2-amino-pyridine or 2-amino-pyrimidine derivatives as cyclin dependent kinase inhibitors

Abstract

This invention relates to compounds of Formula (I),or a pharmaceutically acceptable salt thereof, in which R-groups R1to R23, A, Q, U, V, W, X, Y, Z, n, p and q are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer, in a subject.

Description

[0001] 2-AMINO-PYRIDINE OR 2-AMINO-PYRIMIDINE DERIVATIVES AS CYCLIN

[0002] DEPENDENT KINASE INHIBITORS

[0003] BACKGROUND OF THE INVENTION

[0004] Field of the Invention

[0005] The present invention relates to compounds of Formula (l)-(XII), and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to the uses thereof. The compounds, salts and compositions of the present invention may be useful for the treatment of abnormal cell growth, such as cancer, in a subject.

[0006] Description of the Related Art

[0007] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. The CDK catalytic units are activated by regulatory subunits known as cyclins. At least sixteen mammalian cyclins have been identified (Johnson DG, Walker CL. Cyclins and Cell Cycle Checkpoints. Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Additional functions of Cyclin / CDK heterodynes include regulation of transcription, DNA repair, differentiation and apoptosis (Morgan DO. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell. Dev. Biol. (1997) 13:261 -291 ).

[0008] CDK inhibitors have been demonstrated to be useful in treating cancer. Increased activity ortemporally abnormal activation of CDKs has been shown to result in the development of human tumors, and human tumor development is commonly associated with alterations in either the CDK proteins themselves or their regulators (Cordon-Cardo C. Mutations of cell cycle regulators: biological and clinical implications for human neoplasia. Am. J. Pathol. (1995) 147:545-560; Karp JE, Broder S. Molecular foundations of cancer: new targets for intervention. Nat. Med. (1995) 1 :309-320; Hall M, Peters G. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. Adv. Cancer Res. (1996) 68:67-108).

[0009] CDK4 and CDK6 are important regulators of cell cycle progression at the G1 -S checkpoint, which are controlled by D-type cyclins and INK4 endogenous CDK inhibitors, such as p16INK4a(CDKN2A). Dysregulation of the cyclin D-CDK4 / 6-INK4-retinoblastoma (Rb) pathway has been reported to be associated with development of endocrine therapy resistance.

[0010] Mutations of CDK4 and CDK6 have been described in subgroups of melanoma and other tumors (Zuo L, et al., Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nature Genet. (1996) 12, 97-99; Ortega S, et al. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta (2002) 1602:73-87; Smalley KSM et al. Identification of a novel subgroup of melanomas with KIT / cyclin-dependent kinase-4 overexpression. Cancer Res (2008) 68: 5743-52). Amplifications of the regulatory subunits of CDKs and cyclins, and mutation, gene deletion, or transcriptional silencing of endogenous INK4 CDK inhibitors have also been reported as mechanism by which the pathway can be activated (Smalley KSM (2008)).

[0011] The development of CDK inhibitors has been reviewed in the literature. For example, see Sanchez-Martinez et al. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs, Bioorg. Med. Chem. Lett. (2015) 25: 3420-3435 (and references cited therein). The use of CDK4 / 6 inhibitors in combination with endocrine therapy has demonstrated significant efficacy in the treatment of hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancers, and CDK4 / 6 inhibitors, including palbociclib, ribociclib and abemaciclib, have been approved in combination with endocrine therapy in a first-or second- line setting.

[0012] However, treatment with CDK4 / 6 inhibitors may result in adverse effects, such as gastrointestinal and / or hematologic toxicities, and acquired resistance may develop over time. Emerging data suggest that cyclin D3-CDK6 may be linked to the observed hematologic toxicity. (Malumbres et al., Mammalian Cells Cycle without the D-type Cyclin-Dependent Kinases Cdk4 and Cdk6, (2004) Cell 1 18(4):493-504; Sicinska et al. Essential Role for Cyclin D3 in Granulocyte Colony-Stimulating Factor-Driven Expansion of Neutrophil Granulocytes (2006), Mol. Cell Biol 26(21 ): 8052-8060; Cooper et al. A unique function for cyclin D3 in early B cell development, (2006), Nat. Immunol. 5(7):489-497). CDK4 has been identified as the singular oncogenic driver in many breast cancers. Accordingly, a CDK4 selective inhibitor may provide an improved safety profile or enhanced overall efficacy due to the potential of higher and / or continuous dosing compared to dual CDK4 / 6 inhibitors.

[0013] Accordingly, there remains a need for improved therapies for the treatment of cancers. The compounds, compositions and methods of the present invention are believed to have one or more advantages, such as greater efficacy; potential to reduce side effects; potential to reduce drug-drug interactions; potential to enable an improved dosing schedule; or potential to overcome resistance mechanisms, and the like.

[0014] BRIEF SUMMARY OF THE INVENTION

[0015] The present invention provides, in part, compounds of Formula (l)-(XII) and pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of CDKs, including CDK4 and / or CDK6, thereby effecting biological functions. In some embodiments, the invention provides compounds that are selective for CDK4. Also provided are pharmaceutical compositions and medicaments comprising the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents. The present invention also provides, in part, methods for preparing the compounds, pharmaceutically acceptable salts and compositions of the invention, and methods of using the foregoing alone or in combination with additional anticancer therapeutic agents.

[0016] In one aspect, the invention provides a compound of Formula (I):

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] A is N or CH;

[0020] R1is H, F, Cl, CN, C1-C2 alkyl, CrC2fluoroalkyl or Ci-C2alkoxy, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0021] U is NR2or CR3;

[0022] V is N or CR4when U is NR2; and

[0023] V is NR5when U is CR3;

[0024] X is CR6or N;

[0025] Y is CR7or N;

[0026] Z is CR8or N;

[0027] R2and R3are H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0028] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, C(0)Ra, C(0)NRb2, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20, each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21, Rais CrC2alkyl, and each Rbis independently H or Ci-C2alkyl; and

[0029] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20; or

[0030] R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21;

[0031] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3; R7and R8are independently H , F, Cl, CN , CrC2alkyl, C1-C2 fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0032] R9is H, OH, NH2, NHCHS or N(CH3)2;

[0033] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0034] Q is NR11or O; or

[0035] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0036] R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0037] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0038] each R15and R16is independently H or CH3;

[0039] R17is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0040] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0041] each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NR22R23, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0042] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0043] each R22and R23is independently H, CrC3alkyl, CrC3fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said Ci-C3alkyl and Ci-C3fluoroalkyl is optionally further substituted by OH, CrC2alkoxy or Ci-C2fluoroalkoxy and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy; or

[0044] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or CrC2fluoroalkoxy;

[0045] R24is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0046] R25is C1-C4alkyl or C1-C4fluoroalkyl; each R26and R27is independently H or CH3;

[0047] R28is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2;

[0048] each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, CrC2alkoxy, CrC2fluoroalkoxy, CN, NH2, NHCHSor N(CH3)2;

[0049] m is 0, 1 or 2;

[0050] n is 0, 1 , 2, 3 or 4;

[0051] p is 1 , 2 or 3; and

[0052] q is 0, 1 , 2 or 3;

[0053] wherein the sum of p and q is an integer from 1 to 4.

[0054] In another aspect, the invention provides a compound of Formula (II):

[0055]

[0056] or a pharmaceutically acceptable salt thereof, wherein:

[0057] R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;

[0058] U is NR2or CR3;

[0059] V is N or CR4when U is NR2; and

[0060] V is NR5when U is CR3;

[0061] X is CR6or N;

[0062] Y is CR7or N;

[0063] Z is CR8or N;

[0064] R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0065] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;

[0066] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0067] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3; R7and R8are independently H, F, Cl, CN, CrC2alkyl, C1-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0068] R9is H, OH, NH2, NHCHS or N(CH3)2;

[0069] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0070] Q is NR11or O; or

[0071] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0072] R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0073] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0074] each R15and R16is independently H or CH3;

[0075] R17is C1-C4alkyl, C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0076] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0077] each R20is independently OH, Ci-C2alkoxy, CrC2fluoroalkoxy, CN or NR22R23;

[0078] each R21is independently F, OH, CN, NR22R23, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0079] each R22and R23is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl; or

[0080] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0081] n is 0, 1 , 2, 3 or 4;

[0082] p is 1 , 2 or 3; and

[0083] q is 0, 1 , 2 or 3;

[0084] wherein the sum of p and q is an integer from 1 to 4.

[0085] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, according to any of the formulae described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0086] The invention also provides therapeutic methods and uses comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof. In one aspect, the invention provides a method for the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, ora pharmaceutically acceptable salt thereof. Compounds of the invention may be administered as single agents or may be administered in combination with other anti-cancer therapeutic agents, including standard of care agents appropriate for the particular form of cancer.

[0087] In a further aspect, the invention provides a method for the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional anti-cancer therapeutic agent, which amounts are together effective in treating said abnormal cell growth.

[0088] In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth, in particular, cancer, in a subject.

[0089] In a further aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth, in particular, cancer, in a subject.

[0090] In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, which pharmaceutical composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0091] In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular a medicament for the treatment of abnormal cell growth, such as cancer.

[0092] In yet another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer, in a subject.

[0093] In another aspect, the invention provides a method for the treatment of a disorder mediated by CDK4 in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder, in particular, cancer.

[0094] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, according to any of the formulae described herein, and a second pharmaceutically active agent.

[0095] In another aspect, the invention provides a compound of the invention, according to any of the formulae described herein, for use in the treatment of cancer, wherein said treatment comprises the administration of a second pharmaceutically active agent. Each of the aspects and embodiments of the compounds of the present invention described below can be combined with one or more other embodiments of the compounds of the present invention described herein not inconsistent with the embodiment(s) with which it is combined.

[0096] In addition, each of the embodiments below describing the invention envisions within its scope the pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase “or a pharmaceutically acceptable salt thereof is implicit in the description of all compounds described herein unless explicitly indicated to the contrary.

[0097] DETAILED DESCRIPTION OF THE INVENTION

[0098] The present invention may be understood more readily by reference to the following detailed description of the preferred embodiments of the invention and the Examples included herein. It is to be understood that the terminology used herein is provided for the purpose of describing specific embodiments only and is not intended to be limiting. It is further to be understood that unless specifically defined herein, the terminology used herein is to be given its traditional meaning as known in the relevant art.

[0099] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents. The term "about" means having a value falling within an accepted standard of error of the mean, when considered by one of ordinary skill in the art.

[0100] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of", and "consisting of may be replaced with either of the other two terms.

[0101] "Alkyl" refers to a saturated, monovalent aliphatic hydrocarbon radical including straight chain and branched chain groups having the specified number of carbon atoms. Alkyl substituents typically contain 1 to 12 carbon atoms (“C1-C12 alkyl”), frequently 1 to 8 carbon atoms (“Ci-C8alkyl”), or more frequently 1 to 6 carbon atoms (“Ci-C6alkyl”), 1 to 5 carbon atoms (“C1-C5 alkyl”), 1 to 4 carbon atoms (“C1-C4 alkyl”) or 1 to 2 carbon atoms (“C1-C2 alkyl”). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like.

[0102] Alkyl groups described herein as optionally substituted may be substituted by one or more substituent groups, as further defined by the claims, which substituent groups are selected independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the alkyl moiety, to the extent such substitution makes chemical sense. Optionally substituted alkyl groups typically contain from 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, 1 to 4 optional substituents, or preferably 1 to 3 optional substituents.

[0103] Optional substituent that are suitable for alkyl include, but are not limited to, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl, halo, =0 (oxo), =S (thiono), =N-CN, =N-ORx, =NRX, -CN, -C(0)Rx, -C02Rx, -C(0)NRxRy, - SRX, -SORx, -S02Rx, -S02NRxRy, -N02, -NRxRy, -NRxC(0)Ry, -NRxC(0)NRxRy, - NRxC(0)0Rx, -NRxS02Ry, -NRxS02NRxRy, -ORx, -0C(0)Rxand -0C(0)NRxRy; wherein each Rxand Ryis independently H, Ci-C8alkyl, Ci-C8acyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl, or 5-12 membered heteroaryl, or Rxand Rymay be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N and S(0)qwhere q is 0-2; each Rxand Ryis optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, =0, =S, =N-CN, =N-OR', =NR', -CN, -C(0)R', -C02R', -C(0)NR'2, -SOR', -S02R', -S02NR'2,

[0104] N02, -NR'2, -NR'C(0)R', -NR'C(0)NR'2, -NR'C(0)0R', -NR'S02R', -NR'S02NR'2, -OR', -0C(0)R' and -0C(0)NR'2, wherein each R' is independently H, Ci-C8alkyl, Ci-C8acyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl, or C5-Ci2heteroaryl; and wherein each said C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein.

[0105] Typical substituent groups on alkyl include halo, -OH, C1-C4 alkoxy, -0-C6-Ci2aryl, -CN, =0, -COORx, -0C(0)Rx, -C(0)NRxRy, -NR’O^Ry, -NRxRy, C3-C8cycloalkyl, C6-Ci2aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl; where each Rxand Ryis independently H or C1-C4 alkyl, or Rxand Rymay be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N and S(0)qwhere q is 0-2; wherein each said C3-C8cycloalkyl, C6-Ci2aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy-Ci-C6 alkyl, -CN, -NH2, -NH(C C4alkyl) and -N(CI-C4alkyl)2.

[0106] In some instances, substituted alkyl groups are specifically named by reference to the substituent group. For example,“haloalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more halo substituents, up to the available valence number. Typically, haloalkyl groups contain 1 -6 carbon atoms, 1 -5 carbon atoms, 1 -4 carbon atoms or 1 -2 carbon atoms and 1 , 2, 3, 4 or 5 halo atoms (i.e.,“C1-C5 haloalkyl”,“C1-C4 haloalkyl” or“Ci-C2haloalkyl”).

[0107] More specifically, fluorinated alkyl groups may be specifically referred to as“fluoroalkyl” groups, (e.g., C1-C5, Ci-C4or Ci-C2fluoroalkyl groups), which are typically substituted by 1 , 2, 3, 4 or 5 fluoro atoms. Thus, a CrC4fluoroalkyl includes trifluoromethyl (-CF3), difluoromethyl (-CF2H), fluoromethyl (-CFH2), difluoroethyl (-CH2CF2H), and the like. Such groups may be further substituted by groups suitable for alkyl groups, as further described herein.

[0108] In some embodiments of the present invention, alkyl and fluoroalkyl groups are optionally substituted by one or more optional substituents, and preferably by 1 to 3 optional substituents, which are independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR’2, where each R’ is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl.

[0109] Similarly,“alkoxyalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more alkoxy substituents. Alkoxyalkyl groups typically contain

[0110] 1 -4 carbon atoms in the alkyl portion and are substituted by 1 , 2 or 3 C1-C4 alkyoxy substituents. Such groups are sometimes described herein as Ci-C4alkyoxy-CrC4alkyl.

[0111] “Aminoalkyl” refers to alkyl group having the specified number of carbon atoms that is substituted by one or more substituted or unsubstituted amino groups, as such groups are further defined herein . Aminoalkyl groups typically contain 1 -6 carbon atoms in the alkyl portion and are substituted by 1 , 2 or 3 amino substituents. Thus, a Ci-C6aminoalkyl includes, for example, aminomethyl (-CH2NH2), A / ,A / -dimethylaminoethyl (-CH2CH2N(CH3)2), 3-(A / -cyclopropylamino)- propyl (-CH2CH2CH2NH-cPr) and / V-pyrrolidinylethyl (-CH2CH2-N-pyrrolidinyl).

[0112] “Hydroxyalkyl” refers to an alkyl group having the specified number of carbon atoms that is substituted by one or more hydroxy substituents, and typically contain 1 -6 carbon atoms, preferably 1 -4 carbon atoms, and 1 , 2 or 3 hydroxy (i.e.,“C1-C6 hydroxyalkyl”). Thus, C1-C6 hydroxyalkyl includes hydroxymethyl (-CH2OH) and 2-hydroxyethyl (-CH2CH2OH).

[0113] "Alkenyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Typically, alkenyl groups have 2 to 20 carbon atoms (“C2-C2o alkenyl”), preferably 2 to 12 carbon atoms (“C2-Ci2alkenyl”), more preferably 2 to 8 carbon atoms (“C2-C8alkenyl”), or 2 to 6 carbon atoms (“C2-C6alkenyl”), or 2 to 4 carbon atoms (“C2-C4alkenyl”). Representative examples include, but are not limited to, ethenyl, 1 -propenyl,

[0114] 2-propenyl, 1 -, 2-, or 3-butenyl, and the like. Alkenyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

[0115] "Alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups have 2 to 20 carbon atoms (“C2-C2o alkynyl”), preferably 2 to 12 carbon atoms (“C2-Ci2alkynyl”), more preferably 2 to 8 carbon atoms (“C2-C8alkynyl”), or 2 to 6 carbon atoms (“C2-C6alkynyl”), or 2 to 4 carbon atoms (“C2-C4alkynyl”). Representative examples include, but are not limited to, ethynyl, 1 -propynyl, 2-propynyl, 1 -, 2-, or 3-butynyl, and the like. Alkynyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl.

[0116] "Alkylene" as used herein refers to a divalent hydrocarbyl group having the specified number of carbon atoms which can link two other groups together. Sometimes it refers to a group -(CH2)t- where t is 1-8, and preferably t is 1 -6, t is 1-4 or t is 1-2. Such groups may be referred to as a Ci-C8alkylene, Ci-C6alkylene, C1-C4 alkylene, etc. Where specified, an alkylene can also be substituted by other groups and may include one or more degrees of unsaturation (i.e. , an alkenylene or alkynlene moiety) or rings. The open valences of an alkylene need not be at opposite ends of the chain. Thus branched alkylene groups such as -CH(Me)- , -CH2CH(Me)- and -C(Me)2- are also included within the scope of the term'alkylenes', as are cyclic groups such as cyclopropan-1 ,1-diyl and unsaturated groups such as ethylene (-CH=CH-) or propylene (-CH2-CH=CH-). Where an alkylene group is described as optionally substituted, the substituents include those typically present on alkyl groups as described herein.

[0117] "Heteroalkylene" refers to an alkylene group as described above, wherein one or more non-contiguous carbon atoms of the alkylene chain are replaced by -N(R)-, -O- or -S(0)x-, where R is H or a substituent group suitable for a secondary amino moiety and x is 0-2. For example, the group -0-(CH2)i-3- is a‘C2-C4’-heteroalkylene group, where one of the carbon atoms of the corresponding alkylene is replaced by O.

[0118] “Alkoxy” refers to a monovalent -O-alkyl group, wherein the alkyl portion has the specified number of carbon atoms. Alkoxy groups typically contain 1 to 8 carbon atoms (“Ci-C8alkoxy”), or 1 to 6 carbon atoms (“CrC6alkoxy”), or 1 to 4 carbon atoms (“CrC4alkoxy”). For example, Ci-C4alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy (i.e., OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3), and the like. Alkoxy groups are unsubstituted or substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl. In particular, alkoxy groups may be optionally substituted by one or more halo atoms, and in particular one or more fluoro atoms, up to the total number of hydrogen atoms present on the alkyl portion. Such groups are referred to as“haloalkoxy” (or, where fluorinated, more specifically as“fluoroalkoxy”) groups having the specified number of carbon atoms and substituted by one or more halo substituents, Typically such groups contain from 1 -6 carbon atoms, preferably 1 -4 carbon atoms, and sometimes 1 -2 carbon atoms, and 1 , 2 or 3 halo atoms (i.e., “CrC6haloalkoxy”, “Ci-C4haloalkoxy” or“CrC2haloalkoxy”). More specifically, fluorinated alkoxy groups may be specifically referred to as“fluoroalkoxy” groups, e.g., C1-C6, Ci-C4or Ci-C2fluoroalkoxy groups, which are typically substituted by 1 , 2 or 3 fluoro atoms. Thus, a CrC4fluoroalkoxy includes trifluoromethyloxy (-OCF3), difluoromethyloxy (-OCF2H), fluoromethyloxy (-OCFH2), difluoroethyloxy (-OCH2CF2H), and the like.

[0119] Similarly,“thioalkoxy” refers to a monovalent -S-alkyl group, wherein the alkyl portion has the specified number of carbon atoms and is optionally substituted on the alkyl portion by the same groups that are described herein as suitable for alkyl. For example, a Ci-C4thioalkoxy includes -SCH3and -SCH2CH3

[0120] "Cycloalkyl" refers to a non-aromatic, saturated carbocyclic ring system containing the specified number of carbon atoms, which may be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system that is connected to the base molecule through a carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 12 carbon atoms (“C3-C12 cycloalkyl”), preferably 3 to 8 carbon atoms (“C3-C8cycloalkyl”). Partially unsaturated carbocyclic rings may be referred to as “cycloalkenyl” rings. Representative examples of cycloalkyl and cycloalkenyl rings include, e.g., cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkyl groups are unsubstituted or substituted by the same groups that are described herein as suitable for alkyl, except that cycloalkyl rings may also be substituted by alkyl groups having the specified number of carbon atoms, which may be further optionally substituted as described herein.

[0121] Illustrative examples of cycloalkyl and cycloalkenyl rings include, but are not limited to, the following:

[0122]

[0123] "Cycloalkylalkyl" is used to describe a cycloalkyl ring, typically a C3-C8cycloalkyl, which is connected to the base molecule through an alkylene linker, typically a C1-C4 alkylene. Cycloalkylalkyl groups are sometimes described by the total number of carbon atoms in the carbocyclic ring and linker, and typically contain from 4-12 carbon atoms (“C4-C12 cycloalkylalkyl”). Thus a cyclopropylmethyl group is a C4-cycloalkylalkyl group and a cyclohexylethyl is a Cs-cycloalkylalkyl. Cycloalkylalkyl groups are unsubstituted or substituted on the cycloalkyl and / or alkylene portions by the same groups that are described herein as suitable for alkyl groups.

