This application claims the priority to the U.S. provisional application No. 62/154,082, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

Provided are certain compounds and/or pharmaceutically acceptable salts thereof which can inhibit kinase activity of CDK4/6 and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation.

BACKGROUND OF THE INVENTION

Hyper-proliferative diseases like cancer and inflammation are attracting the scientific community to provide therapeutic benefits. In this regard efforts have been made to identify and target specific mechanisms which play a role in proliferating the diseases.

Tumor development is closely associated with genetic alteration and deregulation of cyclin-dependent kinases (CDKs) and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics.

CDKs are serine/threonine protein kinases, which are the driving force behind the cell cycle and cell proliferation. CDKs regulate initiation, progression, and completion of mammalian cell cycle, and they are critical for cell growth. Most of the known CDK's, including CDK1 through CDK9, are involved either directly or indirectly in cell cycle progression. Those directly involved with cell cycle progression, such as CDK1-4 and 6, can be classified as G1, S, or G2M phase enzymes. Uncontrolled proliferation is a hallmark of cancer cells and the alteration of CDK function occurs with high frequency in many solid tumors.

The pivotal roles of CDKs, and their associated proteins, in coordinating and driving the cell cycle in proliferating cells have been outlined. The development of monotherapies for the treatment of proliferative disorders, such as cancers, using therapeutics targeted generically at CDKs, or at specific CDKs, is therefore potentially highly desirable. CDK inhibitors could conceivably also be used to treat other conditions such as viral infections, autoimmune diseases and neuro-degenerative diseases, amongst others. CDKs targeted therapeutics may also provide clinical benefits in the treatment of the previously described diseases when used in combination therapy with either existing, or new, therapeutic agents.

Therefore, a compound having an inhibitory activity on CDK will be useful for the prevention or treatment of cancer. Although CDK4/6 inhibitors were disclosed in the arts, e.g., WO2010075074, many suffer from having short half-life or toxicity. Therefore, there is a need for new CDK4/6 inhibitors that have at least one advantageous property selected from potency, stability, selectivity, toxicity and pharmacodynamics properties as an alternative for the treatment of hyper-proliferative diseases. In this regard, a novel class of CDK4/6 inhibitors is provided herein.

DISCLOSURE OF THE INVENTION

Disclosed herein are certain novel fused tricyclic ring derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals.

In one aspect, disclosed herein is a compound of formula (I):

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from aryl and heteroaryl;

W is selected from N and CR⁶;

Z is selected from N and CR⁶;

R¹is selected from hydrogen, halogen, hydroxyl, CN, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, di(C_1-10alkylamino, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R²is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A1R^B1, —OR^A1, —SR^A1, —S(O)_rR^A1, —S(O)₂OR^A1, —OS(O)₂R^B1, —S(O)_rNR^A1R^B1, —P(O)R^A1R^B1, —P(O)(OR^A1)(OR^B1), —(CR^C1R^D1)_tNR^A1R^B1, —(CR^C1R^D1)_tOR^B1, —(CR^C1R^D1)_tSR^B1, —(CR^C1R^D1)_tS(O)_rR^B1, —(CR^C1R^D1)_tP(O)R^A1R^B1, —(CR^C1R^D1)_tP(O)(OR^A1)(OR^B1), —(CR^C1R^D1)_tCO₂R^B1, —(CR^C1R^D1)_tC(O)NR^A1R^B1, —(CR^C1R^D1)_tNR^A1C(O)R^B1, —(CR^C1R^D1)_tNR^A1CO₂R^B1, —(CR^C1R^D1)_tOC(O)NR^A1R^B1, —(CR^C1R^D1)_tNR^A1CONR^A1R^B1, —(CR^C1R^D1)_tNR^A1SO₂NR^A1R^B1, —NR^A1(CR^C1R^D1)_tNR^A1R^B1, —O(CR^C1R^D1)_tNR^A1R^B1, —S(CR^C1R^D1)_tNR^A1R^B1, —S(O)_r(CR^C1R^D1)_tNR^A1R^B1, —C(O)R^A1, —C(O)(CR^C1R^D1)_tNR^A1R^B1, —C(O)(CR^C1R^D1)_tOR^B1, —C(O)(CR^C1R^D1)_tSR^B1, —C(O)(CR^C1R^D1)_tS(O)_rR^B1, —CO₂R^B1, —CO₂(CR^C1R^D1)_tC(O)NR^A1R^B1, —OC(O)R^A1, —CN, —C(O)NR^A1R^B1, —NR^A1C(O)R^B1, —NR^A1CO₂R^B1, —OC(O)NR^A1R^B1, —NR^A1C(O)NR^A1R^B1, —NR^A1S(O)_rR^B1, —CR^A1(═N—OR^B1), —C(═NR^E1)R^A1, —C(═NR^E1)NR^A1R^B1, —NR^A1C(═NR^E1)NR^A1R^B1, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R³is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A2R^B2, —OR^A2, —SR^A2, —S(O)_rR^A2, —S(O)₂OR^A2, —OS(O)₂R^B2, —S(O)_rNR^A2R^B2, —P(O)R^A2R^B2, —P(O)(OR^A2)(OR^B2), —(CR^C2R^D2)_tNR^A2R^B2, —(CR^C2R^D2)_tOR^B2, —(CR^C2R^D2)_tSR^B2, —(CR^C2R^D2)_tS(O)_rR^B2, —(CR^C2R^D2)_tP(O)R^A2R^B2, —(CR^C2R^D2)_tP(O)(OR^A2)(OR^B2), —(CR^C2R^D2)_tCO₂R^B2, —(CR^C2R^D2)_tC(O)NR^A2R^B2, —(CR^C2R^D2)_tNR^A2C(O)R^B2, —(CR^C2R^D2)_tNR^A2CO₂R^B2, —(CR^C2R^D2)_tOC(O)NR^A2R^B2, —(CR^C2R^D2)_tNR^A2CONR^A2R^B2, —(CR^C2R^D2)_tNR^A2SO₂NR^A2R^B2, —NR^A2(CR^C2R^D2)_tNR^A2R^B2, —O(CR^C2R^D2)_tNR^A2R^B2, —S(CR^C2R^D2)_tNR^A2R^B2, —S(O)_r(CR^C2R^D2)_tNR^A2R^B2, —C(O)R^A2, —C(O)(CR^C2R^D2)_tNR^A2R^B2, —C(O)(CR^C2R^D2)_tOR^B2, —C(O)(CR^C2R^D2)_tSR^B2, —C(O)(CR^C2R^D2)_tS(O)_rR^B2, —CO₂R^B2, —CO₂(CR^C2R^D2)_tC(O)NR^A2R^B2, —OC(O)R^A2, —CN, —C(O)NR^A2R^B2, —NR^A2C(O)R^B2, —NR^A2CO₂R^B2, —OC(O)NR^A2R^B2, —NR^A2C(O)NR^A2R^B2, —NR^A2S(O)_rR^B2, —CR^A2(═N—OR^B2), —C(═NR^E2)R^A2, —C(═NR^E2)NR^A2R^B2, —NR^A2C(═NR^E2)NR^A2R^B2, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or two R³together with the carbon atoms to which they are attached form a cyclic ring of 3 to 7 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R^Xgroups;

