a solution of 2-(methylamino)-2-oxoacetic acid (13.33 mg) and TBTU (41.5 mg) in DMF (Volume: 2 mL) was added In-1002 (50 mg). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 1003 (20 mg).

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoate, 1003MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.1Retention Time4.26 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1004, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate

[Image Omitted]

To a solution of 2-(dimethylamino)-2-oxoacetic acid (15.14 mg) and TBTU (41.5 mg) in DMF (2 mL) was added In-1002 (50 mgl). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 1004 (28 mg).

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate, 1004MS (M + H)⁺ Calcd.679.2MS (M + H)⁺ Observ.679.1Retention Time3.61 minLC ConditionSolvent A90% Water -10% Methanol-0.1% TFASolvent B10% Water -90% Methanol-0.1% TFAStart % Bâ€‚40Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1005, (S)-3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoic acid

[Image Omitted]

A suspension of 1002 (14 mg) and K₂CO₃(8.92 mg) in acetone-water (1:1, 4 mL) was stirred at room temperature for 16 hours. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1005 (12.6 mg).

(S)-3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoic acid, 1005MS (M + H)⁺ Calcd.637.2MS (M + H)⁺ Observ.637.0Retention Time2.83 minLC ConditionSolvent A90% Water -10% Methanol-0.1% TFASolvent B10% Water -90% Methanol-0.1% TFAStart % Bâ€‚60Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1006, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoic acid

[Image Omitted]

A suspension of 1003 (12 mg) and K₂CO₃(7.48 mg) in acetone-water (1:1, 4 mL) was stirred at room temperature for 16 hours. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1006 (8.4 mg).

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoic acid, 1006MS (M + H)⁺ Calcd.651.2MS (M + H)⁺ Observ.651.1Retention Time3.01 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚60Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1007, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoic acid

[Image Omitted]

A suspension of 1004 (20 mg) and K₂CO₃(12.2 mg) in acetone-water (1:1, 4 mL) was stirred at room temperature for 16 hours. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1007 (7 mg).

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoic acid, 1007MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.1Retention Time3.10 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚60Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1008, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide

[Image Omitted]

iPr₂NEt (0.037 g) and O-benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetra-methyluronium tetrafluoroborate (0.068 g) was added into the solution of crude In-1005 (0.080 g) and 2-(dimethylamino)-2-oxoacetic acid (0.017 g) in DMF (2 mL). The reaction was stirred at room temperature for 6 hours. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1008 (40 mg).

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropy1)-N2,N2-dimethyloxalamide, 1008MS (M + H)⁺ Calcd.663.2MS (M + H)⁺ Observ.663.1Retention Time2.00 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€ƒ0Final % B100Gradient Timeâ€ƒâ€‰2 minFlow Rateâ€ƒâ€‰5 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 4.6 Ã— 50 mm S10

Synthesis of Compound 1479, N1-(3-(4-((4-(1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)-N2-(4-fluorophenyl)oxalamide

Compound 1479 was prepared by using the same procedure of synthesizing 1008, using 2-((4-fluorophenyl)amino)-2-oxoacetic acid as one of the starting materials. Its LCMS is shown in a later section.

[Image Omitted]

The following selected examples were prepared by using the same procedure of synthesizing 1479, using the corresponding mono-Boc diamines rather than mono-Boc 2,2-dimethylpropane-1,3-diamine as starting materials:

3335

MS (M + H)⁺ Calcd.715.2MS (M + H)⁺ Observ.715.1Retention Time4.48 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um3360 [Image Omitted]

MS (M + H)⁺ Calcd.701.2MS (M + H)⁺ Observ.701.0Retention Time4.42 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um3365 [Image Omitted]

MS (M + H)⁺ Calcd.717.2MS (M + H)⁺ Observ.717.2Retention Time4.42 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um3373 [Image Omitted]

MS (M + H)⁺ Calcd.687.2MS (M + H)⁺ Observ.687.0Retention Time4.40 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um3395 [Image Omitted]

MS (M + H)⁺ Calcd.715.2MS (M + H)⁺ Observ.715.3Retention Time1.89 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3412 [Image Omitted]

MS (M + H)⁺ Calcd.729.2MS (M + H)⁺ Observ.729.3Retention Time1.87 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3418 [Image Omitted]

MS (M + H)⁺ Calcd.715.2MS (M + H)⁺ Observ.715.3Retention Time2.01 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3448 [Image Omitted]

MS (M + H)⁺ Calcd.715.2MS (M + H)⁺ Observ.715.5Retention Time2.36 minLC ConditionSolvent A90% Water -10% Methanol-0.1% TFASolvent B10% Water -90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um3482 [Image Omitted]

MS (M + H)⁺ Calcd.741.2MS (M + H)⁺ Observ.741.3Retention Time1.89 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3499 [Image Omitted]

MS (M + H)⁺ Calcd.745.2MS (M + H)⁺ Observ.745.3Retention Time3.18 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 50 Ã— 2, 3u

Synthesis of Compound 1009, (S)-methyl 4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate

[Image Omitted]

To a solution of In-1003 (50 mg) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (54 mg) in DMF (1.5 mL) was aded 2-amino-2-oxoacetic acid (15 mg). After stirring at romm temperatur for 4 hours, the mixture was purified by preparative HPLC to give 1009 (23 mg).

(S)-methyl 4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate, 1009MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.1Retention Time3.61 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1010, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoate

[Image Omitted]

1010 was prepared by using the same procedure of synthesizing 1009, using 2-(methylamino)-2-oxoacetic acid as a starting material.

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoate, 1010MS (M + H)⁺ Calcd.679.2MS (M + H)⁺ Observ.679.1Retention Time3.57 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1011, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoate

[Image Omitted]

1011 was prepared by using the same procedure of synthesizing 1009, using 2-(dimethylamino)-2-oxoacetic acid as a starting material.

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoate, 1011MS (M + H)⁺ Calcd.693.2MS (M + H)⁺ Observ.693.1Retention Time3.53 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1012, (S)-methyl 5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate

[Image Omitted]

1012 was prepared by using the same procedure of synthesizing 1009, using In-1004 as a starting material.

(S)-methyl 5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate, 1012MS (M + H)⁺ Calcd.679.2MS (M + H)⁺ Observ.679.1Retention Time3.64 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1013, (S)-4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoic acid

[Image Omitted]

A mixture of 1009 (21 mg) and K₂CO₃(18 mg) in acetone (2 mL)/water (2 mL) was stirred at room temperature for 16 hours. All the solvents were removed under vacuum. The residue was dissolved in MeOH and purified by preparative HPLC to give 1013 (7.5 mg).