[0124] The terms "heterocyclyl" or "heterocyclic" may be used interchangeably to refer to a non-aromatic, saturated ring system containing the specified number of ring atoms, including at least one heteroatom selected from N, O and S as a ring member, where ring S atoms are optionally substituted by one or two oxo groups (i.e., S(0)x, where x is 0, 1 or 2) and where the heterocyclic ring is connected to the base molecule via a ring atom, which may be C or N. Where specifically indicated, such heterocyclic rings may be partially unsaturated. Heterocyclic rings include rings which are spirocyclic, bridged, or fused to one or more other heterocyclic or carbocyclic rings, where such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent unsaturation or aromaticity makes chemical sense, provided the point of attachment to the base molecule is an atom of the heterocyclic portion of the ring system. Preferably, heterocyclic rings contain 1 to 4 heteroatoms selected from N, O, and S(0)qas ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two contiguous oxygen atoms.

[0125] Heterocyclyl groups are unsubstituted or substituted by suitable substituent groups, for example the same groups that are described herein as suitable for alkyl, except that heterocycyl rings may also be substituted by alkyl groups having the specified number of carbon atoms, which may be further optionally substituted as described herein. Such substituents may be present on the heterocycylic ring attached to the base molecule, or on a spirocyclic, bridged or fused ring attached thereto. In addition, ring N atoms are optionally substituted by groups suitable for an amine, e.g., alkyl, acyl, carbamoyl, sulfonyl, and the like.

[0126] Heterocycles typically include 3-12 membered heterocyclyl groups, 3-10 membered heterocyclyl groups, 3-8 membered heterocyclyl groups, and more preferably 3-6 membered heterocyclyl groups, in accordance with the definition herein.

[0127] Illustrative examples of saturated heterocycles include, but are not limited to:

[0128]

[0129] 1 ,4-oxaazepane 1 ,4-thieazepane 1 ,4-diazepane 1 ,4-dithiepane

[0130] (1 ,4-oxaazepanyl) (1 ,4-thieazapanyl) (1 ,-diazepanyl) (1 ,4-dithiepanyl)

[0131] Illustrative examples of partially unsaturated heterocycles include, but are not limited to:

[0132]

[0133] Illustrative examples of bridged, fused and spiro heterocycles include, but are not limited to:

[0134] 2-oxa-5-azabicyclo- 3-oxa-8-azabicyclo- 3-azabicyclo- 2-azabicyclo- 8-azabicyclo- 2-azabicyclo- [3 1 OJhexane

[0310] hexane [2 2.1 ]octane [2.2.1]heptane

[0135] [2.2 1]heptane [3 2.1]octane

[0136]

[0137] 3-oxooctahydro- 1 ,1-dioxidohexahydro- 1 ,1 -dioxidohexahydro- 3-oxohexahydro[1 ,3]- 2,2-dioxido-2-thiaspiro- indolizine pyrido[1 ,2-d][1 ,3,4]- pyrido[1 ,2]thiazolo[2,3-a]- oxazolo[3,4-a]pyridine [3.5]nonane

[0138] oxathiazine pyridine

[0139] In some embodiments, heterocyclic groups contain 3-12 ring members, including both carbon and non-carbon heteroatoms, and frequently 3-8 or 3-6 ring members. In certain preferred embodiments, substituent groups comprising 3-12 membered heterocycles are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl rings, each of which are optionally substituted as described for the particular substituent group, to the extent such substitution makes chemical sense.

[0140] In some embodiments of the present invention, cycloalkyl and heterocyclyl groups are optionally substituted by one or more optional substituents, and preferably by 1 to 3 optional substituents, which are independently F, OH, CN, NR’2 (where each R’ is independently H, C1-C2 alkyl or C1-C2fluoroalkyl), CrC4alkyl, CrC4fluoroalkyl, CrC4alkoxy or CrC4fluoroalkoxy, where each said Ci-C4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy and Ci-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2

[0141] It is understood that no more than two N, O or S atoms are ordinarily connected sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group, or in the case of certain heteroaromatic rings, such as triazine, triazole, tetrazole, oxadiazole, thiadiazole, and the like.

[0142] The term "heterocyclylalkyl" may be used to describe a heterocyclic group of the specified size that is connected to the base molecule through an alkylene linker of the specified length. Typically, such groups contain an optionally substituted 3-12 membered heterocycle attached to the base molecule through a Ci-C4alkylene linker. Where so indicated, such groups are optionally substituted on the alkylene portion by the same groups that are described herein as suitable for alkyl groups and on the heterocyclic portion by groups described as suitable for heterocyclic rings.

[0143] "Aryl" or“aromatic” refer to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having the well-known characteristics of aromaticity, wherein at least one ring contains a completely conjugated pi-electron system. Typically, aryl groups contain 6 to 20 carbon atoms ("C6-C20aryl") as ring members, preferably 6 to 14 carbon atoms ("C6-Ci4aryl") or more preferably, 6 to 12 carbon atoms ("C6-Ci2aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the aromatic portion of the ring system. Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group is unsubstituted or substituted as further described herein.

[0144] Similarly, "heteroaryl" or “heteroaromatic” refer to monocyclic or fused bicyclic or polycyclic ring systems having the well-known characteristics of aromaticity that contain the specified number of ring atoms and include at least one heteroatom selected from N, O and S as a ring member in an aromatic ring. The inclusion of a heteroatom permits aromaticity in 5-membered rings as well as 6-membered rings. Typically, heteroaryl groups contain 5 to 20 ring atoms (“5-20 membered heteroaryl”), preferably 5 to 14 ring atoms (“5-14 membered heteroaryl”), and more preferably 5 to 12 ring atoms (“5-12 membered heteroaryl”). Heteroaryl rings are attached to the base molecule via a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Thus, 6-membered heteroaryl rings may be attached to the base molecule via a ring C atom, while 5-membered heteroaryl rings may be attached to the base molecule via a ring C or N atom. Heteroaryl groups may also be fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided the point of attachment to the base molecule on such fused ring systems is an atom of the heteroaromatic portion of the ring system. Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthryidine and carbazole. In frequent preferred embodiments, 5- or 6-membered heteroaryl groups are selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, pyrazinyl or pyridazinyl rings. The heteroaryl group is unsubstituted or substituted as further described herein.

[0145] Aryl and heteroaryl moieties described herein as optionally substituted may be substituted by one or more substituent groups, which are selected independently unless otherwise indicated. The total number of substituent groups may equal the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, to the extent such substitution makes chemical sense and aromaticity is maintained in the case of aryl and heteroaryl rings. Optionally substituted aryl or heteroaryl groups typically contain from 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably from 1 -2 optional substituents.

[0146] Optional substituent groups suitable for use with aryl and heteroaryl rings include, but are not limited to: Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl and 5-12 membered heteroaryl; and halo, =0, -CN, -C(0)Rx, -C02Rx, -C(0)NRxRy, - SRX, -SORx, -S02Rx, -S02NRxRy, -N02, -NRxRy, -N R’CiOJR», -NRxC(0)NRxRy, -NRxC(0)0Rx, -NRxS02Ry, -NRxS02NRxRy, -ORx, -0C(0)Rxand -0C(0)NRxRy; where each Rxand Ryis independently H, Ci-Cs alkyl, Ci-Cs acyl, C2-C8 alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl, or 5-12 membered heteroaryl, or Rxand Rymay be taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N and S(0)zwhere z is 0-2; each Rxand Ryis optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, =0, =S, =N-CN, =N-OR', =NR', -CN, -C(0)R', -C02R', -C(0)NR'2, SR', -SOR', -SO2R', -S02NR'2, -NO2, -NR'2, -NR'C(0)R', -NR'C(0)NR'2, -NR'C(0)0R', -NR'S02R', -NR'S02NR'2, -OR', -0C(0)R' and -0C(0)NR'2, wherein each R' is independently H, C C8alkyl, Ci-C8acyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2 aryl, or 5-12 membered heteroaryl; and each said CrC8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-Cs cycloalkyl, 3-12 membered heterocyclyl, C6-C12 aryl and 5-12 membered heteroaryl is optionally substituted as further defined herein. In typical embodiments, optional substitution on aryl, heteroaryl and heterocyclyl rings includes one or more substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of halo, Ci-C8alkyl, -OH, CrC8alkoxy, -CN,

[0147] =0, -C(0)Rx, -COORx, -0C(0)RX, -C(0)NRxRy, -NRxC(0)Ry, -SRX, SORx, -S02Rx, -S02NRxRy, -N02, -NRxRy, -NRxC(0)Ry, -NRxC(0)NRxRy, -NRxC(0)0Ry- NRxS02Ry, -NRxS02NRxRy, -0C(0)Rx, -0C(0)NRxRy, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl, 5-12 membered heteroaryl, -0-(C3-C8cycloalkyl), -0-(3-12 membered heterocyclyl), -0-(C6-Ci2aryl) and -0-(5-12 membered heteroaryl); where each Rxand Ryis independently H or CrC4alkyl, or Rxand Rymay be taken togetherwith the N to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each optionally containing 1 , 2 or 3 additional heteroatoms selected from O, N and S(0)qwhere q is 0-2; and wherein each said Ci-C8alkyl, Ci-C8alkoxy, C3-C8cycloalkyl, 3-12 membered heterocyclyl, C6-Ci2aryl, 5-12 membered heteroaryl, -0-(C3-C8cycloalkyl), -0-(3-12 membered heterocyclyl), -0-(C6-Ci2aryl) and -0-(5-12 membered heteroaryl) that is described as an optional substituent or is part of Rxor Ryis optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, -OH, =0, C1-C4 alkyl, C1-C4 alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, C1-C4 alkoxy-Ci-C6alkyl, -CN, -NH2, -NH(CrC4alkyl), -N(CI-C4alkyl)2and N-pyrrolidinyl.

[0148] Examples of monocyclic heteroaryl groups include, but are not limited to:

[0149]

[0150] Illustrative examples of fused heteroaryl groups include, but are not limited to:

[0151] benzofuran benzothiophene indole benzimidazole indazole

[0152] (benzofuranyl) (benzothiophenyl) (indolyl) (benzimidazolyl) (indazolyl)

[0153] benzotriazole pyrrolo[2,3-b]pyridine pyrrolo[2,3-c]pyridine pyrrolo[3,2-c]pyridine

[0154] (benzotriazolyl) (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c]pyridinyl) (pyrrolo[3,2-c]pyridinyl)

[0155] pyrrolo[3,2-b]pyridine imidazo[4,5-b]pyridine imidazo[4,5-c]pyridine pyrazolo[4,3-d]pyridine

[0156] (pyrrolo[3,2-b]pyridinyl) (imidazo[4,5-b]pyridinyl) (imidazo[4,5-c]pyridinyl) (pyrazolo[4,3-d]pyidinyl)

[0157] pyrazolo[4,3-c]pyridine pyrazolo[3,4-c]pyridine pyrazolo[3,4-b]pyridine isoindole

[0158] (pyrazolo[4,3-c]pyidinyl) (pyrazolo[3,4-c]pyidinyl) (pyrazolo[3,4-b]pyidinyl) (isoindolyl)

[0159] indazole purine indolizine imidazo[1 ,2-a]pyridine imidazo[1 ,5-a]pyridine

[0160] (indazolyl) (purinyl) (indolininyl) (imidazo[1 ,2-a]pyridinyl) (imidazo[1 ,5-a]pyridinyl)

[0161] pyrazolo[1 ,5-a]pyridine pyrrolo[1 ,2-b]pyridazine imidazo[1 ,2-c]pyrimidine

[0162] (pyrazolo[1 ,5-a]pyridinyl) (pyrrolo[1 -2,b]pyridazinyl) (imidazo[1 ,2-c]pyrimidinyl)

[0163]

[0164] pyrimido[5,4-d]pyrimidine pyrazino[2,3-b]pyrazine pyrimido[4,5-d]pyrimidine

[0165] (pyrimido[5,4-d]pyri midinyl) (pyrazino[2,3-b]pyrazinyl) (pyrimido[4,5-d]pyrimidinyl)

[0166] An "arylalkyl" group refers to an aryl group as described herein which is linked to the base molecule through an alkylene or similar linker. Arylalkyl groups are described by the total number of carbon atoms in the ring and linker. Thus, a benzyl group is a Cyarylalkyl group and a phenylethyl is a Cs-arylalkyl. Typically, arylalkyl groups contain 7-16 carbon atoms (“C7-C16 arylalkyl”), wherein the aryl portion contains 6-12 carbon atoms and the alkylene portion contains 1 -4 carbon atoms. Such groups may also be represented as -C1-C4 alkylene-C6-Ci2aryl.

[0167] "Heteroarylalkyl" refers to a heteroaryl group as described above that is attached to the base molecule through an alkylene linker, and differs from "arylalkyl" in that at least one ring atom of the aromatic moiety is a heteroatom selected from N, O and S. Heteroarylalkyl groups are sometimes described herein according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined, excluding substituent groups. Thus, for example, pyridinylmethyl may be referred to as a “C7”-heteroarylalkyl. Typically, unsubstituted heteroarylalkyl groups contain 6-20 non-hydrogen atoms (including C, N, S and O atoms), wherein the heteroaryl portion typically contains 5-12 atoms and the alkylene portion typically contains 1 -4 carbon atoms. Such groups may also be represented as -C1-C4 alkylene-5-12 membered heteroaryl.

[0168] Similarly,“arylalkoxy” and“heteroarylalkoxy” refer to aryl and heteroaryl groups, attached to the base molecule through a heteroalkylene linker (i.e., -O-alkylene-), wherein the groups are described according to the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) in the ring and linker combined. Thus, -0-CH2-phenyi and -0-CH2-pyridinyl groups would be referred to as Cs-arylalkoxy and C8-heteroarylalkoxy groups, respectively.

[0169] Where an arylalkyl, arylalkoxy, heteroarylalkyl or heteroarylalkoxy group is described as optionally substituted, the substituents may be on either the divalent linker portion or on the aryl or heteroaryl portion of the group. The substituents optionally present on the alkylene or heteroalkylene portion are the same as those described above for alkyl or alkoxy groups generally, while the substituents optionally present on the aryl or heteroaryl portion are the same as those described above for aryl or heteroaryl groups generally.

[0170] "Hydroxy" refers to an OH group.

[0171] “Acyloxy” refers to a monovalent group -0C(0)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically CrC8, preferably CrC6or C1-C4) that are optionally substituted by groups suitable for alkyl. Thus, C1-C4 acyloxy includes an -0C(0)Ci-C4alkyl substituent, e.g., -0C(0)CH3.

[0172] “Acyl” refers to a monovalent group -C(0)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically Ci-C8, preferably C1-C6 or C1-C4) and may be optionally substituted by groups suitable for alkyl, e.g., by F, OH or alkoxy. Thus, optionally substituted -C(0)Ci-C4alkyl includes unsubstituted acyl groups, such as -C(0)CH3(i.e., acetyl) and -C(0)CH2CH3(i.e., propionyl), as well as substituted acyl groups such as -C(0)CF3(trifluoroacetyl), -C(0)CH20H (hydroxyacetyl), -C(0)CH20CH3(methoxyacetyl), -C(0)CF2H (difluoroacetyl), and the like.

[0173] “Acylamino” refers to a monovalent group, -NHC(0)alkyl or -NRC(0)alkyl, wherein the alkyl portion has the specified number of carbon atoms (typically CrC8, preferably CrC6or Ci-C4) and is optionally substituted by groups suitable for alkyl. Thus, C1-C4 acylamino includes an - NHC(0)Ci-C4alkyl substituent, e.g., -NHC(0)CH3.

[0174] “Aryloxy” or“heteroaryloxy” refer to optionally substituted O-aryl or O-heteroaryl, in each case where aryl and heteroaryl are as further defined herein.

[0175] “Arylamino” or“heteroarylamino” refer to an optionally substituted -NH-aryl, -NR-aryl, - NH-heteroaryl or -NR-heteroaryl, in each case where aryl and heteroaryl are as further defined herein and R represents a substituent suitable for an amine, e.g., an alkyl, acyl, carbamoyl or sulfonyl group, or the like.

[0176] "Cyano" refers to a -CºN group.

[0177] "Unsubstituted amino" refers to a group -NH2. Where the amino is described as substituted or optionally substituted, the term includes groups of the form -NRxRy, where each or Rxand Ryis independently H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, acyl, thioacyl, aryl, heteroaryl, cycloalkylalkyl, arylalkyl or heteroarylalkyl, in each case having the specified number of atoms and optionally substituted as described herein. For example,“alkylamino” refers to a group -NRxRy, wherein one of Rxand Ryis an alkyl moiety and the other is H, and“dialkylamino” refers to -NRxRywherein both of Rxand Ryare alkyl moieties, where the alkyl moieties having the specified number of carbon atoms (e.g., -NH-C1-C4 alkyl or -N(Ci-C4alkyl)2). Typically, alkyl substituents on amines contain 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes forms wherein Rxand Ryare taken together with the N atom to which they are attached to form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring , each of which may itself be optionally substituted as described herein for heterocyclyl or heteroaryl rings, and which may contain 1 to 3 additional heteroatoms selected from N, O and S(0)xwhere x is 0-2 as ring members, provided that such rings do not contain two contiguous oxygen atoms.

[0178] “Halogen” or“halo” refers to fluoro, chloro, bromo and iodo (F, Cl, Br, I). Preferably, halo refers to fluoro or chloro (F or Cl).

[0179] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances in which it does not.

[0180] The terms “optionally substituted” and “substituted or unsubstituted” may be used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise specified, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. Where an optional substituent is attached via a double bond, such as an oxo (=0) substituent, the group occupies two available valences, so the total number of other substituents that are included is reduced by two.

[0181] Frequently, optionally substituted groups are substituted by 1 or more substituents independently selected from the list of optional substituents. In some embodiments, optionally substituted groups are substituted by 1 , 2, 3, or more than 3 substituents independently selected from the list of optional substituents. For example, an alkyl group described as optionally substituted by Rxmeans the alkyl group is optionally substituted by 1 or more Rxsubstituents independently selected from the list of Rxsubstituents provided for the alkyl group. Where deemed necessary, the description of an optionally substituted group herein may be revised to state that the group is optionally substituted by 1 or more of the indicated substituents. In the case where optional substituents are selected from a list of alternatives, the selected groups are independently selected and may be the same or different.

[0182] Throughout the disclosure, it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense.

[0183] In one aspect, the invention provides a compound of Formula (I):

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] A is N or CH;

[0187] R1is H, F, Cl, CN, C1-C2 alkyl, CrC2fluoroalkyl or Ci-C2alkoxy, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0188] U is NR2or CR3;

[0189] V is N or CR4when U is NR2; and

[0190] V is NR5when U is CR3;

[0191] X is CR6or N;

[0192] Y is CR7or N;

[0193] Z is CR8or N;

[0194] R2and R3are H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0195] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, C(0)Ra, C(0)NRb2, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20, each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21, Rais CrC2alkyl, and each Rbis independently H or Ci-C2alkyl; and

[0196] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20; or R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21;

[0197] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0198] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0199] R9is H, OH, NH2, NHCHS or N(CH3)2;

[0200] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0201] Q is NR11or O; or

[0202] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0203] R11is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0204] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0205] each R15and R16is independently H or CH3;

[0206] R17is C1-C4alkyl, C1-C4fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0207] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0208] each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NR22R23, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0209] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0210] each R22and R23is independently H, Ci-C3alkyl, Ci-C3fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said CrC3alkyl and Ci-C3fluoroalkyl is optionally further substituted by OH, CrC2alkoxy or Ci-C2fluoroalkoxy and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy; or R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or CrC2fluoroalkoxy;

[0211] R24is H, C1-C4 alkyl, C1-C4fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0212] R25is C1-C4 alkyl or C1-C4 fluoroalkyl;

[0213] each R26and R27is independently H or CH3;

[0214] R28is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, CrC2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2;

[0215] each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, CrC2alkoxy, CrC2fluoroalkoxy, CN, NH2, NHCHSor N(CH3)2;

[0216] m is 0, 1 or 2;

[0217] n is 0, 1 , 2, 3 or 4;

[0218] p is 1 , 2 or 3; and

[0219] q is 0, 1 , 2 or 3;

[0220] wherein the sum of p and q is an integer from 1 to 4.

[0221] In another aspect, the invention provides a compound of Formula (II):

[0222]

[0223] or a pharmaceutically acceptable salt thereof, wherein:

[0224] R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;

[0225] U is NR2or CR3;

[0226] V is N or CR4when U is NR2; and

[0227] V is NR5when U is CR3;

[0228] X is CR6or N;

[0229] Y is CR7or N;

[0230] Z is CR8or N; R2and R3are H, CrC5alkyl, CrC5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said CrC5alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0231] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;

[0232] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0233] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0234] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0235] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0236] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0237] Q is NR11or O; or

[0238] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0239] R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0240] R14is C1-C4 alkyl or C1-C4 fluoroalkyl;

[0241] each R15and R16is independently H or CH3;

[0242] R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0243] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0244] each R20is independently OH, Ci-C2alkoxy, CrC2fluoroalkoxy, CN or NR22R23;

[0245] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0246] each R22and R23is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl; or

[0247] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0248] n is 0, 1 , 2, 3 or 4;

[0249] p is 1 , 2 or 3; and

[0250] q is 0, 1 , 2 or 3;

[0251] wherein the sum of p and q is an integer from 1 to 4. In another aspect, the invention provides a compound of Formula (III):

[0252]

[0253] or a pharmaceutically acceptable salt thereof, wherein:

[0254] R1is H, F, Cl, CN, CrC2alkyl or C1-C2 fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;

[0255] U is NR2or CR3;

[0256] V is N or CR4when U is NR2; and

[0257] V is NR5when U is CR3;

[0258] X is CR6or N;

[0259] Y is CR7or N;

[0260] Z is CR8or N;

[0261] R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0262] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;

[0263] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0264] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0265] R7and R8are independently H, F, Cl, CN, Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0266] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0267] each R10is independently F, CN, Ci-C2alkyl or Ci-C2fluoroalkyl, where each said Ci-C2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0268] Q is NR11or O; or

[0269] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10; R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0270] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0271] each R15and R16is independently H or d-h;

[0272] R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0273] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0274] each R20is independently OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN or NR22R23;

[0275] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2;

[0276] each R22and R23is independently H, C1-C2 alkyl or Ci-C2fluoroalkyl; or

[0277] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0278] n is 0, 1 , 2, 3 or 4;

[0279] p is 1 , 2 or 3; and

[0280] q is 0, 1 , 2 or 3;

[0281] wherein the sum of p and q is an integer from 1 to 4.