R⁴is selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A3R^B3, —OR^A3, —SR^A3, —S(O)_rR^A3, —S(O)₂OR^A3, —OS(O)₂R^B3, —S(O)_rNR^A3R^B3, —P(O)R^A3R^B3, —P(O)(OR^A3)(OR^B3), —(CR^C3R^D3)_tNR^A3R^B3, —(CR^C3R^D3)_tOR^B3, —(CR^C3R^D3)_tSR^B3, —(CR^C3R^D3)_tS(O)_rR^B3, —(CR^C3R^D3)_tP(O)R^A3R^B3, —(CR^C3R^D3)_tP(O)(OR^A3)(OR^B3), —(CR^C3R^D3)_tCO₂R^B3, —(CR^C3R^D3)_tC(O)NR^A3R^B3, —(CR^C3R^D3)_tNR^A3C(O)R^B3, —(CR^C3R^D3)_tNR^A3CO₂R^B3, —(CR^C3R^D3)_tOC(O)NR^A3R^B3, —(CR^C3R^D3)_tNR^A3CONR^A3R^B3, —(CR^C3R^D3)_tNR^A3SO₂NR^A3R^B3, —NR^A3(CR^C3R^D3)_tNR^A3R^B3, —O(CR^C3R^D3)_tNR^A3R^B3, —S(CR^C3R^D3)_tNR^A3R^B3, —S(O)_r(CR^C3R^D3)_tNR^A3R^B3, —C(O)R^A3, —C(O)(CR^C3R^D3)_tNR^A3R^B3, —C(O)(CR^C3R^D3)_tOR^B3, —C(O)(CR^C3R^D3)_tSR^B3, —C(O)(CR^C3R^D3)_tS(O)_rR^B3, —CO₂R^B3, —CO₂(CR^C3R^D3)_tC(O)NR^A3R^B3, —OC(O)R^A3, —CN, —C(O)NR^A3R^B3, —NR^A3C(O)R^B3, —NR^A3CO₂R^B3, —OC(O)NR^A3R^B3, —NR^A3C(O)NR^A3R^B3, —NR^A3S(O)_rR^B3, —CR^A3(═N—OR^B3), —C(═NR^E3)R^A3, —C(═NR^E3)NR^A3R^B3, —NR^A3C(═NR^E3)NR^A3R^B3, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R⁵is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A4R^B4, —OR^A4, —SR^A4, —S(O)_rR^A4, —S(O)₂OR^A4, —OS(O)₂R^B4, —S(O)_rNR^A4R^B4, —P(O)R^A4R^B4, —P(O)(OR^A4)(OR^B4), —(CR^C4R^D4)_tNR^A4R^B4, —(CR^C4R^D4)_tOR^B4, —(CR^C4R^D4)_tSR^B4, —(CR^C4R^D4)_tS(O)_rR^B4, —(CR^C4R^D4)_tP(O)R^A4R^B4, —(CR^C4R^D4)_tP(O)(OR^A4)(OR^B4), —(CR^C4R^D4)_tCO₂R^B4, —(CR^C4R^D4)_tC(O)NR^A4R^B4, —(CR^C4R^D4)_tNR^A4C(O)R^B4, —(CR^C4R^D4)_tNR^A4CO₂R^B4, —(CR^C4R^D4)_tOC(O)NR^A4R^B4, —(CR^C4R^D4)_tNR^A4CONR^A4R^B4, —(CR^C4R^D4)_tNR^A4SO₂NR^A4R^B4, —NR^A4(CR^C4R^D4)_tNR^A4R^B4, —O(CR^C4R^D4)_tNR^A4R^B4, —S(CR^C4R^D4)_tNR^A4R^B4, —S(O)_r(CR^C4R^D4)_tNR^A4R^B4, —C(O)R^A4, —C(O)(CR^C4R^D4)_tNR^A4R^B4, —C(O)(CR^C4R^D4)_tOR^B4, —C(O)(CR^C4R^D4)_tSR^B4, —C(O)(CR^C4R^D4)_tS(O)_rR^B4, —CO₂R^B4, —CO₂(CR^C4R^D4)_tC(O)NR^A4R^B4, —OC(O)R^A4, —CN, —C(O)NR^A4R^B4, —NR^A4C(O)R^B4, —NR^A4CO₂R^B4, —OC(O)NR^A4R^B4, —NR^A4C(O)NR^A4R^B4, —NR^A4S(O)_rR^B4, —CR^A4(═N—OR^B4), —C(═NR^E4)R^A4, —C(═NR^E4)NR^A4R^B4, —NR^A4C(═NR^E4)NR^A4R^B4, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R⁶is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A5R^B5, —OR^A5, —SR^A5, —S(O)_rR^A5, —S(O)₂OR^A5, —OS(O)₂R^B5, —S(O)_rNR^A5R^B5, —P(O)R^A5R^B5, —P(O)(OR^A5)(OR^B5), —(CR^C5R^D5)_tNR^A5R^B5, —(CR^C5R^D5)_tOR^B5, —(CR^C5R^D5)_tSR^B5, —(CR^C5R^D5)_tS(O)_rR^B5, —(CR^C5R^D5)_tP(O)R^A5R^B5, —(CR^C5R^D5)_tP(O)(OR^A5)(OR^B5), —(CR^C5R^D5)_tCO₂R^B5, —(CR^C5R^D5)_tC(O)NR^A5R^B5, —(CR^C5R^D5)_tNR^A5C(O)R^B5, —(CR^C5R^D5)_tNR^A5CO₂R^B5, —(CR^C5R^D5)_tOC(O)NR^A5R^B5, —(CR^C5R^D5)_tNR^A5CONR^A5R^B5, —(CR^C5R^D5)_tNR^A5SO₂NR^A5R^B5, —NR^A5(CR^C5R^D5)_tNR^A5R^B5, —O(CR^C5R^D5)_tNR^A5R^B5, —S(CR^C5R^D5)_tNR^A5R^B5, —S(O)_r(CR^C5R^D5)_tNR^A5R^B5, —C(O)R^A5, —C(O)(CR^C5R^D5)_tNR^A5R^B5, —C(O)(CR^C5R^D5)_tOR^B5, —C(O)(CR^C5R^D5)_tSR^B5, —C(O)(CR^C5R^D5)_tS(O)_rR^B5, —CO₂R^B5, —CO₂(CR^C5R^D5)_tC(O)NR^A5R^B5, —OC(O)R^A5, —CN, —C(O)NR^A5R^B5, —NR^A5C(O)R^B5, —NR^A5CO₂R^B5, —OC(O)NR^A5R^B5, —NR^A5C(O)NR^A5R^B5, —NR^A5S(O)_rR^B5, —CR^A5(═N—OR^B5), —C(═NR^E5)R^A5, —C(═NR^E5)NR^A5R^B5, —NR^A5C(═NR^E5)NR^A5R^B5, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R^A1, R^A2, R^A3, R^A4, R^A5, R^B1, R^B2, R^B3, R^B4, and R^B5are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or each “R^A1and R^B1”, “R^A2and R^B2”, “R^A3and R^B3”, “R^A4and R^B4”, and “R^A5and R^B5”, together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 12, or 3 R^Xgroups;

