THEREFOR

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of 35 U.S.C. § 1 19(e) of United States Provisional

Applications 61/745,409 filed on December 21, 2012 and 61/784,928 filed on March 14, 2013, both of which are incorporated by reference.

FIELD

[0002] The present disclosure relates to protein kinases and compounds which selectively modulate kinases, and uses therefor. Particular embodiments contemplate disease indications which are amenable to treatment by modulation of kinase activity by the compounds of the present disclosure.

BACKGROUND

[0003] Receptor protein tyrosine kinases (RPTKs) regulate key signal transduction cascades that control cellular growth and proliferation. The Stem Cell Factor (SCF) receptor c-kit is a type III transmembrane RPTK that includes five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment. C-kit plays an important role in the development of melanocytes, mast, germ, and hematopoietic cells.

[0004] Stem Cell Factor (SCF) is a protein encoded by the SI locus, and has also been called kit ligand (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J. Endocrinol 1997, 153:337-344;

Vliagoftis, et al., Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90: 1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91: 1101-1 134.). Herein we use the abbreviation SCF to refer to the ligand for the c-Kit RTK (receptor tyrosine kinase).

[0005] SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be

proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizes. Both the soluble and membrane -bound forms of SCF can bind to and activate c-Kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-Kit. In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-Kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-Kit on germ cells. [0006] Aberrant expression and/or activation of c-Kit and/or a mutant form(s) of c-kit has been implicated in a variety of pathologic states (Roskoski, 2005, Biochemical and Biophysical Research Comm. 338: 1307-1315). For example, evidence for a contribution of c-Kit to neoplastic pathology includes its association with leukemias and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been implicated in playing a role in carcinogenesis of the female genital tract sarcomas of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis. It was found that mast cells are involved in modifying the tumor microenvironment and enhancing tumor growth (Yang et al., J Clin Invest. 2003, 112: 1851-1861 ; Viskochil, J Clin Invest. 2003, 112: 1791-1793). Accordingly, there is a need in the art for compounds and methods of use thereof for the modulation of receptor protein kinases. The present disclosure meets this and other needs.

SUMMARY

[0007] In one aspect, the present disclosure provides a compound of formula (Γ):

or a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer, or a deuterated analog thereof, wherein:

(i) R ¹ and R ² are taken together to form an optionally substituted 5- or 6-membered fused ring having from 0-3 heteroatoms as ring members selected from N, O or S, wherein one or two ring carbon atoms are optionally replaced by -C(=0)-; or

(ii) R ¹ is H, halogen, Ci_4 alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl or a lone pair of electrons and R ² is -NH-L ² -R ⁶ , wherein R ⁶ is H, optionally substituted aryl, optionally substituted aryl- Ci_ ₄ alkyl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted Ci_ ₆ alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-Ci_ ₄ alkyl, optionally substituted heterocyclyl or optionally substituted

heterocyclyl-Ci_ ₄ alkyl; and wherein L ² is selected from a bond, -C(O)-, -C(0)N(R ^f )-, -S0 ₂ N(R ^f )-, -S0 ₂ -, - C(0)0-, -C(=NR ^f )N(R ^f )-, wherein each R ^f is independently H or Ci_ ₄ alkyl;

G is an optionally substituted Ci_ ₆ alkyl, an optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl having one or more nitrogen atoms as ring members, wherein the aryl or heteroaryl is optionally fused with an optionally substituted 5- to 8-membered ring having from 0-2 heteroatoms as ring members selected from O, N or S;

L ¹ is selected from -CH(OH)-, -C(0)NR ⁵ -, -NR ⁵ C(0)-, -CH ₂ N(R ⁵ )-, -S0 ₂ N(R ⁵ )- , -N(R ⁵ )C(0)N(R ⁵ )-, -N(R ⁵ )S0 ₂ -, -N(R ⁵ )CH ₂ -, -OC^alkylene-, -C _w alkylene-0-, -C(O)-, -NR ⁵ C(0)- , -S0 ₂ -, -SON(R ⁵ )-, -N(R ⁵ )S0 ₂ N(R ⁵ )-, or -S(O)-, wherein each R ⁵ is independently H or C^alkyl;

Y ¹ is N or C; Y ² is N or optionally substituted =C-; and

Y ³ is N or CH; with the proviso that Y ¹ , Y ² and Y ³ are not simultaneously N.

[0008] In another aspect, the disclosure provides a composition. The composition includes a compound of any of formulas (Γ), (I'a), (I), (II), (III), (IV), (V) or (V) or any of the formulas and subformulas as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt, solvate, tautomer or isomers thereof, and a pharmaceutically acceptable excipient or carrier. The disclosure also provides a composition, which includes a compound as recited in the claims and described herein, a pharmaceutically acceptable excipient or carrier, and another therapeutic agent.

[0009] In another aspect, the disclosure provides a method for preparing a compound of formula (IV), (V) and any of the subgeneric formulas.

[0010] In another aspect, the disclosure provides a method for modulating a protein kinase. The method includes administering to a subject in need thereof a compound of any of formulas (Γ), (I'a), (I), (II), (III), (IV), (V) or (V), or any of the formulas and subformulas as described herein, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt, solvate, tautomer or isomers thereof, or a pharmaceutical composition as described herein. In some

embodiments, the protein kinase is a c-kit protein kinase or a mutant c-kit protein kinase.

[0011] In still another aspect, the disclosure provides a method for treating a subject suffering from or at risk of diseases or conditions mediated by a protein kinase. The method includes administering to the subject an effective amount of a compound of any of formulas (Γ), (I'a), (I), (II),(III), (IV), (V) or (V) or any of the subformulas, or a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof, or a composition comprising a compound of any of formulas (Γ), (I'a), (I), (II),(III), (IV), (V) or (V) or any of the subformulas described herein, or a compound as recited in any of the claims or described herein, or a pharmaceutically acceptable salt, solvate, tautomer or isomer thereof.

DETAILED DESCRIPTION

I. Definitions

[0012] As used herein the following definitions apply unless clearly indicated otherwise:

[0013] It is noted here that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise.

"Halogen" or "halo" refers to all halogens, that is, chloro (CI), fluoro (F), bromo (Br), or iodo [0015] "Hydroxyl" or "hydroxy" refers to the group -OH.

[0016] "Thiol" refers to the group -SH.

[0017] "Heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

[0018] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon, having the number of carbon atoms designated (i.e. C _ ₆ means one to six carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, but-2-enyl (e.g. -CH ₂ CH=CHCH ₃ ), cis-2-buten- 1 -yl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. For each of the definitions herein (e.g., alkyl, alkoxy, alkylamino, alkylthio, alkylene, haloalkyl, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl), when a prefix is not included to indicate the number of carbon atoms in an alkyl portion, the alkyl moiety or portion thereof will have 12 or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms or 6 or fewer main chain carbon atoms. For example, Ci_6 alkyl refers to a straight or branched hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms and includes, but is not limited to, Cui alkyl, Cu ₄ alkyl, C ₂ -6 alkyl, C ₂ -4 alkyl, Ci_6 alkyl, C ₂ -8 alkyl, Ci_ ₇ alkyl, C ₂ -7 alkyl and C ₃ _6 alkyl. "Fluoro substituted alkyl" denotes an alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR (e.g. alkoxy), -SR (e.g. thioalkyl), -NHR (e.g. alkylamino), -C(0)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any O, S, or N of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any O, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkyl carbon bound to any O, S, or N of the moiety. As used herein,

"deuterated Ci_ ₆ alkyl" is meant to include partially deuterated or perdeuterated Ci_ ₆ alkyl groups. Non- limiting examples include -CD ₃ , CD ₃ CH ₂ -, CD ₃ CD ₂ -, -CD(CD ₃ ) ₂ , -CD(CH ₃ ) ₂ , and the like.

[0019] The term "alkylene" by itself or as part of another substituent means a linear or branched saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., Cue means one to six carbons; C alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene and the like). Ci_4 alkylene includes methylene -CH ₂ -, ethylene -CH ₂ CH ₂ -, propylene -CH ₂ CH ₂ CH ₂ -, and

isopropylene -CH(CH ₃ )CH ₂ - , -CH ₂ CH(CH ₃ )-, -CH ₂ -(CH ₂ ) ₂ CH ₂ -, -CH ₂ -CH(CH ₃ )CH ₂ -, -CH ₂ -C(CH ₃ ) ₂ - , -CH ₂ -CH ₂ CH(CH ₃ )- . Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms being preferred in the present disclosure. When a prefix is not included to indicate the number of carbon atoms in an alkylene portion, the alkylene moiety or portion thereof will have 12 or fewer main chain carbon atoms or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms or 4 or fewer main chain carbon atoms.

[0020] The term "alkenyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, (C ₂ -C ₆ )alkenyl is meant to include ethenyl, propenyl, -CH=C(H)(CH ₃ ), - CH=C(CH ₃ ) ₂ , -C(CH ₃ )=C(H) ₂ , -C(CH ₃ )=C(H)(CH ₃ ), -C(CH ₂ CH ₃ )=CH ₂ , butadienyl e.g. 2-(butadienyl), pentadienyl e.g. 2,4-pentadienyl and 3-(l,4-pentadienyl), and hexadienyl, and the like, among others, and higher homologs and stereoisomers thereof. Similarly, the term "alkynyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. Examples include, but are not limited to, ethynyl e.g. -C≡C(H), 1- propynyl e.g. -C≡C(CH ₃ ), -C≡C(CH ₂ CH ₃ ), -C(H ₂ )C≡C(H), -C(H) ₂ C≡C(CH ₃ ), and -C(H) ₂ C≡C(CH ₂ CH ₃ ), among others, and higher homologs and isomers thereof. When a prefix is not included to indicate the number of carbon atoms in an alkenyl or alkynyl portion, the alkenyl or alkynyl moiety or portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms.

[0021] The term "alkenylene" refers to a linear bivalent hydrocarbon moiety or a branched divalent hydrocarbon moiety having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, i.e., C ₂ _ ₆ means two to six carbons; C ₂ _ ₆ alkenylene is meant to include, but are not limited to, -CH=CH-, -CH ₂ -CH=CH-, -CH ₂ -CH=C(CH ₃ )-, -CH=CH-CH=CH-, and the like). Similarly, the term "alkynylene" refers to a linear bivalent hydrocarbon moiety or a branched divalent hydrocarbon moiety containing at least one triple bond and having the number of carbon atoms indicated in the prefix. For example, (i.e., C ₂ _6 means two to six carbons; C ₂ _6 alkynlene is meant to include, but are not limited to, -C≡C-, -C≡CCH ₂ -, -CH ₂ -C≡CCH ₂ -, -C≡CCH(CH ₃ )-, and the like. When a prefix is not included to indicate the number of carbon atoms in an alkenylene or alkynlene portion, the alkenylene moiety or portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms.

[0022] "Cycloalkyl" or "Carbocycle" by itself or as part of another substituent, refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems having the number of carbon atoms indicated in the prefix or if unspecified having 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, adamantyl, and the like, where one or two ring carbon atoms may optionally be replaced by a carbonyl. Cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C ₃ _g cycloalkyl means three to eight ring carbon atoms). "Cycloalkyl" or "carbocycle" refers to a mono- bicyclic or polycyclic group such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. When used in connection with cycloalkyl substituents, the term "polycyclic" refers herein to fused and non-fused alkyl cyclic structures. "Cycloalkyl" or "carbocycle" may form a bridged ring or a spiro ring, The cycloalkyl group may have one or more double or triple bond(s).

[0023] "Cycloalkylene" by itself or as part of another substituent, refers to a divalent cycloalkyl, where the cycloalkyl as defined above having 3- 10, also 3-8, more preferably 3-6, ring members per ring.

Exemplary cycloalkylene includes, e.g., 1,2-, 1,3-, or 1,4- cis or trans-cyclohexylene, 2-methyl- 1 ,4- cyclohexylene, 2,2-dimethyl- 1 ,4-cyclohexylene, and the like.

[0024] "Cycloalkylalkyl" refers to an -(alkylene) -cycloalkyl group where alkylene as defined herein has the indicated number of carbon atoms or if unspecified having six or fewer, preferably four or fewer main chain carbon atoms; and cycloalkyl is as defined herein has the indicated number of carbon atoms or if unspecified having 3-10, also 3-8, more preferably 3-6, ring members per ring. C ₃ _ ₈ cycloalkyl-Ci_ ₂ alkyl is meant to have 3 to 8 ring carbon atoms and 1 to 2 alkylene chain carbon atoms. Exemplary cycloalkylalkyl includes, e.g., cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and the like.

[0025] "Cycloalkylalkenyl" refers to an -(alkenylene)-cycloalkyl group where alkenylene as defined herein has the indicated number of carbon atoms or if unspecified having six or fewer, preferably four or fewer main chain carbon atoms; and cycloalkyl is as defined herein has the indicated number of carbon atoms or if unspecified having 3-10, also 3-8, more preferably 3-6, ring members per ring. C ₃ _

8cycloalkyl-C ₂ - ₄ alkenyl is meant to have 3 to 8 ring carbon atoms and 2 to 4 alkenylene chain carbon atoms. Exemplary cycloalkylalkenyl includes, e.g., 2-cyclopropylvinyl, 2-cyclopentylvinyl, and the like.

[0026] "Cycloalkylalkynyl" refers to an -(alkynylene)-cycloalkyl group where alkynylene as defined herein has the indicated number of carbon atoms or if unspecified having six or fewer, preferably four or fewer main chain carbon atoms; and cycloalkyl is as defined herein has the indicated number of carbon atoms or if unspecified having 3-10, also 3-8, more preferably 3-6, ring members per ring. C ₃ _

8Cycloalkyl-C ₂ _ ₄ alkynyl is meant to have 3 to 8 ring carbon atoms and 2 to 4 alkynylene chain carbon atoms. Exemplary cycloalkylalkynyl includes, e.g., 2-cyclopropylethynyl, 2-cyclobutylethynyl, 2- cyclopentylethynyl and the like.

[0027] "Cycloalkenyl" by itself or as part of another substituent, refers to a non-aromatic monocyclic, bicyclic or tricyclic carbon ring system having the number of carbon atoms indicated in the prefix or if unspecified having 3-10, also 3-8, more preferably 3-6, ring members per ring, which contains at least one carbon-carbon double bond. Exemplary cycloalkenyl includes, e.g., 1 -cyclohexenyl, 4-cyclohexenyl, 1 -cyclopentenyl, 2-cyclopentenyl and the like.

[0028] "Cycloalkenylene" by itself or as part of another substituent, refers to a divalent cycloalkenyl, where the cycloalkenyl as defined herein having 3-10, also 3-8, more preferably 3-6, ring members per ring. Exemplary cycloalkenylene includes, e.g., cyclohexene- 1 ,4-diyl, 2-methyl-cyclohexene- l,4-diyl, 3- methyl-cyclohexene- 1 ,4-diyl, 3,3-dimethyl-cyclohexene- 1,4-diyl, cyclohexene- 1 ,2-diyl, cyclohexene- 1,3-diyl, and the like.

[0029] "Haloalkyl," is meant to include alkyl substituted by one to seven halogen atoms. Haloalkyl includes monohaloalkyl and polyhaloalkyl. For example, the term "C - ₆ haloalkyl" is meant to include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0030] "Haloalkoxy" refers to a -O-haloalkyl group, where haloalkyl is as defined herein, e. g., trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like.

[0031] "Alkoxy" refers to a -O-alkyl group, where alkyl is as defined herein. "Cycloalkoxy" refers to a -O-cycloalkyl group, where cycloalkyl is as defined herein. "Fluoro substituted alkoxy" denotes alkoxy in which the alkyl is substituted with one or more fluoro atoms, where preferably the alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that O, S, or N (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy O. Further, where alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an O, S, or N of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

[0032] "Amino" or "amine" denotes the group -NH ₂ .

[0033] "Alkylamino" refers to a -NH-alkyl group, where alkyl is as defined herein. Exemplary alkylamino groups include CH ₃ NH-, ethylamino, and the like.

[0034] "Dialkylamino" refers to a -N(alkyl)(alkyl) group, where each alkyl is independently as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino, and the like.

[0035] "Cycloalkylamino" denotes the group -NR ^dd R ^ee , where R ^dd and R ^ee combine with the nitrogen to form a 5-7 membered heterocycloalkyl ring, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as O, N, or S, and may also be further substituted with alkyl.

Alternatively, "cycloalkylamino" refers to a -NH-cycloalkyl group, where cycloalkyl is as defined herein.

[0036] "Alkylthio" refers to -S-alkyl, where alkyl is as defined herein. Exemplary alkylthio groups include CH ₃ S-, ethylthio, and the like.

[0037] "Aryl" by itself or as part of another substituent refers to a monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical containing 6 to 14 ring carbon atoms, which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. Non- limiting examples of unsubstituted aryl groups include phenyl, 1 -naphthyl, 2-naphthyl and

4-biphenyl. Exemplary aryl groups, such as phenyl or naphthyl, may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members.

[0038] "Arylene" by itself or as part of another substituent, refers to a divalent aryl, where the aryl is as defined herein. Exemplary arylene includes, e.g., phenylene, biphenylene, and the like.

[0039] "Arylalkyl" refers to -(alkylene)-aryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms or four or fewer main chain carbon atoms; and aryl is as defined herein. Examples of arylalkyl include benzyl, phenethyl, 1 -methylbenzyl, and the like.

[0040] "Arylalkoxy" refers to -0-(alkylene)-aryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms or four or fewer main chain carbon atoms; and aryl is as defined herein. Examples of arylalkoxy include benzyloxy, phenethyloxy, and the like.

[0041] "Aryloxy" refers to -O-aryl, where the aryl group is as defined herein. Exemplary aryloxy includes, e.g., phenoxy.

[0042] "Arylthio" refers to -S-aryl, where the aryl group is as defined herein. Exemplary arylthio includes, e.g., phenylthio.

[0043] "Heteroaryl" by itself or as part of another substituent refers to a monocyclic aromatic ring radical containing 5 or 6 ring atoms, or a bicyclic aromatic radical having 8 to 10 atoms, containing one or more, preferably 1 -4, more preferably 1 -3, even more preferably 1 -2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl,

benzothienyl, quinolyl, isoquinolyl, indazolyl, pteridinyl and thiadiazolyl. "Nitrogen containing heteroaryl" refers to heteroaryl wherein any of the heteroatoms is N. As used herein, "heterocyclic aromatic ring" is meant to be a heteroaryl ring. [0044] "Heteroarylene" by itself or as part of another substituent, refers to a divalent heteroaryl, where the heteroaryl is as defined herein. Exemplary heteroarylene includes, e.g., pyridine-2,5-diyl, pyrimidine-2,5-diyl, pyridazine-3,5-diyl, pyrazine-2,5-diyl, and the like.

[0045] "Heteroarylalkyl" refers to -(alkylene)-heteroaryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms or four or fewer main chain carbon atoms; and heteroaryl is as defined herein. Non-limiting examples of heteroarylalkyl include 2-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylethyl, and the like.

[0046] "Heterocyclyl", "Heterocycle" or "Heterocyclic" refers to a saturated or unsaturated non- aromatic mono- or bicyclic radical group containing at least one heteroatom independently selected from oxygen (O), nitrogen (N) or sulfur (S). Each heterocycle can be attached at any available ring carbon or heteroatom. Each heterocycle may have one or more rings. When multiple rings are present, they can be fused together or linked covalently. Each heterocycle typically contains 1 , 2, 3, 4 or 5, independently selected heteroatoms. Preferably, these groups contain 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, 0, 1, 2, 3, 4 or 5 nitrogen atoms, 0, 1 or 2 sulfur atoms and 0, 1 or 2 oxygen atoms. More preferably, these groups contain 1 , 2 or 3 nitrogen atoms, 0- 1 sulfur atoms and 0- 1 oxygen atoms. Non- limiting examples of heterocyclyl groups include morpholin-3-one, piperazine-2-one, piperazin- 1 -oxide, pyridine-2-one, piperidine, morpholine, piperazinyl, isoxazoline, pyrazolone, imidazoline, pyrazol-5-one, pyrrolidine-2,5- dione, imidazolidine-2,4-dione, pyrrolidine, tetrahydroquinolinyl, decahydroquinolinyl,

tetrahydrobenzooxazepinyl dihydrodibenzooxepin and the like.

[0047] "Heterocyclylene" by itself or as part of another substituent, refers to a divalent heterocyclyl, where the heterocyclyl is as defined herein. Exemplary heterocyclylene includes, e.g., piperazine- 1 ,4- diyl, piperidine- 1 ,4-diyl, l ,2,3,6-tetrahydropyridine- l ,4-diyl, 3-azabicyclo[3.2.1 ]octane-3,8-diyl, 3,8- diazabicyclo[3.2. l ]octane-3,8-diyl, 8-azabicyclo[3.2. l ]octane-3,8-diyl, 2-azabicyclo[2.2.2]octane-2,5- diyl, 2,5-diazabicyclo[2.2.2]octane-2,5-diyl, 2,3,6,7-tetrahydro- lH-azepine- l,4-diyl, 2,3,6,7-tetrahydro- lH-azepine- l ,5-diyl, 2,5-dihydro- lH-pyrrole- l ,3-diyl and the like.

[0048] "Heterocyclylalkyl" refers to -(alkylene)-heterocyclyl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms or four or fewer main chain carbon atoms; and heterocyclyl is as defined herein.

Exemplary heterocyclylalkyl includes, e.g., pyrrolidin- 1 -ylmethyl, 2-piperidinylmethyl, and the like.

[0049] "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group that contains from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized, the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl. The heterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ring system of 3 to 12, preferably 4 to 10 ring atoms, more preferably 5 to 8 ring atoms in which one to five ring atoms are heteroatoms selected from -N=, -N-, -0-, -S-, -S(O)-, or -S(0)2- and further wherein one or two ring atoms are optionally replaced by a -C(O)- group. The heterocycloalkyl can also be a heterocyclic alkyl ring fused with a cycloalkyl, an aryl or a heteroaryl ring. Non limiting examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, butyrolactam moiety, valerolactam moiety, imidazolidinone moiety, hydantoin, dioxolane moiety, phthalimide moiety, piperidine, 1,4-dioxane moiety, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-oxide, piperazinyl, pyranyl, pyridine moiety, 3-pyrrolinyl, thiopyranyl, pyrone moiety, tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. As used herein, the term "Heterocycloalkylene" by itself or as part of another substituent, refers to a divalent heterocycloalkyl, where the heterocycloalkyl is as defined herein. Non- limiting examples of heterocycloalkylene include piperidine- 1 ,4-diyl, l,2,3,6-tetrahydropyridine-l,4-diyl, 1 ,2,3,6-tetrahydropyridine- 1 ,5-diyl, 2,3,6,7-tetrahydro- lH-azepine- 1 ,4-diyl, 2,3,6,7-tetrahydro- 1H- azepine-l,5-diyl, 2,5-dihydro-lH-pyrrole-l,3-diyl and the like.

[0050] "Heterocycloalkylalkyl" refers to -(alkylene)-heterocycloalkyl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms or four or fewer main chain carbon atoms; and heterocycloalkyl is as defined herein. Non- limiting examples of heterocycloalkylalkyl include 2-pyridylmethyl, 2-thiazolylethyl, and the like.