(S)-4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoic acid, 1013MS (M + H)⁺ Calcd.651.2MS (M + H)⁺ Observ.651.1Retention Time3.53 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1014, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoic acid

[Image Omitted]

1014 was prepared by using the same procedure of synthesizing 1013, using 1010 as a starting material.

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoic acid, 1014MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.2Retention Time3.47 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1015, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoic acid

[Image Omitted]

1015 was prepared by using the same procedure of synthesizing 1013, using 1011 as a starting material.

(S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoic acid, 1015MS (M + H)⁺ Calcd.679.2MS (M + H)⁺ Observ.679.2Retention Time3.41 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1016, (S)-5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoic acid

[Image Omitted]

1016 was prepared by using the same procedure of synthesizing 1013, using 1012 as a starting material.

(S)-5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoic acid,1016MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.1Retention Time3.48 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1017, methyl 2-(1-(2-amino-2-oxoacetyl)piperidin-3-yl)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate, and 1018, 2-(1-(2-amino-2-oxoacetyl)piperidin-3-yl)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetic acid, and 1019, N-(1-(1-(2-amino-2-oxoacetyl)piperidin-3-yl)-2-oxo-2-(propylamino)ethyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide

[Image Omitted]

Step 1: To a solution of In-1001 (100 mg) and TBTU (100 mg) in DMF (6 mL) was added tert-butyl 3-(1-amino-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (68.1 mg) and DIPEA (0.146 mL). After stirring at room temperature for 4 hours, the mixture was purified by preparative HPLC to give tert-butyl 3-(1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (90 mg).

tert-Butyl 3-(1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylateMS (M + H)⁺ Calcd.734.2MS (M + H)⁺ Observ.734.1Retention Time4.00 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚50Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 2: To a solution of tert-butyl 3-(1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (85 mg) in DCM (5 mL) was added TFA (0.357 mL). The mixture was stirred at room temperature for 4 hours. All the solvents were removed under vacuum to give methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (70 mg).

Methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetateMS (M + H)⁺ Calcd.634.2MS (M + H)⁺ Observ.634.1Retention Time2.60 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚50Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 3: To a solution of 2-amino-2-oxoacetic acid (18.26 mg) and TBTU (65.8 mg) in DMF (2 mL) was added methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (65 mg). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 1017 (35 mg).

methyl 2-(1-(2-amino-2-oxoacetyl)piperidin-3-y1)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetate, 1017MS (M + H)⁺ Calcd.705.2MS (M + H)⁺ Observ.705.1Retention Time3.72 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 4: A mixture of 1017 (35 mg) and K₂CO₃(21 mg) in acetone (4 mL)/water (4.00 mL) was stirred at room temperature for 16 hours. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 1018 (28 mg).

2-(1-(2-amino-2-oxoacetyl)piperidin-3-yl)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)acetic acid, 1018MS (M + H)⁺ Calcd.691.2MS (M + H)⁺ Observ.691.1Retention Time3.74 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 5: To a solution of 1018 (15 mg) and TBTU (10.5 mg) in DMF (1.5 mL) was added propan-1-amine (6.42 mg). After stirring at room temperature for 16 hours, the mixture was diluted with water (200 mL) and extracted with EtOAc (2Ã—300 mL). The organic layers were combined, washed with water (200 mL), brine (200 mL), dried over MgSO₄and concentrated. The residue was purified by silica gel column to give 1019 (1.1 mg).

N-(1-(1-(2-amino-2-oxoacetyl)piperidin-3-yl)-2-oxo-2-(propylamino)ethyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide, 1019MS (M + Na)⁺ Calcd.754.2MS (M + Na)⁺ Observ.754.2Retention Time3.65 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚50Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1020, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate

[Image Omitted]

Step 1: A mixture of In-1002 (70 mg), K₂CO₃(33.4 mg) and ethanol (2 mL) was stirred at room temperature for three days. The mixture was acidified by 1N HCl, diluted by MeOH and purified by preparative HPLC to give In-1101 (30 mg).

(S)-ethyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoateMS (M + Na)⁺ Calcd.594.2MS (M + Na)⁺ Observ.594.2Retention Time3.38 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 2: To a solution of 2-(dimethylamino)-2-oxoacetic acid (7.6 mg) and TBTU (20.9 mg) in DMF (1 mL) was added In-1101 (30 mg) and DIPEA (0.03 mL). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give 1020 (15.0 mg).

(S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate, 1020MS (M + H)⁺ Calcd.693.2MS (M + H)⁺ Observ.693.2Retention Time3.89 min LC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1021, (S)-isopropyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate

[Image Omitted]

1021 was prepared by using the same procedure of synthesizing 1020, using iPrOH as a starting material.

(S)-isopropyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate, 1021MS (M + H)⁺ Calcd.707.2MS (M + H)⁺ Observ.707.2Retention Time4.03 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1022, (S)-2-morpholinoethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate

[Image Omitted]

1022 was prepared by using the same procedure of synthesizing 1020, using 2-morpholinoethanol as a starting material.

(S)-2-morpholinoethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate, 1022MS (M + H)⁺ Calcd.778.3MS (M + H)⁺ Observ.778.3Retention Time3.22 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1023, (S)-2-(2-hydroxyethoxy)ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate

[Image Omitted]

1023 was prepared by using the same procedure of synthesizing 1020, using 2-morpholinoethanol as a starting material.

(S)-2-(2-hydroxyethoxy)ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(dimethylamino)-2-oxoacetamido)propanoate, 1023MS (M + H)⁺ Calcd.753.2MS (M + H)⁺ Observ.753.3Retention Time3.64 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1024, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoate

[Image Omitted]

1024 was prepared by using the same procedure of synthesizing 1020, using 2-(methylamino)-2-oxoacetic acid as a starting material.

((S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-(methylamino)-2-oxoacetamido)propanoate, 1024MS (M + H)⁺ Calcd.679.2MS (M + H)⁺ Observ.679.1Retention Time3.93 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1025, (S)-ethyl 3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate

[Image Omitted]

1025 was prepared by using the same procedure of synthesizing 1020, using 2-amino-2-oxoacetic acid as a starting material.