each R^C1, R^C2, R^C3, R^C4, R^C5, R^D1, R^D2, R^D3, R^D4, and R^D5are independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or “R^C1and R^D1”, “R^C2and R^D2”, “R^C3and R^D3”, “R^C4and R^D4”, and “R^C5and R^D5” together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 12, or 3 R^Xgroups;

each R^E1, R^E2, R^E3, R^E4, and R^E5is independently selected from hydrogen, C_1-10alkyl, CN, NO₂, OR^a2, SR^a2, —S(O)_rR^a2, —C(O)R^a2, —S(O)_rNR^Δ2R^b2, and —C(O)NR^a2R^b2;

each R^Xis independently selected from C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, halogen, —NO₂, —NR^a1R^b1, —OR^a1, —SR^a1, —S(O)_rR^a1, —S(O)₂OR^a1, —OS(O)₂R^b1, —S(O)_rNR^a1R^b1, —P(O)R^a1R^b1, —P(O)(OR^a1)(OR^b1), —(CR^c1R^d1)_tNR^a1R^b1, —(CR^c1R^d1)_tOR^b1, —(CR^c1R^d1)_tSR^b1, —(CR^c1R^d1)_tS(O)_rR^b1, —(CR^c1R^d1)_tP(O)R^a1R^b1, —(CR^c1R^d1)_tP(O)(OR^a1)(OR^b1), —(CR^c1R^d1)_tCO₂R^b1, —(CR^c1R^d1)_tC(O)NR^a1R^b1, —(CR^c1R^d1)_tNR^a1C(O)R^b1, —(CR^c1R^d1)_tNR^a1CO₂R^b1, —(CR^c1R^d1)_tOC(O)NR^a1R^b1, —(CR^c1R^d1)_tNR^a1C(O)NR^a1R^b1, —(CR^c1R^d1)_tNR^a1SO₂NR^a1R^b1, —NR^a1(CR^c1R^d1)_tNR^a1R^b1, —O(CR^c1R^d1)_tNR^a1R^b1, —S(CR^c1R^d1)_tNR^a1R^b1, —S(O)_r(CR^c1R^d1)_tNR^a1R^b1, —C(O)R^a1, —C(O)(CR^c1R^d1)_tNR^a1R^b1, —C(O)(CR^c1R^d1)_tOR^b1, —C(O)(CR^c1R^d1)_tSR^b1, —C(O)(CR^c1R^d1)_tS(O)_rR^b1, —CO₂R^b1, —CO₂(CR^c1R^d1)_tC(O)NR^a1R^b1, —OC(O)R^a1, —CN, —C(O)NR^a1R^b1, —NR^a1C(O)R^b1, —OC(O)NR^a1R^b1, —NR^a1C(O)OR^b1, —NR^a1C(O)NR^a1R^b1, —NR^a1S(O)_rR^b1, —CR^a1(═N—OR^b1), —C(═NR^e1)R^a1, —C(═NR^e1)NR^a1R^b1, —NR^a1C(═NR^e1)NR^a1R^b1, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^Y;

each R^a1and each R^b1are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^Y;

or R^a1and R^b1together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 12, or 3 R^Ygroups;

each R^c1and each R^d1are independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^Y;

or R^c1and R^d1together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2, or 3 R^Ygroups;

each R^e1is independently selected from hydrogen, C_1-10alkyl, CN, NO₂, OR^a2, SR^a2, —S(O)_rR^a2, —C(O)R^a2, —S(O)_rNR^a2R^b2, and —C(O)NR^a2R^b2;