[0051] The substituents for alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocyclyl, alkylene, alkenylene, or alkynlene include, but are not limited to, R',

halogen, -OH, -NH ₂ , -N0 ₂ , -CN, -C(0)OH, -C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , - NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , -OR , -SR , -OC(0)R , -OC(S)R , -C(0)R , -C(S)R , -C(0)OR , -C(S)OR , -S(0)R , -S(0) ₂ R , -C(0)NHR , -C(S)NHR', -C(0)NR ^' R ^" , -C(S)NR ^' R ^" , -S(0) ₂ NHR', -S(0) ₂ NR ^' R ^" , -C(NH)NHR ^' , -C(NH)NR ^' R ^" , -NHC(0)R ^' , -NHC(S)R ^' , -NR ^" C(0)R ^' , -NR ^' C(S)R ^" , -NHS(0) ₂ R ^' , -NR ^' S(0) ₂ R ^" , -NHC(0)NHR ^' , -NHC(S)NHR ^' , -NR ^' C(0)NH ₂ , -NR ^' C(S)NH ₂ , -NR ^' C(0)NHR ^" , -NR ^' C(S) NHR ^" , -NHC(0)NR ^' R ^" , -NHC(S)NR ^' R ^" , -NR ^' C(0)NR ^" R ^" , -NR ^" C(S)NR ^' R ^" , -NHS(0) ₂ NHR ^' , -NR ^' S( 0) ₂ NH ₂ , -NR ^' S(0) ₂ NHR ^" , -NHS(0) ₂ NR ^' R ^" , -NR ^' S(0) ₂ NR ^" R ^" , -NHR ^' , and -NR ^' R ^" in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such group. R', R" and R'" each independently refer to hydrogen, Ci_g alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, Crg alkoxy, haloalkyl, haloalkoxy or C g thioalkoxy groups, or unsubstituted aryl-Ci-4 alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include 1 -pyrrolidinyl and 4-morpholinyl. R', R" and R'" can be further substituted with R ^al , halogen, -OH, -NH ₂ , -N0 ₂ , -CN, -C(0)OH, -C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , - NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , -OR ^al , -SR ^al , -OC(0)R ^al , -OC(S)R ^al , -C(0)R ^al , -C(S)R ^al , -C( 0)OR ^al , -C(S)OR ^al , -S(0)R ^al , -S(0) ₂ R ^al , -C(0)NHR ^AL , -C(S)NHR ^AL , -C(0)NR ^al R ^a2 , -C(S)NR ^al R ^a2 , -S(O) ₂ NHR ^AL , -S(0) ₂ NR ^al R ^a2 , -C(NH)NHR ^AL , -C(NH)NR ^al R ^a2 , -NHC(0)R ^al , -NHC(S)R ^al , -NR ^a2 C(0)R ^al , -NR ^A ^(S)^ ² , -NHS(0) ₂ R ^al , -NR ^al S(0) ₂ R ^a2 , -NHC(0)NHR ^al , -NHC(S)NHR ^al , -NR ^al C(0)NH ₂ , -NR ^al C(S)N H ₂ , -NR ^al C(0)NHR ^a2 , -NR ^al C(S)NHR ^a2 , -NHC(0)NR ^al R ^a2 , -NHC(S)NR ^al R ^a2 , -NR ^al C(0)NR ^a2 R ^a3 , -NR ^a3 C(S)NR ^al R ^a2 , -NHS(0) ₂ NHR ^al , -NR ^al S(0) ₂ NH ₂ , -NR ^al S(0) ₂ NHR ^a2 , -NHS(0) ₂ NR ^al R ^a2 , -NR ^al S(0) ₂ NR ^a2 R ^a3 , -NHR ^al , and -NR ^al R ^a2 in a number ranging from zero to (2n'+l), where n' is the total number of carbon atoms in such group. R ^al , R ^a2 and R ^a3 each independently refer to hydrogen, Ci_ ₈ alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, Q-g alkoxy, haloalkyl, haloalkoxy or Q-g thioalkoxy groups, or unsubstituted aryl-Cr ₄ alkyl groups. R ^al , R ³² and R ^a3 can be further substituted with R ^bl ,

halogen, -OH, -NH ₂ , -N0 ₂ , -CN, -C(0)OH, -C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , - NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , -OR ^bl , -SR ^bl , -OC(0)R ^bl , -OC(S)R ^bl , -C(0)R ^bl , -C(S)R ^bl , -C( 0)OR ^bl , -C(S)OR ^bl , -S(0)R ^bl , -S(0) ₂ R ^bl , -C(0)NHR ^bl , -C(S)NHR ^bl , -C(0)NR ^bl R ^b2 , -C(S)NR ^bl R ^b2 , -S(0 ) ₂ NHR ^bl , -S(0) ₂ NR ^bl R ^b2 , -C(NH)NHR ^bl , -C(NH)NR ^bl R ^b2 , -NHC(0)R ^bl , -NHC(S)R ^bl , -NR ^b2 C(0)R ^bl , -N R ^bl C(S)R ^b2 , -NHS(0) ₂ R ^bl , -NR ^bl S(0) ₂ R ^b2 , -NHC(0)NHR ^bl , -NHC(S)NHR ^bl , -NR ^bl C(0)NH ₂ , -NR ^bl C(S) NH ₂ , -NR ^bl C(0)NHR ^b2 , -NR ^bl C(S)NHR ^b2 , -NHC(0)NR ^bl R ^b2 , -NHC(S)NR ^bl R ^b2 , -NR ^bl C(0)NR ^b2 R ^b3 , -N R ^b3 C(S)NR ^bl R ^b2 , -NHS(0) ₂ NHR ^bl , -NR ^bl S(0) ₂ NH ₂ , -NR ^bl S(0) ₂ NHR ^b2 , -NHS(0) ₂ NR ^bl R ^b2 , -NR ^bl S(0) ₂ N R ^b2 R ^b3 , -NHR ^bl , and -NR ^bl R ^b2 in a number ranging from zero to (2p'+l), where p' is the total number of carbon atoms in such group. R ^bl , R ^b2 and R ^b3 each independently refer to hydrogen, Ci_g alkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aryl substituted with 1-3 halogens, Q-g alkoxy, haloalkyl, haloalkoxy or Ci-g thioalkoxy groups, or unsubstituted aryl-Ci-4 alkyl groups.

[0052] Substituents for the aryl and heteroaryl groups are varied and are generally selected from: R', halogen, -OH, -NH ₂ , -N0 ₂ , -CN, -C(0)OH, -C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , - NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , -OR ^' , -SR , -0C(0)R ^' , -0C(S)R ^' , -C(0)R ^' , -C(S)R ^' , -C(0)0R ^' , -C(S)OR , -S(0)R , -S(0) ₂ R ^' , -C(0)NHR ^' , -C(S)NHR', -C(0)NR ^' R ^" , -C(S)NR ^' R ^" , -S(0) ₂ NHR', -S(0) ₂ NR ^' R ^" , -C(NH)NHR ^' , -C(NH)NR ^' R ^" , -NHC(0)R ^' , -NHC(S)R ^' , -NR ^" C(0)R ^' , -NR ^' C(S)R ^" , -NHS(0) ₂ R ^' , -NR ^' S(0) ₂ R ^" , -NHC(0)NHR ^' , -NHC(S)NHR ^' , -NR ^' C(0)NH ₂ , -NR ^' C(S)NH ₂ , -NR ^' C(0)NHR ^" , -NR ^' C(S) NHR ^" , -NHC(0)NR ^' R ^" , -NHC(S)NR ^' R ^" , -NR ^' C(0)NR ^" R ^" , -NR ^" C(S)NR ^' R ^" , -NHS(0) ₂ NHR ^' , -NR ^' S( 0) ₂ NH ₂ , -NR ^' S(0) ₂ NHR ^" , -NHS(0) ₂ NR ^' R ^" , -NR ^' S(0) ₂ NR ^" R ^" , -NHR ^' , -NR ^' R ^" , -N ₃ , perfluoro(Ci- Czt)alkoxy, and perfluoro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, haloalkyl, haloalkoxy, Ci_g alkyl, C3.6 cycloalkyl, cycloalkylalkyl, C ₂ _g alkenyl, C ₂ _g alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-Ci- ₄ alkyl, and aryloxy-Ci-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms. R', R" and R'" can be further substituted with R ^al ,

halogen, -OH, -NH ₂ , -N0 ₂ , -CN, -C(0)OH, -C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , - NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , -OR ^al , -SR ^al , -OC(0)R ^al , -OC(S)R ^al , -C(0)R ^al , -C(S)R ^al , -C( 0)OR ^al , -C(S)OR ^al , -S(0)R ^al , -S(0) ₂ R ^al , -C(0)NHR ^al , -C(S)NHR ^al , -C(0)NR ^al R ^a2 , -C(S)NR ^al R ^a2 , -S(O) ₂ NHR ^al , -S(0) ₂ NR ^al R ^a2 , -C(NH)NHR ^al , -C(NH)NR ^al R ^a2 , -NHC(0)R ^al , -NHC(S)R ^al , -NR ^a2 C(0)R ^al , -NR ^a ^(S)^ ² , -NHS(0) ₂ R ^al , -NR ^al S(0) ₂ R ^a2 , -NHC(0)NHR ^al , -NHC(S)NHR ^al , -NR ^al C(0)NH ₂ , -NR ^al C(S)N H ₂ , -NR ^al C(0)NHR ^a2 , -NR ^al C(S)NHR ^a2 , -NHC(0)NR ^al R ^a2 , -NHC(S)NR ^al R ^a2 , -NR ^al C(0)NR ^a2 R ^a3 , -NR ^a3 C(S)NR ^al R ^a2 , -NHS(0) ₂ NHR ^al , -NR ^al S(0) ₂ NH ₂ , -NR ^al S(0) ₂ NHR ^a2 , -NHS(0) ₂ NR ^al R ^a2 , -NR ^al S(0) ₂ NR ^a2 R ^a3 , -NHR ^al ,-NR ^al R ^a2 , -N ₃ , perfluoro(C C ₄ )alkoxy, and perfluoro(CrC ₄ )alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R ^al , R ^a2 and R ^a3 are each independently selected from hydrogen, haloalkyl, haloalkoxy, Ci_ ₈ alkyl, C ₃ _ ₆ cycloalkyl, cycloalkylalkyl, C ₂ _ ₈ alkenyl, C ₂ _ ₈ alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryl-Ci- ₄ alkyl, or aryloxy-Ci-4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.

[0053] When two substituents are present on adjacent atoms of a substituted aryl or a substituted heteroaryl ring, such substituents may optionally be replaced with a substituent of the

formula -T-C(0)-(CH ₂ ) _q -U-, wherein T and U are independently -NH-, -0-, -CH ₂ - or a single bond, and q is an integer of from 0 to 2. Alternatively, when two substituents are present on adjacent atoms of a substituted aryl or a substituted heteroaryl ring, such substituents may optionally be replaced with a substituent of the formula -A-(CH ₂ ) _r -B-, wherein A and B are independently -CH ₂ -, -0-, -NH-, -S-, - S(O)-, -S(0) ₂ -, -S(0) ₂ NR'- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, when two substituents are present on adjacent atoms of a substituted aryl or a substituted heteroaryl ring, such substituents may optionally be replaced with a substituent of the formula -(CH ₂ ) _s -X-(CH ₂ ) , where s and t are independently integers of from 0 to 3, and X is -0-, -NR'-, -S-, -S(O)-, -S(0) ₂ -, or -S(0) ₂ NR'-. The substituent R' in -NR'- and -S(0) ₂ NR'- is selected from hydrogen or unsubstituted d-6 alkyl.

[0054] "Protecting group" refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Greene and P.G. Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006), Beaucage and Iyer, Tetrahedron 48:2223-231 1 (1992), and Harrison and Harrison et al, COMPENDIUM OF

SYNTHETIC ORGANIC METHODS, Vols. 1-8 (John Wiley and Sons. 1971-1996). Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert- butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS), phenylsulphonyl and the like (see also, Boyle, A. L. (Editor), carbamates, amides, N-sulfonyl derivatives, groups of formula -C(0)OR, wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl, CH ₂ =CHCH ₂ -, and the like, groups of the formula -C(0)R', wherein R' is, for example, methyl, phenyl, trifluoromethyl, and the like, groups of the formula -S0 ₂ R", wherein R" is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl, 2,3,6- trimethyl-4-methoxyphenyl, and the like, and silanyl containing groups, such as

2-trimethylsilylethoxymethyl, t-butyldimethylsilyl, triisopropylsilyl, and the like, CURRENT PROTOCOLS IN NUCLEIC ACID CHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000). [0055] "Optional" or "Optionally" as used throughout the specification means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "the aromatic group is optionally substituted with one or two alkyl substituents" means that the alkyl may but need not be present, and the description includes situations where the aromatic group is substituted with an alkyl group and situations where the aromatic group is not substituted with the alkyl group.

[0056] As used herein, the term "composition" refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0057] The term "pharmaceutically acceptable" indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.

[0058] "Pharmaceutically acceptable salt" refers to a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, tertiary and quaternary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N, N'- dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,

methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, meglumine (N-methyl-glucamine) and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable acids include acetic, trifluoroacetic, propionic, ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, glycolic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, hydroiodic, carbonic, tartaric, p- toluenesulfonic, pyruvic, aspartic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, embonic (pamoic), ethanesulfonic, benzenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, hydroxybutyric, galactaric and galacturonic acid and the like.

[0059] Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M. et al, "Pharmaceutical Salts", J. Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0060] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0061] In the present context, the term "therapeutically effective" or "effective amount" indicates that a compound or amount of the compound when administered is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of a disease, disorder or medical condition being treated, and/or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the mammal to be treated. In general, satisfactory results in subjects are indicated to be obtained at a daily dosage of from about 0.1 to about 10 g/kg subject body weight. In some embodiments, a daily dose ranges from about 0.10 to 10.0 mg/kg of body weight, from about 1.0 to 3.0 mg/kg of body weight, from about 3 to 10 mg/kg of body weight, from about 3 to 150 mg/kg of body weight, from about 3 to 100 mg/kg of body weight, from about 10 to 100 mg/kg of body weight, from about 10 to 150 mg/kg of body weight, or from about 150 to 1000 mg/kg of body weight. The dosage can be conveniently administered, e.g., in divided doses up to four times a day or in sustained-release form.

[0062] Reference to particular amino acid residues in human c-kit polypeptide is defined by the numbering corresponding to the Kit sequence in GenBank NP 000213 (SEQ ID NO: 1). Reference to particular nucleotide positions in a nucleotide sequence encoding all or a portion of c-kit is defined by the numbering corresponding to the sequence provided in GenBank NM 000222 (SEQ ID NO: 2).

[0063] The terms "kit", "c-kit", and "c-Kit" mean an enzymatically active kinase that contains a portion with greater than 90% amino acid sequence identity to amino acid residues including the ATP binding site of full-length c-kit (e.g., human c-kit, e.g., the sequence NP 000213, SEQ ID NO: 1), for a maximal alignment over an equal length segment; or that contains a portion with greater than 90% amino acid sequence identity to at least 200 contiguous amino acids of native c-kit and retains kinase activity.

Preferably the sequence identity is at least 95, 97, 98, 99, or even 100%. Preferably the specified level of sequence identity is over a sequence at least 100-500, at least 200-400, or at least 300 contiguous amino acid residues in length. Unless indicated to the contrary, the term includes reference to wild-type c-kit, allelic variants, and mutated forms (e.g., having activating mutations).

[0064] In the present context, the terms "synergistically effective" or "synergistic effect" indicate that two or more compounds that are therapeutically effective, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.

[0065] By "assaying" is meant the creation of experimental conditions and the gathering of data regarding a particular result of the exposure to specific experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. A compound can be assayed based on its ability to bind to a particular target molecule or molecules.

[0066] As used herein, the terms "ligand" and "modulator" are used equivalently to refer to a compound that changes (i.e., increases or decreases) the activity of a target biomolecule, e.g., an enzyme such as a kinase. Generally a ligand or modulator will be a small molecule, where "small molecule refers to a compound with a molecular weight of 1500 Daltons or less, or preferably 1000 Daltons or less, 800 Daltons or less, or 600 Daltons or less. Thus, an "improved ligand" is one that possesses better pharmacological and/or pharmacokinetic properties than a reference compound, where "better" can be defined by one skilled in the relevant art for a particular biological system or therapeutic use.

[0067] The term "binds" in connection with the interaction between a target and a potential binding compound indicates that the potential binding compound associates with the target to a statistically significant degree as compared to association with proteins generally (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that has a statistically significant association with a target molecule. Preferably a binding compound interacts with a specified target with a dissociation constant (K _D ) of 1 mM or less, 1 μΜ or less, 100 nM or less, 10 nM or less, or 1 nM or less.

[0068] In the context of compounds binding to a target, the terms "greater affinity" and "selective" indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i.e., with a lower dissociation constant. In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity.

[0069] As used herein in connection with compounds of the disclosure, the term "synthesizing" and like terms means chemical synthesis from one or more precursor materials. Further, by "assaying" is meant the creation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. A compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.

[0070] As used herein, the term "lone pair" or "lone pair of electrons" refers to a pair of electrons in the outermost shell of an atom, in particular a nitrogen atom, that are not used in bonding

[0071] As used herein, the term "modulating" or "modulate" refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule, such as an enzyme. Such activity is typically indicated in terms of an inhibitory concentration (IC ₅ o) or excitation concentration (EC ₅ o) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.

[0072] "Prodrugs" means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., Ν,Ν-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I, and the like. Preparation, selection, and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series; "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0073] "Tautomer" means compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992). The tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. Examples of include keto-enol tautomers, such as acetone/propen-2-ol, imine-enamine tautomers and the like, ring-chain tautomers, such as glucose/2,3,4,5, 6-pentahydroxy-hexanal and the like, the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. The compounds described herein may have one or more tautomers and therefore include various isomers. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure,

[0074] "Isomers" mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture". Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 6th edition J. March, John Wiley and Sons, New York, 2007) differ in the chirality of one or more stereocenters.

[0075] Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. "Hydrate" refers to a complex formed by combination of water molecules with molecules or ions of the solute. "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate. Some examples of solvents include, but are not limited to, methanol, Ν,Ν-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0076] In the context of the use, testing, or screening of compounds that are or may be modulators, the term "contacting" means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur. [0077] As used herein, the term "subject" refers to a living organism that is treated with compounds as described herein, including, but not limited to, any mammal, such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0078] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous

administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.

[0079] "Solid form" refers to a solid preparation (i.e. a preparation that is neither gas nor liquid) of a pharmaceutically active compound that is suitable for administration to an intended animal subject for therapeutic purposes. The solid form includes any complex, such as a salt, co-crystal or an amorphous complex, as well as any polymorph of the compound. The solid form may be substantially crystalline, semi-crystalline or substantially amorphous. The solid form may be administered directly or used in the preparation of a suitable composition having improved pharmaceutical properties. For example, the solid form may be used in a formulation comprising at least one pharmaceutically acceptable carrier or excipient.

[0080] The terms "prevent", "preventing", "prevention" and grammatical variations thereof as used herein, refers to a method of partially or completely delaying or precluding the onset or recurrence of a disease, disorder or condition and/or one or more of its attendant symptoms or barring a subject from acquiring or reacquiring a disorder or condition or reducing a subject's risk of acquiring or reacquiring a disorder or condition or one or more of its attendant symptoms.

[0081] "Pain" or a "pain condition" can be acute and/or chronic pain, including, without limitation, arachnoiditis; arthritis (e.g. osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, gout); back pain (e.g. sciatica, ruptured disc, spondylolisthesis, radiculopathy); burn pain; cancer pain; dysmenorrhea; headaches (e.g. migraine, cluster headaches, tension headaches); head and facial pain (e.g. cranial neuralgia, trigeminal neuralgia); hyperalgesia; hyperpathia; inflammatory pain (e.g. pain associated with irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, cystitis, pain from bacterial, fungal or viral infection); keloid or scar tissue formation; labor or delivery pain; muscle pain (e.g. as a result of polymyositis, dermatomyositis, inclusion body myositis, repetitive stress injury (e.g. writer's cramp, carpal tunnel syndrome, tendonitis, tenosynovitis)); myofascial pain syndromes (e.g. fibromyalgia); neuropathic pain (e.g. diabetic neuropathy, causalgia, entrapment neuropathy, brachial plexus avulsion, occipital neuralgia, gout, reflex sympathetic dystrophy syndrome, phantom limb or post- amputation pain, postherpetic neuralgia, central pain syndrome, or nerve pain resulting from trauma (e.g. nerve injury), disease (e.g. diabetes, multiple sclerosis, Guillan-Barre Syndrome, myasthenia gravis, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, or cancer treatment); pain associated with skin disorders (e.g. shingles, herpes simplex, skin tumors, cysts, neurofibromatosis); sports injuries (e.g. cuts, sprains, strains, bruises, dislocations, fractures, spinal cord, head); spinal stenosis; surgical pain; tactile allodynia; temporomandibular disorders; vascular disease or injury (e.g. vasculitis, coronary artery disease, reperfusion injury (e.g. following ischemia, stroke, or myocardial infarcts)); other specific organ or tissue pain (e.g. ocular pain, corneal pain, bone pain, heart pain, visceral pain (e.g. kidney, gallbladder, gastrointestinal), joint pain, dental pain, pelvic hypersensitivity, pelvic pain, renal colic, urinary incontinence); other disease associated pain (e.g. sickle cell anemia, AIDS, herpes zoster, psoriasis, endometriosis, asthma, chronic obstructive pulmonary disease (COPD), silicosis, pulmonary sarcoidosis, esophagitis, heart burn, gastroesophageal reflux disorder, stomach and duodenal ulcers, functional dyspepsia, bone resorption disease, osteoporosis, cerebral malaria, bacterial meningitis); or pain due to graft v. host rejection or allograft rejections.

[0082] "Unit dosage form" refers to a composition intended for a single administration to treat a subject suffering from a disease or medical condition. Each unit dosage form typically comprises each of the active ingredients of this disclosure plus pharmaceutically acceptable excipients. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions or suspensions. Treatment of the disease or condition may require periodic administration of unit dosage forms, for example: one unit dosage form two or more times a day, one with each meal, one every four hours or other interval, or only one per day. The expression "oral unit dosage form" indicates a unit dosage form designed to be taken orally.

[0083] As used herein, the term c-kit-mediated disease or condition or kit-mediated disease or condition or KIT-mediated disease or condition refers to a disease or condition in which the biological function of c-kit and/or mutant c-kit affects the development and/or course of the disease or condition, and/or in which modulation of c-kit and/or mutant c-kit alters the development, course, and/or symptoms. For example, mutations in the c-kit gene such as the W42, Wv, and W41 mutations reported by Herbst et al (J. Biol. Chem., 1992, 267: 13210-13216) confer severe, intermediate, and mild phenotypic characteristics, respectively. These mutations attenuate the intrinsic tyrosine kinase activity of the receptor to different degrees and are models for the effect of modulation of c-kit activity. A c-kit mediated disease or condition includes a disease or condition for which c-kit and/or mutant c-kit inhibition provides a therapeutic benefit, e.g. wherein treatment with c-kit inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. As used herein, mutant c-kit, kit or KIT includes kit having one or more of the mutations selected from D816F, D816H, D816N, D816Y, D816V, K642E, Y823D, Del 550-558, Del 557-561, N822K, V654A, N822H, Del 550-558+V654A, Del 557-561+V654A, Ins503AY, V560G, 558NP, Del 557-558, Del W559-560, F522C, Del 579, R634W, K642E, T801I, C809G, D820Y, N822K, N822H, Y823D, Y823C and T670I. In some instances, KIT mutations include D816F, D816H, D816N, D816Y, D816V, T670I and V654A. In other instances, KIT mutations include D816V and or V560G.