(S)-ethyl 3-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate, 1025MS (M + H)⁺ Calcd.665.2MS (M + H)⁺ Observ.665.1Retention Time3.78 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€‚30Final % B100Gradient Timeâ€ƒâ€‰4 minFlow Rateâ€‚0.8 mL/minWavelength220Solvent PairWater -Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1552, N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)oxalamide

[Image Omitted]

1552 was prepared by using the same procedure of synthesizing 1025, using In-1005 instead of In-1101.

Compound 1552MS (M + H)⁺ Calcd.635.2MS (M + H)⁺ Observ.635.5Retention Time1.83minLC ConditionSolvent Aâ€‚â€‚5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Synthesis of Compound 1026, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoate

[Image Omitted]

To a solution of 1011 (20 mg) in ethanol (2 mL) was added K₂CO₃(20 mg). The mixture was stirred at room temperature for 2 days and then purified by preparative HPLC to give 1026 (5.2 mg).

(S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(dimethylamino)-2-oxoacetamido)butanoate, 1026MS (M + H)⁺ Calcd. 707.2MS (M + H)⁺ Observ.707.1Retention Time3.60minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1027, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoate

[Image Omitted]

1027 was prepared by using the same procedure of synthesizing 1026, using 1010 as a starting material.

(S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-(methylamino)-2-oxoacetamido)butanoate, 1027MS (M + H)⁺ Calcd.693.2MS (M + H)⁺ Observ.693.1Retention Time3.72minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1028, (S)-ethyl 4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate

[Image Omitted]

1028 was prepared by using the same procedure of synthesizing 1026, using 1009 as a starting material.

(S)-ethyl 4-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)butanoate, 1028MS (M + H)⁺ Calcd. 679.2MS (M + H)⁺ Observ.679.1Retention Time3.56minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1029, (S)-ethyl 5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate

[Image Omitted]

1029 was prepared by using the same procedure of synthesizing 1026, using 1012 as a starting material.

(S)-ethyl 5-(2-amino-2-oxoacetamido)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)pentanoate, 1029MS (M + H)⁺ Calcd. 693.2MS (M + H)⁺ Observ.693.1Retention Time3.54minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1030, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(methylamino)-2-oxoacetamido)pentanoate

[Image Omitted]

Step 1: To a solution of 2-(methylamino)-2-oxoacetic acid (16.1 mg) and TBTU (50.1 mg) in DMF (1 mL) was added In-1004 (100 mg) and DIPEA (0.15 mL). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(methylamino)-2-oxoacetamido)pentanoate (58 mg).

(S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(methylamino)-2-oxoacetamido)pentanoateMS (M + H)⁺ Calcd.693.2MS (M + H)⁺ Observ.693.1Retention Time3.54minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 2: 1030 was prepared by using the same procedure of synthesizing 1026, using (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(methylamino)-2-oxoacetamido)pentanoate as a starting material.

(S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(methylamino)-2-oxoacetamido)pentanoate, 1030MS (M + H)⁺ Calcd. 707.2MS (M + H)⁺ Observ.707.1Retention Time3.68minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1031, (S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(dimethylamino)-2-oxoacetamido)pentanoate

[Image Omitted]

Step 1: To a solution of 2-(dimethylamino)-2-oxoacetic acid (18.3 mg) and TBTU (50 mg) in DMF (1 mL) was added In-1004 (100 mg) and DIPEA (0.15 mL). After stirring at room temperature for 2 hours, the mixture was purified by preparative HPLC to give (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-5-(2-(dimethylamino)-2-oxoacetamido)pentanoate (48 mg).

(S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-5-(2-(dimethylamino)-2-oxoacetamido)pentanoateMS (M + H)⁺ Calcd. 707.2MS (M + H)⁺ Observ.707.1Retention Time3.44minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 2: 1031 was prepared by using the same procedure of synthesizing 1026, using (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-5-(2-(dimethylamino)-2-oxoacetamido)pentanoate as a starting material.

(S)-ethyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-5-(2-(dimethylamino)-2-oxoacetamido)pentanoate, 1031MS (M + H)⁺ Calcd. 721.2MS (M + H)⁺ Observ.721.1Retention Time3.70minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4minFlow Rate0.8mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1032, cyclopropylmethyl 2-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylamino)-2-oxoacetate

[Image Omitted]

A mixture of In-1005 (50 mg) and diphenyl oxalate (100 mg) in THF (5 mL) was stirred at room temperature for 16 hours, before cyclopropylmethanamine hydrochloride (191 mg) and iPr2NEt (0.5 mL) were added. The reaction was carried out at room temperature for 4 hours. Removal of solvents gave a residue which was purified by preparative HPLC to offer 1032 (20.7 mg).

cyclopropylmethyl 2-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylamino)-2-oxoacetate, 1032MS (M + Na)⁺ Calcd. 712.2MS (M + Na)⁺ Observ.712.2Retention Time2.38minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Synthesis of Compound 1033, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-cycloheptyloxalamide

[Image Omitted]

1033 was prepared by using the same procedure of synthesizing 1032, using cycloheptanamine as a starting material.

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-cycloheptyloxalamide, 1033MS (M + H)⁺ Calcd.731.3MS (M + H)⁺ Observ.731.4Retention Time2.53minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Synthesis of Compound 1034, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-(2,4-difluorobenzyl)oxalamide

[Image Omitted]

1034 was prepared by using the same procedure of synthesizing 1032, using (2,4-difluorophenyl)methanamine as a starting material.

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-(2,4-difluorobenzyl)oxalamide, 1034MS (M + H)⁺ Calcd.761.2MS (M + H)⁺ Observ.761.3Retention Time2.47minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Synthesis of Compound 1035, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-phenyloxalamide

[Image Omitted]

1035 was prepared by using the same procedure of synthesizing 1032, using aniline as a starting material.

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-phenyloxalamide, 1035MS (M + H)⁺ Calcd.711.2MS (M + H)⁺ Observ.711.3Retention Time2.45minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Synthesis of Compound 1036, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)oxalamide

[Image Omitted]

1036 was prepared by using the same procedure of synthesizing 1032, using (1-(pyrrolidin-1-ylmethyl)cyclopropyl)methanamine as a starting material.