R^Yis independently selected from C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, halogen, —NO₂, —NR^a2R^b2, —OR^a2, —SR^a2, —S(O)_rR^a2, —S(O)₂OR^a2, —OS(O)₂R^b2, —S(O)_rNR^a2R^b2, —P(O)R^a2R^b2, —P(O)(OR^a2)(OR^b2), —(CR^c2R^d2)_tNR^a2R^b2, —(CR^c2R^d2)_tOR^b2, —(CR^c2R^d2)_tSR^b2, —(CR^c2R^d2)_tS(O)_rR^b2, —(CR^c2R^d2)_tP(O)R^a2R^b2, —(CR^c2R^d2)_tP(O)(OR^a2)(OR^b2), —(CR^c2R^d2)_tCO₂R^b2, —(CR^c2R^d2)_tC(O)NR^a2R^b2, —(CR^c2R^d2)_tNR^a2C(O)R^b2, —(CR^c2R^d2)_tNR^a2CO₂R^b2, —(CR^c2R^d2)_tOC(O)NR^a2R^b2, —(CR^c2R^d2)_tNR^a2C(O)NR^a2R^b2, —(CR^c2R^d2)_tNR^a2SO₂NR^a2R^b2, —NR^a2(CR^c2R^d2)_tNR^a2R^b2, —O(CR^c2R^d2)_tNR^a2R^b2, —S(CR^c2R^d2)_tNR^a2R^b2, —S(O)_r(CR^c2R^d2)_tNR^a2R^b2, —C(O)R^a2, —C(O)(CR^c2R^d2)_tOR^b2, —C(O)(CR^c2R^d2)_tNR^a2R^b2, —C(O)(CR^c2R^d2)_tSR^b2, —C(O)(CR^c2R^d2)_tS(O)_rR^b2, —CO₂R^b2, —CO₂(CR^c2R^d2)_tC(O)NR^a2R^b2, —OC(O)R^a2, —CN, —C(O)NR^a2R^b2, —NR^a2C(O)R^b2, —OC(O)NR^a2R^b2, —NR^a2C(O)OR^b2, —NR^a2C(O)NR^a2R^b2, —NR^a2S(O)_rR^b2, —CR^a2(═N—OR^b2), —C(═NR^e2)R^a2, —C(═NR^e2)NR^a2R^b2, —NR^a2C(═NR^e2)NR^a2R^b2, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from OH, CN, amino, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino and di(C_1-10alkylamino;

each R^a2and each R^b2are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, di(C_1-10alkylamino, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from OH, CN, amino, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, and di(C_1-10alkylamino;

or R^a2and R^b2together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from OH, CN, amino, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, and di(C_1-10alkylamino;

each R^c2and each R^d2are independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, di(C_1-10alkylamino, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from OH, CN, amino, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, and di(C_1-10alkylamino;

or R^c2and R^d2together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1 or 2 substituents, independently selected from OH, CN, amino, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, and di(C_1-10alkylamino;

each R^e2is independently selected from hydrogen, C_1-10alkyl, CN and NO₂;

m is selected from 0, 1, 2, 3 and 4;

n is selected from 0, 1, and 2;

p is selected from 0, 1, 2 and 3;

q is selected from 1, 2, and 3;

each r is independently selected from 1 and 2;

each t is independently selected from 1, 2, 3 and 4.

In yet another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In yet another aspect, the disclosure provides methods for modulating CDK4/6, comprising administering to a system or a subject in need thereof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, thereby modulating said CDK4/6.

In yet another aspect, disclosed is a method to treat, ameliorate or prevent a condition which responds to inhibition of CDK4/6 comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by CDK4/6. In particular embodiments, the compounds of the disclosure may be used alone or in combination with a second therapeutic agent to treat a condition mediated by CDK4/6.

Alternatively, disclosed is a compound of formula (I) for treating a condition mediated by CDK4/6.

Specifically, the condition herein includes but not limited to, an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.

Furthermore, the disclosure provides methods for treating a cell proliferative disorder, comprising administering to a system or subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof, and optionally in combination with a second therapeutic agent, thereby treating said condition.

Alternatively, the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell-proliferative disorder. In particular examples, the compounds of the disclosure may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder.

Specifically, the cell proliferative disorder disclosed herein includes but not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

In the above methods for using the compounds of the disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to a subject including a mammalian subject such as a human or animal subject.

Certain Terminology

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail.

It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. It should also be noted that use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included” is not limiting. Likewise, use of the term “comprising” as well as other forms, such as “comprise”, “comprises”, and “comprised” is not limiting.

Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^THED.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

Where substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left. As a non-limiting example, CH₂O is equivalent to OCH₂.

The term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency. Throughout the definitions, the term “C_i-j” indicates a range which includes the endpoints, wherein i and j are integers and indicate the number of carbons. Examples include C_1-4, C_1-10, C_3-10, and the like.

The term “alkyl”, employed alone or in combination with other terms, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Unless otherwise specified, “alkyl” refers to C₁-C₆alkyl. For example, C₁-C₆, as in “Q_1-6alkyl” is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. For example, “C_1-8alkyl” includes but is not limited to methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl.

The term “cycloalkyl”, employed alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system. The monocyclic cycloalkyl is a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or two alkylene bridges, each consisting of one, two, or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Representative examples of such bridged cycloalkyl ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, tricyclo[3.3.1.03,7]nonane, and tricyclo[3.3.1.13,7]decane (adamantane). The monocyclic and bridged cycloalkyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term “alkenyl”, employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. In some embodiments, one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, “C_2-6alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include but are not limited to ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.

The term “alkynyl”, employed alone or in combination with other terms, refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds may be present. Thus, “C_2-6alkynyl” means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include but are not limited to ethynyl, propynyl, butynyl, and 3-methylbutynyl. The straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine and iodine.