[0084] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( ³ H), iodine- 125 ( ¹²⁵ I), carbon- 14 ( ¹⁴ C), carbon- 11 ( ^U C) or fluorine- 18 ( ¹⁸ F). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0085] The term "deuterated" as used herein alone or as part of a group, means substituted deuterium atoms. When a particular position is designated as holding deuterium (stated as "D" or "deuterium"), it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).

[0086] The term "deuterated analog" as used herein alone or as part of a group, means substituted deuterium atoms in place of hydrogen. The deuterated analog of the disclosure may be a fully or partially deuterium substituted derivative. Preferably the deuterium substituted compound of the disclosure holds a fully or partially deuterium substituted alkyl, aryl or heteroaryl group. In one embodiment, the deuterium substituted compound of the disclosure holds a fully or partially deuterium substituted alkyl group, e.g., -CD ₃ , CD ₂ CD ₃ , -CD ₂ CD ₂ CD ₃ (n-propyl-D7), -CD(CD ₃ ) ₂ (iso-propyl-D7), -CD ₂ CD ₂ CD ₂ CD ₃ (n-butyl-D9), -CD ₂ -CD(CD ₃ ) ₂ (iso-butyl-D9) and the like. In another embodiment, the deuterium substituted compound of the disclosure holds a fully or partially deuterium substituted aryl, such as phenyl, e.g., C ₆ D ₅ or a fully or partially deuterium substituted heteroaryl, e.g., pyrazoly-d ₂ , thiazoly-d ₂ , pyridyl-d ₃ , and the like.

[0087] As used herein in connection with amino acid or nucleic acid sequence, the term "isolate" indicates that the sequence is separated from at least a portion of the amino acid and/or nucleic acid sequences with which it would normally be associated.

[0088] In connection with amino acid or nucleic sequences, the term "purified" indicates that the subject molecule constitutes a significantly greater proportion of the biomolecules in a composition than the proportion observed in a prior composition, e.g., in a cell culture. The greater proportion can be 2- fold, 5-fold, 10-fold, or more than 10-fold, with respect to the proportion found in the prior composition.

[0089] The disclosure also embraces isotopically-labeled compounds of the present disclosure which are identical to those recited herein, 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. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ^U C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ C1, and ¹²⁵ I. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition or its isotopes, such as deuterium (D) or tritium ( ³ H). Certain isotopically-labeled compounds of the present disclosure (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) and fluorine- 18 ( ¹⁸ F) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage

requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

II. General

[0090] The present disclosure concerns compounds of Formulas (Γ), (I), (II), (III), (IV), (V) or (V) and all sub-generic formulae, compounds as recited in the claims, and compounds described herein that are modulators of protein kinases, for example without limitation, the compounds are modulators of wild type KIT and/or mutant forms of KIT protein kinases and the use of such compounds in the treatment of diseases or conditions.

III. Compounds

[0091] In one aspect, the present disclosure provides compounds of formula (Γ):

or pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers thereof; wherein the variables and substituents are as defined in the Summary.

[0092] In some embodiments of compounds of formula (Γ), the compounds have molecular weights less than 600. In some preferred embodiments, the compounds have molecular weights less than 500. In other preferred embodiments, the compounds have molecular weights less than 450. In other preferred embodiments, the compounds have molecular weights less than 400. In yet other preferred

embodiments, the compounds have molecular weights less than 350. In still other preferred

embodiments, the compounds have molecular weights less than 300.

[0093] In some embodiments of compounds of formula (Γ), G is an optionally substituted aryl or an optionally substituted 5- or 6-membered heteroaryl having from one to three nitrogen atoms as ring members, wherein the aryl or heteroaryl is optionally fused with an optionally substituted 5 to 8- membered ring having from 0-2 heteroatoms as ring members selected from O, N or S. R ¹ and R ² are taken together to form an optionally substituted aryl or an optionally substituted 5- or 6-membered fused heteroaryl ring having from 0-3 heteroatoms as ring members selected from N, O or S, wherein one or two ring carbon atoms are optionally replaced by -C(=0)-.

[0094] In some embodiments of compounds of formula (Γ), the disclosure provides compounds having formula (I):

or pharmaceutically acceptable salts, hydrates, solvates, tautomers and isomers thereof; wherein:

R ¹ and R ² are taken together to form an optionally substituted 5- or 6-membered fused ring having from 0-3 heteroatoms as ring members selected from N, O or S, wherein one or two ring carbon atoms are optionally replaced by -C(=0)-; or

(ii) R ¹ is H, halogen, C _w alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl or a lone pair of electrons and R ² is -NH-L ² -R ⁶ , wherein R ⁶ is H, optionally substituted aryl, optionally substituted aryl-Ci_ ₄ alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl-Ci_4 alkyl, optionally substituted heterocycloalkyl, optionally substituted Ci_ ₆ alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkyl-Ci_ ₄ alkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl-Ci_ ₄ alkyl; and wherein L ² is selected from a bond, -C(O)-, -C(0)N(R ^f )-, -S0 ₂ N(R ^f )-, -S0 ₂ -, -C(0)0-, - C(=NR ^f )N(R ^f )-, wherein each R ^f , is independently H or d^alkyl;

R ³ and R ⁴ are each independently selected from H, halogen, d_4 alkyl, Ci_ ₄ haloalkyl, Ci_

4haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, C^alkoxy, R ^s or a lone pair of electrons; or R ³ and R ⁴ are taken together with the atoms to which they are attached form an optionally substituted 5 to 8- membered ring having from 0-2 heteroatoms as ring members selected from O, N or S; wherein R ^s is -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - -C(0)R ^h , -C(S)R ^h , -C(0)OR ^h , -C(S)OR ^h , -S(0)R ^h , -S(0) ₂ R ^h , -C(0)NH R ^h , -C(S)NHR ^h , -C(0)NR ^h R ^h , -C(S)NR ^h R ^h , -S(0) ₂ NHR ^h , -S(0) ₂ NR ^h R ^h , -C(NH)NHR ^h , -C(NH)NR ^h R ^h , -N HC(0)R ^h , -NHC(S)R ^h , -NR ^h C(0)R ^h , -NR ^h C(S)R ^h , -NHS(0) ₂ R ^h , -NR ^h S(0) ₂ R ^h , -NHC(0)NHR ^h , -NHC(S) -NR ^h C(0)NH ₂ , -NR ^h C(S)NH ₂ , -NR ^h C(0)NHR ^h , -NR ^h C(S)NHR ^h , -NHC(0)NR ^h R ^h , -NHC(S)NR ^h R ^h , -NR ^h C(0)NR ^h R ^h , -NR ^h C(S)NR ^h R ^h , -NHS(0) ₂ NHR ^h , -NR ^h S(0) ₂ NH ₂ , -NR ^h S(0) ₂ NHR ^h , -NHS(0) ₂ NR ^h R ^h , -NR ^h S(0) ₂ NR ^h R ^h , -NHR ^h or -NR ^h R ^h , wherein each R ^h is independently H or C^alkyl; In certain instances, R ³ and R ⁴ are not simultaneously hydrogen; L ¹ is selected from -C(0)NR ⁵ -, -CH ₂ N(R ⁵ )-, -S0 ₂ N(R ⁵ )-, -N(R ⁵ )C(0)N(R ⁵ )-, -N(R ⁵ )S0 ₂ - , -N(R ⁵ )CH ₂ -, -OCi_ ₄ alkylene-, -Ci_ ₄ alkylene-0-, -C(O)-, -NR ⁵ C(0)-, -S0 ₂ -, -SON(R ⁵ )- or -S(O)-, wherein each R ⁵ is independently H or

Y ¹ is N or C;

Y ² is N or optionally substituted =C-;

Y ³ is N or CH; with the proviso that Y ¹ , Y ² and Y ³ are not simultaneously N;

Z ¹ is N or CH;

Z ³ is N, C or CH;

Z 2 and Z 4 are each independently N or C, with the proviso that Z 1 , Z 2 , Z 3 and Z 4 are not simultaneously N; and

is a single or a doubl ome embodiments of compounds of Formula (I), Z ² and Z ³ are C.

tances, moiety in compounds of formula (I) can exist in a tautomeric form: , where the wavy line indicates the point of attachment to the rest of the molecule.

[0095] In some embodiments of compounds of Formula (I), Z ¹ is N, Z ² , Z ³ and Z ⁴ are C. In other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is C, Z ³ and Z ⁴ are N. In yet other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is C, Z ³ is CH and Z ⁴ is N. In still other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is C, Z ³ is N and Z ⁴ is C. In other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is N, Z ³ is N and Z ⁴ is C. In other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is N, Z ³ is CH and Z ⁴ is N. In other embodiments of compounds of Formula (I), Z ¹ is N, Z ² is N, Z ³ and Z ⁴ are C. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² , Z ³ and Z ⁴ are C. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is C, Z ³ is N and Z ⁴ is C. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is C, Z ³ is C and Z ⁴ is N. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is C, Z ³ and Z ⁴ are N. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is N, Z ³ is C and Z ⁴ is C. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is N, Z ³ is N and Z ⁴ is C. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² is N, Z ³ is CH and Z ⁴ is N. In other embodiments of compounds of Formula (I), Z ¹ is CH, Z ² , Z ³ and Z ⁴

1 2 3 1 2 1 3 4

are N. All the other variables and substituents Y , Y , Y , R , R , L , R and R are as defined in any of the subgeneric formulas of formula (I) or in any the embodiments of compounds of formula (I) as described herein.

[0096] In some embodiments of compounds of Formulas (Γ) or (I), the disclosure provides compounds of Formula (II):

The variables Y , Y , Y , R , R , Z ¹ , L , R and R^ are as defined in any of the embodiments of compounds of Formulas (Γ), (I) or (IV), or any of the subgeneric formulas of Formulas (Γ (I), (II) or

(IV). In one instance, Z ¹ is N. In another instance, Z ¹ is CH. In certain instances, moiety in

compounds of formula (II) exist in a tautomeric form: , where the wavy line indicates the point of attachment to the rest of the molecule.

[0097] In some embodiments of compounds of Formulas (Γ), (I) or (II), L ¹ is selected from -C(0)NR ⁵ - , -CH ₂ N(R ⁵ )-, -S0 ₂ N(R ⁵ )-, -N(R ⁵ )C(0)N(R ⁵ )-, -N(R ⁵ )S0 ₂ -, -N(R ⁵ )CH ₂ -, -OCi_ ₄ alkylene-, -Ci_ ₄ alkylene- 0-, -C(O)-, -S0 ₂ -, -SON(R ⁵ )- or -S(O)-. In other embodiments, L ¹ is selected from -C(0)N(R ⁵ )-, - S0 ₂ N(R ⁵ )-, -C(O)-, -S0 ₂ -, -CH ₂ 0-, -CH ₂ N(R ⁵ )- or -SON(R ⁵ )-. In other embodiments, L ¹ is C(0)N(R ⁵ )-. In yet other embodiments, L ¹ is -C(0)NH- or -S0 ₂ NH-. In one embodiment, L ¹ is -C(0)NH-. In certain instances, R ⁵ is H. In other instances, R ⁵ is Ci_ ₄ alkyl. In yet other instances, R ⁵ is H, or Ci_ ₄ haloalkyl. In one instance, R ⁵ is H, -CH ₃ , -CHF ₂ , -CH ₂ F or -CF ₃ . All the other variables and

1 2 3 1 2 1 2 3 4 3 4

substituents Y , Y Y R , R", Z ¹ , Z Z ΖΓ, R ^J and R" are as defined in any of the subgeneric formulas of formulas (Γ), (I) or (II) or in any of the embodiments of compounds of formulas formula (Γ), (I) or (II) as described herein.

[0098] In some embodiments of compounds of Formulas (Γ), (I) or (II), L ¹ is -NHS0 ₂ -, -S0 ₂ NH- , -NHC(0)NH-, -NHC(O)-, -CH ₂ 0-, -OCH ₂ -, -C(0)NH-, -S0 ₂ -, -C(0)0-, -C(O)-, -C(=NH)NH- or -NHC(=NH)-. In certain embodiments, L ¹ is -NHS0 ₂ -, -S0 ₂ NH-, -NHC(0)NH-, -NHC(O)-, - C(0)NH-, -S0 ₂ -, -C(0)0-, -OC(O)-, -C(O)- or -C(=NH)NH-. In certain instances, L ¹ is -NHS0 ₂ -, - S0 ₂ NH-, -NHC(0)NH- or -NHC(O)-. In other instances, L ¹ is -C(0)NH-, -S0 ₂ -, -S0 ₂ NH-, -C(0)0- or - C(O)-. In other instances, L ¹ is -NHS0 ₂ - or -S0 ₂ NH-. In yet other instances, L ¹ is -C(0)NH-, -NHS0 ₂ - , -S0 ₂ NH- or -C(=NH)NH-. In still other instances, L ¹ is -NHS0 ₂ -, -S0 ₂ NH- or -S0 ₂ -. In other instances, L ¹ is -NH-C(O)-. All the other variables and substituents Y ¹ , Y ² , Y ³ , R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , R ³ and R ⁴ are as defined in any of the embodiments as described herein.

[0099] In some embodiments of compounds of Formulas (Γ), (I) (II), the disclosure provides compounds of Formula (III):

1 2 3 1 2 3 4 1

The variables Y , Y Y R , R R R ^* and L are as defined in any of the embodiments of compounds of Formulas (Γ), (I), (II) or (IV) as described herein or in any of the subgeneric formulas of Formulas (Γ), (I), (II) or (IV). In some instances of compounds of formula (III), L ¹ is -C(0)NR ⁵ -, wherein the carbonyl group in L is covalently linked to the pyrazole ring and the nitrogen atom in L is covalently bonded to the 6-membered aromatic ring in formula (III).

[0100] In some embodiments of compounds of formulas (Γ), (I), (II) or (III), R ¹ and R ² taken together with the atoms to which they attach form an optionally substituted 5- or 6-membered fused heterocyclic aromatic ring having from 1-3 heteroatoms as ring members selected from O, N or S; or an optionally substituted fused benzene ring. In some instances, the substituents for the fused aromatic ring are R ⁷ groups as defined in any of the embodiments of compounds of formula (Γ), (I), (II), (III), (IV) as described herein or in any of the subgeneric formulas of Formulas (Γ), (I), (II), (III) or (IV).

[0101] In some embodiments of compounds of formula (Γ), the disclosure provides compounds having formula (I'a):

The substituent G is as defined in any of the embodiments of compounds of formula (Γ). R ⁵ is H, Ci_ ₄ alkyl or Ring A is a 5- or 6-membered fused heterocyclic aromatic ring having from 1-3 heteroatoms as ring members selected from O, N or S; or a fused benzene ring; each R ⁷ is independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, -X^aryl, aryl-Ci_ ₄ alkyl-X ¹ -, heteroaryl-X ¹ -, heteroaryl-C _w alkyl-X ¹ -, Cs-ecycloalkyl-X ¹ -, C ₃ - ₆ cycloalkyl-Ci_ ₄ alkyl-X ¹ -, C ₃ . scycloalkenyl-X ¹ -, CH ₂ =CH-X ¹ , Cs-ecycloalkyl-C^alkenyl-X ¹ , Cs-ecycloalkyl-C^alkynyl-X ¹ , heterocyclyl-X ¹ -, heterocyclyl-C^alkyl-X ¹ - or R ⁸ , wherein R ⁸ is selected from halogen, CN, -OH, - NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^a , -SR ^a , -OC(0)R ^a , -OC(S)R ^a , -C(0)R ^a , -C(S)R ^a , -C(0)OR ^a , -C(S)OR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -C(0)NHR ^a , -C(S)NHR ^a , -C(0)NR ^a R ^a , -C(S)NR ^a R ^a , -S(0) ₂ NHR ^a , -S(0) ₂ NR ^a R ^a , -C(NH)NHR ^a , -C(NH)NR ^a R ^a , -NH C(0)R ^a , -NHC(S)R ^a , -NR ^a C(0)R ^a , -NR ^a C(S)R ^a , -NHS(0) ₂ R ^a , -NR ^a S(0) ₂ R ^a , -NHC(0)NHR ^a , -NHC(S)N HR ^a , -NR ^a C(0)NH ₂ , -NR ^a C(S)NH ₂ , -NR ^a C(0)NHR ^a , -NR ^a C(S)NHR ^a , -NHC(0)NR ^a R ^a , -NHC(S)NR ^a R ^a , -NR ^a C(0)NR ^a R ^a , -NR ^a C(S)NR ^a R ^a , -NHS(0) ₂ NHR ^a , -NR ^a S(0) ₂ NH ₂ , -NR ^a S(0) ₂ NHR ^a , -NHS(0) ₂ NR ^a R ^a , - NR ^a S(0) ₂ NR ^a R ^a , -NHR ^a or -NR ^a R ^a , wherein each R ^a is independently selected from Ci_ ₆ alkyl, aryl, aryl- Ci_ ₂ alkyl, C3_ ₆ cycloalkyl, C3_ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heteroaryl-Ci_ ₄ alkyl, heterocycloalkyl or wherein each R ^a is further optionally substituted with 1-3 R ^b substituents independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, halogen, d_6 haloalkyl or Ci_ ₆ haloalkoxy; wherein X ¹ is a bond or -C(O)- and wherein R ⁷ is optionally substituted with from 1-5 R ⁹ members selected from halogen, -CH=CH ₂ , CN, -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^c , -SR ^C , -OC(0)R ^c , -OC(S)R ^c , -P(=0)HR ^c , -P(=0)R ^c R ^c , -PH(=0)OR ^c , -P(=0)(OR ^c ) ₂ , - OP(=0)(OR ^c ) ₂ , -C(0)R ^c , -C(S)R ^C , -C(0)OR ^c , -C(S)OR ^c , -S(0)R ^c , -S(0) ₂ R ^c , -C(0)NHR ^c , -C(S)NHR ^C , -C (0)NR ^c R ^c , -C(S)NR ^C R ^C , -S(0) ₂ NHR ^c , -S(0) ₂ NR ^c R ^c , -C(NH)NHR ^C , -C(NH)NR ^C R ^C , -NHC(0)R ^c , -NHC(S) R ^c , -NR ^c C(0)R ^c , -NR ^C C(S)R ^C , -NHS(0) ₂ R ^c , -NR ^c S(0) ₂ R ^c , -NHC(0)NHR ^c , -NHC(S)NHR ^C , -NR ^c C(0)NH ₂ , -NR ^C C(S)NH ₂ , -NR ^c C(0)NHR ^c , -NR ^C C(S)NHR ^C , -NHC(0)NR ^c R ^c , -NHC(S)NR ^C R ^C , -NR ^c C(0)NR ^c R ^c , - NR ^C C(S)NR ^C R ^C , -NHS(0) ₂ NHR ^c , -NR ^c S(0) ₂ NH ₂ , -NR ^c S(0) ₂ NHR ^c , -NHS(0) ₂ NR ^c R ^c , -NR ^c S(0) ₂ NR ^c R ^c , - NHR ^C , R ^c or -NR ^C R ^C , wherein each R ^c is independently selected from Ci_ ₆ alkyl, aryl, aryl-Ci_ ₂ alkyl, C3_ ₆ cycloalkyl, C3_ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heteroaryl-Ci_ ₄ alkyl, heterocycloalkyl or

heterocycloalkyl-Ci^alkyl, wherein each R ^c is further optionally substituted with from 1-3 R ^d groups independently selected from CN, -OH, -N(R ^e )(R ^e ), -N0 ₂ , -C(0)OH, -P(=0)HR ^e , -P(=0)R ^e R ^e , - PH(=0)OR ^e , -P(=0)(OR ^e ) ₂ , -OP(=0)(OR ^e ) ₂ , -

C(0)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -C(NH)NH ₂ , -OC(0)R ^e , -OC(S)R ^e , -C(0)R ^e , -C(S)R ^e , -C(0)OR ^e , - S(0) ₂ R ^e , -C(0)NHR ^e , Ci_ ₆ alkyl, Ci_ ₆ alkoxy, halogen, d_6 haloalkyl or Ci_ ₆ haloalkoxy, wherein each R ^e is independently Ci_ ₆ alkyl; or two adjacent R ⁷ substituents together with the atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic ring or heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S;

Y ² is C-R ¹⁰ , wherein R ¹⁰ is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl- Ci_4 alkyl-, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci^alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1-5 R ⁹ groups or 1-5 R ^c groups or 1-5 R ^d groups or 1-5 R ^e groups; wherein X ² is Q_ ₄ alkylene, -0-, -S- or -NH-; Y ¹ is N or C; and the subscript m is 0, 1 or 2. In some embodiments, R ¹⁰ is H. In some embodiments, R ¹⁰ is H, halogen, Ci_ ₂ alkoxy, CN, NH ₂ , Ci_ ₂ alkylNH, (Ci_ ₂ alkyl) ₂ N. In some embodiments, R ¹⁰ is Ci_ ₄ alkyl, halogen, -NH ₂ , -CN, -OCH ₃ , CF ₃ , CN, -OCF ₃ , -CHF ₂ , -CH ₂ F, - OCH ₂ F or -OCHF ₂ . In other embodiments, R ¹⁰ is In other embodiments, R ⁷ is Ci_4 alkyl, halogen, -CN, -OCH ₃ , CF ₃ , CN, -OCF ₃ , -CHF ₂ , -CH ₂ F, -OCH ₂ F or -OCHF ₂ . In other embodiments, R ⁷ is Ci_ ₄ alkyl. In some embodiments, the subscript m is 0, 1, 2 or 3. In one embodiment, Y ¹ is N or C. In another embodiment, Y ³ is CH.

[0102] In some embodiments, the variables and substituents G, Y ¹ , Y ² , Y ³ , A, R ⁷ and the subscript m are as defined in any of the subgeneric formulas of (Γ), (I'a) or (IV), or any of the embodiments of compounds of formula (IV). In any of the embodiments of compounds of formulas (I'a), the hydrogen atoms in G are optionally replaced by 1 to 12, or 1 to 8, or 1 to 6, or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12 deuterium atoms with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. In certain embodiments, each hydrogen atom in G is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium.