[0282] In another aspect, the invention provides a compound of Formula (IV):

[0283]

[0284] or a pharmaceutically acceptable salt thereof, wherein:

[0285] R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20;

[0286] U is NR2or CR3;

[0287] V is N or CR4when U is NR2; and

[0288] V is NR5when U is CR3;

[0289] X is CR6or N;

[0290] Y is CR7or N; Z is CR8or N;

[0291] R2and R3are H, CrC5alkyl, CrC5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said CrC5alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0292] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20; and

[0293] R5is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20; or

[0294] R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21;

[0295] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0296] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0297] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0298] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0299] Q is NR11or O; or

[0300] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0301] R11is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0302] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0303] each R15and R16is independently H or CH3;

[0304] R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0305] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0306] each R20is independently OH, Ci-C2alkoxy, CrC2fluoroalkoxy, CN or NR22R23;

[0307] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0308] each R22and R23is independently H, CrC2alkyl or Ci-C2fluoroalkyl; or R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0309] R24is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0310] R25is C1-C4 alkyl or C1-C4 fluoroalkyl;

[0311] each R26and R27is independently H or CH3;

[0312] R28is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2; each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, CrC2alkoxy, CrC2fluoroalkoxy, CN, NH2, NHCHSor N(CH3)2;

[0313] m is 0, 1 or 2;

[0314] n is 0, 1 , 2, 3 or 4;

[0315] p is 1 , 2 or 3; and

[0316] q is 0, 1 , 2 or 3;

[0317] wherein the sum of p and q is an integer from 1 to 4.

[0318] In another aspect, the invention provides a compound of Formula (V):

[0319]

[0320] or a pharmaceutically acceptable salt thereof, wherein:

[0321] R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;

[0322] U is NR2or CR3;

[0323] V is N or CR4when U is NR2; and

[0324] V is NR5when U is CR3;

[0325] X is CR6or N;

[0326] Y is CR7or N;

[0327] Z is CR8or N;

[0328] R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21; R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20; and

[0329] R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20; or

[0330] R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21;

[0331] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0332] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0333] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0334] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0335] Q is NR11or O; or

[0336] Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;

[0337] R11is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0338] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0339] each R15and R16is independently H or CH3;

[0340] R17is C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20;

[0341] each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0342] each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR22R23;

[0343] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0344] each R22and R23is independently H, CrC2alkyl or Ci-C2fluoroalkyl; or

[0345] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0346] R24is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0347] R25is C1-C4alkyl or C1-C4fluoroalkyl; each R26and R27is independently H or CH3;

[0348] R28is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2; each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, CrC2alkoxy, CrC2fluoroalkoxy,

[0349] CN, NH2, NHCHSor N(CH3)2;

[0350] m is 0, 1 or 2;

[0351] n is 0, 1 , 2, 3 or 4;

[0352] p is 1 , 2 or 3; and

[0353] q is 0, 1 , 2 or 3;

[0354] wherein the sum of p and q is an integer from 1 to 4.

[0355] In frequent embodiments of Formula (IV) and Formula (V), R2is taken together with R4, or R3is taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21.

[0356] In some embodiments, the compounds of Formulae (I) to (V) have the absolute stereochemistry as shown in one of Formulae (l-A), (l-B), (l-C) or (l-D); (ll-A), (ll-B), (ll-C) or (II- D); (I I l-A), (I I l-B), (lll-C) or (lll-D); (IV-A), (IV-B), (IV-C) or (IV-D); and (V-A), (V-B), (V-C) or (V-D):

[0357]

[0358] (l-C) to (V-C) (l-D) to (V-D)

[0359] wherein A in Formula (l-A) to (l-D) is N or CH; A in Formula (ll-A) to (I l-D) is replaced by N; A in Formula (I ll-A) to (I I l-D) is replaced by CH; A in Formula (IV-A) to (IV-D) is replaced by N; and A in Formula (V-A) to (V-D) is replaced by CH; or a pharmaceutically acceptable salt of one of the foregoing.

[0360] Each of the aspects and embodiments described herein with respect to Formula (I) is also applicable to compounds of Formulae (l-A), (l-B), (l-C) or (l-D).

[0361] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formulae (I l-A), (ll-B), (I l-C) or (ll-D).

[0362] Each of the aspects and embodiments described herein with respect to Formula (III) is also applicable to compounds of Formulae (I I l-A), (I I l-B), (II l-C) or (I ll-D).

[0363] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulae (IV-A), (IV-B), (IV-C) or (IV-D).

[0364] Each of the aspects and embodiments described herein with respect to Formula (V) is also applicable to compounds of Formulae (V-A), (V-B), (V-C) or (V-D).

[0365] In compounds of Formula (I), A is N or CH. In some embodiments, A is N. In other embodiments, A is CH.

[0366] In compounds of Formula (I), R1is H, F, Cl, CN, CrC2alkyl, C1-C2 fluoroalkyl or CrC2alkoxy, where each said Ci-C2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20. In some embodiments, R1is F or Cl. In some such embodiments, R1is F. In some such embodiments, R1is Cl.

[0367] In compounds of Formula (I), U is NR2or CR3; V is N or CR4when U is NR2; and V is NR5when U is CR3. In some embodiments, U is NR2and V is N or CR4. In some such embodiments, U is NR2and V is CR4. In some such embodiments, U is NR2and V is N. In some embodiments, U is CR3and V is NR5.

[0368] In compounds of Formula (I), X is CR6or N. In some embodiments, X is CR6. In some embodiments, X is N,

[0369] In compounds of Formula (I), Y is CR7or N. In some embodiments, Y is CR7. In some embodiments, Y is N.

[0370] In compounds of Formula (I), Z is CR8or N. In some embodiments, Z is CR8. In some embodiments, Z is N.

[0371] In frequent embodiments of Formula (I), X is CR6, Y is CR7and Z is CR8. In other embodiments of Formula (I), at least one of X, Y and Z is N.

[0372] In some embodiments of Formula (I), R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0373] In some such embodiments, R2and R3are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20. In other such embodiments, R2and R3are C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0374] In some embodiments of Formula (I), R2is C1-C5alkyl or C1-C5fluoroalkyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20. In some embodiments of Formula (I), R3is C1-C5alky or Ci-C5fluoroalkyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20.

[0375] In some embodiments of Formula (I), R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, C(0)Ra, C(0)NRb2, C3-C8cycloalkyl or 3-6 membered heterocyclyl; where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20, each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21, Rais C1-C2alkyl, and each Rbis independently H or C1-C2alkyl.

[0376] In some such embodiments, R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or Ci-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20In some such embodiments, R4is C1-C4alkyl or Ci-C4fluoroalkyl,

[0377] , where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some such embodiments, R20is OH. In other such embodiments, R20is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0378] In other such embodiments, R4is C(0)Raor C(0)NRb2, where Rais C1-C2 alkyl, and each Rbis independently H or C1-C2 alkyl. In still other such embodiments, R4is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0379] In some embodiments of Formula (I), R5is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20.

[0380] In other embodiments of Formula (I), R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21.

[0381] In some embodiments of Formula (I), R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5- 7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0382] In some embodiments of Formula (I), R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5- 7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0383] In compounds of Formula (I), R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3. In some embodiments, R6is F or Cl. In some such embodiments, R6is F. In some such embodiments, R6is Cl. In some embodiments, R6is H. In other embodiments, R6is CN, CH3, CH2F, CHF2or CF3.

[0384] In compounds of Formula (I), R7and R8are independently H, F, Cl, CN, CrC2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy and Ci-C2fluoroalkoxy is optionally substituted by R20. In some such embodiments, R7is H. In some such embodiments, R8is H. In some such embodiments, R7and R8are H.

[0385] In compounds of Formula (I), R9is H, OH, NH2, NHCH3or N(CH3)2. In preferred embodiments of Formula (I), R9is OH.

[0386] In compounds of Formula (I), each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 or 2 and R10is independently F, CN, Ci-C2alkyl or Ci-C2fluoroalkyl. In some embodiments, n is 1 or 2 and R10is independently F or CH3.

[0387] In some embodiments of Formula (I), Q is NR11or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1 . In some such embodiments, n is 0 and R10is absent.

[0388] In other embodiments of Formula (I), Q is NR11. In some embodiments, Q is NR11, p is 2 and q is 1. In some such embodiments, R11is S02R14. In other such embodiments, R11is COR17. In some such embodiments, n is 0 and R10is absent.

[0389] In some embodiments of Formula (I), Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, n is 0 and R10is absent.

[0390] In compounds of Formula (I), R11is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20, S02R14, S02NR15R16, COR17, COOR17or CONR18R19.

[0391] In some embodiments, R11is S02R14. In other embodiments, R11is COR17. In still other embodiments, R11is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20, S02R14, S02NR15R16, COR17, COOR17or CONR18R19. In some such embodiments, R11is C1-C4alkyl substituted by S02R14or COR17. In some such embodiments, R11is C1-C4alkyl substituted by R20.

[0392] In compounds of Formula (I), R14is C1-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, R14is C1-C4alkyl. In some such embodiments, R14is CrC2alkyl. In some embodiments, R14is C1-C4fluoroalkyl. In some such embodiments, R14is CrC2fluoroalkyl. In particular embodiments, R14is CHs or C2H5.

[0393] In compounds of Formula (I), each R15and R16is independently H or CH3.

[0394] In compounds of Formula (I), R17is C1-C4alkyl, C1-C4fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some embodiments, R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R17is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0395] In compounds of Formula (I), each R18and R19is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20.

[0396] In compounds of Formula (I), each R20is independently OH, CrC2alkoxy, CrC2fluoroalkoxy, CN, NR22R23, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0397] In some embodiments, each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR22R23. In some such embodiments, R20is OH. In some such embodiments, R20is OH, Ci-C2alkoxy or NR22R23. In some such embodiments, R20is OH, In some embodiments, R20is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0398] In compounds of Formula (I), each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2. In some embodiments, each R21is independently F, OH or C1-C4alkyl.

[0399] In some embodiments of Formula (I), each R22and R23is independently H, CrC3alkyl, Ci-C3fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said Ci-C3alkyl and Ci-C3fluoroalkyl is optionally further substituted by OH, Ci-C2alkoxy or Ci-C2fluoroalkoxy and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or CrC2fluoroalkoxy.

[0400] In some such embodiments, each R22and R23is independently H, Ci-C2alkyl or CrC2fluoroalkyl. In some such embodiments, each R22and R23is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl.

[0401] In some embodiments of Formula (I), R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy. In some such embodiments, R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F, OH or Ci-C2alkyl. In compounds of Formula (I), R24is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R25, S02NR26R27, COR28, COOR28or CONR29R30. In some embodiments, R24is H or CrC4alkyl. In some embodiments, R24is H or Ci-C2alkyl.

[0402] In compounds of Formula (I), R25is Ci-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, R25is Ci-C2alkyl.

[0403] In compounds of Formula (I), each R26and R27is independently H or CH3.

[0404] In compounds of Formula (I), R28is Ci-C4alkyl or CrC4fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, R28is CrC4alkyl optionally substituted by OH or Ci-C2alkoxy. In some embodiments, R28is Ci-C2alkyl.

[0405] In compounds of Formula (I), each R29and R30is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, each R29and R30is independently H or Ci-C4alkyl where each said Ci-C4alkyl is optionally substituted by OH or CrC2alkoxy. In some embodiments, each R29and R30is independently H or CrC2alkyl.

[0406] In compounds of Formula (I), m is 0, 1 or 2. In some embodiments, m is 2.

[0407] In compounds of Formula (I), n is 0, 1 , 2, 3 or 4. In some embodiments, n is 0 and R10is absent. In some embodiments, n is 1 or 2.

[0408] In compounds of Formula (I), p is 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1 . In some embodiments, the sum of p and q is an integer from 1 to 3.

[0409] In compounds of Formula (I), q is 0, 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1 . In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

[0410] In some embodiments, p is 2 and q is 1 . In other embodiments, p is 1 and q is 1 . In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer from 1 to 3.

[0411] In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (I- C) or (l-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R1is Cl; U is NR2and V is CR4; R2is C1-C5 alkyl; or R2is i-C3H7; R4is Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0412] In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (I- C) or (l-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R1 is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is C1-C4 alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR1 1, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0413] In a preferred embodiment, the invention provides a compound of Formula (I), (l-A), (l-B), (l-C) or (l-D), or a pharmaceutically acceptable salt thereof, wherein: A is N; R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is CrC4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0414] In another preferred embodiment, the invention provides a compound of Formula (I), (I- A), (l-B), (l-C) or (l-D), or a pharmaceutically acceptable salt thereof, wherein: A is N; R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0415] In another embodiment, the invention provides a compound of Formula (I), (l-A), (l-B), (I- C) or (l-D), or a pharmaceutically acceptable salt thereof, wherein: A is N; R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0416] In another preferred embodiment, the invention provides a compound of Formula (I), (I- A), (l-B), (l-C) or (l-D), or a pharmaceutically acceptable salt thereof, wherein: A is CH; R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is CrC4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0417] In certain embodiments, the invention provides a compound of Formula (I), (l-A), (l-B), (I- C) or (l-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is CH; R1is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is Ci-C4alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR1 1, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0418] Each of the aspects and embodiments described herein with respect to Formula (I) is also applicable to compounds of Formulae (ll)-(XII) that are not inconsistent with such aspect or embodiment. In compounds of Formula (II), R1is H, F, Cl, CN , CrC2alkyl or C1-C2 fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, R1is F or Cl. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0419] In compounds of Formula (II), X is CR6or N. In some embodiments, X is CR6. In some embodiments, X is N,

[0420] In compounds of Formula (II), Y is CR7or N. In some embodiments, Y is CR7. In some embodiments, Y is N.

[0421] In compounds of Formula (II), Z is CR8or N. In some embodiments, Z is CR8. In some embodiments, Z is N.

[0422] In frequent embodiments of Formula (II), X is CR6, Y is CR7and Z is CR8. In other embodiments of Formula (II), at least one of X, Y and Z is N.

[0423] In compounds of Formula (II), U is NR2or CR3; V is N or CR4when U is NR2; and V is NR5when U is CR3. In some embodiments, U is NR2and V is N or CR4. In some such embodiments, U is NR2and V is CR4. In some such embodiments, U is NR2and V is N. In other embodiments, U is CR3and V is NR5.

[0424] In some embodiments of Formula (II), U is NR2and R2is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0425] In compounds of Formula (II), R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0426] In some such embodiments, R2is C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20. In some such embodiments, R2is C1-C5 alkyl optionally substituted by R20. In some such embodiments, R20is OH. In particular embodiments, R2is CH3, C2H5,n-C3H7, i-C3H7, n-C4H9, s-C4H9,i-C4H9,t-C4H9,CHF2or CH2CHF2(i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl or difluoroethyl), each optionally substituted by R20. In specific embodiments, R2is isopropyl or tert- butyl. In specific embodiments, R2is isopropyl (i-CsHY In some embodiments, R2is C1-C5 alkyl or C1-C5 fluoroalkyl optionally substituted by R20where R20is OH.

[0427] In other embodiments, R2is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some such embodiments, R2is 3-6 membered heterocyclyl optionally substituted by R21. In particular embodiments, R2is oxetan-3-yl or azetidin-3-yl, each optionally substituted by R21. In specific embodiments, R2is oxetan-3-yl. In other embodiments, R2is C3-C8cycloalkyl, where said C3-C8 cycloalkyl is optionally substituted by R21. In some such embodiments, R21is F, OH or CrC4alkyl.

[0428] In some embodiments of the foregoing where U is NR2, V is N. In other embodiments of the foregoing where U is NR2, V is CR4.

[0429] In other embodiments of Formula (II), U is CR3and R3is H, C1-C5 alkyl, CrC5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0430] In some such embodiments, R3is C1-C5alkyl or C1-C5fluoroalkyl, where each said CrC5alkyl and C1-C5fluoroalkyl is optionally substituted by R20. In some such embodiments, R3is CrC5alkyl optionally substituted by R20. In some such embodiments, R20is OH or NR22R23. In some such embodiments, R20is OH. In some such embodiments, R3is CH3, C2H5,n-C3H7, i-C3H7, n- C4H9, S-C4H9i-C4Hg,t-C4H9,CHF2or CH2CHF2, each optionally substituted by R20. In specific embodiments, R3is i-C3H7or t-C4H9(i.e., isopropyl or tert-butyl). In specific embodiments, R2is isopropyl.

[0431] In other embodiments, R3is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some such embodiments, R3is 3-6 membered heterocyclyl optionally substituted by R21. In particular embodiments, R3is oxetan-3-yl or azetidin3-yl optionally substituted by R21. In some such embodiments, R21is F, OH or Ci-C4alkyl. In specific embodiments, R3is oxetan-3-yl. In other embodiments, R3is C3-C8cycloalkyl, where said C3-C8cycloalkyl is optionally substituted by R21. In some such embodiments, R21is F, OH or Ci-C4alkyl.

[0432] In the foregoing embodiments where U is CR3, V is NR5.

[0433] In some embodiments of Formula (II), V is CR4when U is NR2.

[0434] In compounds of Formula (II), R4is H, Ci-C4alkyl, Ci-C4fluoroalkyl, CrC4alkoxy or CrC4fluoroalkoxy, where each said Ci-C4alkyl, CrC4fluoroalkyl, CrC4alkoxy and Ci-C4fluoroalkoxy is optionally substituted by R20. In some embodiments, R4is H. In other embodiments, R4is Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some such embodiments, R4is Ci-C4alkyl optionally substituted by R20. In some such embodiments, R20is OH, OCH3, NH2, NHCH3or NH(CH3)2. In some such embodiments, R20is OH or NH2. In some such embodiments, R20is OH. In certain embodiments, R4is Ci-C2alkyl optionally substituted by R20, where R20is OH or NH2. In specific embodiments, R4optionally substituted by R20(i.e., R4-R20) is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2(i.e., methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R4substituted by R20is CH(OH)CH3or C(OH)(CH3)2. In other such embodiments, R4is CrC4fluoroalkyl optionally substituted by R20. In other embodiments, R4is C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20.

[0435] In some embodiments of Formula (II), V is NR5when U is CR3.

[0436] In compounds of Formula (II), R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R5is H. In other embodiments, R5is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some such embodiments, R5is C1-C4alkyl optionally substituted by R20. In other such embodiments, R5is C1-C4fluoroalkyl optionally substituted by R20. In specific embodiments, R5is C1-C2alkyl or C1-C2fluoroalkyl. In specific embodiments, R5is CH3, C2H5,CHF2or CH2CHF2(i.e., methyl, ethyl, difluoromethyl or difluoroethyl).

[0437] In compounds of Formula (II), R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3. In some embodiments, R6is H. In other embodiments, R6is F. In other embodiments, R6is Cl. In further embodiments, R6is CN. In other embodiments, R6is CH3, CH2F, CHF2or CF3.

[0438] In compounds of Formula (II), R7and R8are independently H, F, Cl, CN, C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy or C1-C2fluoroalkoxy, where each said C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy and C1-C2fluoroalkoxy is optionally substituted by R20.

[0439] In some embodiments of Formula (II), R7is H. In other embodiments, R7is F or Cl. In further embodiments, R7is C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some such embodiments, R7is CH3, optionally substituted by R20. In some embodiments, R7is CH3.

[0440] In some embodiments of Formula (II), R8is H. In other embodiments, R8is F or Cl. In further embodiments, R8is C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some such embodiments, R8is CH3, optionally substituted by R20. In some embodiments, R8is CH3.

[0441] In some embodiments, R7and R8are H.

[0442] In compounds of Formula (II), R9is H, OH, NH2, NHCH3or N(CH3)2. In some preferred embodiments, R9is OH. In other embodiments, R9is NH2, NHCH3 or N(CH3)2. In further embodiments, R9is H.

[0443] In compounds of Formula (II), each R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 , 2, 3 or 4 and each R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In other embodiments, n is 1 or 2 and R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl. In some embodiments, n is 1 or 2 and R10is independently F or CH3. In compounds of Formula (II), Q is NR11or O; or Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10.

[0444] In some embodiments of Formula (II), Q is NR11. In some embodiments, Q is NR11, p is 2 and q is 1 . In some such embodiments, R11is S02R14. In other such embodiments, R11is COR17. In some such embodiments, n is 0 and R10is absent.

[0445] In compounds of Formula (II), R1 1is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R11is H, Ci-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, R11is H. In other embodiments, R11is CrC4alkyl or Ci-C4fluoroalkyl. In some embodiments, R11is CrC4alkyl. In other embodiments, R11is CrC4fluoroalkyl. In some embodiments, R11is S02R14, S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R11is S02R14or S02NR15R16. In some embodiments, R11is S02R14. In other embodiments, R11is S02NR15R16. In some embodiments, R11is COR17, COOR17or CONR18R19. In some embodiments, R11is COR17. In some embodiments, R11is COOR17. In other embodiments, R11is CONR18R19.