The term “alkoxy”, employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to an oxygen atom. The attachment point of an alkoxy radical to a molecule is through the oxygen atom. An alkoxy radical may be depicted as —O-alkyl. The term “C_1-10alkoxy” refers to an alkoxy radical containing from one to ten carbon atoms, having straight or branched moieties. Alkoxy groups, includes but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

The term “cycloalkoxy”, employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to an oxygen atom. The attachment point of a cycloalkoxy radical to a molecule is through the oxygen atom. A cycloalkoxy radical may be depicted as —O-cycloalkyl. “C_3-10cycloalkoxy” refers to a cycloalkoxy radical containing from three to ten carbon atoms. Cycloalkoxy groups, includes but is not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

The term “alkylthio”, employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to a sulfur atom. The attachment point of an alkylthio radical to a molecule is through the sulfur atom. An alkylthio radical may be depicted as —S-alkyl. The term “C_1-10alkylthio” refers to an alkylthio radical containing from one to ten carbon atoms, having straight or branched moieties. Alkylthio groups, includes but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

The term “cycloalkylthio”, employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to a sulfur atom. The attachment point of a cycloalkylthio radical to a molecule is through the sulfur atom. A cycloalkylthio radical may be depicted as —S-cycloalkyl. “C_3-10cycloalkylthio” refers to a cycloalkylthio radical containing from three to ten carbon atoms. Cycloalkylthio groups, includes but is not limited to, cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

The term “alkylamino”, employed alone or in combination with other terms, refers to an alkyl radical that is single bonded to a nitrogen atom. The attachment point of an alkylamino radical to a molecule is through the nitrogen atom. An alkylamino radical may be depicted as —NH(alkyl). The term “C_1-10alkylamino” refers to an alkylamino radical containing from one to ten carbon atoms, having straight or branched moieties. Alkylamino groups, includes but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamoino, and the like.

The term “cycloalkylamino”, employed alone or in combination with other terms, refers to cycloalkyl radical that is single bonded to a nitrogen atom. The attachment point of a cycloalkylamino radical to a molecule is through the nitrogen atom. A cycloalkylamino radical may be depicted as —NH(cycloalkyl). “C_3-10cycloalkylamino” refers to a cycloalkylamino radical containing from three to ten carbon atoms. Cycloalkylamino groups, includes but is not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino, and the like.

The term “di(alkyl)amino”, employed alone or in combination with other terms, refers to two alkyl radicals that are single bonded to a nitrogen atom. The attachment point of an di(alkyl)amino radical to a molecule is through the nitrogen atom. A dialkylamino radical may be depicted as —N(alkyl)₂. The term “di(C_1-10alkylamino” refers to a di(C_1-10alkylamino radical wherein the alkyl radicals each independently contains from one to ten carbon atoms, having straight or branched moieties.

The term “aryl”, employed alone or in combination with other terms, encompasses: 5- and 6-membered carbocyclic aromatic rings, for example, benzene; bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene. In cases where the aryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

For example, aryl includes 5- and 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring. Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Aryl, however, does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.

The term “heteroaryl”, employed alone or in combination with other terms, refers to

- 5- to 8-membered aromatic, monocyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon;
- 8- to 12-membered bicyclic rings containing one or more, for example, from 1 to 4, or, in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
- 11- to 14-membered tricyclic rings containing one or more, for example, from 1 to 4, or in some embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzoimidazolinyl, indolinyl, pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline.

Further heteroaryl groups include but are not limited to pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. As with the definition of heterocycle below, “heteroaryl” is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.

Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a pyridyl group with two points of attachment is a pyridylidene. Heteroaryl does not encompass or overlap with aryl as defined above.

In cases where the heteroaryl substituent is bicyclic or tricyclic and at least one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle”, employed alone or in combination with other terms, (and variations thereof such as “heterocyclic”, or “heterocyclyl”) broadly refers to a single aliphatic ring, usually with 3 to 12 ring atoms, containing at least 2 carbon atoms in addition to one or more, preferably one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms. Alternatively, a heterocycle as defined above may be multicyclic ring system (e.g. bicyclic) in which two or more rings may be fused or bridged or spiro together, wherein at least one such ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen. “Heterocycle” also refers to 5- to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O, and S fused with 5- and 6-membered carbocyclic aromatic ring, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have one or more double bonds (i.e. partially unsaturated). The heterocycle can be substituted by oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring, provided that attachment results in the creation of a stable structure. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Heterocycle does not overlap with heteroaryl.

Suitable heterocycles include, for example (as numbered from the linkage position assigned priority 1), 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl. 1,4-piperazinyl, and 2,3-pyridazinyl. Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1). Substituted heterocycle also includes ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl. Bicyclic heterocycles include, for example:

[Image Omitted]

As used herein, “aryl-alkyl” refers to an alkyl moiety substituted by an aryl group. Example arylalkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, arylalkyl groups have from 7 to 20 or 7 to 11 carbon atoms. When used in the phrase “arylC_1-4alkyl”, the term “C_1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the aryl portion of the moiety.

As used herein, “heterocyclyl-alkyl” refers to alkyl substituted by heterocyclyl. When used in the phrase “heterocyclyl-C_1-6alkyl”, the term “C_1-6” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety.

As used herein, “cycloalkyl-alkyl” refers to alkyl substituted by cycloalkyl. When used in the phrase “C_3-10cycloalkyl-C_1-4alkyl”, the term “C_3-10” refers to the cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety, and the term “C_1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the cycloalkyl portion of the moiety.

As used herein, “heteroaryl-alkyl” refers to alkyl substituted by heteroaryl. When used in the phrase “heteroaryl-C_1-4alkyl”, the term “C_1-4” refers to the alkyl portion of the moiety and does not describe the number of atoms in the heteroaryl portion of the moiety.

For avoidance of doubt, reference, for example, to substitution of alkyl, cycloalkyl, heterocyclyl, aryl, and/or heteroaryl refers to substitution of each of those groups individually as well as to substitutions of combinations of those groups. That is, if R¹is aryl-C_1-4alkyl, the aryl portion may be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^Xand the alkyl portion may also be unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X.