[0103] In some embodiments of compounds of formulas (Γ) or (I'a), G is an optionally substituted Q alkyl. In other embodiments, G is an optionally substituted aryl or an optionally substituted 5- or 6- membered heteroaryl having one or more nitrogen atoms as ring members, wherein the aryl or heteroaryl is optionally fused with an optionally substituted 5 to 8-membered ring having from 0-2 heteroatoms as ring members selected from O, N or S. In certain instances, the alkyl or aromatic portion of G is optionally substituted with 1-3 R ⁷ ; or 1 -3 R ⁸ ; or 1-3 R ⁹ ; or 1 -3 R ^a ; or 1 -3 R ^c ; or 1 -3 R ^d ; or 1-3 R ^s substituents. In other instances, the alkyl or aromatic portion of G is optionally substituted with from 1 - 3 R ²¹ groups selected from halogen, Ci alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, Ci_ ₄ alkoxy, -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^; , -SR ^; , -OC(0)R, -OC(S)R ^; , -C(0)R ^; , -C(S)R, -C(0)OR, -C(S)OR ^; , -S(0)R ^; , -S(0) ₂ R ^; , -C(0)NHR ^; , - C(S)NHR ^; , -C(0)NRR, -C(S)NR ^; R, -S(0) ₂ NHR ^; , -SCO^NR^, -C(NH)NHR ^; , -0(ΝΗ)Ν^^, -NHC(O) R ^; , -NHC(S)R, -NRC(0)R ^; , -NRC(S)R, -NHS(0) ₂ R, -NRS(0) ₂ R, -NHC(0)NHR ^; , -NHC(S)NHR, -N ^0(0)ΝΗ ₂ , -NRC(S)NH ₂ , -Ν^Ο(0)ΝΗ^, -NRt^NHR^ -ΝΗΟ(0)Ν^^, -NHC(S)NRR, -NRC(O) NR'R, -NRC^NR , -ΝΗ8(0) ₂ ΝΗ^, -NRS(0) ₂ NH ₂ , -Ν^8(0) ₂ ΝΗ^, -ΝΗ8(0) ₂ Ν^, -NRS(0) ₂ NR 'R', -NHR ¹ or -NR'R ¹ , wherein R is Ci_ ₂ alkyl or optionally substituted phenyl.

[0104] In some embodiments of compounds of formula (Γ) or (I'a), G is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, lH- l ,2,4-triazol-5-yl, lH- l ,2,4-triazol-3-yl, lH- l ,2,5-triazol-3-yl, lH-5-pyrazolyl, 1H-4- pyrazolyl, lH l-3-yl, lH-indazol-4-yl, lH-indazol-5-

yl, lH-indazo of which is optionally substituted with from 1 -3 R ²² groups independently selected from halogen, Ci_ ₄ alkyl, Q^haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, Ci_ ₄ alkoxy or R ^s ; or 1 -3 R ^s groups, wherein the hydrogen atoms in R ²² are optionally replaced with from 1 -8 deuterium atoms. In some embodiments, G is 2-pyridyl, 3- pyridyl or 4-pyridyl, each of which is optionally substituted with from 1 -3 R ²² groups independently selected from halogen, Q_ ₄ alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, Q_ alkoxy or R ^s ; or 1-3 R ^s groups. In other instances, G is lH-5-pyrazolyl, lH-4-pyrazolyl or 1H-3- pyrazolyl, each of which is optionally substituted with from 1 -3 R ²² groups independently selected from halogen, Ci_ ₄ alkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, Ci_ ₄ alkoxy or R ^s ; or 1 -3 R ^s groups. In yet other instances, G is lH-5-pyrazolyl, which is optionally substituted with from 1 - 3 R ²² groups independently selected from halogen, Ci_ ₄ alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, C^alkoxy or R ^s ; or 1-3 R ^s groups. In some instances, R is -CD ₃ , -C ₆ D ₅ , partially deuterated Ci_ ₆ alkyl or perdeuterated Ci_ ₆ alkyl.

[0105] In some embodiments of compounds of Formulas (Γ), (I'a), (I), (II) or (III), the disclosure provides compounds of Formula (IV):

ring A is a 5- or 6-membered fused heterocyclic aromatic ring having from 1-3 heteroatoms as ring members selected from O, N or S; or a fused benzene ring;

each R ⁷ is independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, -X^aryl, alkyl-X ¹ -, Cs-ecycloalkyl-X ¹ -, C3_ ₆ cycloalkyl-Ci_ ₄ alkyl- X ¹ -, Cs-ecycloalkenyl-X ¹ -, CH ₂ =CH-X ¹ , Cs-ecycloalkyl-C^alkenyl-X ¹ , Cs-ecycloalkyl-C^alkynyl-X ¹ , heterocyclyl-X ¹ -, heterocyclyl-Ci_ ₄ alkyl-X ¹ - or R ⁸ , wherein R ⁸ is selected from halogen, CN, -OH, - NH ₂ , -NO ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^a , -SR ^a , -OC(0)R ^a , -OC(S)R ^a , -C(0)R ^a , -C(S)R ^a , -C(0)OR ^a , -C(S)OR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -C(0)NHR ^a , -C(S)NHR ^a , -C(0)NR ^a R ^a , -C(S)NR ^a R ^a , -S(0) ₂ NHR ^a , -S(0) ₂ NR ^a R ^a , -C(NH)NHR ^a , -C(NH)NR ^a R ^a , -NH C(0)R ^a , -NHC(S)R ^a , -NR ^a C(0)R ^a , -NR ^a C(S)R ^a , -NHS(0) ₂ R ^a , -NR ^a S(0) ₂ R ^a , -NHC(0)NHR ^a , -NHC(S)N HR ^a , -NR ^a C(0)NH ₂ , -NR ^a C(S)NH ₂ , -NR ^a C(0)NHR ^a , -NR ^a C(S)NHR ^a , -NHC(0)NR ^a R ^a , -NHC(S)NR ^a R ^a , -NR ^a C(0)NR ^a R ^a , -NR ^a C(S)NR ^a R ^a , -NHS(0) ₂ NHR ^a , -NR ^a S(0) ₂ NH ₂ , -NR ^a S(0) ₂ NHR ^a , -NHS(0) ₂ NR ^a R ^a , - NR ^a S(0) ₂ NR ^a R ^a , -NHR ^a or -NR ^a R ^a , wherein each R ^a is independently selected from d_ ₆ alkyl, aryl, aryl- Ci_ ₂ alkyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heteroaryl-Ci_ ₄ alkyl, heterocycloalkyl or heterocycloalkyl-Ci^alkyl, wherein each R ^a is further optionally substituted with 1-3 R ^b substituents independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, halogen, d_6 haloalkyl or Ci_ ₆ haloalkoxy; wherein X ¹ is a bond or -C(O)- and wherein R ⁷ is optionally substituted with from 1-5 R ⁹ members selected from halogen, -CH=CH ₂ , CN, -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^c , -SR ^C , -OC(0)R ^c , -OC(S)R ^c , -P(=0)HR ^c , -P(=0)R ^c R ^c , -PH(=0)OR ^c , -P(=0)(OR ^c ) ₂ , - OP(=0)(OR ^c ) ₂ , -C(0)R ^c , -C(S)R ^C , -C(0)OR ^c , -C(S)OR ^c , -S(0)R ^c , -S(0) ₂ R ^c , -C(0)NHR ^c , -C(S)NHR ^C , -C (0)NR ^c R ^c , -C(S)NR ^C R ^C , -S(0) ₂ NHR ^c , -S(0) ₂ NR ^c R ^c , -C(NH)NHR ^C , -C(NH)NR ^C R ^C , -NHC(0)R ^c , -NHC(S) R ^c , -NR ^c C(0)R ^c , -NR ^C C(S)R ^C , -NHS(0) ₂ R ^c , -NR ^c S(0) ₂ R ^c , -NHC(0)NHR ^c , -NHC(S)NHR ^C , -NR ^c C(0)NH ₂ , -NR ^C C(S)NH ₂ , -NR ^c C(0)NHR ^c , -NR ^C C(S)NHR ^C , -NHC(0)NR ^c R ^c , -NHC(S)NR ^C R ^C , -NR ^c C(0)NR ^c R ^c , - NR ^C C(S)NR ^C R ^C , -NHS(0) ₂ NHR ^c , -NR ^c S(0) ₂ NH ₂ , -NR ^c S(0) ₂ NHR ^c , -NHS(0) ₂ NR ^c R ^c , -NR ^c S(0) ₂ NR ^c R ^c , - NHR ^C , R ^c or -NR ^C R ^C , wherein each R ^c is independently selected from Ci_ ₆ alkyl, aryl, aryl-Ci_ ₂ alkyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heteroaryl-Ci_ ₄ alkyl, heterocycloalkyl or

wherein each R ^c is further optionally substituted with from 1-3 R ^d groups independently selected from CN, -OH, -N(R ^e )(R ^e ), -N0 ₂ , -C(0)OH, -

C(0)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -C(NH)NH ₂ , -P(=0)HR ^e , -P(=0)R ^e R ^e , -PH(=0)OR ^e , -

P(=0)(OR ^e ) ₂ , -

OP(=0)(OR ^e ) ₂ , -OC(0)R ^e , -OC(S)R ^e , -C(0)R ^e , -C(S)R ^e , -C(0)OR ^e , -S(0) ₂ R ^e , -C(0)NHR ^e , C^aUcyl, d_ ₆ alkoxy, halogen, Ci_ ₆ haloalkyl or Ci_ ₆ haloalkoxy, wherein each R ^e is independently Ci_ ₆ alkyl; or two adjacent R ⁷ substituents together with the atoms to which they are attached form a 4-, 5- or 6-membered carbocyclic ring or heterocyclic ring having from 1 -2 heteroatoms as ring members selected from O, N or S;

Y ² is C-R ¹⁰ , wherein R ¹⁰ is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C ₃ _ ₆ cycloalkyl-Ci^alkyl-, C ₃ _ ₆ cycloalkenyl-Ci^alkyl-, CH ₂ =CH-X ² -, C ₃ _

6cycloalkyl-C ₂ _ ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups or 1 -5 R ^c groups or 1 -5 R ^d groups or 1-5 R ^e groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-; Y ¹ is N or C; and the subscript m is 0, 1 or 2. In some embodiments, R ¹⁰ is H. In other embodiments, R ¹⁰ is H, halogen, Ci_ ₄ alkyl, Ci_ ₂ alkoxy, CN, NH ₂ , Ci_ ₂ alkylNH, (Ci_ ₂ alkyl) ₂ N. In other embodiments, R ¹⁰ is Ci_ ₄ alkyl, halogen, -CN, -NH ₂ , -OCH ₃ , CF ₃ , CN, - OCF ₃ , -CHF ₂ , -CH ₂ F, -OCH ₂ F or -OCHF ₂ . In other embodiments, R ¹⁰ is Ci_ ₄ alkyl. In other

embodiments, R ⁷ is C _iA alkyl, halogen, -CN, -OCH ₃ , CF ₃ , CN, -OCF ₃ , -CHF ₂ , -CH ₂ F, -OCH ₂ F or - OCHF ₂ . In other embodiments, R ⁷ is Ci_ ₄ alkyl. In one embodiment, Y ¹ is C. In one embodiment, Y ³ is CH.

[0106] In some embodiments of compounds of formula (IV) or (I'a), the subscript m is 1 or 2 and all the other substituents of formula (IV) are as defined in any of the embodiments described herein. In one instance, the subscript m is 1. In another instance, the subscript m is 2. In yet another instance, the subscript m is 0. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and R ⁷ of formula (IV) are as defined in any of the embodiments described herein.

[0107] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is independently selected from Ci_ ₆ alkyl, deuterated Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, -X^aryl, aryl-C^alkyl-X ¹ -,

heteroaryl-X ¹ -, heteroaryl-Ci_4 alkyl-X ¹ -, Cs-ecycloalkyl-X ¹ -, Cs-ecycloalkenyl-X ¹ -, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-X ¹ -, heterocyclyl-X ¹ -, heterocyclyl-Ci_ ₄ alkyl-X ¹ -, CH^CH-X ¹ , Cs-ecycloalkyl-C^alkenyl-X ¹ , C ₃ . ₆ cycloalkyl-C ₂ _ ₄ alkynyl-X ¹ , halogen, CN, -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^a , -SR ^a , -OC(0)R ^a , -OC(S)R ^a , -C(0)R ^a , -C(S)R ^a , -C(0)OR ^a , -C(S)OR ^a , -S(0)R ^a , -S(0) ₂ R ^a , -C(0)NHR ^a , -C(S)NHR ^a , -C(0)NR ^a R ^a , -C(S)NR ^a R ^a , -S(0) ₂ NHR ^a , -S(0) ₂ NR ^a R ^a , -C(NH)NHR ^a , -C(NH)NR ^a R ^a , -NH C(0)R ^a , -NHC(S)R ^a , -NR ^a C(0)R ^a , -NR ^a C(S)R ^a , -NHS(0) ₂ R ^a , -NR ^a S(0) ₂ R ^a , -NHC(0)NHR ^a , -NHC(S)N HR ^a , -NR ^a C(0)NH ₂ , -NR ^a C(S)NH ₂ , -NR ^a C(0)NHR ^a , -NR ^a C(S)NHR ^a , -NHC(0)NR ^a R ^a , -NHC(S)NR ^a R ^a , -NR ^a C(0)NR ^a R ^a , -NR ^a C(S)NR ^a R ^a , -NHS(0) ₂ NHR ^a , -NR ^a S(0) ₂ NH ₂ , -NR ^a S(0) ₂ NHR ^a , -NHS(0) ₂ NR ^a R ^a , - NR ^a S(0) ₂ NR ^a R ^a , -NHR ^a or -NR ^a R ^a , wherein each R ^a is independently C^ancyl, aryl, aryl-C^alkyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heteroaryl-Ci_ ₄ alkyl, heterocycloalkyl or heterocycloalkyl-Ci^alkyl, wherein each R ^a is further optionally substituted with 1-3 R ^b substituents independently selected from Ci_ ₆ alkyl, -OCH ₃ , -OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , - OCF ₃ , -OCHF ₂ or -OCH ₂ F; wherein X ¹ is a bond or -C(O)- and wherein the aliphatic or aromatic portion of R ⁷ is optionally substituted with from 1-5 R ⁹ members selected from halogen, CN, -OH, -NH ₂ , - N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^c , -SR ^C , -P(=0)HR ^c , -P(=0)R ^c R ^c , -PH(=0)OR ^c , -P(=0)(OR ^c ) ₂ , -

OP(=0)(OR ^c ) ₂ , -OC(0)R ^c , -OC(S)R ^c , -C(0)R ^c , -C(S)R ^C , -C(0)OR ^c , -C(S)OR ^c , -S(0)R ^c , -S(0) ₂ R ^c , -C(O) NHR ^C , -C(S)NHR ^C , -C(0)NR ^c R ^c , -C(S)NR ^C R ^C , -S(0) ₂ NHR ^c , -S(0) ₂ NR ^c R ^c , -C(NH)NHR ^C , -C(NH)NR ^C R ^C , -NHC(0)R ^c , -NHC(S)R ^C , -NR ^c C(0)R ^c , -NR ^C C(S)R ^C , -NHS(0) ₂ R ^c , -NR ^c S(0) ₂ R ^c , -NHC(0)NHR ^c , -NHC( S)NHR ^C , -NR ^c C(0)NH ₂ , -NR ^C C(S)NH ₂ , -NR ^c C(0)NHR ^c , -NR ^C C(S)NHR ^C , -NHC(0)NR ^c R ^c , -NHC(S)NR ^C R ^c , -NR ^c C(0)NR ^c R ^c , -NR ^C C(S)NR ^C R ^C , -NHS(0) ₂ NHR ^c , -NR ^c S(0) ₂ NH ₂ , -NR ^c S(0) ₂ NHR ^c , -NHS(0) ₂ NR ^c R ^c , -NR ^c S(0) ₂ NR ^c R ^c , -NHR ^C , R ^c or -NR ^C R ^C , wherein each R ^c is independently Ci_ ₆ alkyl, aryl, aryl-Ci_ ₂ alkyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heteroaryl, heterocycloalkyl or heterocycloalkyl-Ci^alkyl, wherein each R ^c is further optionally substituted with from 1-3 R ^d groups independently selected from CN, -OH, -N(R ^e )(R ^e ), -N0 ₂ , -C(0)OH, - C(0)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -C(NH)NH ₂ , -P(=0)HR ^e , -P(=0)R ^e R ^e , -PH(=0)OR ^e , - P(=0)(OR ^e ) ₂ , -

OP(=0)(OR ^e ) ₂ , -OC(0)R ^e , -OC(S)R ^e , -C(0)R ^e , -C(S)R ^e , -C(0)OR ^e , -S(0) ₂ R ^e , -C(0)NHR ^e , Ci_ ₆ alkyl, Ci_ ₆ alkoxy, halogen, Ci_ ₆ haloalkyl or Ci_ ₆ haloalkoxy, wherein R ^e is Ci_ ₆ alkyl; or two adjacent R ⁷ substituents together with the atom to which they are attached form a 4-, 5- or 6-membered carbocyclic ring or heterocyclic ring having from 1-2 heteroatoms as ring members selected from O, N or S; and the subscript m is 0, 1 or 2. In some instances, X ¹ is a bond. In other instances, X ¹ is -C(O)-. In some instances, R ⁹ is CN, -CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , - OCHF ₂ or -OCH ₂ F, -P(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)0(C _w alkyl), -P(=0)(OC _w alkyl) ₂ , - OP(=0)(OCi_ ₄ alkyl) ₂ , Ci_ ₆ alkyl, phenyl, perdeuterated phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5-oxazolyl, 4-oxazolyl, 2-thiophenyl, 3- thiophenyl, 1 -piperidinyl, 4-piperidinyl or 4-morpholinyl, 4-morpholinylcarbonyl, cyclopropylcarbonyl, 1 -piperazinyl, 4-methyl- 1 -piperazinyl, 1 -pyrrolidinyl, 1 - piperazinylcarbonyl, 1-piperidinylcarbonyl, 1- pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropoxy, dimethylcarbamoyl, acetamido, propanoyl, thiomorpholino, 1 , pyrrolidinyl, methylsofonylamino, methylsulfonyl, propanoylamino, 1 -cyclopentenyl, 1 -cyclohexenyl, l,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6- tetrahydropyridin-5-yl, 2,5-dihydro-lH-pyrrol-3-yl, 2,5-dihydro-pyrrol-l-yl, each of which is optionally substituted with 1-3 groups independently selected from OH, NH ₂ , CN, -CH ₃ , -OCH ₃ , -OCH ₂ CH ₃ , -O- CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, Ci_ ₆ alkyl, 4-morpholinyl, 4- morpholinylcarbonyl, cyclopropyl, cyclopropylmethyl, cyclopropylcarbonyl, 1 -piperazinyl, 4-methyl- 1- piperazinyl, 1 -pyrrolidinyl, 1 - piperazinylcarbonyl, 1 -piperidinylcarbonyl, 1-pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropoxy, acetamido, propanoyl,

methylsofonylamino, methylsulfonyl, propanoylamino, dimethylcarbamoyl or ethoxycarbonylamino. In other instances, R ^a is Ci_ ₆ alkyl, phenyl, perdeuterated phenyl, benzyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5-oxazolyl, 4-oxazolyl, 2-thiophenyl, 3- thiophenyl, 1 -piperidinyl, 4-piperidinyl or 4-morpholinyl, 4-morpholinylcarbonyl, cyclopropylcarbonyl, 1 -piperazinyl, 4-methyl- 1 -piperazinyl, 1 -pyrrolidinyl, 1 - piperazinylcarbonyl, 1 -piperidinylcarbonyl, 1- pyrrolidinylcarbonyl, dimethylamino, 2-(4-morpholinyl)ethoxy, 3-methoxypropoxy, dimethylcarbamoyl, acetamido, propanoyl, thiomorpholino, 1 -pyrrolidinyl, methylsulfonylamino, methylsulfonyl, propanoylamino, 1 -cyclopentenyl, 1 -cyclohexenyl, l,2,3,6-tetrahydropyridin-4-yl, 1,2,3,6- tetrahydropyridin-5-yl, 2,5-dihydro-lH-pyrrol-3-yl, 2,5-dihydro-pyrrol-l-yl, each of which is optionally substituted with 1-3 R ^J groups. In other instances, R ^a , R ^c or R ⁹ is each independently Ci_ ₆ alkyl or Ci_ ₄ alkoxy, each of which is optionally substituted with a member selected from Ci_ ₆ alkyl, methoxy, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-oxazolyl, 5- oxazolyl, 4-oxazolyl, 2-thiophenyl, 3-thiophenyl, 1 -piperidinyl, 4-piperidinyl or 4-morpholinyl. In yet other instances, R ^d is selected from Ci_ ₆ alkyl, -CN, -OCH ₃ , -OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, - CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -NH-Ci_ ₆ alkyl, -N(Ci_ ₆ alkyl)( Ci_ ₆ alkyl). All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments described herein.

[0108] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from halogen, -CN, vinyl-X ¹ , C^alkyl-X ¹ , C^alkoxy-X ¹ , C ₂ _ ₆ alkynyl-X ¹ , C ₃ _ ₆ cycloalkyl-X ¹ , C^cycloalkenyl-X ¹ -, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-X ¹ , C ₃ _6 cycloalkyl-C^alkynyl-X ¹ , aryl-X ¹ , aryl-Ci_ ₄ alkyl-X ¹ , heteroaryl-X ¹ , heteroaryl-Ci_ ₄ alkyl-X ¹ , heterocyclyl-X ¹ , heterocyclyl-C^alkyl, -C(0)-R ^a , -C(0)NHR ^a , - C(0)NR ^a R ^a , -NHC(0)R ^a , -NHC(0)OR ^a , -NHC(0)NHR ^a , -NHC(0)NR ^a R ^a , -NR ^a R ^a , -NHR ^a , -C(0)OR ^a , - OC(0)R ^a , -S0 ₂ R ^a , -NHS0 ₂ R ^a , -NHS0 ₂ NHR ^a , -NHS0 ₂ NR ^a R ^a , -S0 ₂ NHR ^a or -S0 ₂ NR ^a R ^a , wherein at each occurrence R ⁷ is optionally substituted with from 1-4 R ⁹ members. In some instances, each R ⁹ is independently selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, d_6 haloalkoxy, C ₃ _ ₆ cycloalkyl, C ₃ _6 heteroaryl, heteroaryl-Ci_4 alkyl, heterocyclyl or or R ⁸ . In one instance, R ⁷ is H. In other instances, two adjacent R ⁹ substituents on an aromatic ring are taken together to form a 5 or 6-membered ring having from 0-2 heteroatoms selected from O, N or S. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments described herein.