[0446] In other embodiments of Formula (II), Q is O. In some embodiments, Q is O, p is 2 and q is 1 . In some such embodiments, n is 0 and R10is absent.

[0447] In further embodiments of Formula (II), Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11as a ring member, which ring is optionally further substituted by R10. In other such embodiments, R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, R12and R13are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R12and R13are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R12and R13are taken together to form a 6- membered optionally substituted heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR11or O as a ring member and is optionally further substituted by R10, where each of R10and R11is as further defined herein. In some such embodiments, n is 0 and R10is absent.

[0448] In the foregoing embodiments, each R10is independently selected from the group as defined herein .

[0449] In compounds of Formula (II), R14is Ci-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, R14is Ci-C4alkyl. In some embodiments, R14is Ci-C4fluoroalkyl. In specific embodiments, R14is CH3or C2H5(i.e., methyl or ethyl).

[0450] In compounds of Formula (II), each R15and R16is independently H or CH3. In compounds of Formula (II), R17is CrC4alkyl or CrC4fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R17is CrC4alkyl or Ci-C4fluoroalkyl. In some embodiments, R17is CrC4alkyl optionally substituted by R20. In some embodiments, R17is Ci-C4fluoroalkyl optionally substituted by R20. In specific embodiments, R17is CH3or C2H5.

[0451] In compounds of Formula (II), each R18and R19is independently H, Ci-C4alkyl or CrC4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20. In some embodiments, each R18and R19is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, each R18and R19is independently H or Ci-C4alkyl optionally substituted by R20. In some embodiments, each R18and R19is independently H or CrC4fluoroalkyl optionally substituted by R20. In specific embodiments, each R18and R19is independently H, CH3or C2H5.

[0452] In compounds of Formula (II), each R20is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or NR22R23. In some embodiments, R20is OH. In some such embodiments,

[0453] R20is OH, C1-C2 alkoxy or NR22R23. In other embodiments, R20is C1-C2 alkoxy or C1-C2 fluoroalkoxy. In further embodiments, R20is CN. In still other embodiments, R20is NR22R23.

[0454] In compounds of Formula (II), each R21is independently F, OH, CN, NR22R23, Ci-C4alkyl, Ci-C4fluoroalkyl, CrC4alkoxy or Ci-C4fluoroalkoxy, where each said Ci-C4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy and CrC4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2. In some embodiments, R21is F. In some embodiments, R21is OH. In some embodiments, each R21is independently F, OH or Ci-C4alkyl. In other embodiments, R21is CN. In other embodiments, R21is Ci-C4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy or Ci-C4

[0455] fluoroalkoxy, where each said Ci-C4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy and Ci-C4

[0456] fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2

[0457] In compounds of Formula (II), each R22and R23is independently H, C1-C2 alkyl or Ci-C2 fluoroalkyl; or R22and R23may be taken togetherwith the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

[0458] In some embodiments, each R22and R23is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl. In specific embodiments, each R22and R23is independently H or CH3. In other embodiments, R22and R23are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

[0459] In compounds of Formula (II), n is 0, 1 , 2, 3 or 4. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 , 2, 3 or 4 and R10is as defined herein. In some embodiments, n is 1 or 2.

[0460] In compounds of Formula (I I), p is 1 , 2 or 3; and q is 0, 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, the sum of p and q is an integer from 1 to 3.

[0461] In some embodiments, p is 2 and q is 1 . In other embodiments, p is 2 and q is 2. In some embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1 . In still other embodiments, p is 1 and q is 2. In further embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1 . In some embodiments, q is 1 . In other embodiments, q is 0.

[0462] In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is NR2and V is CR4; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; X is CR6; R6is F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; Q is O; or Q is NR11, where R11is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0463] In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20; R20is OH; X is CR6; R6is F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is CrC4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0464] In a preferred embodiment, the invention provides a compound of Formula (II), (ll-A), (II- B), (ll-C) or (l l-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0465] In another preferred embodiment, the invention provides a compound of Formula (II), (II- A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0466] In compounds of Formula (III), R1is H, F, Cl, CN, Ci-C2alkyl or Ci-C2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, R1is F or Cl. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0467] In compounds of Formula (III), X is CR6or N. In some embodiments, X is CR6. In some embodiments, X is N,

[0468] In compounds of Formula (III), Y is CR7or N. In some embodiments, Y is CR7. In some embodiments, Y is N.

[0469] In compounds of Formula (I II), Z is CR8or N. In some embodiments, Z is CR8. In some embodiments, Z is N. In frequent embodiments of Formula (III), X is CR6, Y is CR7and Z is CR8. In other embodiments of Formula (III), at least one of X, Y and Z is N.

[0470] In compounds of Formula (III), U is NR2or CR3; V is N or CR4when U is NR2; and V is NR5when U is CR3. In some embodiments, U is NR2and V is N or CR4. In some such embodiments, U is NR2and V is CR4. In some such embodiments, U is NR2and V is N. In other embodiments, U is CR3and V is NR5.

[0471] In some embodiments of Formula (III), U is NR2and R2is H, CrC5alkyl, CrC5fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0472] In compounds of Formula (III), R2and R3are H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0473] In some such embodiments, R2is C1-C5alkyl or C1-C5fluoroalkyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20. In some such embodiments, R2is C1-C5alkyl optionally substituted by R20. In some such embodiments, R20is OH. In particular embodiments, R2is CH3, C2H5,n-C3H7, i-C3H7, n-C4H9, s-C4H9,i-C4H9,t-C4H9,CHF2or CH2CHF2(i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, difluoromethyl or difluoroethyl), each optionally substituted by R20. In specific embodiments, R2is isopropyl or tert- butyl. In specific embodiments, R2is isopropyl. In some embodiments, R2is C1-C5alkyl or C1-C5fluoroalkyl optionally substituted by R20where R20is OH.

[0474] In other embodiments, R2is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some such embodiments, R2is 3-6 membered heterocyclyl optionally substituted by R21. In particular embodiments, R2is oxetan-3-yl or azetidin-3-yl, each optionally substituted by R21. In specific embodiments, R2is oxetan-3-yl. In other embodiments, R2is C3-C8cycloalkyl, where said C3-C8cycloalkyl is optionally substituted by R21. In some such embodiments, R21is F, OH or Ci-C4alkyl.

[0475] In some such embodiments, R3is C1-C5alkyl or C1-C5fluoroalkyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20. In some such embodiments, R3is C1-C5alkyl optionally substituted by R20. In some such embodiments, R20is OH or NR22R23. In some such embodiments, R20is OH. In some such embodiments, R3is CH3, C2H5,n-C3H7, i-C3H7, n- C4H9, S-C4H9,i-C4H9,t-C4H9,CHF2or CH2CHF2, each optionally substituted by R20. In specific embodiments, R3is i-C3H7or t-C4H9(i.e., isopropyl or tert-butyl). In specific embodiments, R2is isopropyl. In other embodiments, R3is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some such embodiments, R3is 3-6 membered heterocyclyl optionally substituted by R21. In particular embodiments, R3is oxetan-3-yl or azetidin3-yl optionally substituted by R21. In some such embodiments, R21is F, OH or C1-C4 alkyl. In specific embodiments, R3is oxetan-3-yl. In other embodiments, R3is C3-C8cycloalkyl, where said C3-C8cycloalkyl is optionally substituted by R21. In some such embodiments, R21is F, OH or C1-C4 alkyl.

[0476] In the foregoing embodiments where U is CR3, V is NR5.

[0477] In some embodiments of Formula (III), V is CR4when U is NR2.

[0478] In compounds of Formula (III), R4is H, Ci-C4alkyl, Ci-C4fluoroalkyl, CrC4alkoxy or Ci-C4fluoroalkoxy, where each said Ci-C4alkyl, CrC4fluoroalkyl, CrC4alkoxy and Ci-C4fluoroalkoxy is optionally substituted by R20. In some embodiments, R4is H. In other embodiments, R4is Ci-C4alkyl or CrC4fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some such embodiments, R4is Ci-C4alkyl optionally substituted by R20. In some such embodiments, R20is OH, OCH3, NH2, NHCH3or NH(CH3)2. In some such embodiments, R20is OH or NH2. In some such embodiments, R20is OH. In certain embodiments, R4is Ci-C2alkyl optionally substituted by R20, where R20is OH or NH2. In specific embodiments, R4-R20is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2(i.e., methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl or aminomethyl). In some embodiments, R4substituted by R20is CH(OH)CH3or C(OH)(CH3)2. In other such embodiments, R4is Ci-C4fluoroalkyl optionally substituted by R20. In other embodiments, R4is CrC4alkoxy or CrC4fluoroalkoxy, where each said CrC4alkoxy and Ci-C4fluoroalkoxy is optionally substituted by R20.

[0479] In some embodiments of Formula (III), V is NR5when U is CR3.

[0480] In compounds of Formula (III), R5is H, Ci-C4alkyl or CrC4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20. In some embodiments, R5is H. In other embodiments, R5is CrC4alkyl or CrC4fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some such embodiments, R5is Ci-C4alkyl optionally substituted by R20. In other such embodiments, R5is Ci-C4fluoroalkyl optionally substituted by R20. In specific embodiments, R5is CrC2alkyl or Ci-C2fluoroalkyl. In specific embodiments, R5is CH3, C2Hs,CHF2or CH2CHF2(i.e., methyl, ethyl, difluoromethyl or difluoroethyl).

[0481] In compounds of Formula (III), R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3. In some embodiments, R6is H. In other embodiments, R6is F. In other embodiments, R6is Cl. In further embodiments, R6is CN. In other embodiments, R6is CH3, CH2F, CHF2or CF3. In compounds of Formula (III), R7and R8are independently H, F, Cl, CN, CrC2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy or Ci-C2fluoroalkoxy, where each said C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy and C1-C2fluoroalkoxy is optionally substituted by R20.

[0482] In some embodiments of Formula (III), R7is H. In other embodiments, R7is F or Cl. In further embodiments, R7is C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some such embodiments, R7is CH3, optionally substituted by R20. In some embodiments, R7is CH3.

[0483] In some embodiments of Formula (III), R8is H. In other embodiments, R8is F or Cl. In further embodiments, R8is C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some such embodiments, R8is CH3, optionally substituted by R20. In some embodiments, R8is CH3.

[0484] In some embodiments, R7and R8are H.

[0485] In compounds of Formula (III), R9is H, OH, NH2, NHCH3or N(CH3)2. In some preferred embodiments, R9is OH. In other embodiments, R9is NH2, NHCH3or N(CH3)2. In further embodiments, R9is H.

[0486] In compounds of Formula (III), each R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 , 2, 3 or 4 and each R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20. In other embodiments, n is 1 or 2 and R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl. In some embodiments, n is 1 or 2 and R10is independently F or CH3.

[0487] In compounds of Formula (III), Q is NR1 1or O; or Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR1 1or O as a ring member, which ring is optionally further substituted by R10.

[0488] In some embodiments of Formula (III), Q is NR11. In some embodiments, Q is NR11, p is 2 and q is 1 . In some such embodiments, R1 1is S02R14. In other such embodiments, R1 1is COR17. In some such embodiments, n is 0 and R10is absent.

[0489] In compounds of Formula (III), R1 1is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R1 1is H, C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R1 1is H. In other embodiments, R1 1is C1-C4 alkyl or C1-C4 fluoroalkyl. In some embodiments, R1 1is C1-C4 alkyl. In other embodiments, R1 1is C1-C4 fluoroalkyl. In some embodiments, R1 1is S02R14, S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R1 1is S02R14or S02NR15R16. In some embodiments, R1 1is S02R14. In other embodiments, R1 1is S02NR15R16. In some embodiments, R1 1is COR17, COOR17or CONR18R19. In some embodiments, R1 1is COR17. In some embodiments, R1 1is COOR17. In other embodiments, R1 1is CONR18R19. In other embodiments of Formula (III), Q is O. In some embodiments, Q is O, p is 2 and q is 1 . In some such embodiments, n is 0 and R10is absent.

[0490] In further embodiments of Formula (III), Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, n is 0 and R10is absent. In some such embodiments, R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11as a ring member, which ring is optionally further substituted by R10. In other such embodiments, R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, R12and R13are taken together to form a 4-membered optionally substituted heterocyclic ring. In other such embodiments, R12and R13are taken together to form a 5-membered optionally substituted heterocyclic ring. In other such embodiments, R12and R13are taken together to form a 6-membered optionally substituted heterocyclic ring. In each case, said 4-6 membered heterocyclic ring contains NR11or O as a ring member and is optionally further substituted by R10, where each of R10and R11is as further defined herein. In some such embodiments, n is 0 and R10is absent.

[0491] In the foregoing embodiments, each R10is independently selected from the group as defined herein.

[0492] In compounds of Formula (III), R14is C1-C4alkyl or C1-C4fluoroalkyl. In some embodiments, R14is C1-C4alkyl. In some embodiments, R14is C1-C4fluoroalkyl. In specific embodiments, R14is CH3or C2H5(i.e., methyl or ethyl).

[0493] In compounds of Formula (III), each R15and R16is independently H or CH3.

[0494] In compounds of Formula (III), R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R17is C1-C4alkyl or C1-C4fluoroalkyl. In some embodiments, R17is C1-C4alkyl optionally substituted by R20. In some embodiments, R17is C1-C4fluoroalkyl optionally substituted by R20. In specific embodiments, R17is CH3 or C2H5.

[0495] In compounds of Formula (III), each R18and R19is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20. In some embodiments, each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl. In some embodiments, each R18and R19is independently H or Ci-C4alkyl optionally substituted by R20. In some embodiments, each R18and R19is independently H or C1-C4fluoroalkyl optionally substituted by R20. In specific embodiments, each R18and R19is independently H, CH3or C2H5.

[0496] In compounds of Formula (III), each R20is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN or NR22R23. In some embodiments, R20is OH. In some such embodiments, R20is OH, C1-C2 alkoxy or NR22R23. In other embodiments, R20is C1-C2 alkoxy or C1-C2 fluoroalkoxy. In further embodiments, R20is CN. In still other embodiments, R20is NR22R23.

[0497] In compounds of Formula (III), each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2. In some embodiments, R21is F. In some embodiments, R21is OH. In some embodiments, each R21is independently F, OH or C1-C4alkyl. In other embodiments, R21is CN. In other embodiments, R21is C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2

[0498] In compounds of Formula (III), each R22and R23is independently H, C1-C2 alkyl or Ci-C2fluoroalkyl; or R22and R23may be taken togetherwith the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

[0499] In some embodiments, each R22and R23is independently H, C1-C2 alkyl or C1-C2 fluoroalkyl. In specific embodiments, each R22and R23is independently H or CH3. In other embodiments, R22and R23are taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH.

[0500] In compounds of Formula (III), n is 0, 1 , 2, 3 or 4. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 , 2, 3 or 4 and R10is as defined herein. In some embodiments, n is 1 or 2.

[0501] In compounds of Formula (III), p is 1 , 2 or 3; and q is 0, 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, the sum of p and q is an integer from 1 to 3.

[0502] In some embodiments, p is 2 and q is 1 . In other embodiments, p is 2 and q is 2. In some embodiments, p is 1 and q is 0. In other embodiments, p is 1 and q is 1 . In still other embodiments, p is 1 and q is 2. In further embodiments, p is 1 and q is 3. In some embodiments, p is 2. In other embodiments, p is 1 . In some embodiments, q is 1 . In other embodiments, q is 0.

[0503] In certain embodiments, the invention provides a compound of Formula (III), (lll-A), (III- B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is NR2and V is CR4; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4alkyl, where said C1-C4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; Q is O; or Q is NR11, where R11is SO2R14; R14is C1-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0504] In certain embodiments, the invention provides a compound of Formula (III), (lll-A), (III- B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is C1-C4 alkyl, where said CrC4alkyl is optionally substituted by R20; R20is OH; X is CR6; R6is F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is CrC4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0505] In a preferred embodiment, the invention provides a compound of Formula (III), (ll l-A), (ll l-B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is CrC4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0506] In another preferred embodiment, the invention provides a compound of Formula (III), (III- A), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; or R2is i-C3H7; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0507] In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; U is NR2and V is CR4; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9,s-C4H9, t-C4H9, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or CrC4alkyl, where said CrC4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; X is CR6; R6is H or F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; n is 0 and R10is absent; Q is NR11; R11is S02R14; and R14is Ci-C4alkyl; p is 2; and q is 1 .

[0508] In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; U is CR3and V is NR5; R3is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R3is CH3, i-C3H7, i-C4H9,s-C4H9, t-C4H9, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R5is H or CrC4alkyl; or R5is H or CH3; X is CR6; R6is H or F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; n is 0 and R10is absent; Q is NR11; R11is S02R14; and R14is CrC4alkyl; p is 2; and q is 1 .

[0509] In certain embodiments, the invention provides a compound of Formula (II), (ll-A), (ll-B), (ll-C) or (ll-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (III), (III- A), (lll-B), (lll-C) or (lll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; U is NR2and V is N; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9,s-C4H9, t-C4H9, CH2F,CHF2, CH2CHF2or oxetan-3-yl; X is CR6; R6is H or F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; n is 0 and R10is absent; Q is NR11; R11is S02R14; and R14is CrC4alkyl; p is 2; and q is 1 .

[0510] In compounds of Formula (IV), R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, R1is F or Cl. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0511] In compounds of Formula (IV), U is NR2or CR3; V is N or CR4when U is NR2; and V is NR5when U is CR3. In some embodiments, U is NR2and V is N or CR4. In some such embodiments, U is NR2and V is N. In some such embodiments, U is NR2and V is CR4. In some embodiments, U is CR3and V is NR5.

[0512] In compounds of Formula (IV), X is CR6or N. In some embodiments, X is CR6. In some embodiments, X is N,

[0513] In compounds of Formula (IV), Y is CR7or N. In some embodiments, Y is CR7. In some embodiments, Y is N.

[0514] In compounds of Formula (IV), Z is CR8or N. In some embodiments, Z is CR8. In some embodiments, Z is N.

[0515] In frequent embodiments of Formula (IV), X is CR6, Y is CR7and Z is CR8. In other embodiments of Formula (IV), at least one of X, Y and Z is N.

[0516] In some embodiments of Formula (IV), R2and R3are H, C1-C5 alkyl, CrC5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0517] In some such embodiments, R2and R3are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20. In other such embodiments, R2and R3are C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some embodiments, R2is Ci-C4alkyl optionally substituted by R20where R20is OH. In some embodiments, R3is Ci-C4alkyl optionally substituted by R20where R20is OH.

[0518] In some embodiments of Formula (IV), R4is H, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy or CrC4fluoroalkoxy, where each said CrC4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy and CrC4fluoroalkoxy is optionally substituted by R20. In some embodiments, R4is CrC4alkyl optionally substituted by R20where R20is OH.

[0519] In some embodiments of Formula (IV), R5is H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20. In some embodiments, R5is Ci-C4alkyl optionally substituted by R20. In some such embodiments, R20is OH. In some embodiments of Formula (IV), R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. It will be understood that R2is taken together with R4, or R3is taken together with R5in combination with the atoms to which they are attached through a C3-C5alkylene or C3.C5heteroalkylene linker, which linker is optionally substituted as further defined herein.

[0520] In some embodiments of Formula (IV), R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0521] In some embodiments, R2is taken together with R4to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R21. In other embodiments, R2is taken together with R4to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R21. In other embodiments, R2is taken together with R4to form a 6-membered ring containing NR24(i.e., piperazine), which is optionally substituted by R21. In further embodiments, R2is taken together with R4to form a 6- membered ring containing O or S (i.e., morpholine or thiomorpholine), which is optionally substituted by R21. In further embodiments, R2is taken together with R4to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR24(i.e., homopiperazine), in each case optionally substituted by R21.

[0522] In other embodiments of Formula (IV), R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5-7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0523] In some embodiments, R3is taken together with R5to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R21. In other embodiments, R3is taken together with R5to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R21. In other embodiments, R3is taken together with R5to form a 6-membered ring containing NR24(i.e., piperazine), which is optionally substituted by R21. In further embodiments, R3is taken together with R5to form a 6- membered ring containing O or S(0)m(i.e., morpholine or thiomorpholine), which is optionally substituted by R21. In further embodiments, R3is taken together with R5to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR24(i.e., homopiperazine), in each case optionally substituted by R21.

[0524] In compounds of Formula (IV), R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3. In some embodiments, R6is F or Cl. In some such embodiments, R6is F. In some such embodiments, R6is Cl. In some embodiments, R6is H. In other embodiments, R6is CN, CH3, CH2F, CHF2or CF3.

[0525] In compounds of Formula (IV), R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20. In some such embodiments, R7is H. In some such embodiments, R8is H. In some such embodiments, R7and R8are H.

[0526] In compounds of Formula (IV), R9is H, OH, NH2, NHCH3or N(CH3)2. In preferred embodiments of Formula (IV), R9is OH.

[0527] In compounds of Formula (IV), each R10is independently F, CN, Ci-C2alkyl or CrC2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 or 2 and R10is independently F, CN, CrC2alkyl or Ci-C2fluoroalkyl. In some embodiments, n is 1 or 2 and R10is independently F or CH3.

[0528] In some embodiments of Formula (IV), Q is NR11or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1 . In some such embodiments, n is 0 and R10is absent.

[0529] In other embodiments of Formula (IV), Q is NR11. In some embodiments, Q is NR11, p is 2 and q is 1 . In some such embodiments, R11is S02R14. In other such embodiments, R11is COR17. In some such embodiments, n is 0 and R10is absent.

[0530] In some embodiments of Formula (VI), Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, n is 0 and R10is absent.

[0531] In compounds of Formula (IV), R1 1is H, C1-C4 alkyl, CrC4fluoroalkyl, S02R14,

[0532] S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R11is S02R14. In other embodiments, R11is COR17.