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropyl)-N2-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)oxalamide, 1036MS (M + H)⁺ Calcd.772.3MS (M + H)⁺ Observ. 772.4Retention Time2.11minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

The following selected examples were prepared by using the same procedure of synthesizing 1032, using the corresponding amines rather than cyclopropylmethanamine hydrochloride as starting materials:

LC Condition ASolvent Aâ€‚5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2minFlow Rate1mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3 u

MSMSHPLCCompd.(M + H)⁺(M + H)⁺Rt#StructureCalcd.Obs.(min)Method1479 [Image Omitted]

729.2729.52.07A 1536 [Image Omitted]

725.3725.32.12A 3002 [Image Omitted]

665.2665.51.78A 3006 [Image Omitted]

741.2741.62.11A 3007 [Image Omitted]

741.2741.52.03A 3009 [Image Omitted]

759.2759.52.07A 3010 [Image Omitted]

732.2732.51.91A 3012 [Image Omitted]

755.3755.51.99A 3013 [Image Omitted]

769.3769.62.04A 3017 [Image Omitted]

801.3801.52.19A 3032 [Image Omitted]

739.2739.51.54A 3033 [Image Omitted]

701.2701.51.73A 3036 [Image Omitted]

715.2715.51.81A 3037 [Image Omitted]

796.3796.51.91A 3038 [Image Omitted]

762.3762.51.94A 3040 [Image Omitted]

702.2702.41.89A 3041 [Image Omitted]

753.3753.51.73A 3043 [Image Omitted]

767.3767.51.64A 3071 [Image Omitted]

763.2763.22.25A 3074 [Image Omitted]

651.2651.41.76A 3141 [Image Omitted]

815.3815.42.15A 3143 [Image Omitted]

813.3813.42.27A 3146 [Image Omitted]

777.2777.32.01A 3176 [Image Omitted]

715.2715.41.80A 3178 [Image Omitted]

715.2715.41.77A 3239 [Image Omitted]

736.2736.31.98A 3241 [Image Omitted]

712.2712.31.83A 3245 [Image Omitted]

712.2712.31.86A 3248 [Image Omitted]

712.2712.31.97A 3250 [Image Omitted]

797.2797.32.25A 3253 [Image Omitted]

700.2702.31.52A 3256 [Image Omitted]

778.3778.42.14A 3262 [Image Omitted]

765.2765.32.10A 3337 [Image Omitted]

750.3750.32.00A 3350 [Image Omitted]

772.2772.42.15A 3352 [Image Omitted]

752.2752.41.80A 3355 [Image Omitted]

765.2765.42.04A 3359 [Image Omitted]

767.2767.31.96A 3361 [Image Omitted]

797.3797.41.75A 3375 [Image Omitted]

754.2754.41.88A 3376 [Image Omitted]

768.2768.42.16A 3378 [Image Omitted]

759.2759.42.31A 3400 [Image Omitted]

830.3830.42.05A 3404 [Image Omitted]

829.3829.42.06A 3452 [Image Omitted]

763.2763.42.17A 3454 [Image Omitted]

750.3750.42.09A 3805 [Image Omitted]

782.2782.22.23A 3808 [Image Omitted]

769.2769.31.89A 2824 [Image Omitted]

785.2786.22.10A 3826 [Image Omitted]

782.2782.22.13A 3836 [Image Omitted]

743.3743.31.99A

Preparation of 1465, N¹-(2-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yDamino)benzamido)methyl)cyclopentyl)-N²-(4-fluorophenyl)oxalamide

iPr₂NEt (0.2 mL) and 4-fluoroaniline (39.2 mg) added into the soultion of ethyl 2-((2-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopentyl)amino)-2-oxoacetate (40 mg) in EtOH (2 mL) and the reaction was stirred at 155Â° C. for 3 days. The product was isolated by preparative HPLC system.

[Image Omitted]

Compound 1465MS (M + H)⁺ Calcd.741.2MS (M + H)⁺ Observ. 741.5Retention Time2.07 minLC ConditionSolvent A5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparation of 1492, N¹â€”((1-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopropyl)methyl)-N²-(4-fluorophenyl)oxalamide

To a solution of 2-(((1-((4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)methyl)cyclopropyl)methyl)amino)-2-oxoacetic acid (17 mg) and TBTU (10.33 mg) in DMF (2 mL) was added 4-fluoroaniline (3.58 mg). The mixture was stirred at room temperature for 16 hours, before being purified by preparative HPLC.

[Image Omitted]

Compound 1492MS (M + H)⁺ Calcd. 727.3MS (M + H)⁺ Observ.727.2Retention Time2.09 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Preparation of 3388, N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)oxalamide

[Image Omitted]

To a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzoic acid (10 mg) and TBTU (7.74 mg) in DMF (1 mL) was added N¹-(3-amino-2,2-dimethylpropyl)oxalamide (4.18 mg) and DIPEA (0.018 mL). The mixture was stirred at room temperature for 2 hours. The product was isolated by using preparative HPLC system.

Compound 3388MS (M + H)⁺ Calcd. 653.2MS (M + H)⁺ Observ.653.0Retention Time2.11 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B30Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

The following selected examples were prepared by using the same synthetic route of synthesizing 3388, using the corresponding substituted alkyl 4-aminobenzoates rather than methyl 4-amino-2-fluorobenzoate or substituted benzamines rather than 1-(4-chlorophenyl)cyclopropanamine as starting materials:

LC Condition ASolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B30Final % B100Gradient Time 2 minFlow Rate1 mL/minWavelength220Solvent Pair Water-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

LC Condition BSolvent A5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent Pair ACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 50 Ã— 2, 3u

MSMSHPLCCompd.(M + H)⁺(M + H)⁺Rt#StructureCalcd.Obs.(min)Method3386 [Image Omitted]

653.2653.02.08A 3387 [Image Omitted]

665.2665.02.11A 3389 [Image Omitted]

651.2651.02.16A 3477 [Image Omitted]

669.2669.32.16A 3478 [Image Omitted]

651.2651.32.07A 3511 [Image Omitted]

711.2711.42.08A 3519 [Image Omitted]

717.2717.41.88A 3812 [Image Omitted]

671.2671.23.25B 3243 [Image Omitted]

619.2619.12.12A 3244 [Image Omitted]

601.2601.22.06A 3247 [Image Omitted]

619.2619.12.10A 3265 [Image Omitted]

635.2635.12.11A 3333 [Image Omitted]

665.2665.11.94A 3351 [Image Omitted]

699.2699.22.01A 4001 [Image Omitted]