[0109] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from halogen, CN, vinyl, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _6 alkynyl, C ₃ _6 cycloalkyl, C ₃ _ ₆ cycloalkenyl, C ₃ _6 cycloalkyl-Ci_ ₄ alkyl, C ₃ _6 cycloalkyl-C ₂ - ₄ alkynyl, aryl, heteroaryl, heteroaryl-Ci_4 alkyl, heterocycloalkyl, heterocycloalkyl-C^alkyl, -C(0)-R ^a , -C(0)NHR ^a , -C(0)NR ^a R ^a , -NHC(0)R ^a , - NHC(0)OR ^a , -NHC(0)NHR ^a , -NHC(0)NR ^a R ^a , -NR ^a R ^a , -NHR ^a , -C(0)OR ^a , -OC(0)R ^a , -S0 ₂ R ^a , - NHS0 ₂ R ^a , -NHS0 ₂ NHR ^a , -NHS0 ₂ NR ^a R ^a , -S0 ₂ NHR ^a or -S0 ₂ NR ^a R ^a , each of which is optionally independently substituted with from 1 -4 R ⁹ substituents; or optionally independently substituted with from 1 -4 R ^c substituents; or optionally independently substituted with from 1 -4 R ^d substituents; or optionally substituted with from 1 -4 R ¹⁵ substituents selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, Ci_ ₆ haloalkoxy, C3_ ₆ cycloalkyl, heterocycloalkyl-Ci_ ₄ alkyl, - C(0)-R ^c , -C(0)NHR ^c , -C(0)NR ^c R ^c , -NHC(0)R ^c , -P(=0)HR ^c , -P(=0)R ^c R ^c , -PH(=0)OR ^c , - P(=0)(OR ^c ) ₂ , -OP(=0)(OR ^c ) ₂ , -NHC(0)OR ^c , -NHC(0)NHR ^c , -NR ^C R ^C , -NHR ^C , -C(0)OR ^c , -OC(0)R ^c , - OC(0)NHR ^c , -S0 ₂ R ^c , -NHS0 ₂ R ^c , -S0 ₂ NHR ^c or -S0 ₂ NR ^c R ^c ; or optionally independently substituted with from 1 -4 R ¹⁶ substituents selected from Ci_ ₆ alkyl, -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , - OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, 4-morpholinyl, cyclopropyl, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -pyrrolidinylcarbonyl, 1 - piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, methylsulfonyl or methylsulfonylamino. In some instances, R ^c is C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heterocycloalkyl or heterocycloalkyl-Ci^alkyl. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0110] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from aryl, heteroaryl, C ₂ _ ₆ alkynyl, C ₃ _ ₆ cycloalkenyl, heterocycloalkyl, -C(0)-R ^a , -C(0)NHR ^a , - C(0)NR ^a R ^a , -C(0)OR ^a , -S0 ₂ NHR ^a or -S0 ₂ NR ^a R ^a , each of which is optionally substituted with from (i) 1 -4 R ⁹ substituents; or (ii) 1 -4 R ^c substituents; or (iii) 1 -4 R ^d substituents; or (iv) 1 -4 R ¹⁵ substituents selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, Ci_ ₆ haloalkoxy, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl, heterocycloalkyl-Ci_ ₄ alkyl, -C(0)-R ^c , -C(0)NHR ^c , -C(0)NR ^c R ^c , -NHC(0)R ^c , - NHC(0)OR ^c , -NHC(0)NHR ^c , -NR ^C R ^C , -NHR ^C , -C(0)OR ^c , -P(=0)HR ^c , -P(=0)R ^c R ^c , -PH(=0)OR ^c , - P(=0)(OR ^c ) ₂ , -OP(=0)(OR ^c ) ₂ , -OC(0)R ^c , -OC(0)NHR ^c , -S0 ₂ R ^c , -NHS0 ₂ R ^c , -S0 ₂ NHR ^c or -S0 ₂ NR ^c R ^c ; or (v) 1-4 R ¹⁶ groups; or (vi) 1 -4 R ¹⁷ substituents independently selected from Ci_ ₆ alkyl, -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , - OCHF ₂ , -OCH ₂ F, 4-morpholinyl, thiomorpholino, 1 -piperidinyl, cyclopropyl, 1 -cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -piperazinyl, 1 -piperazinylcarbonyl, 1 - pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, methylsulfonyl, methylsulfonylamino, -Ci_ ₂ alkyl-R ^k , -C(0)-R ^k , -C(0)NHR ^k , - C(0)NR ^k R ^k , -NHC(0)R ^k , -P(=0)HR ^k , -P(=0)R ^k R ^k , -PH(=0)OR ^k , -P(=0)(OR ^k ) ₂ , -OP(=0)(OR ^k ) ₂ , - C(0)OR ^k , -OC(0)R ^k , -S0 ₂ R ^k , -NHS0 ₂ R ^k , -S0 ₂ NHR ^k , -S0 ₂ NR ^k R ^k , wherein each R ^k is independently d_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, phenyl or heterocycloalkyl, wherein R ^k is further optionally substituted with from 1-3 R ^d , R ^e or R group; or (vii) 1 -4 R ¹⁸ substituents selected from F, CI, I, -CH ₃ , -OCH ₃ , OCH ₂ CH ₃ , -O- CH(CH ₃ ) ₂ , -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, cyclopropylmethyl, 1 -cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -PH(=0)-Ci_ ₆ alkyl, -P(=0)(C ₁ . ₆ alkyl) ₂ , -PH(=0)0(C ₁ _ ₆ alkyl), -P(=0)(OC ₁ . ₆ alkyl) ₂ , -OP(=0)(OC ₁ . ₆ alkyl) ₂ , -NHS0 ₂ -d_ salkyl, -S0 ₂ NH-Ci_ ₆ alkyl, -NHC(0)-Ci_ ₆ alkyl, -C(0)NH-Ci_ ₆ alkyl, -NHC(0)NH-Ci_ ₆ alkyl, NHC(0)0-Ci_ salkyl, -C(0)-Ci_ ₆ alkyl, -C(0)0-Ci_ ₆ alkyl, -OC(0)-Ci_ ₆ alkyl, -NHS0 ₂ CH ₃ , NH ₂ C(0)-, CH ₃ NHC(0)-, NH ₂ S0 ₂ -, CH ₃ S0 ₂ -, (CH ₃ ) ₂ NC(0)-, CH ₃ C(0)NH-, CH ₃ S0 ₂ NH-, benzyl, benzyl-C(O), (C _M alkyl)OC(0)- , cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-, cyclobutylmethyl-C(O)-, Ph-NH-C(O)-, 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, thiomorpholino, 4-thiomorpholinyl-C(0)-, 4- morpholinyl-C(O)-, 1 -piperidinyl, l -piperidinyl-C(O)-, p-CH ₃ -Ph-S0 ₂ NH-, Ph-S0 ₂ NH-, propyl- S0 ₂ NH-, cyclopropyl-S0 ₂ NH-, cyclobutyl-S0 ₂ NH-, butylS0 ₂ NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -piperazinyl, 1 -piperazinylcarbonyl, 4-methyl- 1 - piperazinylcarbonyl, 1-pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, ethoxycarbonylamino, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2- oxetanyl, 3-oxetanyl, 1 -morpholinylethyl, 3-methoxypropoxy, 2-(4-morpholinyl)ethoxy, 4- morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, wherein at each occurrence, R ¹⁸ is further optionally substituted with from 1 -3 substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-,

CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments of compounds of formulas (I'a) or (IV) as described herein.

[0111] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from aryl, heteroaryl, C ₂ _6 alkynyl, C ₃ _ ₆ cycloalkenyl or heterocycloalkyl, each of which is optionally substituted with (i) 1 -4 R ⁹ substituents; or (ii) 1-4 R ^c substituents; or (iii) 1 -4 R ^d substituents; or (iv) 1 -4 R ¹⁵ substituents; or (v) 1 -4 R ¹⁶ groups; or (vi) 1 -4 R ¹⁷ substituents independently selected from Ci_ ₆ alkyl, - OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, 4-morpholinyl, 1 -piperidinyl, cyclopropyl, 1 -cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -piperazinyl, 1 -piperazinylcarbonyl, 1 - pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, methylsulfonyl, methylsulfonylamino, -Ci_ ₂ alkyl-R ^k , -C(0)-R ^k , -P(=0)HR ^k , - P(=0)R ^k R ^k , -PH(=0)OR ^k , -P(=0)(OR ^k ) ₂ , -OP(=0)(OR ^k ) ₂ , -C(0)NHR ^k , -C(0)NR ^k R ^k , -NHC(0)R ^k , - C(0)OR ^k , -OC(0)R ^k , -S0 ₂ R ^k , -NHS0 ₂ R ^k , -S0 ₂ NHR ^k , -S0 ₂ NR ^k R ^k , wherein each R ^k is independently Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, phenyl or heterocycloalkyl, wherein R ^k is further optionally substituted with from 1 -3 R ^d , R ^e or R group; or (vii) 1 -4 R ¹⁸ substituents selected from F, CI, I, -CH ₃ , -OCH ₃ , OCH ₂ CH ₃ , -O- CH(CH ₃ ) ₂ , -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, 1 -cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHS0 ₂ CH ₃ , NH ₂ C(0)-, CH ₃ NHC(0)-, NH ₂ S0 ₂ -, CH ₃ S0 ₂ -, -PH(=0)-C ₁ _ ₆ alkyl, -P(=0)(C ₁ . ₆ alkyl) ₂ , -PH(=0)(OC ₁ . ₆ alkyl), - P(=0)(OC ₁ . ₆ alkyl) ₂ , -OP(=0)(OC ₁ . ₆ alkyl) ₂ , (CH ₃ ) ₂ NC(0)-, CH ₃ C(0)NH-, CH ₃ S0 ₂ NH-, benzyl, benzyl- C(O), (d^alky OCiO)-, cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-,

cyclobutylmethyl-C(O)-, Ph-NH-C(O)-, 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, 4- morpholinyl-C(O)-, 1 -piperidinyl, l-piperidinyl-C(O)-, p-CH ₃ -Ph-S0 ₂ NH-, Ph-S0 ₂ NH-, propyl- S0 ₂ NH-, cyclopropyl-S0 ₂ NH-, cyclobutyl-S0 ₂ NH-, butylS0 ₂ NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -piperazinyl, 1 -piperazinylcarbonyl, 4-methyl- 1 - piperazinylcarbonyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, 1- pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, ethoxycarbonylamino, 1 -morpholinylethyl, 3-methoxypropoxy, 2-(4- morpholinyl)ethoxy, 4-morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, wherein at each occurrence, R ¹⁸ is further optionally substituted with from 1-3 substituents independently selected from - CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments of compounds of formulas (I'a) or (IV) as described herein.

[0112] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, perdeuterated pyridyl, phenyl, perdeuterated phenyl, 1-pyrazolyl, 3-lH-pyrazolyl, 4-lH-pyrazolyl, vinyl, ethynyl, propynyl, 3-fluoropropynyl, cyclopropyl-ethynyl, cyclobutyl-ethynyl, cyclopentyl-ethynyl, cyclohexyl- ethynyl, 1 -cyclopentenyl- ethynyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 -piperazinyl, 1 - piperidinyl, morpholinyl, l,2,5,6-tetrahydropyridin-4-yl, l,2,5,6-tetrahydropyridin-3-yl, 2,3-dihydro-l,4- benzodioxin-5-yl, l,3-benzodioxol-4-yl, l,3-benzodioxol-5-yl, indanyl, 1 ,2-benzoxazolyl, 1,3- benzoxazolyl, 1 -cyclohexenyl, 1 -cyclopentenyl, 1 -cyclooctenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 5,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H- pyran-3-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 2-pyrazolyl, 3- pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 1,2,3-triazol-l-yl, l,2,3-triazol-2-yl, l,2,3-triazol-3-yl, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl, 1 ,2,4-triazol- 1 -yl, 1 ,2,4-triazol-2-yl, l,2,4-triazol-3-yl, 1 ,2,4-triazol-4-yl, 1 ,2,4-triazol- 5-yl, l-oxa-2,3-diazol-4-yl, l-oxa-2,3-diazol-5-yl, l-oxa-2,4-diazol-3-yl, l-oxa-2,4-diazol-5-yl, 1-oxa- 2,5-diazol-3-yl, l-oxa-2,5-diazol-4-yl, l-thia-2,3-diazol-4-yl, l-thia-2,3-diazol-5-yl, l-thia-2,4-diazol-3- yl, l-thia-2,4-diazol-5-yl, l-thia-2,5-diazol-3-yl, l-thia-2,5-diazol-4-yl, 1 -tetrazolyl, 3-tetrazolyl, 1H-5- tetrazolyl, 3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiophenyl or 3-thiophenyl, each of which is optionally substituted with from (i) 1-4 R ⁹ substituents; or (ii) 1-4 R ^c substituents; or (iii) 1-4 R ^d substituents; or (iv) 1-4 R ¹⁵ substituents selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, Ci_ ₆ haloalkoxy, C ₃ _ ₆ cycloalkyl, C ₃ . ₆ cycloalkyl-C ₁ . ₄ alkyl, heterocycloalkyl-C^alkyl, -C(0)-R ^c , -C(0)NHR ^c , -C(0)NR ^c R ^c , - NHC(0)R ^c , -NHC(0)OR ^c , -NHC(0)NHR ^c , -NR ^C R ^C , -NHR ^C , -C(0)OR ^c , -OC(0)R ^c , -OC(0)NHR ^c , - S0 ₂ R ^c , -NHS0 ₂ R ^c , -S0 ₂ NHR ^c or -S0 ₂ NR ^c R ^c ; or (v) 1-4 R ¹⁶ groups; or (vi) 1-4 R ¹⁷ substituents independently selected from C _L galkyl, -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -OCH ₃ , -OCH ₂ CH ₃ , - 0-CH(CH ₃ ) ₂ , -CI, -F, -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, 4-morpholinyl, thiomorpholino, 1- piperidinyl, cyclopropyl, 1 -cyanocyclopropyl, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 - piperazinyl, 1 -piperazinylcarbonyl, 1 -pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl,

methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, methylsulfonyl,

methylsulfonylamino, -Ci _-2 alkyl-R ^k , -C(0)-R ^k , -C(0)NHR ^k , -C(0)NR ^k R ^k , -NHC(0)R ^k , -C(0)OR ^k , - PH(=0)R ^k , -P(=0)R ^k R ^k , -PH(=0)OR ^k , -P(=0)(OR ^k ) ₂ , -OP(=0)(OR ^k ) ₂ , -OC(0)R ^k , -S0 ₂ R ^k , -NHS0 ₂ R ^k , - S0 ₂ NHR ^k , -S0 ₂ NR ^k R ^k , wherein each R ^k is independently d_ ₆ alkyl, C _3-6 cycloalkyl, phenyl or heterocycloalkyl, wherein R ^k is further optionally substituted with from 1 -3 R ^d , R ^e or R ^J group; or (vii) 1 - 4 R ¹⁸ substituents selected from F, CI, I, -CH ₃ , -OCH ₃ , OCH ₂ CH ₃ , -0-CH(CH ₃ ) ₂ , -OH, -CN, -N0 ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, cyclopropyl, 1 -cyanocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -NHS0 ₂ CH ₃ , NH ₂ C(0)-, CH ₃ NHC(0)-, NH ₂ S0 ₂ -, CH ₃ S0 ₂ -, (CH ₃ ) ₂ NC(0)-, CH ₃ C(0)NH-, CH ₃ S0 ₂ NH-, benzyl, benzyl-C(O), (C^alkyl)OC(O)-, cyclopropyl-C(O)-, cyclopropylethyl-C(O)-, cyclobutyl-C(O)-, cyclobutylmethyl-C(O)-, Ph-NH-C(O)-, thiomropholino, 4- thiomorpholinyl-C(O)-, -PH(=0)-Ci_ ₆ alkyl, -P(=0)(Ci_ ₆ alkyl) ₂ , -PH(=0)(OCi_ ₆ alkyl), -P(=0)(OCi_ ₆ alkyl) ₂ , -OP(=0)(OCi_ ₆ alkyl) ₂ , 4-morpholinyl, 4-morpholinylmethyl, 4-morpholinylethyl, 4- morpholinyl-C(O)-, 1 -piperidinyl, l -piperidinyl-C(O)-, p-CH ₃ -Ph-S0 ₂ NH-, Ph-S0 ₂ NH-, propyl- S0 ₂ NH-, cyclopropyl-S0 ₂ NH-, cyclobutyl-S0 ₂ NH-, butylS0 ₂ NH-, ethoxycarbonyl-NH-, methoxycarbonyl-NH-, cyclopropoxy, cyclopropylmethyl, 1 -pyrrolidinyl, 1 -piperazinyl, 1 -piperazinylcarbonyl, 4-methyl- 1 - piperazinylcarbonyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, 1 - pyrrolidinylcarbonyl, 1 -piperidinylcarbonyl, acetyl, methoxycarbonyl, acetamido, dimethylcarbamoyl, methylcarbamoyl, ethoxycarbonylamino, 1 -morpholinylethyl, 3-methoxypropoxy, 2-(4- morpholinyl)ethoxy, 4-morpholinylmethylcarbonyl or 4-morpholinylethylcarbonyl, wherein at each occurrence, R ¹⁸ is further optionally substituted with from 1 -3 substituents independently selected from - CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In certain embodiments, the hydrogen atoms in R ⁷ are optionally replaced by 1 to 12, or 1 to 8, or 1 to 6, or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12 deuterium atoms with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. In certain embodiments, each hydrogen atom in R ⁷ is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments of compounds of formulas (I'a) or (IV) as described herein.

[0113] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from halogen, -CN, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-4-pyridyl, phenyl, 1-pyrazolyl, 3- 1H- pyrazolyl, 4- lH-pyrazolyl, 1 -methyl-4-pyrazolyl, l ,3-dimethyl-5-pyrazolyl, vinyl, ethynyl, propynyl, 3- fluoropropynyl, cyclopropyl-ethynyl, cyclobutyl- ethynyl, cyclopentyl-ethynyl, cyclohexyl-ethynyl, 1 - cyclopentenyl-ethynyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- cyclopropylethyl, 2-cyclobutylethyl, 1 -methyl- 1 -cyclopropyl, 1 -cyclopropylethyl, 1 -methyl- 1 -cyclobutyl, 1 -cyclobutylethyl, methoxymethoxy, 4-morpholinylmethoxy, 1 -piperidinylmethoxy, 4,4- difluoropiperidinyl, 4-ethoxycarbonyl- 1 -piperazinyl, 1 -piperazinyl, 1 -piperidinyl, 4-morpholinyl, 1 ,2,3,6- tetrahydropyridin-4-yl, 1 ,2,3,6-tetrahydropyridin-5-yl, 1 -cyclopropylcarbonyl-2,3,6-trihydropyridin-4-yl, 2,2,6,6-tetramethyl- 1 ,5-dihydropyridin-4-yl, 2,2,6,6-tetramethyl- 1 ,5-dihydropyridin-3-yl, 1 - cyclopropylcarbonyl-2,3,6-trihydropyridin-5-yl, l -methylsulfonyl-2,3,6-trihydropyridin-4-yl, 1- methylsulfonyl-2,3,6-trihydropyridin-5-yl, 1 -(4-morpholinylcarbonyl)-2,3,6-trihydropyridin-4-yl, 1 -(4- morpholinylcarbonyl)-2,3,6-trihydropyridin-5-yl, 1 -t-butoxycarbonyl-2,3,6-trihydropyridin-4-yl, 1 -t- butoxycarbonyl-2,3,6-trihydropyridin-5-yl, 2,3-dihydro- l,4-benzodioxin-5-yl, l,3-benzodioxol-4-yl, 1 ,3- benzodioxol-5-yl, indanyl, 1 ,2-benzoxazolyl, 1 ,3-benzoxazolyl, 1 -cyclohexenyl, 1 -cyclopentenyl, 1- cyclooctenyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-cyclopropyl-5-pyrimidinyl, 2-cyclopropyl- pyrimidin-5-yl, 2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 5,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-2H- pyran-3-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1 -pyrazolyl, 2-pyrazolyl, 3- pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4- isothiazolyl, 5-isothiazolyl, 1 ,2,3-triazol- l -yl, l ,2,3-triazol-2-yl, l ,2,3-triazol-3-yl, l ,2,3-triazol-4-yl, l ,2,3-triazol-5-yl, 1 ,2,4-triazol- 1 -yl, 1 ,2,4-triazol-2-yl, l ,2,4-triazol-3-yl, 1 ,2,4-triazol-4-yl, 1 ,2,4-triazol- 5-yl, l -oxa-2,3-diazol-4-yl, l -oxa-2,3-diazol-5-yl, l -oxa-2,4-diazol-3-yl, l -oxa-2,4-diazol-5-yl, 1 -oxa- 2,5-diazol-3-yl, l -oxa-2,5-diazol-4-yl, l -thia-2,3-diazol-4-yl, l -thia-2,3-diazol-5-yl, l -thia-2,4-diazol-3- yl, l -thia-2,4-diazol-5-yl, l-thia-2,5-diazol-3-yl, l -thia-2,5-diazol-4-yl, 1 -tetrazolyl, 3-tetrazolyl, 1H-5- tetrazolyl, 3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiophenyl, 3-thiophenyl, 3-chloro-5-thiophenyl or 1 - cyclopropylcarbonyl-piperidin-4-yl, each of which is optionally substituted with from 1 -4 R ¹⁶ or R ¹⁷ substituents; or 1 -4 R ¹⁸ substituents, wherein at each occurrence, R ¹⁸ is further optionally substituted with from 1 -3 R ¹⁹ substituents selected from CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, -OH, -NH ₂ , - NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ -. In some instances, R ^k is Ci_ ₆ alkyl, C ₃ _ ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₂ alkyl, 4-morpholinyl, 1 -pyrrolidinyl, 2- pyrrolidinyl, 3 -pyrrolidinyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxatanyl, 3-oxatanyl, 2-oxo- l - pyrrolidinyl, 1 -piperidinyl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl, piperazinyl, phenyl or benzyl, each of which is optionally substituted with 1 -3 substituents selected from -CH ₃ , -OCH ₃ , F, CI, CN, CF ₃ , CHF ₂ , CH ₂ F, -OCF ₃ , -N(CH ₃ ) ₂ , -NHCH ₃ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0114] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from 3- fluoropropynyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-4-pyridyl, phenyl, 1 -pyrazolyl, 3- 1H- pyrazolyl, 4- lH-pyrazolyl, 1 -methyl-4-pyrazolyl, l ,3-dimethyl-5-pyrazolyl, 4-morpholinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2,5-dimethyl-4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-methyl-5- thiazolyl, 1 -isopropyl-pyrazol-4-yl, 1 -cyclohexenyl, 1 -cyclopentenyl, 1-cyclooctenyl, 1 ,2,3,6- tetrahydropyridin-4-yl, 1,2,3, 6-tetrahydropyridin-5-yl, cyclopropyl, 2,5-dihydro-lH-pyrrol-3-yl, 2,5- dihydro-lH-pyrrol-2-yl or 2,5-dihydropyrrol-l-yl, each of which is optionally substituted with from 1-4 R ¹⁶ or R ¹⁷ substituents; or 1-4 R ¹⁸ substituents, wherein at each occurrence, R ¹⁸ is further optionally substituted with from 1-3 R ¹⁹ substituents selected from CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1- azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, - CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH- , (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ -. In some instances, R ^k is C _L galkyl, C ₃ . ₆ cycloalkyl, C ₃ _ ₆ cycloalkyl-Ci_ ₂ alkyl, 4-morpholinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-oxo- 1 -pyrrolidinyl, 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, piperazinyl, phenyl or benzyl, each of which is optionally substituted with 1-3 substituents selected from -CH ₃ , -OCH ₃ , F, CI, CN, CF ₃ , CHF ₂ , CH ₂ F, -OCF ₃ , -N(CH ₃ ) ₂ , -NHCH ₃ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0115] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is H, CN, vinyl, Ci_ ₆ alkyl, deuterated Ci_ ₆ alkyl, perdeuterated Ci_ ₆ alkyl, halogen, Ci_ ₆ alkoxy, 2-cyclopropylethynyl, pyridyl, phenyl, benzyl, pyrazolyl, oxazolyl, thiozolyl, pyrimidinyl, pyrazinyl, pyridazinyl, cyclopropyl,

cyclopropylmethyl, cyclopropylcarbonyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, benzoyl, phenylcarbamoyl, piperidinyl, piperazinyl, morpholinyl, cyclopentenyl, cyclohexenyl, l,2,3,6-tetrahydropyridin-4-yl, 2,3-dihydro-l,4-benzodioxin-5-yl, 1,3- benzodioxol-4-yl, l,3-benzodioxol-5-yl, indanyl, 1,2-benzoxazolyl, 1,3-benzoxazolyl, each of which is optionally substituted with from 1-4 members independently selected from halogen, -CH ₃ , CD ₃ , -OCH ₃ , CN, CF ₃ , CF ₃ 0-, -CF ₂ H, CHF ₂ 0-, -N(CH ₃ ) ₂ , -NHCH ₃ , CH ₃ CONH-, NH ₂ C(0)-, CH ₃ NHC(0)-,