[0533] In compounds of Formula (IV), R14is CrC4alkyl or Ci-C4fluoroalkyl. In some embodiments, R14is CrC4alkyl. In some such embodiments, R14is Ci-C2alkyl. In some embodiments, R14is Ci-C4fluoroalkyl. In some such embodiments, R14is Ci-C2fluoroalkyl. In particular embodiments, R14is CH3or C2Hs.

[0534] In compounds of Formula (IV), each R15and R16is independently H or CH3. In compounds of Formula (IV), R17is CrC4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R17is Ci-C4alkyl, where each said CrC4alkyl is optionally substituted by R20.

[0535] In compounds of Formula (IV), each R18and R19is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20.

[0536] In compounds of Formula (IV), each R20is independently OH, CrC2alkoxy, C1-C2 fluoroalkoxy, CN, or NR22R23.

[0537] In compounds of Formula (IV), each R21is independently F, OH, CN, NR22R23, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy or CrC4fluoroalkoxy, where each said CrC4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy and Ci-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2. In some embodiments, each R21is independently F, OH or Ci-C4alkyl.

[0538] In some embodiments of Formula (IV), each R22and R23is independently H, Ci-C2alkyl, Ci-C2fluoroalkyl. In other embodiments of Formula (IV), R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F or OH.

[0539] In compounds of Formula (IV), R24is H, Ci-C4alkyl, Ci-C4fluoroalkyl, S02R25,

[0540] S02NR26R27, COR28, COOR28or CONR29R30. In some embodiments, R24is H or CrC4alkyl. In some embodiments, R24is H or Ci-C2alkyl.

[0541] In compounds of Formula (IV), R25is Ci-C4alkyl or Ci-C4fluoroalkyl. . In some embodiments, R25is Ci-C2alkyl.

[0542] In compounds of Formula (IV), each R26and R27is independently H or CH3.

[0543] In compounds of Formula (IV), R28is CrC4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2

[0544] fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, R28is Ci-C4alkyl optionally substituted by OH or Ci-C2alkoxy. In some embodiments, R28is CrC2alkyl.

[0545] In compounds of Formula (IV), each R29and R30is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, each R29and R30is independently H or Ci-C4alkyl where each said Ci-C4alkyl is optionally substituted by OH or Ci-C2alkoxy. In some embodiments, each R29and R30is independently H or Ci-C2alkyl.

[0546] In compounds of Formula (IV), m is 0, 1 or 2. In some embodiments, m is 2.

[0547] In compounds of Formula (IV), n is 0, 1 , 2, 3 or 4. In some embodiments, n is 0 and R10is absent. In some embodiments, n is 1 or 2.

[0548] In compounds of Formula (IV), p is 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1 . In some embodiments, the sum of p and q is an integer from 1 to 3. In compounds of Formula (IV), q is 0, 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1 . In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

[0549] In some embodiments, p is 2 and q is 1 . In other embodiments, p is 1 and q is 1 . In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer from 1 to 3.

[0550] In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV- B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is NR2and V is CR4; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0551] In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV- B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is Ci-C4alkyl, where said CrC4alkyl is optionally substituted by R20; R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R1 1is S02R14; R14is CrC4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0552] In a preferred embodiment, the invention provides a compound of Formula (IV), (IV-A), (IV-B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0553] In another preferred embodiment, the invention provides a compound of Formula (IV), (IV-

[0554] A), (IV-B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0555] In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV-

[0556] B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; V is CR4; R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; each R21is independently F, OH or Ci-C4alkyl; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 . In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV- B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3; V is NR5; R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; each R21is independently F, OH or CrC4alkyl; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is SO2R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0557] In compounds of Formula (V), R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20. In some embodiments, R1is F or Cl. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0558] In compounds of Formula (V), U is NR2or CR3; V is N or CR4when U is NR2; and V is NR5when U is CR3. In some embodiments, U is NR2and V is N or CR4. In some such embodiments, U is NR2and V is N. In some such embodiments, U is NR2and V is CR4. In some embodiments, U is CR3and V is NR5.

[0559] In compounds of Formula (V), X is CR6or N. In some embodiments, X is CR6. In some embodiments, X is N,

[0560] In compounds of Formula (V), Y is CR7or N. In some embodiments, Y is CR7. In some embodiments, Y is N.

[0561] In compounds of Formula (V), Z is CR8or N. In some embodiments, Z is CR8. In some embodiments, Z is N.

[0562] In frequent embodiments of Formula (V), X is CR6, Y is CR7and Z is CR8. In other embodiments of Formula (V), at least one of X, Y and Z is N.

[0563] In some embodiments of Formula (V), R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0564] In some such embodiments, R2and R3are H, C1-C5 alkyl or C1-C5 fluoroalkyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20. In other such embodiments, R2and R3are C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some embodiments, R2is C1-C4 alkyl optionally substituted by R20where R20is OH. In some embodiments, R3is C1-C4 alkyl optionally substituted by R20where R20is OH.

[0565] In some embodiments of Formula (V), R4is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R20. In some embodiments, R4is C1-C4 alkyl optionally substituted by R20where R20is OH. In some embodiments of Formula (V), R5is H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R5is Ci-C4alkyl optionally substituted by R20. In some such embodiments, R20is OH.

[0566] In some embodiments of Formula (V), R2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. It will be understood that R2is taken together with R4, or R3is taken together with R5in combination with the atoms to which they are attached through a C3-C5 alkylene or C3- C5heteroalkylene linker, which linker is optionally substituted as further defined herein.

[0567] In some embodiments of Formula (V), R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5- 7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0568] In some embodiments, R2is taken together with R4to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R21. In other embodiments, R2is taken together with R4to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R21. In other embodiments, R2is taken together with R4to form a 6-membered ring containing NR24(i.e., piperazine), which is optionally substituted by R21. In further embodiments, R2is taken together with R4to form a 6- membered ring containing O or S (i.e., morpholine or thiomorpholine), which is optionally substituted by R21. In further embodiments, R2is taken together with R4to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR24(i.e., homopiperazine), in each case optionally substituted by R21.

[0569] In other embodiments of Formula (V), R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21. In some such embodiments, the 5- 7 membered heterocyclic ring contains O as an additional heteroatom. In some such embodiments, the 5-7 membered heterocyclic ring contains NR24as an additional heteroatom.

[0570] In some embodiments, R3is taken together with R5to form a 5-membered ring containing no additional heteroatoms (i.e., pyrrolidine), which is optionally substituted by R21. In other embodiments, R3is taken together with R5to form a 6-membered ring containing no additional heteroatoms (i.e., piperidine), which is optionally substituted by R21. In other embodiments, R3is taken together with R5to form a 6-membered ring containing NR24(i.e., piperazine), which is optionally substituted by R21. In further embodiments, R3is taken together with R5to form a 6- membered ring containing O or S(0)m(i.e., morpholine or thiomorpholine), which is optionally substituted by R21. In further embodiments, R3is taken together with R5to form a 7-membered ring which may contain no additional heteroatoms (i.e., homopiperidine) or may contain NR24(i.e., homopiperazine), in each case optionally substituted by R21.

[0571] In compounds of Formula (V), R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3. In some embodiments, R6is F or Cl. In some such embodiments, R6is F. In some such embodiments, R6is Cl. In some embodiments, R6is H. In other embodiments, R6is CN, CH3, CH2F, CHF2or CF3.

[0572] In compounds of Formula (V), R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20. In some such embodiments, R7is H. In some such embodiments, R8is H. In some such embodiments, R7and R8are H.

[0573] In compounds of Formula (V), R9is H, OH, NH2, NHCH3or N(CH3)2. In preferred embodiments of Formula (V), R9is OH.

[0574] In compounds of Formula (V), each R10is independently F, CN, Ci-C2alkyl or CrC2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some embodiments, n is 0 and R10is absent. In other embodiments, n is 1 or 2 and R10is independently F, CN, CrC2alkyl or Ci-C2fluoroalkyl. In some embodiments, n is 1 or 2 and R10is independently F or CH3.

[0575] In some embodiments of Formula (V), Q is NR11or O. In some embodiments, Q is O. In some embodiments, Q is O, p is 2 and q is 1 . In some such embodiments, n is 0 and R10is absent.

[0576] In other embodiments of Formula (V), Q is NR11. In some embodiments, Q is NR11, p is 2 and q is 1. In some such embodiments, R11is S02R14. In other such embodiments, R11is COR17. In some such embodiments, n is 0 and R10is absent.

[0577] In some embodiments of Formula (V), Q is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10. In some such embodiments, n is 0 and R10is absent.

[0578] In compounds of Formula (V), R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14,

[0579] S02NR15R16, COR17, COOR17or CONR18R19. In some embodiments, R11is S02R14. In other embodiments, R11is COR17.

[0580] In compounds of Formula (V), R14is Ci-C4alkyl or Ci-C4fluoroalkyl. In some embodiments, R14is CrC4alkyl. In some such embodiments, R14is Ci-C2alkyl. In some embodiments, R14is Ci-C4fluoroalkyl. In some such embodiments, R14is Ci-C2fluoroalkyl. In particular embodiments, R14is CH3or C2Hs.

[0581] In compounds of Formula (V), each R15and R16is independently H or CH3. In compounds of Formula (V), R17is C1-C4 alkyl or CrC4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by R20. In some embodiments, R17is Ci-C4alkyl, where each said CrC4alkyl is optionally substituted by R20.

[0582] In compounds of Formula (V), each R18and R19is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20.

[0583] In compounds of Formula (V), each R20is independently OH, CrC2alkoxy, C1-C2 fluoroalkoxy, CN, or NR22R23.

[0584] In compounds of Formula (V), each R21is independently F, OH, CN, NR22R23, Ci-C4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy or CrC4fluoroalkoxy, where each said CrC4alkyl, CrC4fluoroalkyl, Ci-C4alkoxy and Ci-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2. In some embodiments, each R21is independently F, OH or Ci-C4alkyl.

[0585] In some embodiments of Formula (V), each R22and R23is independently H, Ci-C2alkyl, Ci-C2fluoroalkyl. In other embodiments of Formula (V), R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F or OH.

[0586] In compounds of Formula (V), R24is H, Ci-C4alkyl, Ci-C4fluoroalkyl, S02R25,

[0587] S02NR26R27, COR28, COOR28or CONR29R30. In some embodiments, R24is H or CrC4alkyl. In some embodiments, R24is H or Ci-C2alkyl.

[0588] In compounds of Formula (V), R25is CrC4alkyl or Ci-C4fluoroalkyl. . In some embodiments, R25is Ci-C2alkyl.

[0589] In compounds of Formula (V), each R26and R27is independently H or CH3.

[0590] In compounds of Formula (V), R28is Ci-C4alkyl or CrC4fluoroalkyl, where each said

[0591] Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2

[0592] fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, R28is Ci-C4alkyl optionally substituted by OH or Ci-C2alkoxy. In some embodiments, R28is CrC2alkyl.

[0593] In compounds of Formula (V), each R29and R30is independently H, Ci-C4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2. In some embodiments, each R29and R30is independently H or Ci-C4alkyl where each said Ci-C4alkyl is optionally substituted by OH or Ci-C2alkoxy. In some embodiments, each R29and R30is independently H or Ci-C2alkyl.

[0594] In compounds of Formula (V), m is 0, 1 or 2. In some embodiments, m is 2.

[0595] In compounds of Formula (V), n is 0, 1 , 2, 3 or 4. In some embodiments, n is 0 and R10is absent. In some embodiments, n is 1 or 2.

[0596] In compounds of Formula (V), p is 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, p is 2. In other embodiments, p is 1 . In some embodiments, the sum of p and q is an integer from 1 to 3. In compounds of Formula (V), q is 0, 1 , 2 or 3; wherein the sum of p and q is an integer from 1 to 4. In some embodiments, q is 1 . In other embodiments, q is 0. In some embodiments, the sum of p and q is an integer from 1 to 3.

[0597] In some embodiments, p is 2 and q is 1 . In other embodiments, p is 1 and q is 1 . In other embodiments, p is 1 and q is 0. In further embodiments, the sum of p and q is an integer from 1 to 3.

[0598] In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is NR2and V is CR4; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0599] In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3and V is NR5; R3is C1-C5 alkyl; or R3is i-C3H7; R5is Ci-C4alkyl, where said CrC4alkyl is optionally substituted by R20; R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R1 1is S02R14; R14is CrC4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0600] In a preferred embodiment, the invention provides a compound of Formula (V), (V-A), (V- B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0601] In another preferred embodiment, the invention provides a compound of Formula (V), (V- A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; R2is C1-C5 alkyl; V is CR4; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0602] In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; U is NR2; V is CR4; R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; each R21is independently F, OH or Ci-C4alkyl; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is C C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 . In certain embodiments, the invention provides a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; U is CR3; V is NR5; R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; each R21is independently F, OH or CrC4alkyl; X is CR6; R6is F; Y is CR7; R7is H; Z is CR8; R8is H; R9is OH; Q is O; or Q is NR11, where R11is SO2R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0603] In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV- B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; U is NR2and V is CR4; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9s-C4H9, t-C4H9, CH2F CHF2, CH2CHF2or oxetan-3-yl; R4is H or CrC4alkyl, where said CrC4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CHs, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; or R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; or R4is CH(OH)CH3or C(OH)(CH3)2; X is CR6; R6is H or F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; Q is NR1 1; R11is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0604] In certain embodiments, the invention provides a compound of Formula (IV), (IV-A), (IV- B), (IV-C) or (IV-D), or a pharmaceutically acceptable salt thereof, or a compound of Formula (V), (V-A), (V-B), (V-C) or (V-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; U is CR3and V is NR5; R3is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R3is CH3, i-C3H7, i-C4H9,s-C4H9, t-C4H9, CH2F CHF2, CH2CHF2or oxetan-3-yl; R5is H or Ci-C4alkyl; or R5is H or CH3; or R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; X is CR6; R6is H or F; Y is CR7; Z is CR8; R7and R8are H; R9is OH; n is 0 and R10is absent; Q is NR11; R11is S02R14; and R14is Ci-C4alkyl; p is 2; and q is 1 .

[0605] In compounds of Formula (II) and (IV), R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20.

[0606] In some embodiments of Formula (II) and (IV), R1is H. In other embodiments, R1is F or Cl. In other embodiments, R1is Cl. In further embodiments, R1is C1-C2 alkyl or Ci-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20. In some such embodiments, R1is CH3, optionally substituted by R20. In particular embodiments, R1is CH3. In compounds of Formula (II) and (IV), the ring system comprising U, V, X, Y and Z is a fused biaryl ring system.

[0607] In compounds of Formula (II) and (IV), U is NR2or CR3. In some embodiments, U is NR2. In other embodiments, U is CR3.

[0608] In compounds of Formula (II) and (IV), V is N or CR4when U is NR2; and V is NR5when U is CR3. In some such embodiments, V is CR4. In other such embodiments, V is N. In further such embodiments, V is NR5.

[0609] In compounds of Formula (II) and (IV), X is CR6or N. In some embodiments, X is CR6.

[0610] In other embodiments, X is N.

[0611] In compounds of Formula (II) and (IV), Y is CR7or N. In some embodiments, Y is CR7.

[0612] In other embodiments, Y is N.

[0613] In compounds of Formula (II) and (IV), Z is CR8or N. In some embodiments, Z is CR8.

[0614] In other embodiments, Z is N.

[0615] In some embodiments of Formula (II) and (IV), X is CR6, Y is CR7and Z is CR8. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0616] In some embodiments of Formula (II) and (IV), X is N, Y is CR7, and Z is CR8.

[0617] In some embodiments of Formula (II) and (IV), X is CR6, Y is N, and Z is CR8.

[0618] In some embodiments of Formula (II) and (IV), X is CR6, Y is CR7, and Z is N.

[0619] In some embodiments of Formula (II) and (IV), X is N, Y is N, and Z is CR8.

[0620] In some embodiments of Formula (II) and (IV), X is CR6, Y is N, and Z is N.

[0621] In some embodiments of Formula (II) and (IV), X is N, Y is CR7, and Z is N.

[0622] In other embodiments of Formula (II) and (IV), at least one of X, Y and Z is N. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0623] In further embodiments of Formula (II) and (IV), two of X, Y and Z are N. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0624] In compounds of Formula (III) and (V), R1is H, F, Cl, CN, C1-C2 alkyl or CrC2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20.

[0625] In some embodiments of Formula (III) and (V), R1is H. In other embodiments, R1is F or Cl. In other embodiments, R1is Cl. In further embodiments, R1is CrC2alkyl or Ci-C2fluoroalkyl, where each said Ci-C2alkyl and CrC2fluoroalkyl is optionally substituted by R20. In some such embodiments, R1is CH3, optionally substituted by R20. In particular embodiments, R1is CH3.

[0626] In compounds of Formula (III) and (V), the ring system comprising U, V, X, Y and Z is a fused biaryl ring system. In compounds of Formula (III) and (V), U is NR2or CR3. In some embodiments, U is NR2. In other embodiments, U is CR3.

[0627] In compounds of Formula (III) and (V), V is N or CR4when U is NR2; and V is NR5when U is CR3. In some such embodiments, V is CR4. In other such embodiments, V is N. In further such embodiments, V is NR5.

[0628] In compounds of Formula (III) and (V), X is CR6or N. In some embodiments, X is CR6.

[0629] In other embodiments, X is N.

[0630] In compounds of Formula (III) and (V), Y is CR7or N. In some embodiments, Y is CR7.

[0631] In other embodiments, Y is N.

[0632] In compounds of Formula (III) and (V), Z is CR8or N. In some embodiments, Z is CR8.

[0633] In other embodiments, Z is N.

[0634] In some embodiments of Formula (III) and (V), X is CR6, Y is CR7and Z is CR8. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0635] In some embodiments of Formula (III) and (V), X is N, Y is CR7, and Z is CR8.

[0636] In some embodiments of Formula (III) and (V), X is CR6, Y is N, and Z is CR8.

[0637] In some embodiments of Formula (III) and (V), X is CR6, Y is CR7, and Z is N.

[0638] In some embodiments of Formula (III) and (V), X is N, Y is N, and Z is CR8.

[0639] In some embodiments of Formula (III) and (V), X is CR6, Y is N, and Z is N.

[0640] In some embodiments of Formula (III) and (V), X is N, Y is CR7, and Z is N.

[0641] In other embodiments of Formula (III) and (V), at least one of X, Y and Z is N. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0642] In further embodiments of Formula (III) and (V), two of X, Y and Z are N. In some such embodiments, U is NR2and V is CR4. In other such embodiments, U is NR2and V is N. In still other such embodiments, U is CR3and V is NR5.

[0643] In particular embodiments of each of Formulae (I), (II), (III), (IV) and (V), the fused biaryl ring system comprising U, V, X, Y and Z is selected from the group consisting of:

[0644]

[0645]

[0646] where the * represents the point of attachment to the pyrimidine ring or pyridine ring, and R2, R3, R4, R5, R6, R7and R8are as further defined herein.

[0647] In another aspect, the invention provides a compound of Formula (VI):

[0648]

[0649] or a pharmaceutically acceptable salt thereof, wherein:

[0650] R1, R2, R4, R6to R23, Q, n, p and q are as defined for Formula (II); or

[0651] R1, R2, R4, R6to R30, Q, m, n, p and q are as defined for Formula (IV). In particular embodiments, the invention provides a compound of Formula (VI), (Vl-A), (Vl-B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, wherein:

[0652] R1, R2, R4, R6to R23and n are as defined for Formula (I I).

[0653] In other embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VI- B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, wherein:

[0654] R1, R2, R4, R6to R30, m and n are as defined for Formula (IV).

[0655] In some embodiments, the compound of Formula (VI) has the absolute stereochemistry as shown in one of Formulae (Vl-A), (Vl-B), (Vl-C) or (Vl-D):

[0656]

[0657] or a pharmaceutically acceptable salt thereof.

[0658] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VI) that are not inconsistent with such aspect or embodiment.

[0659] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VI) that are not inconsistent with such aspect or embodiment.

[0660] In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VI- B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0661] In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VI- B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R3is C1-C5alkyl; or R3is i-C3H7; R5is C1-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20; R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is O; or Q is NR11, where R11is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0662] In a preferred embodiment, the invention provides a compound of Formula (VI), (Vl-A), (Vl-B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is C1-C5alkyl; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0663] In another preferred embodiment, the invention provides a compound of Formula (VI), (VI-

[0664] A), (Vl-B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is C1-C5alkyl; R4is Ci-C4alkyl optionally substituted by R20, where R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is NR11, where R1 1is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0665] In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VI-

[0666] B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5alkyl, C1-C5fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9,S-C4H9, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; R6is H or F; R7and R8are H; R9is OH; Q is NR11; R11is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0667] In certain embodiments, the invention provides a compound of Formula (VI), (Vl-A), (VI- B), (Vl-C) or (Vl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4Hg,s-C4Hg, t-C4H9, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; or R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21; R6is H or F; R7and R8are H; R9is OH; Q is NR11; R11is SO2R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0668] In another aspect, the invention provides a compound of Formula (VII):

[0669]

[0670] or a pharmaceutically acceptable salt thereof, wherein:

[0671] R1, R3, R5to R23, Q, n, p and q are as defined for Formula (II); or

[0672] R1, R3, R5to R30, Q, m, n, p and q are as defined for Formula (IV).

[0673] In particular embodiments, the invention provides a compound of Formula (VII), (VI I -A) ,

[0674] (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, wherein:

[0675] R1, R2, R4, R6to R23and n are as defined for Formula (II).

[0676] In other embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VII- B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, wherein:

[0677] R1, R2, R4, R6to R30, m and n are as defined for Formula (IV).