635.2635.12.02A

The following selected examples were prepared by using the same synthetic route of synthesizing 1032, using In-1006 rather than In-1005 as one of the starting materials, alone with the corresponding amines or their salts instead of cyclopropylmethanamine hydrochloride:

LC Condition ASolvent A5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent Pair ACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

MS (M + H)⁺MS (M + H)⁺HPLC RtCompd. #StructureCalcd.Obs.(min)Method3512 [Image Omitted]

763.2763.22.16A 3513 [Image Omitted]

781.2781.12.19A 3514 [Image Omitted]

761.2761.32.05A 3515 [Image Omitted]

755.2755.32.54A 3516 [Image Omitted]

754.2754.32.13A 3553 [Image Omitted]

797.2797.32.23A 3554 [Image Omitted]

743.2743.32.18A 3555 [Image Omitted]

765.2765.22.23A 3556 [Image Omitted]

805.3805.32.28A 3557 [Image Omitted]

759.2759.32.06A 3559 [Image Omitted]

813.2813.22.24A 3560 [Image Omitted]

789.3789.32.12A 3561 [Image Omitted]

891.3891.32.35A 3562 [Image Omitted]

795.2795.32.08A 3563 [Image Omitted]

835.3835.22.21A 3564 [Image Omitted]

831.3831.32.31A 3565 [Image Omitted]

784.2784.31.97A 3566 [Image Omitted]

786.2786.22.00A 3567 [Image Omitted]

733.2733.21.87A 3568 [Image Omitted]

786.2786.22.09A 3664 [Image Omitted]

777.2777.12.26A 3676 [Image Omitted]

802.2802.31.87A 3677 [Image Omitted]

846.2846.22.13A 3678 [Image Omitted]

865.2865.12.10A 3680 [Image Omitted]

850.2850.12.16A 3681 [Image Omitted]

854.2854.12.29A 3814 [Image Omitted]

816.2816.22.08A

General Procedure for Parallel Synthesis of OxalamidesMethod 1 and Method 2

Method 1:

A 0.08 M stock solution of the (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-4-(2-ethoxy-2-oxoacetamido)butanoate in DMF was prepared and DIPEA (5.0 eq) was charged in. To each of the amines (15 eq) weighed into 16Ã—100 mm threaded vials was added 1000 Î¼Ls of the (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-3-(2-ethoxy-2-oxoacetamido)propanoate/DIPEA solution. The reactions were agitated at 350 rpm on an Innova platform shaker at room temperature for 48 hours. Mixtures were transferred to a 96 well filter plate collecting into a 96 well deep-well plate. Each reaction vial was rinsed with 500 Î¼Ls of DMF and rinses were transferred to the appropriate wells of the filter plate. The desired products were isolated by preparative HPLC.

Method 2:

A 0.08 M stock solution of the (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-4-(2-ethoxy-2-oxoacetamido)butanoate in NMP was prepared and DIPEA (5.0 eq) was charged in. To each of the amines (15 eq) weighed into 16Ã—100 mm threaded vials was added 1000 Î¼Ls of the (S)-methyl 2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-3-(2-ethoxy-2-oxoacetamido)propanoate/DIPEA solution. The reactions were agitated at 350 rpm on an Innova platform shaker at room temperature for 48 hours. Samples were blown down using a Zymark tabletop dryer at 30Â° C. for 3 hours. A 1.8M solution of potassium carbonate in water was prepared. To each of the reaction vials was added 0.5 mL of acetone followed by 0.5 mls of the potassium carbonate solution. Vials were capped and agitated at 350 rpm on an Innova platform shaker at room temperature for 72 hours. Samples were blown down using a Zymark tabletop dryer at 30Â° C. for 3 hours before redissolving in 1 mL DMF each. Mixtures were transferred to a 96 well filter plate collecting into a 96 well deep-well plate. Reaction vials were rinsed with 500 Î¼Ls of DMF each and rinses were transferred to the appropriate wells of the filter plate. The desired products were isolated by preparative HPLC.

Analytical Methods

A:

Column. Supelco Ascentis Express C18, 4.6Ã—50 mm, 2.7-Î¼m particles; Mobile

Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40Â° C.;

Gradient: 0-100% B over 8 minutes, then a 1-minute hold at 100% B, then 100-0% B over 1 minute; Flow: 1 mL/min.

B:

Column: Waters Sunfire C18, 4.6Ã—100 mm, 3.5-Î¼m particles; Mobile Phase A: water with 0.1% TFA; Mobile Phase B: acetonitrile:water with 0.1% TFA;

Temperature: 40Â° C.; Gradient: 10-95% B over 6 minutes, then a 2-minute hold at 95% B, then 95-10% B over 0.50 minutes, then a 1.5 minute hold at 10% B; Flow: 1.2 mL/min.

C:

Column. Waters BEH C18, 2.1Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B;

Flow: 1 mL/min.

D:

Column. Waters BEH C18, 2.1Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 0.83 mL/min.

E:

Column. Waters BEH C18, 2.1Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 1 mL/min.

F:

Column. Waters BEH C18, 2.0Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B;

Flow: 0.5 mL/min.

General Procedure for Parallel Synthesis of OxalamidesMethod 3

[Image Omitted]

Step 1: To a solution of (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-(2-ethoxy-2-oxoacetamido)butanoate (1.0 g) in methanol (10 mL) was added Et₃N (10.0 mL) at room temperature. The reaction mixture was heated to 55Â° C. for 24 hours. The solvent was concentrated in vacuo. The reaction mixture was diluted with water and acidified with 1.5; N HCl. The aqueous layer was extracted with ethylacetate (3Ã—100 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford desired crude acid as white solid (850 mg).

Step 2: To a solution of (S)-2-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-4-methoxy-4-oxobutylamino)-2-oxoacetic acid (20 mg) in DMF (1.0 mL) were added HCTU (17.91 mg) and DIPEA (16 Î¼L) at rt and stirred for 15 minutes. Amine (1.2 eq.) was added to above solution and stirred at room temperature for 2 hour. Initial LCMS analysis showed formation of desired product. The solvent was evaporated and crude mixture was purified using preparative HPLC to afford desired product.

Step 3: To a solution of crude amide from step 2 in MeOH:H₂O (5:1, 1.0 mL) was added K₂CO₃(8.3 mg) and stirred for 24 hours at room temperature. The crude mixture was purified using preparative HPLC to afford desired product.