(CH ₃ ) ₂ NC(0)-, cyclopropyl, 1 -cyanocyclopropyl, CH ₃ S0 ₂ NH-, cyclopropyl-S0 ₂ NH-, butyl- S0 ₂ NH-, p- CH ₃ C ₆ H ₄ S0 ₂ NH-, NH ₂ S0 ₂ -, CH ₃ NHS0 ₂ -, (CH ₃ ) ₂ NS0 ₂ -, 4-morpholinyl, piperidinyl, 4-methyl-l- piperazinyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4- morpholinylcarbonyl, piperdinylcarbonyl, piperazinylcarbonyl, t-butoxycarbonyl or 2-(4-morpholinyl)- ethyl. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0116] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from CI, Br, phenyl, 4-fluorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1- cyclopropylcarbonyl- 1 ,2,3,6-tetrahydropyridin-4-yl, 1 -morpholinocarbonyl, 1 ,2,3,6-tetrahydropyridin-4- yl, l,2,3,6-tetrahydropyridin-5-yl, l,3-dimethyl-pyrazol-4-yl or 1 -(4-piperidinyl)pyrazol-4-yl, 3,4- dimethyl-lH-pyrazol-5-yl, l-(cyclopropylcarbonyl)-2,5-dihydro-pyrrol-3-yl, 3-fluoro-propynyl, 3,5- dimethyl-isoxazol-4-yl, 5-thiazolyl, each of which is optionally substituted with from 1-3 R ¹⁴ substituents independently selected from F, CI, -CH ₃ ,-Et, propyl, isopropyl, 2-methylpropyl, CD ₃ , -OCH ₃ , CN, CH ₂ F, -CF ₂ H, CF ₃ , CF ₃ 0-, CHF ₂ 0-, CH ₂ FO-, NH ₂ , -N(CH ₃ ) ₂ , -NHCH ₃ , CH ₃ CONH-, NH ₂ C(0)-, CH ₃ NHC(0)-, (CH ₃ ) ₂ NC(0)-, cyclopropyl, 1- cyanocyclopropyl, 4-morpholinyl, 4-morpholinylmethyl, 4-thiomorpholinyl, 4-morpholinylcarbonyl, 4- thiomorpholinylcarbonyl, 4-morpholinylmethylcarbonyl, 4-thiomorpholinylmethylcarbonyl, cyclopropylcarbonyl, cyclobuylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 4-piperidinyl, 4- piperidinylcarbonyl, 1 -piperidinylcarbonyl, 1 -piperazinylcarbonyl, t-butoxycarbonyl, 2-(4-morpholinyl)- ethyl, 2-(4-morpholinyl)-ethoxy, 1 ,2-dihydroxyethylcarbonyl, 3-methoxypropoxy, 1 -pyrrolidinyl, PhS0 ₂ NH-, C^alkyl-SOzNH-, cyclopropyl-S0 ₂ NH-, p-CH ₃ C ₆ H ₄ S0 ₂ NH-, NH ₂ S0 ₂ -, C _w alkyl-NHS0 ₂ -, (C^alkyl^NSOz-, C^alkyl-NHC(O)-, C^alkyl-C(O)-, C^alkyl-SC , 4-morpholinyl-C ₁ . ₄ alkoxy, or 1- pyrrolidinylcarbonyl, each of which is optionally substituted with from 1-2 Ci_ ₄ alkyl groups. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I 'a) or (IV) are as defined in any of the embodiments as described herein.

[0117] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is aryl optionally substituted with from: (i) 1-3 R ⁹ substituents; or two adjacent R ⁹ substituents on R ⁷ , together with the atoms to which they are attached, form a 5- or 6-membered ring having from 0-2 additional heteroatoms selected from O, N or S and optionally substituted with from 1-3 R ^d substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ or R ¹⁷ substituents; or (vi) 1-3 R ¹⁸ substituents, wherein each of R ⁷ , R ⁹ , R ^c ' R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1- azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , - CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In some instances, R ⁷ is phenyl or perdeuterated phenyl (CeD ₅ ), each of which is optionally substituted with from 1-3 R ¹⁶ or R ¹⁷ substituents; or 1-3 R ¹⁸ substituents, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are each further optionally substituted with 1-3 R ¹⁹ groups. In other instances, R ⁷ is phenyl optionally substituted with from 1-3 substituents independently selected from F, CI, CH ₃ , -OCH ₃ , CF ₃ , CF ₃ 0-, -CFH ₂ , -CF ₂ H, CHF ₂ 0-, CH ₂ FO-, -NHCH ₃ , -N(CH ₃ ) ₂ , -CN, 4-morpholinyl, 4-morpholinylmethyl, 1 -piperidinyl, 4-methyl- 1 -piperazinyl, 1- pyrrolidinyl, 1 -pyrrolidinylcarbonyl, 4-morpholinylcarbonyl, 1 -piperidinylcarbonyl, 4-methyl- 1 - piperazinylcarbonyl, 1 -pyrrolidinylcarbonyl, cyclopropyl, cyclopropylcarbonyl, 4-morpholinylethyl, CH ₃ S0 ₂ , CH ₃ S0 ₂ NH-, CH ₃ C(0)-, 4-morpholinylmethylcarbonyl, 1 ,2-dihydroxypropanoyl,

(CH ₃ ) ₂ NC(0)- or methoxycarbonylamino, each of which is optionally substituted with 1-2 groups independently selected from Ci_ ₆ alkyl, 4-morphilinyl or 4-morpholinylmethyl. In other instances, R ⁷ is 1-naphthyl, or 2-naphthyl, each of which is optionally substituted with from 1 1-3 R ¹⁶ or R ¹⁷ substituents; or 1-3 R ¹⁸ substituents, wherein R ¹⁶ , R ¹⁷ and R ¹⁸ are each further optionally substituted with 1-3 R ¹⁹ groups. In certain embodiments, the hydrogen atoms in R ⁷ are optionally replaced by 1 to 12, or 1 to 8, or 1 to 6, or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12 deuterium atoms with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. In certain embodiments, each hydrogen atom in R ⁷ is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium

incorporation for each deuterium. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein. [0118] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is lH-4-benzotriazolyl, 1H-5- benzotriazolyl, lH-4-benzimidazolyl, lH-5-benzimidazolyl, lH-4-indazolyl, lH-5-indazolyl, 1H-6- indazolyl, lH-7-indazolyl, lH-4-indolyl, lH-5-indolyl, lH-6-indolyl, lH-7-indolyl, 2-oxo-6-indolinyl, 2- oxo-4-indolinyl, 2-oxo-5-indolinyl, 2-oxo-7-indolinyl, l,2-benzoxazol-4-yl, l,2-benzoxazol-5-yl, 1,2- benzoxazol-6-yl, l,2-benzoxazol-7-yl, l,3-benzoxazol-4-yl, l,3-benzoxazol-5-yl, l,3-benzoxazol-6-yl, l,3-benzoxazol-7-yl, 1 ,2-benzothiazol-4-yl, l,2-benzothiazol-5-yl, 1 ,2-benzothiazol-6-yl, 1,2- benzothiazol-7-yl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl, 5-quinazolinyl, 6- quinazolinyl, 7-quinazolinyl, 8-quinazolinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, 8- quinoxalinyl, 4-indanyl, 5-indanyl, 5-tetralinyl, 6-tetralinyl, l,3-dihydroisobenzofuran-4-yl, 1,3- dihydroisobenzofuran-5-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3- dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, l,3-dihydroisobenzothiophen-4-yl, 1,3- dihydroisobenzothiophen-5-yl, 2,3-dihydrobenzothiophen-4-yl, 2,3-dihydrobenzothiophen-5-yl, 2,3- dihydrobenzothiophen-6-yl, 2,3-dihydrobenzothiophen-7-yl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7- indolinyl, 5-isochromanyl, 6-isochromanyl, 7-isochromanyl, 8-isochromanyl, 5-chromanyl, 6-chromanyl, 7-chromanyl, 8-chromanyl, 2,3-dihydro-l,3-benzothiazo-4-yl, 2,3-dihydro-l,3-benzothiazo-5-yl, 2,3- dihydro- 1 ,3-benzothiazo-6-yl, 2,3-dihydro- 1 ,3-benzothiazo-7-yl, 2,3-dihydro- 1 ,2-benzothiazo-4-yl, 2,3- dihydro- 1 ,2-benzothiazo-5-yl, 2,3-dihydro- 1 ,2-benzothiazo-6-yl, 2,3-dihydro- 1 ,2-benzothiazo-7-yl, 2,3- dihydro- 1,3 -benzoxazol-4-yl, 2,3-dihydro- l,3-benzoxazol-5-yl, 2,3-dihydro- l,3-benzoxazol-6-yl, 2,3- dihydro- 1 ,3-benzoxazol-7-yl, 2,3-dihydro- 1 ,2-benzoxazol-4-yl, 2,3-dihydro- 1 ,2-benzoxazol-5-yl, 2,3- dihydro- 1 ,2-benzoxazol-6-yl, 2,3-dihydro- l,2-benzoxazol-7-yl, 4-benzofuranyl, 5-benzofuranyl, 6- benzofuranyl, 7-benzofuranyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7- benzo[b]thiophenyl, 4-benzo[c]thiophenyl, 5-benzo[c]thiophenyl 2,3-dihydro- l,4-benzodioxin-5-yl, 1,3- benzodioxol-4-yl, l,3-benzodioxol-5-yl, indanyl, 1 ,2-benzoxazol-4-yl, l,2-benzoxazol-5-yl, 1,2- benzoxazol-6-yl, l,2-benzoxazol-7-yl, l,3-benzoxazol-4-yl, l,3-benzoxazol-5-yl, l,3-benzoxazol-6-yl or l,3-benzoxazol-7-yl, each of which is optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)OCH ₃ , -P(=0)(OCH ₃ ) ₂ , - OP(=0)(OCH ₃ ) ₂ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0119] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is a heteroaryl optionally substituted with from: (i) 1-3 R ⁹ substituents; or two adjacent R ⁹ substituents on R ⁷ , together with the atoms to which they are attached, form a 5- or 6-membered ring having from 0-2 additional heteroatoms selected from O, N or S and optionally substituted with from 1 -3 R ^d substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, - NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)OCH ₃ , -P(=0)(OCH ₃ ) ₂ , - OP(=0)(OCH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In some instances, R ⁷ is an optionally substituted 5- or 6-membered heteroaryl. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0120] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is 5-pyrimidinyl, 2- pyrimidinyl, 4-pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyridazinyl, 3-pyridazinyl, 1 - pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 1 -pyrazolyl, 2-pyrazolyl, 3-pyrazolyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 1 ,2,3-triazol- l -yl, l ,2,3-triazol-2-yl, 1 ,2,3- triazol-3-yl, l,2,3-triazol-4-yl, l ,2,3-triazol-5-yl, 1 ,2,4-triazol- 1 -yl, l,2,4-triazol-2-yl, l ,2,4-triazol-3-yl, 1 ,2,4-triazol-4-yl, l ,2,4-triazol-5-yl, l -oxa-2,3-diazol-4-yl, l -oxa-2,3-diazol-5-yl, l-oxa-2,4-diazol-3-yl, l -oxa-2,4-diazol-5-yl, l -oxa-2,5-diazol-3-yl, l -oxa-2,5-diazol-4-yl, l -thia-2,3-diazol-4-yl, l -thia-2,3- diazol-5-yl, l -thia-2,4-diazol-3-yl, l -thia-2,4-diazol-5-yl, l -thia-2,5-diazol-3-yl, l -thia-2,5-diazol-4-yl, 1- tetrazolyl, 3-tetrazolyl, lH-5-tetrazolyl, 3H-5-tetrazolyl, 2-furanyl, 3-furanyl, 2-thiophenyl or 3- thiophenyl, each of which is optionally substituted with from: (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, - OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)OCH ₃ , -P(=0)(OCH ₃ ) ₂ , - OP(=0)(OCH ₃ ) ₂ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0121] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from 1 - benzotriazolyl, 1 -benzimidazolyl, lH-2-benzimidazolyl, 1 -indazolyl, lH-3-indazolyl, 1 -indolyl, 1H-2- indolyl, lH-3-indolyl, l ,2-benzoxazol-3-yl, l ,3-benzoxazol-2-yl, l ,2-benzothiazol-3-yl, 1,3- benzothiazol-2-yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 1 -isoquinolinyl, 3-isoquinolinyl, 4- isoquinolinyl, 3-cinnolinyl, 4-cinnolinyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 2-benzofuranyl, 3-benzofuranyl, 2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl or l-benzo[c]thiophenyl each of which is optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituents is further optionally substituted with from 1-3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I 'a) or (IV) are as defined in any of the embodiments as described herein.

[0122] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from:

optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , - N(CH ₃ ) ₂ , -CH ₂ F, -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OC ₁ . ₆ alkyl), -P(=0)(OC ₁ . ₆ alkyl) ₂ , -OP(=0)( OCi_ ₆ alkyl) ₂ , -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , where the wavy line indicate the point of attachment to the rest of the molecule. The notation i means R ⁷ can be attached to the any of the available positions of the R ⁷ group set forth above. For example, to include 1 -indolizinyl, 2-indolizinyl, 3-indolizinyl, 4-indolizinyl, 5-indolizinyl,

6-indolizinyl, 7-indolizinyl, and 8-indolizinyl (i.e., substitutions can be at 1, 2, 3, 5, 6, 7 or 8 positions of the indolizine ring).

[0123] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from:

each of which is optionally substituted with from (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2- oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OCi_ ₆ alkyl), -P(=0)(OCi_

6alkyl) ₂ , -OP(=0)( OCi_ ₆ alkyl) ₂ , CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-,

(CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , where the wavy line indicates the point of attachment to the rest of the molecule. The notation \ means R ⁷ can be attache rest of the molecule at any of the

available positions of the R ⁷ group set forth above. For example, meant to include 1H- pyrrolo[3,2-b]pyridin- l -yl, lH-pyrrolo[3,2-b]pyridin-2-yl, lH-pyrrolo[3,2-b]pyridin-3-yl, 1H- pyrrolo[3,2-b]pyridin-5-yl, lH-pyrrolo[3,2-b]pyridin-6-yl and lH-pyrrolo[3,2-b]pyridin-7-yl (i.e., substitutions can be at 1 , 2, 3, 5, 6, or 7 positions of the pyrrolo[3,2-b]pyridine ring). All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0124] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from:

substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2- oxetanyl, 3-oxetanyl, -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OCi_ ₆ alkyl), -P(=0)(OCi_

6alkyl) ₂ , -OP(=0)(OC ₁ . ₆ alkyl) ₂ , -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , - OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-,

(CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , where the wavy line indicates the point of attachment to the rest of the molecule. The notation 1 means R ⁷ can be attache of the molecule at any of the

available positions of the meant to include

5H-pyrrolo[3,2-c]pyridazin-3-yl, 5H-pyrrolo[3,2-c]pyridazin-4-yl, 5H-pyrrolo[3,2-c]pyridazin-5-yl, 5H- pyrrolo[3,2-c]pyridazin-6-yl, 5H-pyrrolo[3,2-c]pyridazin-7-yl (i.e., substitutions can be at 3, 4, 5, 6, or 7 positions of the 5H-pyrrolo[3,2-c]pyridazine ring). All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I 'a) or (IV) are as defined in any of the embodiments as described herein.

[0125] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from:

each of which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 2- oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-,-PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OCi_ ₆ alkyl), -P(=0)(OCi_

6alkyl) ₂ , -OP(=0)( OCi_ ₆ alkyl) ₂ , CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-,

(CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , where the wavy line indicates the point of attachment to the rest of the molecule. The notation \ means R ⁷ can be attache the molecule at any of the

available positions of the R group set forth above. For example, to include 5H- pyrrolo[3,2-c]pyrimidin-2-yl, 5H-pyrrolo[3,2-c]pyrimidin-4-yl, 5H-pyrrolo[3,2-c]pyrimidin-5-yl, 5H- pyrrolo[3,2-c]pyrimidin-6-yl and 5H-pyrrolo[3,2-c]pyrimidin-7-yl (i.e., substitutions can be at 2, 4, 5, 6, or 7 positions of the 5H-pyrrolo[3,2-c]pyrimidine ring). All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I 'a) or (IV) are as defined in any of the embodiments as described herein.

[0126] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is selected from:

substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl, 2- oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OC ₁ . ₆ alkyl), -P(=0)(OC ₁ . ₆ alkyl) ₂ , -OP(=0)( OQ. ₆ alkyl) ₂ , CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ - ,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , where the wavy line indicates the point of attachment to the rest of the molecule. The notation I means R ⁷ can be attached to the rest of the molecule at any of the available

positions of the R group set ort a ove. For examp e, i is meant to include 5H- pyrrolo[2,3-b]pyrazin-2-yl, 5H-pyrrolo[2,3-b]pyrazin-3-yl, 5H-pyrrolo[2,3-b]pyrazin-5-yl, 5H- pyrrolo[2,3-b]pyrazin-6-yl, 5H-pyrrolo[2,3-b]pyrazin-7-yl, (i.e., substitutions can be at 2, 3, 5, 6, or 7 positions of the 5H-pyrrolo[2,3-b]pyrazine ring). All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0127] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is cycloalkyl or cycloalkenyl, each of which is optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein. [0128] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-cyclopentenyl, 3-cyclopentenyl, 4-cyclopentenyl, 1- cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclohexenyl, 1-octenyl, 1,4-cyclohexadienyl, 1,4- cyclohexadien-3-yl or cyclooctatetraene, each of which is optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. In some instances, R ⁷ is cyclopentenyl, cyclohexenyl or cyclopropyl, each of which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formula (IV) are as defined in any of the embodiments as described herein.

[0129] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is heterocycloalkyl, optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0130] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is 1 -aziridinyl, 2-aziridinyl, 1- 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 1 -pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2,3-dihydro- lH- pyrrol- l-yl, 2,3-dihydro- lH-pyrrol-2-yl, 2,3-dihydro-lH-pyrrol-3-yl, 2,3-dihydro- lH-pyrrol-4-yl, 2,3- dihydro- 1 H-pyrrol-5-yl, 2,5-dihydro- 1 H-pyrrol- 1 -yl, 2,5-dihydro- 1 H-pyrrol-2-yl, 2,5-dihydro- 1 H-pyrrol- 3-yl, 2,3-dihydro-lH-imidazol-l-yl, 2,3-dihydro-lH-imidazol-2-yl, 2,3-dihydro-lH-imidazol-4-yl, 2,3- dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl, 2,3-dihydrothiazol-5-yl, 2,3-dihydrofuran-2-yl, 2,3- dihydrofuran-3-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,5-dihydrofuran-2-yl, 2,5- dihydrofuran-3-yl, 2,3-dihydropyran-2-yl, 2,3-dihydropyran-3-yl, 2,3-dihydropyran-4-yl, 2,3- dihydropyran-5-yl, 2,3-dihydropyran-6-yl, 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6- dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl, 3,6-dihydro-2H-pyran-6-yl, 1 -piperidinyl, 2- piperidinyl, 3 -piperidinyl, 4-piperidinyl, 1 -piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, 4- morpholinyl, 1 ,2,3,6-tetrahydropyridin- 1 -yl, 1 ,2,3,6-tetrahydropyridin- 1 -yl, 1 ,2,3,6-tetrahydropyridin-2- yl, l,2,3,6-tetrahydropyridin-3-yl, l,2,3,6-tetrahydropyridin-4-yl, l,2,3,6-tetrahydropyridin-5-yl, or l,2,3,6-tetrahydropyridin-6-yl, each of which is optionally substituted with from: (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. In some instances, R ⁷ is 1- aziridinyl, 2-aziridinyl, 2,3-dihydro-lH-pyrrol-5-yl, 2,5-dihydro-lH-pyrrol-3-yl, 2,3-dihydro-lH- imidazol-4-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5-yl, 2,3-dihydrofuran-4-yl, 2,3-dihydrofuran-5- yl, 2,5-dihydrofuran-3-yl, 2,3-dihydropyran-5-yl, 2,3-dihydropyran-6-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6- dihydro-2H-pyran-5-yl, l ,2,3,6-tetrahydropyridin-4-yl or l ,2,3,6-tetrahydropyridin-5-yl, each of which is optionally substituted with from (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1 -3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents. In other instances, R ⁷ is l ,2,3,6-tetrahydropyridin-4-yl or 1 ,2,3,6- tetrahydropyridin-5-yl, 2,5-dihydro- lH-pyrrol- l -yl, 2,5-dihydro- lH-pyrrol-2-yl or 2,5-dihydro- lH- pyrrol-3-yl, each of which is optionally substituted with from (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I 'a) or (IV) are as defined in any of the embodiments as described herein.

[0131] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is C ₂ ^alkenyl or C2- ₄ alkynyl, each of which is optionally substituted with from: each of which is optionally substituted with from (i) 1 - 3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0132] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is vinyl, ethynyl, 1 -propynyl, 3-fluoro-propynyl or cyclopropylethynyl, each of which is optionally substituted with from: (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents. In some instances, R ⁷ is ethynyl, 1 -propynyl, 3-fluoro-propynyl or cyclopropylethynyl, each of which is optionally substituted with from: (i) 1 -3 R ⁹ substituents; or (ii) 1 -3 R ^c substituents; or (iii) 1 -3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents . All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0133] In some embodiments of compounds of formula (IV) or (I'a), R ⁷ is halogen, Ci_ ₆ alkyl, CN, -Ci_ ₂ alkyl-R ^k , -C(0)-R ^k , -C(0)NHR ^k , -C(0)NR ^k R ^k , -NHC(0)R ^k , -C(0)OR ^k , -OC(0)R ^k , -S0 ₂ R ^k , - NHS0 ₂ R ^k , -S0 ₂ NHR ^k , -S0 ₂ NR ^k R ^k , wherein each R ^k is independently Ci_ ₆ alkyl, C ₃ - ₆ cycloalkyl, phenyl or heterocycloalkyl, wherein R ^k is further optionally substituted with from 1 -3 R ^d groups. In some instances, R ^k is Ci_ ₆ alkyl, C3_ ₆ cycloalkyl, phenyl, 4-morpholinyl, 1 -piperidinyl, 3-piperidinyl, 4- piperidinyl, 1 -piperazinyl or 2-piperazinyl, wherein R ^k is further optionally substituted with from 1-3 R ^d group. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0134] In some embodiments of compounds of formula (IV) or (I'a), two adjacent R ⁷ substituents together with the atoms to which they are attached form a 5- or 6-membered ring having from 0-2 heteroatoms selected from N, O or S, wherein in the ring is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ , wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. In certain embodiments, the 5- or 6-membered ring is selected from cyclopentane, cyclohexane, pyrrolidine, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, tetrahydrofuran, tetrahydropyran, 1 ,4-dioxane, pyridine, pyrazine, piperidine, piperazine, pyrimidine or pyridazine ring system, each of which is optionally substituted with from 1-3 R ¹⁶ ; or 1-3 R ¹⁷ ; or 1-3 R ¹⁸ substituents wherein R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ and the subscript m of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0135] In some embodiments of compounds of formula (IV) or (I'a), ring A is an optionally substituted 5-membered fused heterocyclic aromatic ring having from 1-3 heteroatoms as ring members selected from O, N or S; or an optionally substituted fused benzene ring; or when ring A is substituted with two or more substituents, two such substituents, together with the atoms to which they are attached, optionally form a 5- or 6-membered ring. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ of formulas (I'a) or (IV) are as defined in any of the embodiments as described herein.