The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases may be selected, for example, from aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts. Further, for example, the pharmaceutically acceptable salts derived from inorganic bases may be selected from ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in one or more crystal structures, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases may be selected, for example, from salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine.

When the compound disclosed herein is basic, salts may be prepared using at least one pharmaceutically acceptable non-toxic acid, selected from inorganic and organic acids. Such acid may be selected, for example, from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acids. In some embodiments, such acid may be selected, for example, from citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.

The terms “administration of” and or “administering” at least one compound and/or at least one pharmaceutically acceptable salt should be understood to mean providing at least one compound and/or at least one pharmaceutically acceptable salt thereof to the individual in recognized need of treatment.

The term “effective amount” means the amount of the at least one compound and/or at least one pharmaceutically acceptable salt that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredient (s), and the inert ingredient (s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term “pharmaceutically acceptable” it is meant compatible with the other ingredients of the formulation and not unacceptably deleterious to the recipient thereof.

The term “subject” as used herein in reference to individuals suffering from a disorder, a condition, and the like, encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

The term “protecting group” or “Pg” refers to a substituent that can be commonly employed to block or protect a certain functionality while reacting other functional groups on the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include but are not limited to acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include —CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

The term “NH protecting group” as used herein includes, but not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenylmethyl, 2-nitrophenylthio, methanesulfonyl, para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group” as used herein includes, but not limited to, methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl, para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group” as used herein includes, but not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxy carbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxy ethoxymethyl, 2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Geometric isomers may exist in the present compounds. Compounds of this invention may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term “E” represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond and the term “Z” represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond as determined by the Cahn-Ingold-Prelog Priority Rules. The compounds of this invention may also exist as a mixture of “E” and “Z” isomers. Substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuration. For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le Noble J. Org. Chem. 1998, 63, 2758-2760.

Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, in which the terms “R” and “S” are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those carbon atoms. Atoms with an excess of one configuration over the other are assigned the configuration present in the higher amount, preferably an excess of about 85-90%, more preferably an excess of about 95-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.

In another embodiment, the isotope-labeled compounds contain deuterium (²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such isotope-labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples disclosed herein and Schemes by substituting a readily available isotope-labeled reagent for a non-labeled reagent. In some instances, compounds may be treated with isotope-labeled reagents to exchange a normal atom with its isotope, for example, hydrogen for deuterium can be exchanged by the action of a deuterated acid such as D₂SO₄/D₂O. In addition to the above, relevant procedures and intermediates are disclosed, for instance, in Lizondo, J et al, Drugs Fut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B et al, Org Lett, 5(7), 963 (2003); PCT publications WO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068; 7,511,013; and US Patent Application Publication Nos. 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standards to determine the effectiveness of CDK4/6 inhibitors in binding assays. Isotope containing compounds have been used in pharmaceutical research to investigate the in vivo metabolic fate of the compounds by evaluation of the mechanism of action and metabolic pathway of the nonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic studies are important in the design of safe, effective therapeutic drugs, either because the in vivo active compound administered to the patient or because the metabolites produced from the parent compound prove to be toxic or carcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al, J. Labelled Comp. Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol, 77, 79-88 (1999).

In addition, non-radio active isotope containing drugs, such as deuterated drugs called “heavy drugs” can be used for the treatment of diseases and conditions related to CDK4/6 activity. Increasing the amount of an isotope present in a compound above its natural abundance is called enrichment. Examples of the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15% of normal atom with a heavy isotope has been effected and maintained for a period of days to weeks in mammals, including rodents and dogs, with minimal observed adverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al., Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in human fluids with deuterium was found not to cause toxicity (Blagojevic N et al. in “Dosimetry & Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab. 23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemical properties such as pKa and lipid solubility. These effects and alterations can affect the pharmacodynamic response of the drug molecule if the isotopic substitution affects a region involved in a ligand-receptor interaction. While some of the physical properties of a stable isotope-labeled molecule are different from those of the unlabeled one, the chemical and biological properties are the same, with one important exception: because of the increased mass of the heavy isotope, any bond involving the heavy isotope and another atom will be stronger than the same bond between the light isotope and that atom. Accordingly, the incorporation of an isotope at a site of metabolism or enzymatic transformation will slow said reactions potentially altering the pharmacokinetic profile or efficacy relative to the non-isotopic compound.

1. A compound of formula (I)

[Image Omitted]

or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from aryl and heteroaryl;

W is selected from N and CR⁶;

Z is selected from N and CR⁶;