[0678] In some embodiments, the compound of Formula (VII) has the absolute stereochemistry as shown in one of Formulae (Vll-A), (Vll-B), (Vll-C) or (Vll-D):

[0679]

[0680] (Vll-C) (Vll-D) or a pharmaceutically acceptable salt thereof.

[0681] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VII) that are not inconsistent with such aspect or embodiment.

[0682] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VII), that are not inconsistent with such aspect or embodiment.

[0683] In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VII- B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R3is C1-C5 alkyl; or R3is i-C3H7; R5is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20; R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is O; or Q is NR11, where R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0684] In a preferred embodiment, the invention provides a compound of Formula (VII), (Vll-A), (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R3is C1-C5 alkyl; R5is Ci-C4alkyl optionally substituted by R20, where R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is O; n is 0 and R10is absent; p is 2; and q is 1 .

[0685] In another preferred embodiment, the invention provides a compound of Formula (VII), (Vll-A), (Vll-B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R3is C1-C5 alkyl; R5is Ci-C4alkyl optionally substituted by R20, where R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is NR11, where R11is S02R14; R14is C C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0686] In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VII- B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R3is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R3is CH3, i-C3H7, i-C4Hg,s-C4Hg, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R5is H or CrC4alkyl; or R5is H or CH3;R6is H or F; R7and R8are H; R9is OH; Q is NR11; R11is S02R14; R14is Ci-C4alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0687] In certain embodiments, the invention provides a compound of Formula (VII), (Vll-A), (VII- B), (Vll-C) or (Vll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R3is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R3is CH3, i-C3H7, i-C4Hs,s-C4H9, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R5is H or CrC4alkyl; or R5is H or CH3; or R3is taken together with R5to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21; R6is H or F; R7and R8are H; R9is OH; Q is NR11;R11is S02R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0688] In another aspect, the invention provides a compound of Formula (VII I):

[0689]

[0690] or a pharmaceutically acceptable salt thereof, wherein:

[0691] R1, R2, R6to R23, Q, n, p and q are as defined for Formula (II); or

[0692] R1, R2, R6to R30, Q, m, n, p and q are as defined for Formula (IV).

[0693] In particular embodiments, the invention provides a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0694] R1, R2, R4, R6to R23and n are as defined for Formula (I I).

[0695] In other embodiments, the invention provides a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof, wherein:

[0696] R1, R2, R4, R6to R30, m and n are as defined for Formula (IV).

[0697] In some embodiments, the compound of Formula (VIII) has the absolute stereochemistry as shown in one of Formulae (Vlll-A), (Vlll-B), (Vlll-C) or (Vlll-D):

[0698]

[0699]

[0700] (Vlll-C) (Vlll-D) or a pharmaceutically acceptable salt thereof.

[0701] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formula (VIII) that are not inconsistent with such aspect or embodiment.

[0702] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formula (VIII) that are not inconsistent with such aspect or embodiment.

[0703] In an embodiment, the invention provides a compound of Formula (VIII), (Vlll-A), (Vlll-B),

[0704] (Vlll-C) or (Vlll-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is C1-C5 alkyl optionally substituted by R20, where R20is OH; R6is F; R7is H; R8is H; R9is OH; Q is O; or Q is NR11; R11is S02R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0705] In certain embodiments, the invention provides a compound of Formula (VIII), (Vlll-A), (Vlll-B), (Vlll-C) or (Vlll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CHs, i-CsHy, i-C4Hg,s-C4Hg, t-C4H9, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R6is H or F; R7and R8are H; R9is OH; Q is O; or Q is NR11; R11is S02R14; R14is C1-C4 alkyl; n is 0 and R10is absent; p is 2; and q is 1 .

[0706] In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

[0707]

[0708] where the * represents the point of attachment to the 2-amino substituent.

[0709] In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

[0710]

[0711]

[0712] where the * represents the point of attachment to the 2-amino substituent.

[0713] In particular embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

[0714]

[0715] where the * represents the point of attachment to the 2-amino substituent.

[0716] In specific embodiments of Formulae (I) to (VIII), the ring comprising Q is selected from the group consisting of:

[0717]

[0718] where the * represents the point of attachment to the 2-amino substituent. In another aspect, the invention provides a compound of Formula (IX):

[0719]

[0720] or a pharmaceutically acceptable salt thereof, wherein: R1, R2, R4, R6to R11, R14to R23and n are as defined for Formula (II); or

[0721] R1, R2, R4, R6to R11, R14to R30, m and n are as defined for Formula (IV).

[0722] In some embodiments, the invention provides a compound of Formula (IX), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R6to R11, R14to R23and n are as defined for Formula (I I).

[0723] In embodiments of Formula (IX) wherein the substituent groups are as defined for Formula (II), the invention provides a compound of Formula (IX):

[0724]

[0725] or a pharmaceutically acceptable salt thereof, wherein:

[0726] R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0727] R2is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0728] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;

[0729] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0730] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy and Ci-C2fluoroalkoxy is optionally substituted by R20;

[0731] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0732] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0733] R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0734] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0735] each R15and R16is independently H or CH3; R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0736] each R18and R19is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0737] each R20is independently OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN or NR22R23;

[0738] each R21is independently F, OH, CN , NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3 or N(CH3)2;

[0739] each R22and R23is independently H, C1-C2alkyl or Ci-C2fluoroalkyl; or

[0740] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; and

[0741] n is 0, 1 , 2, 3 or 4.

[0742] In other embodiments, the invention provides a compound of Formula (IX’), or a pharmaceutically acceptable salt thereof, wherein R1, R2, R4, R6to R11, R14to R23and n are as defined for Formula (IV).

[0743] In embodiments of Formula (IX) wherein the substituent groups are as defined for Formula (IV), the invention provides a compound of Formula (IX’):

[0744]

[0745] or a pharmaceutically acceptable salt thereof, wherein:

[0746] R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20;

[0747] R2is H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21; and

[0748] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20; or R2can be taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21;

[0749] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0750] R7and R8are independently H, F, Cl, CN , CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0751] R9is H, OH, NH2, NHCHS or N(CH3)2;

[0752] each R10is independently F, CN , CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0753] R11is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;

[0754] R14is C1-C4alkyl or C1-C4fluoroalkyl;

[0755] each R15and R16is independently H or CH3;

[0756] R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0757] each R18and R19is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;

[0758] each R20is independently OH, Ci-C2alkoxy, CrC2fluoroalkoxy, CN or NR22R23;

[0759] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0760] each R22and R23is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl; or

[0761] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0762] R24is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0763] R25is C1-C4alkyl or C1-C4fluoroalkyl;

[0764] each R26and R27is independently H or CH3;

[0765] R28is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2; each R29and R30is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, Ci-C2alkoxy, CrC2

[0766] fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2;

[0767] m is 0, 1 or 2; and

[0768] n is 0, 1 , 2, 3 or 4. In some embodiments, the compound of Formula (IX) or (IX’) has the absolute stereochemistry as shown in one of Formulae (IX-A), (IX-B), (IX-C) or (IX-D), or Formulae (IX’-

[0769] A), (IX’-B), (IX’-C) or (IX’-D)

[0770]

[0771] or a pharmaceutically acceptable salt thereof.

[0772] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formulae (IX), (IX-A), (IX-B), (IX-C) or (IX-D) that are not inconsistent with such aspect or embodiment.

[0773] Each of the aspects and embodiments described herein with respect to Formula (IX) is also applicable to compounds of Formulae (IX-A), (IX-B), (IX-C) or (IX-D).

[0774] In certain embodiments, the invention provides a compound of Formula (IX), (IX-A), (IX- B), (IX-C) or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; R11is S02R14; R14is CrC4alkyl; n is 0 and R10is absent. In a preferred embodiment, the invention provides a compound of Formula (IX), (IX-A), (IX-B), (IX-C) or (IX-D),or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is CrC5alkyl; or R2is i-C3H7; R4is CrC4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; R11is S02R14; R14is CrC4alkyl; n is 0 and R10is absent.

[0775] In certain embodiments, the invention provides a compound of Formulae (IX), (IX-A), (IX- B), (IX-C) or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features:R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9,S-C4H9, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; R6is H or F; R7and R8are H; R9is OH; n is 0 and R10is absent; R11is S02R14; and R14is CrC4alkyl.

[0776] In specific embodiments, the invention provides a compound of Formulae (IX), (IX-A), (IX- B), (IX-C) or (IX-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; R4is H or Ci-C4alkyl, where said CrC4alkyl is optionally substituted by R20; R6is F; R7and R8are H; R9is OH; R11is S02R14; R14is Ci-C4alkyl; and R20is OH.

[0777] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D) that are not inconsistent with such aspect or embodiment.

[0778] Each of the aspects and embodiments described herein with respect to Formula (IX’) is also applicable to compounds of Formulae (IX’-A), (IX’-B), (IX’-C) or (IX’-D).

[0779] In certain embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i- C3H7, i-C4H9,s-C4Hg, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or Ci-C4alkyl, where said CrC4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; or R2is taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21; R6is H or F; R7and R8are H; R9is OH; n is 0 and R10is absent; R11is S02R14; and R14is CrC4alkyl.

[0780] In specific embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features:R1is F or Cl; R2is CH3, i-C3H7, i-C4Hg,s-C4Hg, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan- 3-yl; R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, CH2CH2OH or CH2NH2; or R2is taken together with R4to form a 5-membered heterocyclic ring optionally substituted by R21; each R21is independently F, OH, NH2, Ci-C2alkyl or Ci-C2fluoroalkyl; R6is F; R7and R8are H; R9is OH; n is 0 and R10is absent; R11is S02R14; and R14is CH3.

[0781] In specific embodiments, the invention provides a compound of Formulae (IX’), (IX’-A), (IX’-B), (IX’-C) or (IX’-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; R4is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20; R6is F; R7and R8are H; R9is OH; R11is S02R14; R14is C1-C4 alkyl; and R20is OH.

[0782] In another aspect, the invention provides a compound of Formula (X):

[0783]

[0784] or a pharmaceutically acceptable salt thereof, wherein:

[0785] R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;

[0786] R2is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Cs cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0787] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;

[0788] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0789] R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;

[0790] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0791] each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;

[0792] each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR22R23; each R21is independently F, OH, CN, NR22R23, C1-C4 alkyl, Ci-C4fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0793] each R22and R23is independently H, C1-C2alkyl or Ci-C2fluoroalkyl; or

[0794] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; and

[0795] n is 0, 1 , 2, 3 or 4.

[0796] In another aspect, the invention provides a compound of Formula (XI):

[0797]

[0798] or a pharmaceutically acceptable salt thereof, wherein:

[0799] R1is H, F, Cl, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20;

[0800] R2is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-Cs cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0801] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20; or

[0802] R2can be taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21;

[0803] R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;

[0804] R7and R8are independently H, F, Cl, CN, C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy or C1-C2fluoroalkoxy, where each said C1-C2alkyl, C1-C2fluoroalkyl, C1-C2alkoxy and C1-C2fluoroalkoxy is optionally substituted by R20;

[0805] R9is H, OH, NH2, NHCHSor N(CH3)2;

[0806] each R10is independently F, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said C1-C2alkyl and C1-C2fluoroalkyl is optionally substituted by R20;

[0807] each R20is independently OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN or NR22R23; each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0808] each R22and R23is independently H, C1-C2 alkyl or Ci-C2 fluoroalkyl; or

[0809] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;

[0810] R24is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;

[0811] R25is C1-C4 alkyl or C1-C4 fluoroalkyl;

[0812] each R26and R27is independently H or CH3;

[0813] R28is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN, NH2, NHCH3 or N(CH3)2; each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCHS or N(CH3)2;

[0814] m is 0, 1 or 2; and

[0815] n is 0, 1 , 2, 3 or 4.

[0816] In some embodiments, the compound of Formula (X) or (XI) has the absolute stereochemistry as shown in one of Formulae (X-A), (X-B), (X-C) or (X-D) or (Xl-A), (Xl-B), (Xl-C) or (Xl-D):

[0817]

[0818] (X-C) (X-D) (Xl-C) (Xl-D)

[0819] or a pharmaceutically acceptable salt thereof.

[0820] Each of the aspects and embodiments described herein with respect to Formula (II) is also applicable to compounds of Formulae (X), (X- A), (X-B), (X-C) or (X-D) that are not inconsistent with such aspect or embodiment.

[0821] Each of the aspects and embodiments described herein with respect to Formula (X) is also applicable to compounds of Formulae (X-A), (X-B), (X-C) or (X-D).

[0822] In certain embodiments, the invention provides a compound of Formula (X), (X-A), (X-B), (X-C) or (X-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; n is 0 and R10is absent.

[0823] In a preferred embodiment, the invention provides a compound of Formula (X), (X-A), (X- B), (X-C) or (X-D), or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; n is 0 and R10is absent.

[0824] In certain embodiments, the invention provides a compound of Formulae (X), (X-A), (X- B), (X-C) or (X-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i- C4H9, S-C4H9, t-C4Hg, CH2F, CHF2, CH2CHF2or oxetan-3-yl; R4is H or C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2Hs, CH2OH, CH(OH)CH3, C(OH)(CH3)2or CH2CH2OH; R6is H or F; R7is H; R8is H; R9is OH; n is 0 and R10is absent.

[0825] Each of the aspects and embodiments described herein with respect to Formula (IV) is also applicable to compounds of Formulae (XI), (Xl-A), (Xl-B), (Xl-C) or (Xl-D) that are not inconsistent with such aspect or embodiment.

[0826] Each of the aspects and embodiments described herein with respect to Formula (XI) is also applicable to compounds of Formulae (Xl-A), (Xl-B), (Xl-C) or (Xl-D).

[0827] In certain embodiments, the invention provides a compound of Formula (XI), (Xl-A), (XI- B), (Xl-C) or (Xl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is C1-C4 alkyl, where said C1-C4 alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; n is 0 and R10is absent. In a preferred embodiment, the invention provides a compound of Formula (XI), (Xl-A), (Xl-B), (Xl-C) or (XI-D),or a pharmaceutically acceptable salt thereof, wherein: R1is Cl; R2is C1-C5alkyl; or R2is i-C3H7; R4is C1-C4alkyl optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3orC(OH)(CH3)2; R6is F; R7is H; R8is H; R9is OH; n is 0 and R10is absent.

[0828] In certain embodiments, the invention provides a compound of Formulae (XI), (Xl-A), (XI- B), (Xl-C) or (Xl-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: R1is F or Cl; R2is C1-C5 alkyl, C1-C5 fluoroalkyl or 3-6 membered heterocyclyl; or R2is CH3, i-C3H7, i-C4H9,S-C4H9, t-C4Hg, CH2F,CHF2, CH2CHF2or oxetan-3-yl; R4is H or C1-C4alkyl, where said C1-C4alkyl is optionally substituted by OH, NH2, NHCH3or N(CH3)2; or R4is H, CH3, C2H5, CH2OH, CH(OH)CH3, C(OH)(CH3)2or CH2CH2OH; R6is H or F; R7is H; R8is H; R9is OH; n is 0 and R10is absent.

[0829] In another aspect, the invention provides a compound of Formula (XII):

[0830]

[0831] or a pharmaceutically acceptable salt thereof, wherein:

[0832] A is N or CH;

[0833] R1is H, F or Cl;

[0834] R2is H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0835] R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, C(0)Ra, C(0)NRb2, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20, each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21, Rais CrC2alkyl, and each Rbis independently H or Ci-C2alkyl;

[0836] R6is H or F;

[0837] R7and R8are independently H , F, Cl, CN , CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy;

[0838] Q is O; or

[0839] Q is NR11; R11is S02R14or COR17;

[0840] R14is C1-C4 alkyl or C1-C4 fluoroalkyl;

[0841] R17is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0842] each R20is independently OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NR22R23, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;

[0843] each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;

[0844] each R22and R23is independently H, Ci-C3alkyl, Ci-C3fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said CrC3alkyl and Ci-C3fluoroalkyl is optionally further substituted by OH, C1-C2 alkoxy or C1-C2 fluoroalkoxy and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH , C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy; or

[0845] R22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, C1-C2 alkyl, C1-C2 fluoroalkyl, C1-C2 alkoxy or C1-C2 fluoroalkoxy.

[0846] In some embodiments, the compound of Formula (XII) has the absolute stereochemistry as shown in one of Formulae (Xll-A), (Xll-B), (Xll-C) or (Xll-D):

[0847]

[0848] (Xll-C) (Xll-D) or a pharmaceutically acceptable salt thereof.

[0849] Each of the aspects and embodiments described herein with respect to Formula (l)-(XI) is also applicable to compounds of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D) that are not inconsistent with such aspect or embodiment.

[0850] Each of the aspects and embodiments described herein with respect to Formula (XII) is also applicable to compounds of Formulae (Xll-A), (Xll-B), (Xll-C) or (Xll-D).

[0851] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), A is N. In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), A is CH.

[0852] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R1is Cl.

[0853] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R2is CrC5alkyl or C1-C5fluoroalkyl, where each said C1-C5alkyl and CrC5fluoroalkyl is optionally substituted by R20. In some such embodiments, R2is C1-C5alkyl. In specific embodiments, R2is isopropyl.

[0854] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R2is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0855] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20.

[0856] In some such embodiments, R20is OH. In some embodiments, R4is C1-C4alkyl optionally substituted by R20where R20is OH. In specific embodiments, R4is CH(OH)CH3or C(OH)(CH3)2.

[0857] In other such embodiments, R20is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21. In some such embodiments, R4is C1-C4alkyl optionally substituted by R20where R20is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0858] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R4is C(0)Ra, C(0)NRb2, Rais C1-C2 alkyl, and each Rbis independently H or C1-C2 alkyl.

[0859] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R4is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0860] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R6is F.

[0861] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), R7and R8are independently H or F. In some such embodiments, R7and R8are H.

[0862] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), Q is O.

[0863] In some embodiments of Formulae (XII), (Xll-A), (Xll-B), (Xll-C) or (Xll-D), Q is NR11. In some such embodiments, R11is S02R14. In some such embodiments, R14is C1-C4alkyl. In some such embodiments, R11is COR17. In some such embodiments, R17is CrC4alkyl or CrC4fluoroalkyl, where each said Ci-C4alkyl and CrC4fluoroalkyl is optionally substituted by R20. In some such embodiments, R17is C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21.

[0864] In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XII- B), (Xll-C) or (Xll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; and Q is O.

[0865] In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XII- B), (Xll-C) or (Xll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is N; R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is CrC4alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; Q is NR11; R11is S02R14; and R14is Ci-C4alkyl.

[0866] In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XII- B), (Xll-C) or (Xll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is CH; R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; and Q is O.

[0867] In certain embodiments, the invention provides a compound of Formula (XII), (Xll-A), (XII- B), (Xll-C) or (Xll-D), or a pharmaceutically acceptable salt thereof, having a combination of two or more, preferably three or more, and more preferably four or more, of the following features: A is CH; R1is Cl; R2is C1-C5 alkyl; or R2is i-C3H7; R4is CrC4alkyl, where said CrC4alkyl is optionally substituted by R20, where R20is OH; or R4is CH(OH)CH3or C(OH)(CH3)2; R6is F; R7is H; R8is H; Q is NR11; R11is S02R14; and R14is Ci-C4alkyl.

[0868] In another aspect, the invention provides a compound selected from the group consisting of:

[0869] (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0870] (3R,4R)-4-({4-[4-fluoro-2-methyl-1 -(propan-2 -yl)-1 H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0871] 4-(1 -tert-butyl-4-fluoro-1 H-benzimidazol-6-yl)-5-fluoro-N-(1 -methylpiperidin-4- yl)pyrimidin-2-amine; (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0872] (3R,4R)-4-({5-ethyl-4-[4-fluoro-2-methyl-1 -(pro pan-2 -yl)-1 H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0873] (3R,4R)-4-({5-chloro-4-[1 -(propan-2-yl)-1 H-benzotriazol-6-yl]pyrimidin-2-yl}amino)-1 - (methanesulfonyl)piperidin-3-ol;

[0874] (3R,4R)-4-({4-[4-fluoro-2-methyl-1 -(propan-2 -yl)-1 H-benzimidazol-6-yl]-5- methylpyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0875] (3R,4R)-4-({4-[4-fluoro-2-methyl-1 -(propan-2 -yl)-1 H-benzimidazol-6-yl]-5- methoxypyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0876] (3R,4R)-4-({4-[4-fluoro-2-methyl-1 -(propan-2 -yl)-1 H-benzimidazol-6-yl]-5-(propan-2- yl)pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0877] (3R,4R)-4-({5-chloro-4-[4-fluoro-2-methyl-1 -(oxetan-3-yl)-1 H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0878] (3R,4R)-4-({5-chloro-4-[4-fluoro-2-(hydroxymethyl)-1 -(propan-2-yl)-1 H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0879] (3R,4R)-4-({4-[1 -(azetidin-3-yl)-4-fluoro-2-methyl-1 H-benzimidazol-6-yl]-5- fluoropyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0880] (3R,4R)-4-{[4-(1 -tert-butyl-1 H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-1 - (methanesulfonyl)piperidin-3-ol;

[0881] (3R,4R)-4-({5-fluoro-4-[2-methyl-1 -(propan-2 -yl)-1 H-benzimidazol-6-yl]pyrimidin-2- yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0882] (3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)piperidin-3-ol;

[0883] 1 -[(3R,4R)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6- yl]pyrimidin-2-yl}amino)-3-hydroxypiperidin-1 -yl]ethanone;

[0884] (3R,4R)-4-{[4-(1 -tert-butyl-4-fluoro-1 H-benzimidazol-6-yl)-5-fluoropyrimidin-2-yl]amino}-

[0885] 1 -(methanesulfonyl)piperidin-3-ol;

[0886] (3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin-

[0887] 2-yl}amino)-1 -methylpiperidin-3-ol;

[0888] (3S,4S)-4-({5-fluoro-4-[4-fluoro-2-methyl-1 -(propan-2-yl)-1 H-benzimidazol-6-yl]pyrimidin- 2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0889] 1 ,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1 R)- 1 -hydroxyethyl]-1 -(propan-2-yl)-1 H- benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol;

[0890] 1 ,5-anhydro-3-[(5-chloro-4-{4-fluoro-2-[(1 S)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 H- benzimidazol-6-yl}pyrimidin-2-yl)amino]-2,3-dideoxy-D-threo-pentitol; (2S)-1 -[(3R,4R)-4-{[4-(1 -tert-butyl-4-fluoro-1 H-benzimidazol-6-yl)-5-chloropyrimidin-2- yl]amino}-3-hydroxypiperidin-1 -yl]-2-hydroxypropan-1 -one;

[0891] (3R, 4R)-4-({5-chloro-4-[4-fluoro-2-(2-hydroxypro pan-2 -yl)-1 -(propan-2-yl)-1 H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-1 -(methanesulfonyl)piperidin-3-ol;

[0892] (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 / - / - benzimidazol-6-yl}pyrimidin-2-yl)amino]-1 -(methanesulfonyl)piperidin-3-ol; and

[0893] 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / ?reo-pentitol;

[0894] or a pharmaceutically acceptable salt thereof.