General Procedure for Parallel Synthesis of OxalamidesMethod 4

[Image Omitted]

Step 1: To a solution of (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-2-oxoacetamido)propanoate (1.5 g) in methanol (15 mL) was added Et₃N (15.0 mL) at room temperature. The reaction mixture was heated to 55Â° C. for 24 hours. The solvent was concentrated in vacuo. The reaction mixture was diluted with water and acidified with 1.5N HCl. The aqueous layer was extracted with ethylacetate (3Ã—100 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford desired crude acid as white solid (1.35 g).

Step 2: To a solution of (S)-2-(2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-methoxy-3-oxopropylamino)-2-oxoacetic acid (20 mg) in DMF (1.0 mL) were added HCTU (17.91 mg) and DIPEA (16 Î¼L) at room temperature and stirred for 15 minutes. Amine (1.2 eq.) was added to above solution and stirred at room temperature for 2 hours. Initial LCMS analysis showed formation of desired product. The solvent was evaporated and crude mixture was purified using preparative HPLC to afford desired product.

Step 3: To a solution of crude amide from step 2 in MeOH:H₂O (5:1, 1.0 mL) was added K₂CO₃(8.3 mg) and stirred for 24 hours at room temperature. The crude mixture was purified using preparative HPLC to afford desired product.

Preparation of Compound 2001, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2,2-dimethyl-3-(2-oxo-2-(pyrrolidin-1-ypacetamido)propyl)-3-fluorobenzamide

[Image Omitted]

Step 1:

To a solution of 2,4,6-trichloro-1,3,5-triazine (15 g) in THF (300 mL) was added 2,2,2-trifluoroethanol (8.14 g) and Hunig'sBase (15.63 mL). The resulting mixture was stirred for 16 hours. After removal of most THF and precipitate through a plug washing with THF, the filtrate was concentrate to give a crude that will be used as it is.

Step 2:

To a solution of the product in Step 1 above (1.47 g, 5.91 mmol) in THF (10 mL) was added methyl 4-amino-3-fluorobenzoate (1 g, 5.91 mmol) and Hunig'sBase (3.10 mL, 17.74 mmol). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with THF and water and dried to give 1.5 g of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as a solid.

methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoateMS (M + H)⁺ Calcd.381.7MS (M + H)⁺ Observ. 381.0Retention Time1.0 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Step 3:

To a solution of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate (0.93 g, 2.45 mmol) in THF (10 mL) was added 1-(4-chlorophenyl)cyclopropanamine (0.5 g, 2.45 mmol) and Hunig's Base (1.71 mL, 9.8 mmol). The resulting mixture was refluxed at 80Â° C. for 16 hs. The precipitate was filtrated through a plug washing with THF to give a crude product that was purified by Biotage eluting with 4/1 to 3/2 hexane/ethyl acetate to give 1.2 g of methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoro ethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate as product.

methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoateMS (M + H)⁺ Calcd. 512.9MS (M + H)⁺ Observ.512.1Retention Time1.10 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Step 4:

To a solution of methyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoate (1.2 g, 2.34 mmol) in THF/water (1:1, 10 mL) was added LiOH (0.6 g, 25.0 mmol). The reaction mixture was refluxed at 80Â° C. for 7 hours. After cooling to room temperature, the reaction solution was acidified with 1N HCl. The product was extracted by EtOAc. The organic layer was washed with brine, dried over Na₂SO₄and concentrated under vacuum. The crude product 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoic acid was used directly in the next step.

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoic acidMS (M + H)⁺ Calcd. 498.8MS (M + H)⁺ Observ.498.0Retention Time1.00 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent Pair ACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Step 5:

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzoic acid (200 mg, 0.42 mmol) in DCM (3 mL) was added tert-butyl 3-amino-2,2-dimethylpropylcarbamate (98 mg, 0.48 mmol), HATU (229 mg, 0.60 mol) and iPr₂NEt (0.35 mL, 2.00 mmol). The mixture was stirred at r.t. for 16 hours before all the solvents were removed under vacuum. All solvents were removed under vacuum and the residue was purified by silica gel column (EtOAC/Hexanes=20% to 40%) to give tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamate (270 mg, 100%) as a white solid.

tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamateMS (M + H)⁺ Calcd. 683.1MS (M + H)⁺ Observ.682.3Retention Time1.15 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Step 6:

tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropylcarbamate (270 mg, 0.40 mmol) was dissolved in 4 M HCl in dioxane (5 mL) solution. After being stirred at room temperature for 3 hours, the mixture was concentrated to give N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide as crude product.

N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamideMS (M + H)⁺ Calcd. 583.0MS (M + H)⁺ Observ.582.2Retention Time0.92 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Step 7:

To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (80 mg, 0.14 mmol) and 2-oxo-2-(pyrrolidin-1-yl)acetic acid (20 mg, 0.137 mmol) in DMF (2 mL) were added O-(benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium tetrafluoroborate (66 mg, 0.21 mmol) and iPr₂NEt (0.050 ml, 0.28 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2,2-dimethyl-3-(2-oxo-2-(pyrrolidin-1-yl)acetamido)propyl)-3-fluorobenzamide (14.4 mg, 14%) as product. ¹H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.01 (6H, s), 1.42 (4H, m), 1.81-2.02 (4H, m), 3.14 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.60 (2H, t, J=6.9 Hz), 3.91-4.12 (2H, m), 4.70-4.80 (2H, m), 7.14-7.38 (3H, m), 7.48-7.59 (1H, m), 7.69-7.80 (1H, m), 7.94-8.06 (1H, m), 8.24-8.31 (1H, m).

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2,2-dimethyl-3-(2-oxo-2-(pyrrolidin-l-yl)acetamido)propyl)-3-fluorobenzamideMS (M + H)⁺ Calcd. 708.1MS (M + H)⁺ Observ.707.3Retention Time1.07 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent PairACN: Water: TFAColumnAcquity UPLC BEH C18 1.7 uM

Preparation of Compound 2002, N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide

[Image Omitted]

To a solution of N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamide (20 mg, 0.034 mmol) and 2-(dimethylamino)-2-oxoacetic acid (4.83 mg, 0.041 mmol) in DMF (1 mL) were added O-(benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium tetrafluoroborate (16.5 mg, 0.052 mmol) and iPr₂NEt (0.012 ml, 0.069 mmol). After stirring at rt for 16 hs, the mixture was purified by preparative HPLC to give N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamide (13.8 mg, 56%) as product. ¹H NMR (400 MHz, CHLOROFORM-d) 8 ppm 1.03 (6H, s), 1.31-1.53 (4H, m), 3.06 (3H, s), 3.10-3.21 (2H, m), 3.29 (2H, d, J=6.0 Hz), 3.39 (3H, s), 4.75 (2H, m), 7.14-7.29 (3H, m), 7.33-7.48 (1H, m), 7.70-7.81 (1H, m), 7.92-8.04 (1H, m), 8.07-8.15 (1H, m).