[0136] In any of the embodiments of compounds of formulas (I'a) or (IV), the hydrogen atoms in R ⁷ are optionally replaced by 1 to 12, or 1 to 8, or 1 to 6, or 1 to 3 or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 and 12 deuterium atoms with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium. In certain embodiments, each hydrogen atom in R ⁷ is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium.

[0137] In some embodiments of compounds of formulas (I'a) or (IV), ring A is 5-membered fused heterocyclic aromatic ring having from 1-3 heteroatoms as ring members selected from O, N or S; or a fused benzene ring. All the other variables Y ¹ , Y ² , Y ³ , R ³ , R ⁴ , R ⁵ of formula (IV) are as defined in any of the embodiments as described herein. In certain instances, ring A is a fused pyrrole, pyrazole, 1,2,3- triazole, 1 ,2,4-triazole, imidazole, thiophene or benzene ring.

[0138] In certain embodiments of compounds of formula (IV), the moiety: or , each of which is optionally substituted with from 1 -2 R groups and point of attachment to the rest of the molecule. In some embodiments, with from 1 -2 R ⁷ groups. In one embodiment, is

lly substituted with from 1 -2 R ⁷ groups. In other embodiments, iety, optionally substituted with from 1-2 R ⁷

groups. In other embodime (thieno[2,3-b]pyridine moiety), optionally

is

In still other embodiments,

(quinoline moiety), optionally substituted with from 1 -2 R ⁷ groups. All the other variables R ³ , R ⁴ and R ³ of formula (IV) are as defined in any of the embodiments as described

herein. In some embodiments, the hydrogen atoms in are optionally replaced with from 1 to

6 deuteriums with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium

incorporation for each deuterium. In some embodiments, each hydrogen atom in is optionally replaced by a deuterium atom with at least 52.5%, 60%, 70%, 75%, 80%, 90%, 95%, 99%, 99.5% or 99.9% deuterium incorporation for each deuterium.

[0139] In certain embodiments of compounds of formula (IV), the moiety: is selected from

, each of which is optionally substituted with from 1 -2 R ⁷ groups and the wavy line indicates the point of attachment to the rest of the molecule.

[0140] In some embodiments of compounds of compounds of formulas (Γ), (I'a), (I), (II) or (III), the disclosure provides compounds of formula (V):

In certain embodiments, R is H, halogen, Ci_4 alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl or a lone pair of electrons; L ² is a bond, -CH ₂ -, -C(O)- or -SO ₂ ; R ⁶ is alkyl, aryl or heteroaryl, each of which is optionally substituted with from 1-3 R ⁹ members independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, -X^aryl, aryl-Ci_ ₄ alkyl-X ¹ -, heteroaryl-X ¹ -, heteroaryl-Ci_4 alkyl-X ¹ -, C3_ scycloalkyl-X ¹ -, C ₃ - ₆ cycloalkyl-Ci_ ₄ alkyl-X ¹ -, Cs-ecycloalkenyl-X ¹ -, CH ₂ =CH-X ¹ -, C ₃ - ₆ cycloalkyl-C ₂ - ₄ alkenyl-X ¹ -, C3_ ₆ cycloalkyl-C ₂ - ₄ alkynyl-X ¹ -, heterocyclyl-X ¹ -, heterocyclyl-Ci_ ₄ alkyl-X ¹ - or R ⁸ ; or two adjacent R ⁹ members together with the atoms to which they are attached form a 5- or 6-membered fused ring having 0-2 heteroatoms as ring members selected from O, N or S. In some instances, R ¹ is H or a lone pair of electron. In one instance, R ¹ is H. In other instance, Y ¹ is N and R ¹ is a lone pair of electron.

1 2 3 3 4 1 2

The other variables Y , Y Y R R V and of formula (V) are as defined in any of the embodiments as described herein. In some embodiments of compounds of formula (V), L ¹ is -C(0)NR ⁵ -, wherein the carbonyl group in L ¹ is covalently linked to the pyrazole ring and the nitrogen atom in L ¹ is covalently bonded to the 6-membered aromatic ring in formula (V).

[0141] In some embodiments of compounds of compounds of formulas (Γ), (I'a), (I), (II), (III) or (V), the disclosure provides compounds of formula (V):

In certain embodiments, R ¹ is H, halogen, Ci_4 alkyl, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl or a lone pair of electrons; L ² is a bond, -CH ₂ -, -C(O)- or -SO ₂ ; R ⁶ is alkyl, aryl or heteroaryl, each of which is optionally substituted with from 1-3 R ⁹ members independently selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ - ₆ alkynyl, -X^aryl, aryl-Ci_ ₄ alkyl-X ¹ -, heteroaryl-X ¹ -, heteroaryl-Ci_4 alkyl-X ¹ -, C3_ scycloalkyl-X ¹ -, C ₃ - ₆ cycloalkyl-Ci_ ₄ alkyl-X ¹ -, C^cycloalkenyl-X ¹ -, CH ₂ =CH-X ¹ -, C ₃ _ ₆ cycloalkyl-C ₂ _ _{4 4} aalkenyl-X ¹ -, C3_ ₆ cycloalkyl-C ₂ - ₄ alkynyl-X ¹ -, heterocyclyl-X ¹ -, heterocyclyl-Ci_ ₄ alkyl-X ¹ - or R ⁸ ; or two adjacent R ⁹ members together with the atoms to which they are attached form a 5- or 6-membered fused ring having 0-2 heteroatoms as ring members selected from O, N or S. In some instances, R ¹ is H or a lone pair of electron. In one instance, R ¹ is H. In other instance, Y ¹ is N and R ¹ is a lone pair of electron. The other variables Y , Y Y , R , R^ and 1/ of formula (V) are as defined in any of the embodiments as described herein.

[0142] In some embodiments of compounds of compounds of formula (V) or (V), R ⁶ is aryl or heteroaryl, each of which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, - NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In certain instances, R ⁶ is phenyl, 1 -naphthyl or 2-naphthyl, each of which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2- azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , - OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-,

(CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In some instances, R ⁶ is a heteroaryl having from 1-3 heteroatoms as ring members selected from O, N or S. In other instances, R ⁶ is a heteroaryl having from 1-2 heteroatoms as ring members selected from N. The other variables Y ¹ , Y ² , Y ³ , R ¹ , R ³ , R ⁴ , R ⁵ and L ² of formula (V) are as defined in any of the embodiments as described herein.

[0143] In some embodiments of compounds of compounds of formula (V) or (V), R ⁶ is phenyl, which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents; or (viii) 1-3 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from - CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . The other variables Y ¹ , Y ² , Y ³ , R ¹ , R ³ , R ⁴ , R ⁵ and L ² of formula (V) are as defined in any of the embodiments as described herein.

[0144] In some embodiments of compounds of compounds of formula (V) or (V), R ⁶ is 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl or 4- pyridazinyl, each of which is optionally substituted with from (i) 1-3 R ⁹ substituents; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents; or (viii) 1-3 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3- azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-,

(CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . The other variables Y ¹ , Y ² , Y ³ , R ¹ , R ³ , R ⁴ , R ⁵ and L ² of formula (V) or (V) are as defined in any of the embodiments as described herein.

[0145] In some embodiments of compounds of formulas (I), (II), (III), (IV), (V) or (V) and any of the subformulas thereof, R ³ and R ⁴ are each independently selected from H, halogen, Ci_4 alkyl, Ci_

4haloalkyl, Ci_ ₄ haloalkoxy, cyclopropyl, phenyl, CN, CN-CH ₂ -, Ci_ ₄ alkoxy, R ^s or a lone pair of electrons; or R ³ and R ⁴ are taken together with the atoms to which they are attached form an optionally substituted 5 to 8-membered ring having from 0-2 heteroatoms as ring members selected from O, N or S; wherein R ^s is -OH, -NH ₂ , -NO ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - OR ^h , -SR ^h , -OC( -C(0)R ^h , -C(S)R ^h , -C(0)OR ^h , -C(S)OR ^h , -S(0)R ^h , -S(0) ₂ R ^h , -C(0)NH R ^h , -C(S)NHR ^h , S)NR ^h R ^h , -S(0) ₂ NHR ^h , -S(0) ₂ NR ^h R ^h , -C(NH)NHR ^h , -C(NH)NR ^h R ^h , -N HC(0)R ^h , -NHC(S)R ^h , -NR ^h C(0)R ^h , -NR ^h C(S)R ^h , -NHS(0) ₂ R ^h , -NR ^h S(0) ₂ R ^h , -NHC(0)NHR ^h , -NHC(S) -NR ^h C(0)NH ₂ , -NR ^h C(S)NH ₂ , -NR ^h C(0)NHR ^h , -NR ^h C(S)NHR ^h , -NHC(0)NR ^h R ^h , -NHC(S)NR ^h R ^h , -NR ^h C(0)NR ^h R ^h , -NR ^h C(S)NR ^h R ^h , -NHS(0) ₂ NHR ^h , -NR ^h S(0) ₂ NH ₂ , -NR ^h S(0) ₂ NHR ^h , -NHS(0) ₂ NR V, -NR ^h S(0) ₂ NR ^h R ^h , -NHR ^h or -NR ^h R ^h , wherein each R ^h is independently H or Ci_ ₂ alkyl. In certain embodiments, R ³ and R ⁴ are not simultaneously hydrogen. In some instances, R ³ and R ⁴ are each independently selected from H, Ci_ ₆ alkyl, halogen, CN, cyclopropyl, CN-CH ₂ -, phenyl,

cyclopropylmethyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, Ci_ ₆ haloalkoxy or R ^s . In some embodiments, R ³ and R ⁴ are each independently halogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, cyclopropyl, -CN, Ci_ ₄ haloalkyl or In other embodiments, R ³ and R ⁴ are each independently selected from Br, CI, methyl, ethyl, cyclopropyl, - CN, CF ₃ , CHF ₂ , CH ₂ F, -OCH ₃ , -OCF ₃ , -OCHF ₂ or -OCH ₂ F, CNCH ₂ -, NH ₂ C(0)-, CH ₃ NHCO- or CH ₃ C(0)NH-. In other instances, R ³ and R ⁴ are each independently selected from H, -CH ₃ , -CD ₃ , -C ₆ D ₅ , -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F halogen, CN, cyclopropyl, CN-CH ₂ -, phenyl, cyclopropylmethyl or -OCH ₃ . In yet other instances, R ³ and R ⁴ are each independently H, F, CI, Br, NH ₂ C(0)-, CH ₃ , CD ₃ , Et, cyclopropyl, CN, CH ₂ CH ₂ - or CH ₃ C(0)NH-. In other instances, R ³ and R ⁴ are each independently selected from H, -OH, -NH ₂ , -N0 ₂ , -C(0)OH, -

C(S)OH, -C(0)NH ₂ , -C(S)NH ₂ , -S(0) ₂ NH ₂ , -NHC(0)NH ₂ , -NHC(S)NH ₂ , -NHS(0) ₂ NH ₂ , -C(NH)NH ₂ , - -C(0)R ^h , -C(0)OR ^h , -S(0)R ^h , -S(0) ₂ R ^h , -C(0)NHR ^h , -C(0)NR ^h R ^h , -C(S)NR ^h R ^h , -S(0) ₂ NHR \ -S(0) ₂ NR ^h R ^h , -C(NH)NHR ^h , -C(NH)NR ^h R ^h , -NHC(0)R ^h , -NHC(S)R ^h , -NR ^h C(0)R ^h , -NHC(0)NHR ^h , - NHC(S)NHR ^h , -NR ^h C(0)NH ₂ , -NR ^h C(0)NHR ^h , -NHC(0)NR ^h R ^h , -NR ^h C(0)NR ^h R ^h , -NHS(0) ₂ NHR ^h , - NR ^h S(0) ₂ NH ₂ , -NR ^h S(0) ₂ NHR ^h , -NHS(0) ₂ NR ^h R ^h , -NR ^h S(0) ₂ NR ^h R ^h , -NHR ^h or -NR ^h R ^h , wherein R ^h is H or Ci_ ₆ alkyl. In some embodiments, R ³ and R ⁴ are H. In other embodiments, R ³ is H and R ⁴ is a substituent other than hydrogen as described herein. In yet other embodiments, R ⁴ is H and R ³ is a substituent other than hydrogen as described herein. In other embodiments, both R ³ and R ⁴ are a substituent other than hydrogen as described herein. The other variables and substituents are as defined in any of the embodiments as described herein.

[0146] In some embodiments of compounds of Formulas (Γ), (I'a), (I), (II), (III), (IV), (V) or (V), or any of the subgeneric formulas thereof, Y ¹ is C, Y ² is CR ¹⁰ and Y ³ are CH. In other embodiments, Y ¹ is C and Y ² and Y ³ are N. In yet other embodiments, Y ¹ is C, Y ² is N and Y ³ is CH. In still other

embodiments, Y ¹ is C, Y ² is CR ¹⁰ and Y ³ is N. In other embodiments, Y ¹ is N, Y ² is N and Y ³ is N. In other embodiments, Y ¹ is N, Y ² is CR ¹⁰ and Y ³ . In other embodiments, Y ¹ is N, Y ² is CR ¹⁰ and Y ³ is N. In other embodiments, Y ¹ is N, Y ² is CR ¹⁰ and Y ³ is CH. In other embodiments, Y ¹ is N, Y ² is N and Y ³ is CH. In certain instances, R ¹⁰ is H, CN, halogen, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy, Ci_ ₄ alkoxy. In one embodiment, R ¹⁰ is H. All the other variables R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , R ³ , R ⁴ , R ⁵ , L ¹ or L ² are as defined in any of the embodiments as described herein.

[0147] In certain embodiments of compounds of Formula (Γ), (I'a), (I), (II), (III), (IV), (V) or (V) or any of the subformulas thereof, Y ¹ is C, Y ³ is CH and Y ² is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, vinyl, ethynyl, phenyl-Ci_ ₄ alkyl-, heteroaryl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci_ ₄ aikyl-, CH ₂ =CH- X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups or 1 -5 R ^c groups or 1 -5 R ^d groups or 1 -5 R ^e groups. All the other variables R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , R ³ , R ⁴ , R ⁵ , L ¹ or L ² are as defined in any of the embodiments as described herein.

[0148] In certain embodiments of compounds of formulas (IV), (V), (V) or any subgeneric formulas thereof, or any embodiments of compounds of formulas (IV), (V), (V) as described herein, or any of the compounds as described in the Examples, the moiety can exist in a tautomeric form: , where the wavy line indicates the point of attachment to the rest of the molecule.

Subformulae of Formulas (F), (Fa), (I), (II), (III), (IV), (V) or (V)

[0149] In one group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II) or (III) have subformulas (Ilia), (nib), (IIIc), (Hid) or (Hie):

(Ilia) (nib) (IIIc)

(Hid) (Hie)

The variables and substituents R ³ , R ⁴ , R ⁷ , L ¹ , Y ² and Y ³ in subformulas (Ilia), (Illb), (IIIc), (Hid) or (Hie) are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II) or (III) and in any of the embodiments as disclosed herein. In some embodiments, R ⁷ is as defined in any of the embodiments of compounds of formula (IV) as described herein. In some embodiments, L ¹ is as defined in the embodiments of compounds of formulas (Γ), (I'a), (I) or (II) as disclosed herein. In some embodiments, R ⁵ is H. In certain instances, L ¹ is -NHS0 ₂ -, -S0 ₂ NH-, -NHC(0)NH-, -NHC(O)-, - CH ₂ 0-, -OCH ₂ -, -C(0)NH-, -S0 ₂ -, -C(0)0-, -C(O)-, -C(=NH)NH- or -NHC(=NH)-. In some instances, L ¹ is -S0 ₂ NH-, -CH ₂ 0-, -OCH ₂ - or -C(0)NH-. In other instances L ¹ is -C(0)NH-. In one embodiment, the disclosure provides compounds of formula (Ilia). In another embodiment, the disclosure provides compounds of formula (Illb). In another embodiment, the disclosure provides compounds of formula (IIIc). In another embodiment, the disclosure provides compounds of formula (Hid). In another embodiment, the disclosure provides compounds of formula (Hie). In some embodiments of compounds of formulas (Ilia), (Illb), (IIIc), (Hid) or (Hie), Y ² and Y ³ are CH. In other embodiments of compounds of formulas (Ilia), (Illb), (IIIc), (Hid) or (Hie), Y ² is N and Y ³ is CH. In other embodiments of compounds of formulas (Ilia), (Illb), (IIIc), (Hid) or (Hie), Y ² is CR ¹⁰ , wherein R ¹⁰ is a substituent other than hydrogen as described herein for compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) (V) or (V) and Y ³ is CH.

[0150] In a second group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III) or (Ilia) have subformulas (IIIa-1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7) or (IIIa-8):

(IIIa-5) (IIIa-6) (IIIa-7) (IIIa-8)

The variables R ³ _, R ⁴ , L ¹ , R ¹⁰ and R ⁷ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (Ilia). In some embodiments, R ⁷ is as defined in any of the embodiments of compounds of formula (IV) described herein. In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1-5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen,

Ci_ ₄ haloalkoxy or d^alkoxy. In some embodiments of compounds of formulas (Ilia- 1 ) to (IIIa-8), L ¹ is -C(0)NH-, -SO ₂ NH-, -NHSO ₂ -, -CH ₂ O- or -OCH ₂ -. In certain embodiments of compounds of formulas (IIIa-1) to (IIIa-8), L ¹ is -C(0)NH-. In one embodiment, the disclosure provides a compound of formula (IIIa-1). In another embodiment, the disclosure provides a compound of formula (IIIa-2). In another embodiment, the disclosure provides a compound of formula (IIIa-3). In another embodiment, the disclosure provides a compound of formula (IIIa-4). In another embodiment, the disclosure provides a compound of formula (IIIa-5). In another embodiment, the disclosure provides a compound of formula (IIIa-6). In another embodiment, the disclosure provides a compound of formula (IIIa-7). In another embodiment, the disclosure provides a compound of formula (IIIa-8).

[0151] In a third group of embodiments, of the disclosure, compounds of formulas (Γ), (I), (II), (III) or (Illb) have subformulas (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4) or (IIIb-5):

(IIIb-1) (IIIb-2) (IIIb-3) (IIIb-4)

(IIIb-5)

The variables R ³ _, R ⁴ , R ¹⁰ , L ¹ and R ⁷ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (Illb). In some embodiments, R ⁷ is as defined in any of the embodiments of compounds of formula (IV) described herein. In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1-5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen,

Ci_ ₄ haloalkoxy or d^alkoxy. In some embodiments of compounds of formulas (IIIb-1) to (IIIb-5), L ¹ is -C(0)NH-, -SO ₂ NH-, -NHSO ₂ -, -CH ₂ O- or -OCH ₂ -. In certain embodiments of compounds of formulas (IIIb- 1) to (IIIb-5), L ¹ is -C(0)NH-. In one embodiment, the disclosure provides a compound of formula (IIIb-1). In another embodiment, the disclosure provides a compound of formula (IIIb-2). In another embodiment, the disclosure provides a compound of formula (IIIb-3). In another embodiment, the disclosure provides a compound of formula (IIIb-4). In another embodiment, the disclosure provides a compound of formula (IIIb-5).

[0152] In a 4th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III) or (IIIc) have subformulas (IIIc- 1), (IIIc-2), (IIIc-3), (IIIc-4) or (IIIc-5):

(IIIc- 1) (IIIc-2) (IIIc-3)

(IIIc-4) (IIIc-5)

The variables R ³ , R ⁴ , R ¹⁰ , L ¹ and R ⁷ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (IIIc). In some embodiments, R ⁷ is as defined in any of the embodiments of compounds of formula (IV) described herein. In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen,

Ci_ ₄ haloalkoxy or d^alkoxy. In some embodiments of compounds of formulas (IIIc- 1 ) to (IIIc-5), L ¹ is -C(0)NH-, -S0 ₂ NH-, -NHS0 ₂ -, -CH ₂ 0- or -OCH ₂ -. In certain embodiments of compounds of formulas (IIIc- 1) to (IIIc-5), L ¹ is -C(0)NH-. In one embodiment, the disclosure provides a compound of formula (IIIc- 1). In another embodiment, the disclosure provides a compound of formula (IIIc-2). In another embodiment, the disclosure provides a compound of formula (IIIc-3). In another embodiment, the disclosure provides a compound of formula (IIIc-4). In another embodiment, the disclosure provides a compound of formula (IIIc-5).

[0153] In a 5th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III) or (Hid) have subformulas (IIId- 1), (IIId-2), (IIId-3), (IIId-4) or (IIId-5):

(IIId- 1) (IIId-2) (IIId-3)

(IIId-4) (IIId-5) The variables R ³ , R ⁴ , R ¹⁰ and L ¹ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (Hid). In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C _{2- 6} alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl- C^alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-d. ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Q^alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen, Ci_ ₄ haloalkoxy or Ci_ ₄ alkoxy. In some embodiments of compounds of formulas (IIId- 1) to (IIId-5), L ¹ is -C(0)NH-, - SO ₂ NH-, -NHSO ₂ -, -CH ₂ 0- or -OCH ₂ -. In certain embodiments of compounds of formulas (IIId- 1) to (IIId-5), L ¹ is -C(0)NH-. In one embodiment, the disclosure provides a compound of formula (IIId- 1). In another embodiment, the disclosure provides a compound of formula (IIId-2). In another embodiment, the disclosure provides a compound of formula (IIId-3). In another embodiment, the disclosure provides a compound of formula (IIId-4). In another embodiment, the disclosure provides a compound of formula (IIId-5).

[0154] In a 6th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III) or (Hie) have subformulas (IIIe- 1), (IIIe-2), (IIIe-3), (IIIe-4) or (IIIe-5):

(IIIe- 1) (IIIe-2) (IIIe-3)

(IIIe-4) (IIIe-5)

The variables R ³ , R ⁴ , R ¹⁰ , R ⁷ and L ¹ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (Hie). In some embodiments, R ⁷ is as defined in any of the embodiments of compounds of formula (IV) described herein. In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, d_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_ ₄ alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen,

Ci_ ₄ haloalkoxy or d^alkoxy. In some embodiments of compounds of formulas (IIIe- 1) to (IIIe-5), L ¹ is -C(0)NH-, -SO ₂ NH-, -NHSO ₂ -, -CH ₂ O- or -OCH ₂ -. In certain embodiments of compounds of formulas (IIIe-1) to (IIIe-5), L ¹ is -C(0)NH-. In one embodiment, the disclosure provides a compound of formula (IIIe-1). In another embodiment, the disclosure provides a compound of formula (IIIe-2). In another embodiment, the disclosure provides a compound of formula (IIIe-3). In another embodiment, the disclosure provides a compound of formula (IIIe-4). In another embodiment, the disclosure provides a compound of formula (IIIe-5).