[0895] In another aspect, the invention provides a compound selected from the group consisting of the compounds exemplified in the Examples provided herein, including A1 -A94, B1 -B2, C1 - C2, D1 -D6, E1 , F1 -F33, G1 and H1 -H1 1 , inclusive, or a pharmaceutically acceptable salt thereof.

[0896] In another aspect, the invention provides (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 - hydroxyethyl]-1 -(propan-2-yl)-1 / - / -benzimidazol-6-yl}pyrimidin-2-yl)amino]-1 - (methanesulfonyl)piperidin-3-ol, or a pharmaceutically acceptable salt thereof.

[0897] In another aspect, the invention provides (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 - hydroxyethyl]-1 -(propan-2-yl)-1 / - / -benzimidazol-6-yl}pyrimidin-2-yl)amino]-1 - (methanesulfonyl)piperidin-3-ol.

[0898] In another aspect, the invention provides a pharmaceutically acceptable salt of (3R,4R)- 4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1 -(propan-2-yl)-1 / - / -benzimidazol-6-yl}pyrimidin- 2-yl)amino]-1 -(methanesulfonyl)piperidin-3-ol.

[0899] In another aspect, the invention provides 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1 -(propan-2-yl)-1 / - / -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D- fhreo-pentitol, or a pharmaceutically acceptable salt thereof.

[0900] In another aspect, the invention provides 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2- hydroxypropan-2-yl)-1 -(propan-2-yl)-1 / - / -benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D- fhreo-pentitol.

[0901] In another aspect, the invention provides a pharmaceutically acceptable salt of 1 ,5- anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 / - / -benzimidazol-6- yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / ?reo-pentitol.

[0902] A "pharmaceutical composition" refers to a mixture of one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent. In one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0903] In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent. In some such embodiments, the combination provides an additive, greater than additive, or synergistic anti-cancer effect.

[0904] The term“additive” is used to mean that the result of the combination of two compounds, components or targeted agents is no greater than the sum of each compound, component or targeted agent individually.

[0905] The term“synergy” or“synergistic” are used to mean that the result of the combination of two compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the disease, condition or disorder being treated is a“synergistic” effect. A“synergistic amount” is an amount of the combination of the two compounds, components or targeted agents that results in a synergistic effect, as “synergistic” is defined herein.

[0906] Determining a synergistic interaction between one ortwo components, the optimum range for the effect and absolute dose ranges of each component for the effect may be definitively measured by administration of the components over different dose ranges, and / or dose ratios to patients in need of treatment. However, the observation of synergy in in vitro models or in vivo models can be predictive of the effect in humans and other species and in vitro models or in vivo models exist, as described herein, to measure a synergistic effect. The results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species such as by the application of pharmacokinetic and / or pharmacodynamics methods.

[0907] Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers, and isotopically labelled versions thereof.

[0908] Compounds of the invention may exist in the form of pharmaceutically acceptable salts such as, e.g., acid addition salts and base addition salts of the compounds of one of the formulae provided herein. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which retain the biological effectiveness and properties of the parent compound. The phrase “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the formulae disclosed herein. For example, the compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

[0909] The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.

[0910] Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1 ,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, g-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate and valerate salts.

[0911] Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0912] The compounds of the invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.

[0913] Alternatively, the compounds useful that are acidic in nature may be capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds herein. These salts may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.

[0914] The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0915] Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.

[0916] For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically acceptable salts of compounds of the invention, and of interconverting salt and free base forms, are known to one of skill in the art.

[0917] Salts of the present invention can be prepared according to methods known to those of skill in the art. A pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to almost non-ionized.

[0918] It will be understood by those of skill in the art that the compounds of the invention in free base form having a basic functionality may be converted to the acid addition salts by treating with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention may be reconverted to the corresponding free base by treating with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of aqueous solvent, and at a temperature of between about 0° C and 100° C. The free base form may be isolated by conventional means, such as extraction with an organic solvent. In addition, acid addition salts of the compounds of the invention may be interchanged by taking advantage of differential solubilities of the salts, volatilities or acidities of the acids, or by treating with the appropriately loaded ion exchange resin. For example, the interchange may be affected by the reaction of a salt of the compounds of the invention with a slight stoichiometric excess of an acid of a lower pK than the acid component of the starting salt. This conversion is typically carried out at a temperature between about 0°C and the boiling point of the solvent being used as the medium for the procedure. Similar exchanges are possible with base addition salts, typically via the intermediacy of the free base form.

[0919] The compounds of the invention may exist in both unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water / solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term‘hydrate’ is employed when the solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6-DMSO.

[0920] Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and / or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the disclosure of which is incorporated herein by reference in its entirety. The invention also relates to prodrugs of the compounds of the formulae provided herein. Thus, certain derivatives of compounds of the invention which may have little or no pharmacological activity themselves can, when administered to a patient, be converted into the inventive compounds, for example, by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and‘Bioreversible Carriers in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties.

[0921] Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the inventive compounds with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0922] Some non-limiting examples of prodrugs in accordance with the invention include:

[0923] (i) where the compound contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with (Ci-Cs)alkyl;

[0924] (ii) where the compound contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with (Ci-C6)alkanoyloxymethyl, or with a phosphate ether group; and

[0925] (iii) where the compound contains a primary or secondary amino functionality (-NH2 or -NHR where R ¹ H), an amide thereof, for example, replacement of one or both hydrogens with a suitably metabolically labile group, such as an amide, carbamate, urea, phosphonate, sulfonate, etc.

[0926] Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

[0927] Finally, certain inventive compounds may themselves act as prodrugs of other of the inventive compounds.

[0928] Also included within the scope of the invention are metabolites of compounds of the formulae described herein, i.e. , compounds formed in vivo upon administration of the drug.

[0929] The compounds of the formulae provided herein may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention may be depicted herein using a solid line ( - ), a solid wedge (“^^ ), or a dotted wedge ( .Ml). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included and the attached stereocenter. For example, unless stated otherwise, it is intended that the compounds of the invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.

[0930] Compounds of the invention that have chiral centers may exist as stereoisomers, such as racemates, enantiomers, or diastereomers.

[0931] Stereoisomers of the compounds of the formulae herein can include cis and trans isomers, optical isomers such as (R) and (S) enantiomers, diastereomers, geometric isomers, rotational isomers, atropisomers, conformational isomers, and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs).

[0932] Also included are acid addition salts or base addition salts, wherein the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

[0933] When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0934] The compounds of the invention may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds may exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of the invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the compounds of the formulae provided.

[0935] In addition, some of the compounds of the invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers which occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are unsymmetrical. The interconversion of atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization may be determined by the steric hindrance to free rotation of one or more bonds forming a chiral axis. Where a compound of the invention contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0936] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC) or superfluid critical chromatography (SFC).

[0937] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.

[0938] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

[0939] Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art; see, for example,“Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0940] The enantiomeric purity of compounds described herein may be described in terms of enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a single completely pure enantiomer has an ee of 100%. Similarly, diastereomeric purity may be described in terms of diasteriomeric excess (de).

[0941] The present invention also includes isotopically-labeled compounds, which are identical to those recited in one of the formulae provided, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0942] 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.

[0943] Examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as, but not limited to,2H,3H,13C,14C,15N,1sO,170,32P,35S,18F and36CI. Certain isotopically-labeled compounds of the invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically-labeled compounds of the invention may generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples and Preparations below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.

[0944] Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used.

[0945] Therapeutic Methods and Uses

[0946] The invention further provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutic agents or palliative agents.

[0947] In one aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0948] In another aspect, the invention provides a method for the treatment of abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anticancer therapeutic agent), which amounts are together effective in treating said abnormal cell growth.

[0949] In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.

[0950] In a further aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth in a subject.

[0951] In another aspect, the invention provides a pharmaceutical composition for use in the treatment of abnormal cell growth in a subject in need thereof, which pharmaceutical composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0952] In another aspect, the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, in particular a medicament for the treatment of abnormal cell growth .

[0953] In yet another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

[0954] In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. Compounds of the invention may be administered as single agents or may be administered in combination with other anti-cancer therapeutic agents, in particular with standard of care agents appropriate for the particular cancer.

[0955] In some embodiments, the methods provided result in one or more of the following effects: (1 ) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

[0956] In another aspect, the invention provides a method for the treatment of a disorder mediated by CDK4 in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount that is effective for treating said disorder, in particular cancer.

[0957] In preferred aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the invention are selective for CDK4 over CDK6. In frequent embodiments, the binding affinity for CDK6 is at least 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 75-fold, 100-fold, or greater than 100-fold larger than the binding affinity for CDK4.

[0958] In view of the potential role of CDK6 in hematologic toxicities, such as neutropenia or leukopenia, a CDK4 selective inhibitor may provide an improved safety profile, improved dosing schedule (e.g., by decreasing the need for dose reduction or dosing holidays), and / or enhanced overall efficacy, due to the potential of higher dosing, use of a continuous dosing regimen, and / or extended time of overall treatment as compared to current dual CDK4 / 6 inhibitors. Animal models to assess neutropenia are described in the art. For example, see Fine et al. A Specific Stimulator of Granulocyte Colony-Stimulating Factor Accelerates Recover from Cyclophophamide-lnduced Neutropenia in the Mouse (1997) Blood, 90(2):795-802; Hu et al., Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies (2016), Clin. Cancer Res. 22(8):2000-2008.

[0959] It may also be preferable to obtain selectivity for CDK4 over other CDKs, such as CDK1 , CDK2 or CDK9.

[0960] Compounds of the invention include compounds of any of the formulae described herein, or pharmaceutically acceptable salts thereof. In another aspect, the invention provides a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

[0961] In another aspect, the invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell invasiveness.

[0962] In another aspect, the invention provides a method of inducing apoptosis in cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to induce apoptosis.

[0963] In another aspect, the invention provides a method of inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

[0964] In another aspect, the invention provides a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

[0965] In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer and thyroid cancer. In further embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.

[0966] In other embodiments, the cancer is breast cancer, including, e.g., ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine resistant breast cancer, trastuzumab or pertuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0967] In some embodiments, the compound of the invention is administered as first line therapy. In other embodiments, the compound of the invention is administered as second (or later) line therapy. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, e.g., including taxanes or platinum agents. In some embodiments, the compound of the invention is administered as second (or later) line therapy following treatment with HER2 targeted agents, e.g., trastuzumab.

[0968] As used herein, an “effective dosage” or “effective amount” of drug, compound or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired, including biochemical, histological and / or behavioral symptoms, of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, a“therapeutically effective amount” refers to that amount of a compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer, (5) decreasing the dose of other medications required to treat the disease, and / or (6) enhancing the effect of another medication, and / or (7) delaying the progression of the disease in a patient.

[0969] An effective dosage can be administered in one or more administrations. For the purposes of this invention, an effective dosage of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective dosage of drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.

[0970] “Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukaemia’s (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0971] “Tumor burden” or“tumor load’, refers to the total amount of tumorous material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as, e.g., using callipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans. The term“tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using callipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CR or MRI scans.

[0972] As used herein, "subject" refers to a human or animal subject. In certain preferred embodiments, the subject is a human.

[0973] The term“treat” or“treating” a cancer as used herein means to administer a compound of the present invention to a subject having cancer, or diagnosed with cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastases or tumor growth, reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term“treating” also includes adjuvant and neo-adjuvant treatment of a subject.

[0974] For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of a tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression of the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and / or prolonging survival of patients the cancer. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1 : 1 S- 10S (2009). For example, with respect to tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) standards, a T / C less than or equal to 42% is the minimum level of antitumor activity. A T / C <10% is considered a high anti-tumor activity level, with T / C (%) = median tumor volume of the treated / median tumor volume of the control x 100.

[0975] In some embodiments, the treatment achieved by a compound of the invention is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression free survival (PFS), disease free survival (DFS) and overall survival (OS). PFS, also referred to as“Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients have experienced a CR or PR, as well as the amount oftime patients have experienced stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated subjects or patients. In some embodiments, response to a combination of the invention is any of PR, CR, PFS, DFS, OR or OS that is assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.

[0976] The treatment regimen for a compound of the invention that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the invention may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi2-test the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstrat- testy and the Wilcon on-test.

[0977] The terms “treatment regimen”, “dosing protocol” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.

[0978] “Ameliorating” means a lessening or improvement of one or more symptoms upon treatment with a combination described herein, as compared to not administering the combination. “Ameliorating” also includes shortening or reduction in duration of a symptom.

[0979] “Abnormal cell growth”, as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). Abnormal cell growth may be benign (not cancerous), or malignant (cancerous).

[0980] Abnormal cell growth includes the abnormal growth of: (1) tumor cells (tumors) that show increased expression of CDK4 and / or CDK6; (2) tumors that proliferate by aberrant CDK4 and / or CDK6 activation; and (3) tumors that are resistant to endocrine therapy, CDK4 / 6 inhibition, or HER2 antagonists.

[0981] The term“additional anticancer therapeutic agent” as used herein means any one or more therapeutic agent, otherthan a compound of the invention, that is or can be used in the treatment of cancer. In some embodiments, such additional anticancer therapeutic agents include compounds derived from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.

[0982] In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM. In some such embodiments, a compound of the invention may be administered in combination with a standard of care agent, such as tamoxifen, exemestane, letrozole, fulvestrant, or anastrozole. In other embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, such as docetaxel, paclitaxel, paclitaxel protein-bound particles, cisplatin, carboplatin, oxaliplatin, capecitabine, gemcitabine or vinorelbine,

[0983] In some embodiments, the additional anticancer agent is an anti-angiogenesis agent, including for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCp inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha- v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional antiangiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod ( Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet further anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further antiangiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide ( 4 HPR ), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

[0984] In other embodiments, the additional anti-cancer agent is a signal transduction inhibitor (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include for example kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1 R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and multi-targeted kinase inhibitors.

[0985] Additional examples of anti-cancer agents which may be used in conjunction with a compound of the invention and pharmaceutical compositions described herein include palbociclib (Ibrance®), ribociclib (Kisqali®), abemaciclib (Verzenio®), BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), Vandetanib (Zactima™), pazopanib (SB 786034), ALT 1 10 (Alteris Therapeutics), BIBW 2992 (Boehringer lngelheim),and Cervene™ (TP 38). Other examples include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), ado-trastuzumab emtansine (Kadcyla®), pertuzumab (Perjeta®), osimertinib (Tagrisso®), atezolizumab (Tecentriq™), sunitinib (Sutent®), ibrutinib (Imbruvica®), imatinib (Gleevec®), crizotinib (Xalkor®), lorlatinib (Lorbrena®), dacomitinib (Vizimpro®), bosutinib (Bosulif®), glasdegib (Daurismo™), canertinib (Cl 1033), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 1 12 (One Bio), BMS 387032 (Bristol-Myers Squibb), and AG 024322 (Pfizer), or PD-1 or PD-L1 antagonists, e.g., pembrolizumab (Keytruda®), nivolumab (Opdivo™), or avelumab (Bavencio®). abraxane,

[0986] In other embodiments, the additional anti-cancer agent is a so-called classical antineoplastic agent. Classical antineoplastic agents include but are not limited to hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and antiestrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor (such as, e.g., talazoparib (Talzenna®), olaparib, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical antineoplastic agents used in combination therapy with a compound of the invention, optionally with one or more other agents include, but are not limited to, glucocorticoids, such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane and CHF 4227 (Cheisi), Selective Estrogen-Receptor Down regulators (SERD’s; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801 , abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogen agents, such as enzalutamide (Xtandi®), abiraterone acetate, bicalutamide (Casodex); and combinations thereof. Other examples of classical antineoplastic agents used in combination with a compound of the invention include but are not limited to PARP inhibitors, such as talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib; suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101 ; Onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN- 80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10- hydroxycamptothecin, irinotecan HCI (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin, streptozocin, satrplatin, and combinations thereof.

[0987] In still other embodiments, the additional anti-cancer agent is a so called dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists (such as 5- fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5- azacitidine (Vidaza), decitabine, and ethynylcytidine) and other antimetabolites such as eflorn ithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4- dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG- 014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU- 0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc) and combinations thereof.

[0988] Other examples of classical antineoplastic cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol- Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA / paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L- asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE - enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™) and combinations thereof. Further examples of classical antineoplastic agents include, but are not limited to, as Advexin (ING 201), TNFerade (GeneVec, a compound which express TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Pravastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0989] In some embodiments, the additional anti-cancer agent is an epigenetic modulator, for example an inhibitor or EZH2, SMARCA4, PBRM1 , ARID1A, ARID2, ARID1 B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1 L, HKMTsanti, PRMT1-9, LSD1 , UTX, IDH1 / 2 or BCL6.

[0990] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent, such as an inhibitor of CTLA-4, PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab or avelumab), LAG-3, TIM-3, TIGIT, 4-1 BB, 0X40, GITR, CD40, or a CAR-T-cell therapy.

[0991] As used herein“cancer” refers to any malignant and / or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancer of blood, bone marrow, or the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemia, lymphoma and myeloma. Cancer also includes primary cancer that originates at a specific site in the body, a metastatic cancer that has spread from the place in which it started to other parts of the body, a recurrence from the original primary cancer after remission, and a second primary cancer that is a new primary cancer in a person with a history of previous cancer of a different type from the latter one.

[0992] In some embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC), esophageal cancer, head and neck cancer, liver cancer, pancreatic cancer and stomach cancer.

[0993] Dosage Forms and Regimens

[0994] Administration of the compounds of the invention may be affected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0995] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined guantity of active compound calculated to produce the desired therapeutic effect in association with the reguired pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unigue characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.

[0996] Thus, the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient may also be determined, as can the temporal reguirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that may be provided to a patient in practicing the present invention.

[0997] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated and may include single or multiple doses. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by the skilled artisan. Determining appropriate dosages and regimens for administration of the chemotherapeutic agent are well-known in the relevant art and would be understood to be encompassed by the skilled artisan once provided the teachings disclosed herein.

[0998] The amount of the compound of the invention administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

[0999] Formulations and Routes of Administration

[1000] As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[1001] The pharmaceutical acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

[1002] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Non-limiting examples of materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[1003] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.

[1004] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms may be suitably buffered, if desired.

[1005] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.

[1006] Pharmaceutical compositions suitable for the delivery of compounds of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in‘Remington’s Pharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

[1007] The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.

[1008] Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.

[1009] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

[1010] The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V\_ (6), 981 -986 by Liang and Chen (2001), the disclosure of which is incorporated herein by reference in its entirety. For tablet dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.

[1011] Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[1012] Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.

[1013] Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.

[1014] Other conventional ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.

[1015] Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.

[1016] Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting. The final formulation may include one or more layers and may be coated or uncoated; or encapsulated.

[1017] The formulation of tablets is discussed in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[1018] Solid formulations for oral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The disclosures of these references are incorporated herein by reference in their entireties.

[1019] The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.

[1020] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[1021] The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[1022] The solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[1023] Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus, compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.

[1024] The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro needle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The disclosures of these references are incorporated herein by reference in their entireties. Formulations for topical administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[1025] The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 , 1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

[1026] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

[1027] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[1028] Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[1029] A suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 pg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 pl_ to 10OpL. A typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

[1030] Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled / intranasal administration.

[1031] Formulations for inhaled / intranasal administration may be formulated to be immediate and / or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[1032] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or“puff containing a desired mount of the compound of the invention. The overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.

[1033] Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

[1034] Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

[1035] Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

[1036] Formulations for ocular / aural administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

[1037] Other Technologies

[1038] Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[1039] Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91 / 1 1 172, WO 94 / 02518 and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entireties.

[1040] The amount of the active compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, and frequently about 0.01 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 mg / day to about 7000 mg / day, more commonly, from about 10 mg / day to about 1000 mg / day. Sometimes, the dosage is about 10, 20, 30, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 750, 800, 900 or 1000 mg / day. Sometimes, the dosage is from about 10 mg / day to about 1000 mg / day, from about 10 mg / day to about 750 mg / day, from about 10 mg / day to about 600 mg / day, from about 10 mg / day to about 300 mg / day, from about 10 mg / day to about 150 mg / day, from about 20 mg / day to about 750 mg / day, from about 20 mg / day to about to 600 mg / day, from about 20 mg / day to about to 300 mg / day, from about 20 mg / day to about to 150 mg / day, from about 50 mg / day to about 750 mg / day, from about 50 mg / day to about 600 mg / day, from about 50 mg / day to about 300 mg / day, from about 50 mg / day to about 150 mg / day, from about 75 mg / day to about 750 mg / day, from about 75 mg / day to about 600 mg / day, from about 75 mg / day to about 300 mg / day, or from about 75 mg / day to about 150 mg / day.