N1-(3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-3-fluorobenzamido)-2,2-dimethylpropyl)-N2,N2-dimethyloxalamideMS (M + H)⁺ Calcd. 682.1MS (M + H)⁺ Observ.681.3Retention Time1.02 minLC ConditionSolvent A100% Water: 0.05% TFASolvent B100% ACN: 0.05% TFAStart % B2Final % B98Gradient Time2.2 minFlow Rate0.8 mL/minWavelength220Solvent Pair ACN: Water: TFA

Displacement of CF₃CH₂O moiety by benzyl alcohol:

[Image Omitted]

A solution of N1-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)-N2-(p-tolyl)oxalamide (520 mg) in THF was prepared. NaH (19.86 mg) and 500 Î¼L of the N₁-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)-N₂-(p-tolyl)oxalamide solution was added into 16Ã—48 mm each threaded vial containing an individual alcohol (5-10 eq.). Vials were capped and allowed to shake at room temperature for 3 days. Samples were blown down in the Zymark tabletop dryer at 35Â° C. for 2 hours and products were purified by preparitive HPLC systems.

Method M=Column: Waters BEH C18, 2.0Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile

Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min.

Method A=Column: Waters BEH C18, 2.0Ã—50 mm, 1.7-Î¼m particles; Mobile Phase A: 5:95

acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5

acetonitrile:water with 10 mM ammonium acetate; Temperature: 40Â° C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.

MSMSHPLCCompd.(M + H)⁺(M + H)⁺Rt#StructureCalcd.Obs.(min)Method3840 [Image Omitted]

799.3798.93.61A 3841 [Image Omitted]

789.4789.84.86M 3842 [Image Omitted]

761.3761.84.75M 3843 [Image Omitted]

733.3733.74.60M 3844 [Image Omitted]

767.3767.94.68M 3845 [Image Omitted]

751.3751.74.58M 3846 [Image Omitted]

751.3751.84.59M 3847 [Image Omitted]

751.3751.94.60M 3848 [Image Omitted]

747.3747.84.68M 3849 [Image Omitted]

767.3767.74.68M 3850 [Image Omitted]

767.3767.74.71M 3851 [Image Omitted]

801.3800.83.76A 3852 [Image Omitted]

828.3828.04.54M 3853 [Image Omitted]

762.3762.84.43M 3839 [Image Omitted]

775.3775.83.92A 4002 [Image Omitted]

786.3786.83.75A

Preparation of 3827, N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-((4-isopropylbenzyl)oxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)-N²-(p-tolyl)oxalamide

[Image Omitted]

To a suspension of (4-isopropylphenyl)methanol (24.46 mg) and NaH (5.92 mg) in THF (10 mL) was added N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)-N²-(p-tolyl)oxalamide (11 mg). The mixture was heated to reflux for 3 hours. The reaction was quenched by 5% NaHCO₃/H₂O and extracted with EtOAc (2Ã—10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO₄and concentrated. The residue was purified by preparative HPLC system to give Compound 3827.

Compound 3827MS (M + H)⁺ Calcd.793.3MS (M + H)⁺ Observ. 793.4Retention Time2.38 minLC ConditionSolvent A5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparations of 3828, 3829, 3830 and 3835

Compounds 3828, 3829, 3830 and 3835 were prepared under the same condition for the synthesis of Compound 3827, using N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)-N²-(4-methoxyphenyl)oxalamide, N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)-N²-(4-(trifluoromethyl)phenyl)oxalamide, N¹-([1,1â€²-biphenyl]-2-yl)-N²-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-((4-isopropylbenzyl)oxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)oxalamide and N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-((4-isopropylbenzyl)oxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzamido)-2,2-dimethylpropyl)-N²-(2,4-difluorophenyl)oxalamide as starting materials.

3828

MS (M + H)⁺ Calcd.809.3MS (M + H)⁺ Observ.809.3Retention Time2.32 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3829 [Image Omitted]

MS (M + H)⁺ Calcd.847.3MS (M + H)⁺ Observ.847.3Retention Time2.44 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3830 [Image Omitted]

MS (M + H)⁺ Calcd.855.4MS (M + H)⁺ Observ.855.3Retention Time2.51 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u3835 [Image Omitted]

MS (M + H)⁺ Calcd.815.3MS (M + H)⁺ Observ.815.3Retention Time2.29 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparations of 3834 and 4003

Step 1: iPr₂NEt (4 mL) was added into a solution of 2-(chloromethyl)-2-methyloxirane (0.745 g) and (2,4-dimethoxyphenyl)methanamine (2.338 g) in EtOH (20 mL). The reaction was stirred at room temperature for 16 hours, then 115Â° C. for 72 hours before being quenched by water. After removal of solvents under vacuum, the residue was purified by silica gel chromatography or preparative HPLC.

1,3-bis((2,4-dimethoxybenzyl)amino)-2-methylpropan-2-olMS (M + H)⁺ Calcd.405.2MS (M + H)⁺ Observ. 405.2Retention Time2.79 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Step 2: iPr₂NEt (0.5 mL) and HATU (238 mg) were added into the solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (300 mg) and 1,3-bis((2,4-dimethoxybenzyl)amino)-2-methylpropan-2-ol (253 mg) in THF (10 mL). The reaction was stirred at room temperature for 24 hours. The product was isolated by silica gel chromatography.

4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(2,4-dimethoxybenzyl)-N-(3-((2,4-dimethoxybenzyl)amino)-2-hydroxy-2-methylpropyl)benzamideMS (M + H)⁺ Calcd.866.3MS (M + H)⁺ Observ.866.3Retention Time2.01 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 3: iPr₂NEt (0.5 mL), HATU (21.93 mg) were added into the solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(2,4-dimethoxybenzyl)-N-(3-((2,4-dimethoxybenzyl)amino)-2-hydroxy-2-methylpropyl)benzamide (50 mg) in THF (10 mL). The reaction was stirred at room temperature for 24 hours, before being quenched by NaHCO3 aqueous solution (10 mL). The aqueous phase was extracted by EtOAc (3Ã—10 mL). The combined organic layer was dried over MgSO₄and concentrated under vacuum to give a residue which was used as was.