R¹is selected from hydrogen, halogen, hydroxyl, CN, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, C_1-10alkoxy, C_3-10cycloalkoxy, C_1-10alkylthio, C_3-10cycloalkylthio, C_1-10alkylamino, C_3-10cycloalkylamino, di(C_1-10alkylamino, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R²is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A1R^B1, —OR^A1, —SR^A1, —S(O)_rR^A1, —S(O)₂OR^A1, —OS(O)₂R^B1, —S(O)_rNR^A1R^B1, —P(O)R^A1R^B1, —P(O)(OR^A1)(OR^B1), —(CR^C1R^D1)_tNR^A1R^B1, —(CR^C1R^D1)_tOR^B1, —(CR^C1R^D1)_tSR^B1, —(CR^C1R^D1)_tS(O)_rR^B1, —(CR^C1R^D1)_tP(O)R^A1R^B1, —(CR^C1R^D1)_tP(O)(OR^A1)(OR^B1), —(CR^C1R^D1)_tCO₂R^B1, —(CR^C1R^D1)_tC(O)NR^A1R^B1, —(CR^C1R^D1)_tNR^A1C(O)R^B1, —(CR^C1R^D1)_tNR^A1CO₂R^B1, —(CR^C1R^D1)_tOC(O)NR^A1R^B1, —(CR^C1R^D1)_tNR^A1CONR^A1R^B1, —(CR^C1R^D1)_tNR^A1SO₂NR^A1R^B1, —NR^A1(CR^C1R^D1)_tNR^A1R^B1, —O(CR^C1R^D1)_tNR^A1R^B1, —S(CR^C1R^D1)_tNR^A1R^B1, —S(O)_r(CR^C1R^D1)_tNR^A1R^B1, —C(O)R^A1, —C(O)(CR^C1R^D1)_tNR^A1R^B1, —C(O)(CR^C1R^D1)_tOR^B1, —C(O)(CR^C1R^D1)_tSR^B1, —C(O)(CR^C1R^D1)_tS(O)_rR^B1, —CO₂R^B1, —CO₂(CR^C1R^D1)_tC(O)NR^A1R^B1, —OC(O)R^A1, —CN, —C(O)NR^A1R^B1, —NR^A1C(O)R^B1, —NR^A1CO₂R^B1, —OC(O)NR^A1R^B1, —NR^A1C(O)NR^A1R^B1, —NR^A1S(O)_rR^B1, —CR^A1(═N—OR^B1), —C(═NR^E1)R^A1, —C(═NR^E1)NR^A1R^B1, —NR^A1C(═NR^E1)NR^A1R^B1, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R³is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A2R^B2, —OR^A2, —SR^A2, —S(O)_rR^A2, —S(O)₂OR^A2, —OS(O)₂R^B2, —S(O)_rNR^A2R^B2, —P(O)R^A2R^B2, —P(O)(OR^A2)(OR^B2), —(CR^C2R^D2)_tNR^A2R^B2, —(CR^C2R^D2)_tOR^B2, —(CR^C2R^D2)_tSR^B2, —(CR^C2R^D2)_tS(O)_rR^B2, —(CR^C2R^D2)_tP(O)R^A2R^B2, —(CR^C2R^D2)_tP(O)(OR^A2)(OR^B2), —(CR^C2R^D2)_tCO₂R^B2, —(CR^C2R^D2)_tC(O)NR^A2R^B2, —(CR^C2R^D2)_tNR^A2C(O)R^B2, —(CR^C2R^D2)_tNR^A2CO₂R^B2, —(CR^C2R^D2)_tOC(O)NR^A2R^B2, —(CR^C2R^D2)_tNR^A2CONR^A2R^B2, —(CR^C2R^D2)_tNR^A2SO₂NR^A2R^B2, —NR^A2(CR^C2R^D2)_tNR^A2R^B2, —O(CR^C2R^D2)_tNR^A2R^B2, —S(CR^C2R^D2)_tNR^A2R^B2, —S(O)_r(CR^C2R^D2)_tNR^A2R^B2, —C(O)R^A2, —C(O)(CR^C2R^D2)_tNR^A2R^B2, —C(O)(CR^C2R^D2)_tOR^B2, —C(O)(CR^C2R^D2)_tSR^B2, —C(O)(CR^C2R^D2)_tS(O)_rR^B2, —CO₂R^B2, —CO₂(CR^C2R^D2)_tC(O)NR^A2R^B2, —OC(O)R^A2, —CN, —C(O)NR^A2R^B2, —NR^A2C(O)R^B2, —NR^A2CO₂R^B2, —OC(O)NR^A2R^B2, —NR^A2C(O)NR^A2R^B2, —NR^A2S(O)_rR^B2, —CR^A2(═N—OR^B2), —C(═NR^E2)R^A2, —C(═NR^E2)NR^A2R^B2, —NR^A2C(═NR^E2)NR^A2R^B2, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or two R³together with the carbon atoms to which they are attached form a cyclic ring of 3 to 7 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 1, 2 or 3 R^Xgroups; R⁴is selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A3R^B3, —OR^A3, —SR^A3, —S(O)_rR^A3, —S(O)₂OR^A3, —OS(O)₂R^B3, —S(O)_rNR^A3R^B3, —P(O)R^A3R^B3, —P(O)(OR^A3)(OR^B3), —(CR^C3R^D3)_tNR^A3R^B3, —(CR^C3R^D3)_tOR^B3, —(CR^C3R^D3)_tSR^B3, —(CR^C3R^D3)_tS(O)_rR^B3, —(CR^C3R^D3)_tP(O)R^A3R^B3, —(CR^C3R^D3)_tP(O)(OR^A3)(OR^B3), —(CR^C3R^D3)_tCO₂R^B3, —(CR^C3R^D3)_tC(O)NR^A3R^B3, —(CR^C3R^D3)_tNR^A3C(O)R^B3, —(CR^C3R^D3)_tNR^A3CO₂R^B3, —(CR^C3R^D3)_tOC(O)NR^A3R^B3, —(CR^C3R^D3)_tNR^A3CONR^A3R^B3, —(CR^C3R^D3)_tNR^A3SO₂NR^A3R^B3, —NR^A3(CR^C3R^D3)_tNR^A3R^B3, —O(CR^C3R^D3)_tNR^A3R^B3, —S(CR^C3R^D3)_tNR^A3R^B3, —S(O)_r(CR^C3R^D3)_tNR^A3R^B3, —C(O)R^A3, —C(O)(CR^C3R^D3)_tNR^A3R^B3, —C(O)(CR^C3R^D3)_tOR^B3, —C(O)(CR^C3R^D3)_tSR^B3, —C(O)(CR^C3R^D3)_tS(O)_rR^B3, —CO₂R^B3, —CO₂(CR^C3R^D3)_tC(O)NR^A3R^B3, —OC(O)R^A3, —CN, —C(O)NR^A3R^B3, —NR^A3C(O)R^B3, —NR^A3CO₂R^B3, —OC(O)NR^A3R^B3, —NR^A3C(O)NR^A3R^B3, —NR^A3S(O)_rR^B3, —CR^A3(═N—OR^B3), —C(═NR^E3)R^A3, —C(═NR^E3)NR^A3R^B3, —NR^A3C(═NR^E3)NR^A3R^B3, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R⁵is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A4R^B4, —OR^A4, —SR^A4, —S(O)_rR^A4, —S(O)₂OR^A4, —OS(O)₂R^B4, —S(O)_rNR^A4R^B4, —P(O)R^A4R^B4, —P(O)(OR^A4)(OR^B4), —(CR^C4R^D4)_tNR^A4R^B4, —(CR^C4R^D4)_tOR^B4, —(CR^C4R^D4)_tSR^B4, —(CR^C4R^D4)_tS(O)_rR^B4, —(CR^C4R^D4)_tP(O)R^A4R^B4, —(CR^C4R^D4)_tP(O)(OR^A4)(OR^B4), —(CR^C4R^D4)_tCO₂R^B4, —(CR^C4R^D4)_tC(O)NR^A4R^B4, —(CR^C4R^D4)_tNR^A4C(O)R^B4, —(CR^C4R^D4)_tNR^A4CO₂R^B4, —(CR^C4R^D4)_tOC(O)NR^A4R^B4, —(CR^C4R^D4)_tNR^A4CONR^A4R^B4, —(CR^C4R^D4)_tNR^A4SO₂NR^A4R^B4, —NR^A4(CR^C4R^D4)_tNR^A4R^B4, —O(CR^C4R^D4)_tNR^A4R^B4, —S(CR^C4R^D4)_tNR^A4R^B4, —S(O)_r(CR^C4R^D4)_tNR^A4R^B4, —C(O)R^A4, —C(O)(CR^C4R^D4)_tNR^A4R^B4, —C(O)(CR^C4R^D4)_tOR^B4, —C(O)(CR^C4R^D4)_tSR^B4, —C(O)(CR^C4R^D4)_tS(O)_rR^B4, —CO₂R^B4, —CO₂(CR^C4R^D4)_tC(O)NR^A4R^B4, —OC(O)R^A4, —CN, —C(O)NR^A4R^B4, —NR^A4C(O)R^B4, —NR^A4CO₂R^B4, —OC(O)NR^A4R^B4, —NR^A4C(O)NR^A4R^B4, —NR^A4S(O)_rR^B4, —CR^A4(═N—OR^B4), —C(═NR^E4)R^A4, —C(═NR^E4)NR^A4R^B4, —NR^A4C(═NR^E4)NR^A4R^B4, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R⁶is independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, heteroaryl-C_1-4alkyl, —NO₂, —NR^A5R^B5, —OR^A5, —SR^A5, —S(O)_rR^A5, —S(O)₂OR^A5, —OS(O)₂R^B5, —S(O)_rNR^A5R^B5, —P(O)R^A5R^B5, —P(O)(OR^A5)(OR^B5), —(CR^C5R^D5)_tNR^A5R^B5, —(CR^C5R^D5)_tOR^B5, —(CR^C5R^D5)_tSR^B5, —(CR^C5R^D5)_tS(O)_rR^B5, —(CR^C5R^D5)_tP(O)R^A5R^B5, —(CR^C5R^D5)_tP(O)(OR^A5)(OR^B5), —(CR^C5R^D5)_tCO₂R^B5, —(CR^C5R^D5)_tC(O)NR^A5R^B5, —(CR^C5R^D5)_tNR^A5C(O)R^B5, —(CR^C5R^D5)_tNR^A5CO₂R^B5, —(CR^C5R^D5)_tOC(O)NR^A5R^B5, —(CR^C5R^D5)_tNR^A5CONR^A5R^B5, —(CR^C5R^D5)_tNR^A5SO₂NR^A5R^B5, —NR^A5(CR^C5R^D5)_tNR^A5R^B5, —O(CR^C5R^D5)_tNR^A5R^B5, —S(CR^C5R^D5)_tNR^A5R^B5, —S(O)_r(CR^C5R^D5)_tNR^A5R^B5, —C(O)R^A5, —C(O)(CR^C5R^D5)_tNR^A5R^B5, —C(O)(CR^C5R^D5)_tOR^B5, —C(O)(CR^C5R^D5)_tSR^B5, —C(O)(CR^C5R^D5)_tS(O)_rR^B5, —CO₂R^B5, —CO₂(CR^C5R^D5)_tC(O)NR^A5R^B5, —OC(O)R^A5, —CN, —C(O)NR^A5R^B5, —NR^A5C(O)R^B5, —NR^A5CO₂R^B5, —OC(O)NR^A5R^B5, —NR^A5C(O)NR^A5R^B5, —NR^A5S(O)_rR^B5, —CR^A5(═N—OR^B5), —C(═NR^E5)R^A5, —C(═NR^E5)NR^A5R^B5, —NR^A5C(═NR^E5)NR^A5R^B5, —CHF₂, —CF₃, —OCHF₂, and —OCF₃, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