[1041] In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.

[1042] Kit-of-Parts

[1043] Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus, the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

[1044] The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically includes directions for administration and may be provided with a memory aid. Combination Therapy

[1045] As used herein, the term“combination therapy” refers to the administration of a compound of the invention together with an at least one additional pharmaceutical or medicinal agent (e.g., an anti-cancer agent), either sequentially or simultaneously.

[1046] As noted above, the compounds of the invention may be used in combination with one or more additional anti-cancer agents. The efficacy of the compounds of the invention in certain tumors may be enhanced by combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents, such as PD-1 or PD-L1 antagonists and the like.

[1047] When a combination therapy is used, the one or more additional anti-cancer agents may be administered sequentially or simultaneously with the compound of the invention. In one embodiment, the additional anti-cancer agent is administered to a mammal (e.g., a human) prior to administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal after administration of the compound of the invention. In another embodiment, the additional anti-cancer agent is administered to the mammal (e.g., a human) simultaneously with the administration of the compound of the invention.

[1048] The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, which comprises an amount of a compound of the invention, as defined above (including hydrates, solvates and polymorphs of said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) additional anti-cancer therapeutic agents.

[1049] Synthetic Methods

[1050] Compounds of the invention are prepared according to the exemplary procedures and Schemes provided herein , and modifications thereof known to those of skill in the art. Scheme 1 shows a general route for making pyrimidine compounds 6 having varying saturated heterocyclyl or cycloalkyl moieties (comprising Q) and a heteroaromatic ring (comprising U, V, X, Y and Z). It will be understood that the order of the steps could be reversed.

[1051] General Scheme 1 :

[1052] As exemplified in Scheme 1 , substituted dichloropyrimidines 1 are subjected to Suzuki coupling conditions with aryl or heteroaryl boronates 2 in the presence of a suitable catalyst (such as Pd(PPh3)4 or Pd(PPti3)2Cl2) and a suitable base (such as Na2CC>3 or K2CO3) in a suitable solvent system (such as dioxane:water or DME:water) to afford an aryl- or heteroaryl-substituted chloropyrimidines 4. Alternatively, aryl or heteroaryl bromides 3 can be utilized in the Suzuki cross-coupling following treatment of the bromo compound with bis(pinacolato)diboron, a suitable catalyst (such as Pd(OAc)2 or Pd(dppf)Cl2), ligand (such as PCy3) and base (such as KOAc or NaOAc) in a suitable solvent (such as DMSO or dioxane). The resulting heterobiaryl intermediates 4 are treated under nucleophilic chloride displacement conditions with a primary heterocyclylamine or cycloalkylamine 5 in the presence of a suitable base (such as DIPEA) in a suitable solvent (e.g., DMSO), to afford amino-substituted pyrimidine compounds 6. When intermediate 4 is reacted with a primary heterocyclylamine, Q in 5 and 6 represents an appropriately substituted amino group (e.g., NR1 1), an appropriately protected amino group (e.g., a carbamoyl, tetrahyrdopyranyl or trialkylsilyl protected amine) or oxygen. When intermediate 4 is reacted with a primary cycloalkylamine, Q in 5 and 6 represents an optionally substituted carbon.

[1053] Alternatively, the heterobiaryl intermediates 4 can be subjected to Buchwald-Hartwig coupling conditions in the presence of a suitable amine 5, a suitable catalyst (e.g., Pd2(dba)3, chloro-2-(dimethylaminomethyl)-ferrocen-1 -yl-(dinorbornylphosphine)-palladium or Pd(OAc)2, BINAP and a suitable base (e.g., Cs2C03) in a suitable solvent (such as THF, dioxane or 2- methyl-2-butanol) to afford the compounds 6.

[1054] It will be understood that reactive functional groups present at any position in intermediates 1 to 5 and penultimate compounds 6 may be masked using suitable protecting groups known to those of skill in the art. For examples, such compounds may contain amine or hydroxyl moieties masked with protecting groups (such as tert-butylcarbamate or tetrahydropyran) that can be removed via conditions known in art (such as TFA or HCI) in a suitable solvent. In some embodiments, Q in compound 6 may represent a protected amino group, which is removed under standard conditions to provide a free secondary amine that is further we reacted with a suitably reactive reagent (e.g., a sulfonyl halide, acyl halide, alkyl halide or the like) to install the R11substituent.

[1055] Analogous reactions could be used to prepare the corresponding pyridine derivatives, as exemplified in the examples herein.

[1056] General Synthetic Methods:

[1057] Abbreviations:

[1058] The following abbreviations are used throughout the Examples:“Ac” means acetyl,“AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm” means atmosphere(s), “BOC”, “Boc” or“boc” means N-fe / f-butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” means normal-butyl, “tBu” means fe / f-butyl, “DBU” means 1 ,8- diazabicyclo[5.4.0]undec-7-ene, “Cbz” means benzyloxycarbonyl, “DCM” (CH2CI2) means methylene chloride, “de” means diastereomeric excess, “DEA” means diethylamine, “DIPEA” means diisopropyl ethyl amine, “DMA” means A / ,A / -dimethylacetamide, “DME” means 1 ,2- dimethoxyethane, "DMF" means N, A / -di methyl formamide, “DMSO" means dimethylsulfoxide, “EDTA” means ethylenediaminetetraacetic acid,“ee” means enantiomeric excess,“Et” means ethyl,“EtOAc” means ethyl acetate,“EtOH” means ethanol,“HOAc” or“AcOH” means acetic acid, “i-Pr” or“'Pr” means isopropyl,“IPA” means isopropyl alcohol,“LAH” means lithium aluminum hydride, “LHMDS” means lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide), “mCPBA” means meta-chloroperoxy-benzoic acid, “Me” means methyl, “MeOH” means methanol,“MS” means mass spectrometry, "MTBE" means methyl fe / f-butyl ether,“NCS” means N-chlorosuccinimide,“Ph” means phenyl,“TBHP” means fe / f-butyl hydroperoxide,“TFA” means trifluoroacetic acid, “THF” means tetrahydrofuran, “SFC” means supercritical fluid chromatography, “TLC” means thin layer chromatography, “Rf” means retention fraction, means approximately,“rt” means retention time,“h” means hours,“min” means minutes,“equiv” means equivalents,“sat.” means saturated.

[1059] Scheme I:

[1060]

[1061] As exemplified in Scheme I, a compound such as I (purchased or synthesized) can be borylated with B2Pin2 in the presence of a suitable catalyst system (such as PdCl2(dppf) or Pd(OAc)2 + PCy3) with a suitable base (such as KOAc) in an appropriate solvent (such as 1 ,4- dioxane or DMSO) to provide a compound such as II. A compound such as II can be generated and reacted in-situ. Alternatively, a compound such as II can be isolated prior to subsequent reactions to provide the corresponding boronic acid or BPin ester. A compound such as II can undergo arylation with an aryl chloride such as III under standard Suzuki cross-coupling conditions in the presence of a suitable catalyst (such as Pd(PPh3)4 or PdCI2(PPh3)2) with a suitable base (such as K2C03or Na2C03) in an appropriate solvent (such as DMSO or 1 ,4- dioxane) to provide a compound such as IV. A compound such as IV can be coupled with an amine such as V to provide a compound such as VI under standard nucleophilic aromatic substitution conditions (SNAr) in the presence of a suitable base (such as DIPEA) in an appropriate solvent (such as DMSO). Alternatively, a compound such as IV can be coupled with an amine such as V to provide a compound such as VI under standard Buchwald-Hartwig coupling conditions in the presence of a suitable catalyst system (such as Pd(OAc)2+ rac-BINAP or chloro-2-(dimethylaminomethyl)-ferrocen-1 -yl-(dinorbornylphosphine)palladium complex) with a suitable base (such as 0s2CO3) in an appropriate solvent (such as THF or 1 ,4-dioxane). In some cases a compound such as VI may contain protecting groups, which can be removed by an additional step in the synthetic sequence using conditions known in the art ( Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981 or Protecting groups, 10 Georg Thieme Verlag, 1994). Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. If necessary, separation of the enantiomers of VI may be carried out under standard methods known in the art such as chiral SFC or HPLC to afford single enantiomers. Variables Q, U, V, X, Z, R1, and R7, and R9are as defined as in the embodiments, schemes, examples, and claims herein.

[1062] Scheme II:

[1063]

[1064]

[1065] As shown in Scheme II, a compound such a VII (prepared as in Scheme I) can be coupled to an aryl chloride such as VIII under standard Suzuki cross-coupling conditions with a suitable catalyst system (such as Pd(t-Bu3P)2) with a suitable base (such as K2CO3) in an appropriate solvent (such as 1 ,4-dioxane) to provide a compound such as IX. A compound such as IX can be oxidized with a suitable oxidant (such as oxone) to provide a compound such as X. A compound such as X can be coupled to an amine such as XI under standard SnAr conditions in the presence of a suitable base (such as Na2CC>3) in an appropriate solvent (such as THF) to provide a compound such as XII. Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables R1, and R4are as defined as in the embodiments, schemes, examples, and claims herein.

[1066] Scheme III:

[1067] As shown in Scheme III, an aryl bromide such as compound XIII can be converted to a boronate ester such as compound XIV with B2Pin2in the presence of a suitable catalyst (such as Pd2CI2(dppf)) with a suitable base (such as KOAc) in an appropriate solvent (such as 1 ,4- dioxane). A compound such as XIV can be generated and used in-situ or isolated to provide the corresponding boronate ester. A compound such as XIV can be coupled with an aryl chloride such as compound III under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCI2(PPti3)2) and suitable base (such as Na2CC>3) in an appropriate solvent (such as 1 ,4-dioxane) to provide a compound such as XV. A compound such as XV can be converted to a compound such as XVI in the presence of excess / -PrNH2in an appropriate solvent (such as DMSO). A compound such as XVI can be cyclized with an aldehyde such as XVII in the presence of a suitable reductant (such as Na2S2C>4) in an appropriate solvent (such as EtOH) to provide a compound such as XVIII. A compound such as XVIII can be coupled with an amine such as XIX under standard Buchwald-Hartwig conditions in the presence of a suitable catalyst system (such as Pd(OAc)2+ rac-BINAP) and a suitable base (such as Cs2C03) in an appropriate solvent system (such as 1 ,4-dioxane or THF) to provide a compound such as XX. Compounds at every step may be purified by standard techniques, such as column chromatography, crystallization, or reverse phase SFC or HPLC. Variables Q, R1, R4, R6, and R7are as defined as in the embodiments, schemes, examples, and claims herein.

[1068] Scheme IV:

[1069]

[1070] As shown in Scheme IV, a compound such as XXI (prepared as in Scheme I) can be coupled with an aryl chloride such as compound XXII under standard Suzuki cross-coupling conditions with a suitable catalyst (such as PdCI2(PPti3)2) and a suitable base (such as Na2CC>3) in an appropriate solvent (such as 1 ,4-dioxane) to provide a compound such as XXIII. A compound such as XXIII can be coupled with an amine such as XIX under standard Buchwald- Hartwig coupling conditions with a suitable palladium catalyst system (such as Bretphos-Pd-G3 or Pd2(dba)3+ rac-BINAP) with a suitable base (such as f-BuONa, Cs2CC>3, or phosphazene P2- Et) in an appropriate solvent (such as 1 ,4-dioxane o...

Claims

Claims1 . A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:A is N or CH;R1is H, F, Cl, CN, C1-C2 alkyl, CrC2fluoroalkyl or Ci-C2alkoxy, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;U is NR2or CR3;V is N or CR4when U is NR2; andV is NR5when U is CR3;X is CR6or N;Y is CR7or N;Z is CR8or N;R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;R4is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C(0)Ra, C(0)NRb2, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally substituted by R20, each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21, Rais Ci-C2alkyl, and each Rbis independently H or Ci-C2alkyl; andR5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20; orR2can be taken together with R4, or R3can be taken together with R5, to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)m as a ring member, which ring is optionally substituted by R21;R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;R7and R8are independently H , F, Cl, CN , CrC2alkyl, C1-C2 fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;R9is H, OH, NH2, NHCHS or N(CH3)2;each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;Q is NR11or O; orQ is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;R14is C1-C4alkyl or C1-C4fluoroalkyl;each R15and R16is independently H or CH3;R17is C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN, NR22R23, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;each R22and R23is independently H, CrC3alkyl, CrC3fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said Ci-C3alkyl and Ci-C3fluoroalkyl is optionally further substituted by OH, CrC2alkoxy or Ci-C2fluoroalkoxy and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally further substituted by F, OH, Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy; orR22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, where said ring is optionally substituted by F, OH, Ci-C2alkyl, CrC2fluoroalkyl, Ci-C2alkoxy or CrC2fluoroalkoxy;R24is H, C1-C4alkyl, C1-C4fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;R25is C1-C4alkyl or C1-C4fluoroalkyl;each R26and R27is independently H or CH3;R28is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2; each R29and R30is independently H, C1-C4 alkyl or C1-C4 fluoroalkyl, where each said C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCHSor N(CH3)2;m is 0, 1 or 2;n is 0, 1 , 2, 3 or 4;p is 1 , 2 or 3; andq is 0, 1 , 2 or 3;wherein the sum of p and q is an integer from 1 to 4.

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein:R1is H, F, Cl, CN, C1-C2 alkyl or C1-C2 fluoroalkyl, where each said C1-C2 alkyl and C1-C2 fluoroalkyl is optionally substituted by R20;U is NR2or CR3;V is N or CR4when U is NR2; andV is NR5when U is CR3;X is CR6or N;Y is CR7or N;Z is CR8or N;R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;R9is H, OH, NH2, NHCHSor N(CH3)2;each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;Q is NR11or O; orQ is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;R14is C1-C4 alkyl or C1-C4 fluoroalkyl;each R15and R16is independently H or CH3;R17is C1-C4alkyl, C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR22R23;each R21is independently F, OH, CN, NR22R23, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy or C1-C4 fluoroalkoxy, where each said C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy and C1-C4 fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;each R22and R23is independently H, Ci-C2alkyl or Ci-C2fluoroalkyl; orR22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;n is 0, 1 , 2, 3 or 4;p is 1 , 2 or 3; andq is 0, 1 , 2 or 3;wherein the sum of p and q is an integer from 1 to 4.

3. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein:R1is H, F, Cl, CN, CrC2alkyl or C1-C2 fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;U is NR2or CR3;V is N or CR4when U is NR2; andV is NR5when U is CR3;X is CR6or N;Y is CR7or N;Z is CR8or N;R2and R3are H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;R5is H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;R9is H, OH, NH2, NHCHSor N(CH3)2;each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;Q is NR11or O; orQ is CR12R13, where R12and R13are taken together with the C atom to which they are attached to form a 4-6 membered heterocyclic ring containing NR11or O as a ring member, which ring is optionally further substituted by R10;R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;R14is C1-C4 alkyl or C1-C4 fluoroalkyl;each R15and R16is independently H or CH3;R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R18and R19is independently H, C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R20is independently OH, C1-C2alkoxy, C1-C2fluoroalkoxy, CN or NR22R23;each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;each R22and R23is independently H, CrC2alkyl or Ci-C2fluoroalkyl; orR22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;n is 0, 1 , 2, 3 or 4;p is 1 , 2 or 3; andq is 0, 1 , 2 or 3;wherein the sum of p and q is an integer from 1 to 4.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is CR6, Y is CR7and Z is CR8.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein U is NR2and V is CR4.

6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein U is CR3and V is NR5.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Q is O.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Q is NR11.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R9is OH.

10. A compound of Formula (IX):or a pharmaceutically acceptable salt thereof, wherein:R1is H, F, Cl, CN, C1-C2alkyl or C1-C2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;R2is H, C1-C5alkyl, C1-C5fluoroalkyl, C3-C8cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5alkyl and C1-C5fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20;R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy or Ci-C2fluoroalkoxy, where each said Ci-C2alkyl, Ci-C2fluoroalkyl, Ci-C2alkoxy and Ci-C2fluoroalkoxy is optionally substituted by R20;R9is H, OH, NH2, NHCHSor N(CH3)2;each R10is independently F, CN, Ci-C2alkyl or Ci-C2fluoroalkyl, where each said Ci-C2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;R11is H, C1-C4 alkyl, C1-C4 fluoroalkyl, S02R14, S02NR15R16, COR17, COOR17or CONR18R19;R14is C1-C4 alkyl or C1-C4 fluoroalkyl;each R15and R16is independently H or CH3;R17is C1-C4alkyl or C1-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R18and R19is independently H, C1-C4alkyl or Ci-C4fluoroalkyl, where each said C1-C4alkyl and C1-C4fluoroalkyl is optionally substituted by R20;each R20is independently OH, Ci-C2alkoxy, CrC2fluoroalkoxy, CN or NR22R23;each R21is independently F, OH, CN, NR22R23, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;each R22and R23is independently H, CrC2alkyl or Ci-C2fluoroalkyl; orR22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH; andn is 0, 1 , 2, 3 or 4.1 1 . The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R11is S02R14and R14is CrC4alkyl.

12. A compound of Formula (XI):or a pharmaceutically acceptable salt thereof, wherein:R1is H, F, Cl, CN, CrC2alkyl or Ci-C2fluoroalkyl, where each said CrC2alkyl and CrC2fluoroalkyl is optionally substituted by R20;R2is H, C1-C5 alkyl, C1-C5 fluoroalkyl, C3-C8 cycloalkyl or 3-6 membered heterocyclyl, where each said C1-C5 alkyl and C1-C5 fluoroalkyl is optionally substituted by R20and each said C3-C8cycloalkyl and 3-6 membered heterocyclyl is optionally substituted by R21;R4is H, C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy or C1-C4fluoroalkoxy, where each said C1-C4alkyl, C1-C4fluoroalkyl, C1-C4alkoxy and C1-C4fluoroalkoxy is optionally substituted by R20; orR2can be taken together with R4to form a 5-7 membered heterocyclic ring, optionally containing an additional heteroatom selected from NR24, O and S(0)mas a ring member, which ring is optionally substituted by R21;R6is H, F, Cl, CN, CH3, CH2F, CHF2or CF3;R7and R8are independently H, F, Cl, CN, CrC2alkyl, Ci-C2fluoroalkyl, CrC2alkoxy or Ci-C2fluoroalkoxy, where each said CrC2alkyl, CrC2fluoroalkyl, CrC2alkoxy and CrC2fluoroalkoxy is optionally substituted by R20;R9is H, OH, NH2, NHCHSor N(CH3)2;each R10is independently F, CN, CrC2alkyl or CrC2fluoroalkyl, where each said CrC2alkyl and Ci-C2fluoroalkyl is optionally substituted by R20;each R20is independently OH, Ci-C2alkoxy, Ci-C2fluoroalkoxy, CN or NR22R23;each R21is independently F, OH, CN, NR22R23, CrC4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy or CrC4fluoroalkoxy, where each said CrC4alkyl, Ci-C4fluoroalkyl, Ci-C4alkoxy and CrC4fluoroalkoxy is optionally further substituted by OH, NH2, NHCH3or N(CH3)2;each R22and R23is independently H, C1-C2 alkyl or Ci-C2 fluoroalkyl; orR22and R23may be taken together with the nitrogen atom to which they are attached to form an azetidinyl ring, which is optionally substituted by F or OH;R24is H, Ci-C4alkyl, Ci-C4fluoroalkyl, S02R25, SO2NR20R27, COR28, COOR28or CONR29R30;R25is Ci-C4alkyl or CrC4fluoroalkyl;each R26and R27is independently H or CH3;R28is Ci-C4alkyl or Ci-C4fluoroalkyl, where each said CrC4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCH3or N(CH3)2;each R29and R30is independently H, CrC4alkyl or Ci-C4fluoroalkyl, where each said Ci-C4alkyl and Ci-C4fluoroalkyl is optionally substituted by OH, C1-C2 alkoxy, C1-C2 fluoroalkoxy, CN, NH2, NHCHSor N(CH3)2;m is 0, 1 or 2; andn is 0, 1 , 2, 3 or 4.

13. The compound of claim 10, 1 1 or 12, or a pharmaceutically acceptable salt thereof, wherein R1is Cl.

14. The compound of any one of claims 10 to 13, or a pharmaceutically acceptable salt thereof, wherein R2is C1-C5 alkyl, where said C1-C5 alkyl is optionally substituted by R20.

15. The compound of any one of claims 10 to 14, or a pharmaceutically acceptable salt thereof, wherein R4is Ci-C4alkyl, where said Ci-C4alkyl is optionally substituted by R20.

16. The compound of any one of claims 10 to 15, or a pharmaceutically acceptable salt thereof, wherein R6is F, R7is H, and R8is H.

17. The compound of any one of claims 10 to 16, or a pharmaceutically acceptable salt thereof, wherein R9is OH.

18. (3R,4R)-4-[(5-chloro-4-{4-fluoro-2-[(1 R)-1 -hydroxyethyl]-1-(propan-2-yl)-1 / - / - benzimidazol-6-yl}pyrimidin-2-yl)amino]-1 -(methanesulfonyl)piperidin-3-ol, or a pharmaceutically acceptable salt thereof.

19. 1 ,5-anhydro-3-({5-chloro-4-[4-fluoro-2-(2-hydroxypropan-2-yl)-1 -(propan-2-yl)-1 H- benzimidazol-6-yl]pyrimidin-2-yl}amino)-2,3-dideoxy-D-f / ?reo-pentitol, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.21 . A method for the treatment of cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

22. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a subject in need thereof.

23. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein said treatment comprises the administration of a second pharmaceutically active agent.

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