N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(2,4-dimethoxybenzyl)benzamido)-2-hydroxy-2-methylpropyl)-N¹-(2,4-dimethoxybenzyl)oxalamideMS (M + H)⁺ Calcd.937.3MS (M + H)⁺ Observ.937.3Retention Time1.93 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 4: TFA (0.2 mL) was added into a solution of N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(2,4-dimethoxybenzyl)benzamido)-2-hydroxy-2-methylpropyl)-N¹-(2,4-dimethoxybenzyl)oxalamide (50 mg) in CH₂Cl₂(2 mL). The reaction was stirred at room temperature for 24 hours, before all the solvents were removed undr vacuum. The residue was purified by preparative HPLC system.

Compound 3834MS (M + H)⁺ Calcd.637.2MS (M + H)⁺ Observ.637.1Retention Time1.58 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3uCompound 4003MS (M + H)⁺ Calcd.619.2MS (M + H)⁺ Observ.619.1Retention Time1.72 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparation of 3838, N¹-(3-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-bis(hydroxymethyl)propyl)oxalamide

[Image Omitted]

Compound 3838 was prepared by using the same synthetic route of synthesizing 3834, using 2,2-bis(((2,4-dimethoxybenzyl)amino)methyl)propane-1,3-diol instead of 1,3-bis((2,4-dimethoxybenzyl)amino)-2-methylpropan-2-ol as one of the starting materials. And, 2,2-bis(((2,4-dimethoxybenzyl)amino)methyl)propane-1,3-diol was prepared by using the same procedure of synthesizing

1,3-bis((2,4-dimethoxybenzyl)amino)-2-methylpropan-2-ol by using 2,2-bis(bromomethyl)propane-1,3-diol rather than 2-(chloromethyl)-2-methyloxirane as one of the starting materials.

Compound 3838MS (M + H)⁺ Calcd.667.2MS (M + H)⁺ Observ. 667.3Retention Time1.55 minLC ConditionSolvent A5% ACN: 95% Water: 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water: 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparations of 4004, N²â€”((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)-N²-(4-fluorophenyl)oxalamide and 4005, N¹â€”((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)-N²-(cyclopropylmethyl)oxalamide

Step 1: iPr₂NEt (0.5 mL) was added into a solution of tert-butyl (2-(aminomethyl)cyclopentyl)carbamate (300 mg) and ethyl 2-chloro-2-oxoacetate (191 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3Ã—20 mL). The combined organic phase was dried over MgSO₄and concentrated under vacuum to give the crude ethyl 2-(((2-((tert-butoxycarbonyl)amino)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.

[Image Omitted]

Step 2: Ethyl 2-(((2-((tert-butoxycarbonyl)amino)cyclopentyl)methyl)amino)-2-oxoacetate (440 mg) in TFA (1 mL) and CH₂Cl₂(10 mL) was stirred at room temperature for 16 hours. After removal of solvents, the crude ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetate was used as was.

ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetateMS (M + H)⁺ Calcd.215.1MS (M + H)⁺ Observ.215.2Retention Time0.65 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 3: iPr₂NEt (0.5 mL) was added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (300 mg), ethyl 2-(((2-aminocyclopentyl)methyl)amino)-2-oxoacetate (205 mg) and TBTU (201 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3Ã—20 mL). The combined organic phase was dried over MgSO₄and concentrated under vacuum to give the crude ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.

ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetateMS (M + H)⁺ Calcd.676.2MS (M + H)⁺ Observ.676.4Retention Time1.82 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 4: A mixture of ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate (30 mg) and 4-fluoroaniline (49.3 mg) in EtOH (2 mL) was stirred at room temperature for 16 hours, then at 155Â° C. for 16 hours. Then, the product 4004 was isolated by preparative HPLC system.

Compound 4004MS (M + H)⁺ Calcd.741.2MS (M + H)⁺ Observ.741.5Retention Time2.09 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparation of 4005, N²â€”((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)-N²-(cyclopropylmethyl)oxalamide

A mixture of ethyl 2-(((2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)cyclopentyl)methyl)amino)-2-oxoacetate (30 mg) and cyclopropylmethanamine (31.6 mg) in EtOH (2 mL) was stirred at room temperature for 16 hours. Then, the product 4005 was isolated by preparative HPLC system.

Compound 4005MS (M + H)⁺ Calcd.701.3MS (M + H)⁺ Observ.701.5Retention Time1.98 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Preparation of 3492, (R)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yDamino)benzamido)-2-(2-((3-fluorophenyl)amino)-2-oxoacetamido)butanoic acid

Step 1: N,N-Di-iso-propylethylamine (0.054 g) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g) were added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (0.1 g) and (R)-4-amino-2-((tert-butoxycarbonyl)amino)butanoic acid (0.045 g) in DMF (1 mL). The reaction was stirred at room temperature for 16 hours and (R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid was isolated by using preparative HPLC system.

(R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acidMS (M + H)⁺ Calcd.680.2MS (M + H)⁺ Observ.680.2Retention Time1.55 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 2: TFA (0.340 mL) was added into a solution of (R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid (0.2 g) in DCM (1 mL). The reaction was stirred at room temperature for 2 hours. After removal of solvents, the residue was purified by preparative HPLC system.

(R)-2-amino-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acidMS (M + H)⁺ Calcd.580.2MS (M + H)⁺ Observ.580.2Retention Time1.52 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

Step 3: iPr₂NEt (8.91 mg) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.013 g) were added into a solution of (R)-2-amino-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid (0.020 g) and 2-((3-fluorophenyl)amino)-2-oxoacetic acid (6.32 mg) in DMF (1 mL). The reaction was stirred at room temperature for 1 hour and compound 3492 was isolated by using preparative HPLC system.

Compound 3492MS (M + H)⁺ Calcd.745.2MS (M + H)⁺ Observ.745.2Retention Time1.61 minLC ConditionSolvent A5% ACN: 95% Water : 10 mM Ammonium ActetateSolvent B95% ACN: 5% Water : 10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN: Water: Ammonium ActetateColumnPhenomenex Luna C18, 30 Ã— 2, 3u

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

LENGTHY TABLESThe patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).