each R^A1, R^A2, R^A3, R^A4, R^A5, R^B1, R^B2, R^B3, R^B4, and R^B5are independently selected from hydrogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or each “R^A1and R^B1”, “R^A2and R^B2”, “R^A3and R^B3”, “R^A4and R^B4”, and “R^A5and R^B5”, together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 12 members containing 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 12, or 3 R^Xgroups;

each R^C1, R^C2, R^C3, R^C4, R^C5, R^D1, R^D2, R^D3, R^D4, and R^D5are independently selected from hydrogen, halogen, C_1-10alkyl, C_2-10alkenyl, C_2-10alkynyl, C_3-10cycloalkyl, C_3-10cycloalkyl-C_1-4alkyl, heterocyclyl, heterocyclyl-C_1-4alkyl, aryl, aryl-C_1-4alkyl, heteroaryl, and heteroaryl-C_1-4alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each unsubstituted or substituted with at least one substituent, such as one, two, three, or four substituents, independently selected from R^X;

or “R^C1and R^D1”, “R^C2and R^D2”, “R^C3and R^D3”, “R^C4and R^D4”, and “R^C5and R^D5” together with the carbon atom(s) to which they are attached form a ring of 3 to 12 members containing 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, and optionally substituted with 12, or 3 R^Xgroups;

each R^E1, R^E2, R^E3, R^E4, and R^E5is independently selected from hydrogen, C_1-10alkyl, CN, NO₂, OR^a2, SR^a2, —S(O)_rR^a2, —C(O)R^a2, —S(O)_rNR^a2R^b2, and —C(O)NR^a2R^b2;