[0155] In a 7th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia), (IV) have subformula (IVa):

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m, Y ² and Y ³ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia) or (IV) or in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment, R ⁵ is H. In some embodiments, Y ² is N or CR ¹⁰ and Y ³ is N or CH, wherein R ¹⁰ is H, Ci _-6 alkyl, d^alkoxy, C ₂ „ ₆ alkenyl, C ₂ „ ₆ alkynyl, aryl-C^alkyl-, heteroaryl-Ci_ ₄ alkyl-, H-X ² -, C ₃ _

6Cycloalkyl-C ₂ _ ₄ aikeny or R ⁸ , each of which is optionally substituted with from; (i) 1-5 R ⁹ groups; or (ii) 1-5 R ^c substituents; or (iii) 1-5 R ^d substituents; or (iv) 1-5 R ¹⁵ substituents; or (v) 1-5 R ¹⁶ substituents; or (vi) 1-5 R ¹⁷ substituents; or (vii) 1-5 R ¹⁸ substituents; or (viii) 1-5 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from - CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In some embodiments of compounds of formula (IVa), Y ² and Y ³ are CH. In other embodiments, Y ² is N and Y ³ is CH. In other embodiments,

2 is CR 10 , wherein R 10 is a substituent other than hydrogen as described herein and Y 3 is CH. In certain embodiments of compounds of formula (IVa), the subscript m is 0. In other embodiments of compounds of formula (IVa), the subscript m is 1. In other embodiments of compounds of formula (IVa), the subscript m is 2.

[0156] In an 8th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia), (IV) or (IVa) have subformula (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa- 9), (IVa- 10):

(IVa-8) (IVa-9) (IVa- 10)

The variables R ³ , R ⁴ , R ⁵ , R ⁷ and R ¹⁰ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia) or (IV) and in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment, R ⁵ is H. In yet another embodiment, R ⁵ is Q_ ₄ alkyl. In some embodiments, R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C2- ₆ alkenyl, C2- ₆ alkynyl, aryl-Ci_ ₄ alkyl-, alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C2- ₄ alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is C^alkylene, -0-, -S- or -NH-. In other embodiments, R ¹⁰ is CN, Ci_ ₄ alkyl, halogen, Ci_ ₄ haloalkoxy or Ci_ ₄ alkoxy. In other embodiments, R ¹⁰ is CN, CH ₃ , Et, CI, Br, F, CF ₃ , CF ₂ H-, CFH ₂ -, CH ₃ 0-, CF ₃ 0-, CF ₂ HO- or CFH ₂ 0-.

[0157] In a 9th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9) or (IVa- 10) have subformulas (IVa- l a), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a), (IVa- 8a), (IVa-9a) or (IVa- 10a):

(IVa-8a) (IVa-9a) (IVa- l Oa)

The variables R ³ , R ⁴ , R ⁷ and R ¹⁰ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa- 8), (IVa-9) or (IVa- 10) or in any of the embodiments as disclosed herein.

[0158] In a 10th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa- 10), (IVa- l a), (IVa-2a), (IVa-5a) or (IVa-8a) have subformulas (IVa- lb), (IVa-2b), (IVa-5b) or (IVa-6b):

(IVa- lb) (IVa-2b) (IVa-5b)

(IVa-6b)

The variables R ³ , R ⁴ and R ⁷ are as defined in any of the embodiments of compounds of formulas (Γ),

(I'a), (I), (II), (III), (Ilia), (IV), (IVa), (IVa- 1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-

8), (IVa-9) or (IVa- 10) or in any of the embodiments as disclosed herein. In one embodiment, the compounds have subformula (IVa-2b).

[0159] In an 1 1th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) have subformulas (IVb):

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m, Y ² and Y ³ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) and in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment, R ⁵ is H. In some embodiments of compounds of formula (IVb), Y ² is CR ¹⁰ and Y ³ is CH, wherein R ¹⁰ is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ _ ₆ alkynyl, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci_ ₄ alkyl-, C3_ ₆ cycloalkenyl-Ci^alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C2^alkenyl-X ² -, C3_ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from; (i) 1-5 R ⁹ groups; or (ii) 1 -5 R ^c substituents; or (iii) 1 -5 R ^d substituents; or (iv) 1 -5 R ¹⁵ substituents; or (v) 1 -5 R ¹⁶ substituents; or (vi) 1 -5 R ¹⁷ substituents; or (vii) 1 -5 R ¹⁸ substituents; or (viii) 1 -5 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3- oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formula (IVb), Y ² and Y ³ are CH. In other embodiments, Y ² is N and Y ³ is CH. In other embodiments, Y ^A is CR , wherein R ^1U is a substituent other than hydrogen as disclosed herein and Y is CH. In certain embodiments of compounds of formula (IVb), the subscript m is 0. In other embodiments of compounds of formula (IVb), the subscript m is 1. In other embodiments of compounds of formula (IVb), the subscript m is 2. [0160] In a 12th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III) (IV) or (IVb) have subformulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8):

(IVb-7) (IVb- 8)

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m and R ¹⁰ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVb) or in any of the embodiments as disclosed herein. In some embodiments, m is 0. In formulas (IVb-7) or (IVb-8), each R ⁷ is an independently selected member. In one embodiment of compounds of formulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8), R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8), R ⁵ is H. In yet another embodiment, R ⁵ is In some embodiments of compounds of formulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8), R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ . ₆ alkynyl, heteroaryl-Ci_4 alkyl-, C3_ ₆ cycloalkyl-Ci_ ₄ alkyl-, C3_ ₆ cycloalkenyl-Ci^alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C2^alkenyl-X ² -, C3_ ₆ cycloalkyl-C2^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8), R ¹⁰ is CN, C^alkyl, halogen, C^haloalkyl, C^haloalkoxy or d_ ₄ alkoxy. In other embodiments of compounds of formulas (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7) or (IVb-8), R ¹⁰ is CN, CH ₃ , Et, CI, Br, F, CF ₃ , CF ₂ H-, CFH ₂ -, CH ₃ 0-, CF ₃ O-, CF ₂ HO- or CFH ₂ 0-.

[0161] In a 13th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) have sub formulas (IVc):

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m, Y ² and Y ³ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) or in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formula (IVc), R ⁵ is H. In

2 10 3 10 some embodiments of compounds of formula (IVc), Y is N or CR and Y is N or CH, wherein R is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from; (i) 1 -5 R ⁹ groups; or (ii) 1 -5 R ^c substituents; or (iii) 1 -5 R ^d substituents; or (iv) 1 -5 R ¹⁵ substituents; or (v) 1 -5 R ¹⁶ substituents; or (vi) 1 -5 R ¹⁷ substituents; or (vii) 1 -5 R ¹⁸ substituents; or (viii) 1-5 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , - OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-,

(CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , wherein X ² is C^alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formula (IVc), Y ² and Y ³ are CH. In other embodiments, Y ² is N and 3 is bodiments, 2 10 10

Y CH. In other em Y is CR , wherein R is a substituent other than hydrogen as disclosed herein and Y ³ is CH. In certain embodiments of compounds of formula (IVc), the subscript m is 0. In other embodiments of compounds of formula (IVc), the subscript m is 1. In other embodiments of compounds of formula (IVc), the subscript m is 2.

[0162] In a 14th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVc) have subformulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5):

(IVc- 1) (IVc-2) (IVc-3)

(IVc-4) (IVc-5)

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m and R ¹⁰ in formulas (IVc- 1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5) are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVc) or in any of the embodiments as disclosed herein. In one embodiment, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2 and each R ⁷ is an independently selected member. In one embodiment of compounds of formulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R ⁵ is H. In yet another embodiment, R ⁵ is In some embodiments of compounds of formulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, aryl-Ci_ ₄ alkyl-, alkyl-, C3_ ₆ cycloalkyl-Ci^alkyl-, C3_ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C3_ ₆ cycloalkyl-C2- ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1-5 R ⁹ groups; wherein X ² is C^alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R ¹⁰ is CN, Ci_ ₄ alkyl, halogen, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy or In other embodiments of compounds of formulas (IVc-1), (IVc-2), (IVc-3), (IVc-4) or (IVc-5), R ¹⁰ is CN, CH ₃ , Et, CI, Br, F, CF ₃ , CF ₂ H-, CFH , CH ₃ O-, CF ₃ O-, CF ₂ HO- or CFH ₂ 0-.

[0163] In a 15th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) have subformulas (IVd):

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , p, Y ² and Y ³ in formula (IVd) are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) or in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formula (IVd), R ⁵ is H. In some embodiments of compounds of formula (IVd), Y ² is N or CR ¹⁰ and Y ³ is N or CH, wherein R ¹⁰ is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from; (i) 1-5 R ⁹ groups; or (ii) 1-5 R ^c substituents; or (iii) 1-5 R ^d substituents; or (iv) 1-5 R ¹⁵ substituents; or (v) 1-5 R ¹⁶ substituents; or (vi) 1-5 R ¹⁷ substituents; or (vii) 1-5 R ¹⁸ substituents; or (viii) 1-5 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, - CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH- , (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , wherein X ² is C^alkylene, -0-, -S- or - NH-. In other embodiments of compounds of formula (IVd), Y ² and Y ³ are CH. In other embodiments, Y is N and Y is CH. In other embodiments, Y is CR , wherein R is a substituent other than hydrogen as disclosed herein and Y ³ is CH. The subscript p is 0, 1 , 2 or 3. In certain embodiments of compounds of formula (IVd), the subscript p is 0. In other embodiments of compounds of formula (IVd), the subscript p is 1. In other embodiments of compounds of formula (IVd), the subscript p is 2. In other embodiments of compounds of formula (IVd), the subscript p is 3.

[0164] In a 16th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVd) have subformulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5):

(IVd-4) (IVd-5)

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m and R ¹⁰ in formulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5) are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVd) or in any of the embodiments as disclosed herein. In one embodiment, p is 0. In another embodiment, p is 1. In yet another embodiment, p is 2 and each R ⁷ is an independently selected member. In one embodiment of compounds of formulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R ⁵ is H. In yet another embodiment, R ⁵ is In some embodiments of compounds of formulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Q^alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formulas (IVd- 1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R ¹⁰ is CN, Ci_ ₄ alkyl, halogen, Ci_ ₄ haloalkyl, Ci_ ₄ haloalkoxy or In other embodiments of compounds of formulas (IVd-1), (IVd-2), (IVd-3), (IVd-4) or (IVd-5), R ¹⁰ is CN, CH ₃ , Et, CI, Br, F, CF ₃ , CF ₂ H-, CFH ₂ -, CH ₃ O-, CF ₃ O-, CF ₂ HO- or CFH ₂ 0-.

[0165] In a 17th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) have sub formulas (IVe):

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m, Y ² and Y ³ are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III) or (IV) or in any of the embodiments as disclosed herein. In one embodiment, R ⁵ is H or Ci_ ₄ alkyl. In another embodiment of compounds of formula (IVe), R ⁵ is H. In some embodiments of compounds of formula (IVe), Y is N or CR and Y is N or CH, wherein R is H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkyl-Ci_ ₄ alkyl-, C ₃ _ ₆ cycloalkenyl-Ci_ ₄ alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ Cycloalkyl-C ₂ _ ₄ alkenyl-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ _ ₄ alkynyl-X ² -, heterocyclyl-Ci_ ₄ alkyl- or R ⁸ , each of which is optionally substituted with from; (i) 1-5 R ⁹ groups; or (ii) 1-5 R ^c substituents; or (iii) 1-5 R ^d substituents; or (iv) 1-5 R ¹⁵ substituents; or (v) 1-5 R ¹⁶ substituents; or (vi) 1-5 R ¹⁷ substituents; or (vii) 1-5 R ¹⁸ substituents; or (viii) 1-5 R ¹⁹ substituents, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ or R ¹⁸ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ , wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formula (IVe), Y ² and Y ³ are CH. In other embodiments, Y ² is N and Y 3 is CH. In other embodiments, Y 2 is CR 10 , wherein R 10 is a substituent other than hydrogen as disclosed herein and Y ³ is CH.

[0166] In an 18th group of embodiments of the disclosure, compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVe) have subformulas (IVe-1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5):

(IVe-1) (IVe-2) (IVe-3)

(IVe-4) (IVe-5)

The variables R ³ , R ⁴ , R ⁵ , R ⁷ , m and R ¹⁰ in formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5) are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (IV) or (IVe) or in any of the embodiments as disclosed herein. In one embodiment of compounds of formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R ⁵ is H or In another embodiment of compounds of formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R ⁵ is H. In yet another embodiment, R ⁵ is Ci_ ₄ alkyl. In some embodiments of compounds of formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R ¹⁰ is selected from Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C2- ₆ alkenyl, C2- ₆ alkynyl, aryl-Ci_ ₄ alkyl-, heteroaryl-Ci_4 alkyl-, C ₃ _ ₆ cycloalkyl-C _w alkyl-, C ₃ _ ₆ cycloalkenyl-C _w alkyl-, CH ₂ =CH-X ² -, C ₃ _ ₆ cycloalkyl-C ₂ ^alkenyl-X ² -, C ₃ _ ₆ Cycloalkyl-C ₂ - ₄ alkynyl-X ² -, or R ⁸ , each of which is optionally substituted with from 1 -5 R ⁹ groups; wherein X ² is Ci_ ₄ alkylene, -0-, -S- or -NH-. In other embodiments of compounds of formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R ¹⁰ is CN, C^alkyl, halogen, C^haloalkyl, Q. ₄ haloalkoxy or Ci_ ₄ alkoxy. In other embodiments of compounds of formulas (IVe- 1), (IVe-2), (IVe-3), (IVe-4) or (IVe-5), R ¹⁰ is CN, CH ₃ , Et, CI, Br, F, CF ₃ , CF ₂ H-, CFH ₂ -, CH ₃ 0-, CF ₃ 0-, CF ₂ HO- or CFH ₂ 0-

[0167] In a 19 ^th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V) or (V) have subformula (Va):

each of the Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ substituents is independently selected from CH, CR ⁹ or N, wherein at each occurrence, at least two of the Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ substituents are independently selected from CH or CR ⁹ , wherein R ⁹ is as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V) or (V) as described herein. In certain embodiments, R ⁹ is R ^c , or R ^d , or R ^e substituent. In some embodiments, L ² is a bond, -CH ₂ -, -C(O)- or -S0 ₂ -. In one instance, L ² is a bond. In other another instance, L ² is -CH ₂ -, -C(O)- or -S0 ₂ -. In some embodiments of compounds of formula (Va), Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . In other embodiments, Y ⁴ is N and Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . In other embodiments, Y ⁴ is N, Y ⁵ is N and Y ⁶ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . In other embodiments, Y ⁴ is N, Y ⁶ is N and Y ⁵ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . Y ⁴ is N, Y ⁷ is N and Y ⁵ , Y ⁶ and Y ⁸ are each independently CH or CR ⁹ . Y ⁴ is N, Y ⁸ is N and Y ⁵ , Y ⁶ and Y ⁷ are each independently CH or CR ⁹ . Y ⁵ is N and Y ⁴ , Y ⁶ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . Y ⁶ is N and Y ⁴ , Y ⁵ , Y ⁷ and Y ⁸ are each independently CH or CR ⁹ . In certain embodiments of compounds of formula (Va), the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is optionally substituted with from: (i) 1 -3 R ⁹ groups; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1 -3 R ¹⁵ substituents; or (v) 1 -3 R ¹⁶ substituents; or (vi) 1 -3 R ¹⁷ substituents; or (vii) 1 -3 R ¹⁸ substituents; (viii) 1 -3 R ¹⁹ substituents; or (ix) 1 -3 R ²⁰ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, -PH(=0)CH ₃ , -P(=0)(CH ₃ ) ₂ , -PH(=0)(OC ₁ . ₆ alkyl), -P(=0)(OC ₁ . ₆ alkyl) ₂ , -OP(=0)( Od_ ₆ alkyl) ₂ , CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH-, EtNHS0 ₂ -, PhNHS0 ₂ -, CH ₃ S0 ₂ NH-, EtS0 ₂ NH-, PhS0 ₂ NH-, CH ₃ S0 ₂ , EtS0 ₂ , PhS0 ₂ -, 4-morpholinyl,

EtOC(0)NH-, CH ₃ OC(0)NH-, EtNHC(0)NH-, CH ₃ NHC(0)NH-, EtOC(0)0- or CH ₃ OC(0)0-, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ substituent is further optionally substituted with from 1 -3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In one embodiment, R ⁵ is H. In some embodiments, Y ¹ is N and R ¹ is a lone pair of electron. In certain embodiments, Y ¹ is C and R ¹ is H, halogen, Ci_4 alkyl, Ci_4 haloalkoxy or cyclopropyl. In one embodiment, Y ¹ is C and R ¹ is H. The variables R ¹ , R ³ , R ⁴ , R ⁵ , Y ¹ , Y ² , Y ³ and L ² and are as defined in any of the embodiments of compounds of formulas (Γ), (I'a), (I), (II), (III), (Ilia) or (IV) and in any of the embodiments as disclosed herein.

[0168] In a 20 ^th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va) have subformulas (Va- 1), (Va-2) or (Va-3):

(Va- 1) (Va-2)

(Va-3)

The variables, R ³ , R ⁴ , R ⁵ , R ¹⁰ , R ¹ , L ² , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ or Y ⁸ in formulas (Va- 1), (Va-2) or (Va-3) are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va). In some instances of compounds of formulas (Va- 1), (Va-2) or (Va-3), R ⁵ is H. In other instances of compounds of formulas (Va- 1), (Va-2) or (Va-3), R ¹ is H. In other instances of compounds of formulas (Va- 1), (Va-2) or (Va-3), L ² is a bond. In still other instances of compounds of formulas (Va- 1), (Va-2) or (Va-3), R ¹⁰ is H. In one embodiment of compounds of formulas (Va- 1), (Va-2) or (Va-3), R ¹ , R ⁵ and R ¹⁰ are H and L ² is a bond.

[0169] In a 21 ^st group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va- 1), (Va-2) or (Va-3) have subformulas (Va- l a), (Va- l a- 1), (Va-2a), (Va-2a- l) or (Va-3a):

(Va-3a) The variables, R ³ , R ⁴ , R ¹⁰ , R ¹ , L ² , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ or Y ⁸ in formulas (Va-la), (Va- la-1), (Va-2a), (Va-2a-l) or (Va-3a) are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-1), (Va-2) or (Va-3).

[0170] In a 22 ⁿ group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-1), (Va-2), (Va-3), (Va-la), (Va- la-1), (Va-2a), (Va-2a-l) or (Va-3a) have subformulas (Va- lb), (Va-lb-1), (Va-2b), (Va-2b-l) or (Va-3b):

(Va-2b-l) (Va-3b)

The variables, R ³ , R ⁴ , R ¹ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ or Y ⁸ in formulas (Va-lb), (Va-lb-1), (Va-2b), (Va-2b- l) or (Va-3b) are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va- 1), (Va-2), (Va-3, (Va-la), (Va-la-1), (Va-2a) or (Va-2a-l).

[0171] In a 23rd group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va) have subformula (Va-4):

3 4 1 2 3 1 2 9

The variables R R V, Y Y R , and in formula (Va-4) are as defined in any of the

embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va). The subscript n is 0, 1, 2 or 3. In some embodiments of compounds of formula (Va-4), L ¹ is -C(0)N(R ⁵ )-, wherein R ⁵ is H or d_ ₄ alkyl. In some embodiments of compounds of formula (Va-4), L ² is a bond. In some embodiments of compounds of formula (Va-4), Y ³ is N and Y ² is CR ¹⁰ . In other embodiments of compounds of formula (Va-4), Y ³ is N and Y ² is CH. In other embodiments of compounds of formula (Va-4), Y ³ and Y ² are CH. In other embodiments of compounds of formula (Va-4), Y ³ is CH and Y ² is N. In some embodiments of compounds of formula (Va-4), R ⁹ is a R ^c ; or R ^d ; or R ^e ; or R ¹⁵ ; or R ¹⁶ ; or R ¹⁷ ; or R ¹⁹ ; or R ²⁰ group.

[0172] In a 24th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va) or (Va-4) have subformula (Va-4a):

3 4 5 2 3 1 2 9

The variables R R R Y Y R , and R ^y are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va) or (Va-4a). The subscript n is 0, 1, 2 or 3. In some embodiments of compounds of formula (Va-4a), R ⁵ is H. In other embodiments of compounds of formula (Va-4a), R ⁵ is In some embodiments of compounds of formula (Va-4a), L ² is a bond, - CH ₂ -, -C(O)- or -SO ₂ . In some embodiments of compounds of formula (Va-4a), L ² is a bond. In some embodiments of compounds of formula (Va-4a), Y ³ is N and Y ² is CR ¹⁰ . In other embodiments of compounds of formula (Va-4a), Y ³ is N and Y ² is CH. In other embodiments of compounds of formula (Va-4a), Y ³ and Y ² are CH. In other embodiments of compounds of formula (Va-4a), Y ³ is CH and Y ² is N. In some embodiments of compounds of formula (Va-4a), R ⁹ is a R ^c ; or R ^d ; or R ^e ; or R ¹⁵ ; or R ¹⁶ ; or R ¹⁷ ; or R ¹⁹ ; or R ²⁰ group.

[0173] In a 25th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-4) or (Va-4a) have subformula (Va-4a-l):

3 4 5 2 3 1 2 9

The variables R R R Y Y R , V, W and the script n are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-4) or (Va-4a). In some embodiments of compounds of formula (Va-4a-l), L ² is a bond, -CH ₂ -, -C(O)- or -S0 ₂ .

[0174] In a 26th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-4), (Va-4a) or (Va-4a-l) have subformula (Va-4a- la):

The variables R ³ , R ⁴ , R ⁵ , Y ² , Y ³ , R ¹ , R ⁹ and the script n are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va), (Va-4), (Va-4a) or (Va-4a-l). In some embodiments of compounds of formula (Va-4a-l), Y ³ is N and Y ² is CR ¹⁰ . In other embodiments of compounds of formula (Va-4a-l), Y ³ is N and Y ² is CH. In other embodiments of compounds of formula (Va-4a-l), Y ³ and Y ² are CH. In other embodiments of compounds of formula (Va-4a-l), Y ³ is CH and

Y ² is N.

[0175] In a 27th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va) have subformulas (Va-5a), (Va-5b) or (Va-5c):

(Va-5a) (Va-5b) (Va-5c)

3 4 1 2 3 1 2 9

The variables R R V, Y Y R , and are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va). The subscript n is 0, 1, 2 or 3. In some embodiments of compounds of formulas (Va-5a), (Va-5b) or (Va-5c), L ¹ is -C(0)N(R ⁵ )-, wherein R ⁵ is H or C ₁ _ ₄ alkyl. In some embodiments of compounds of formula (Vb), L ² is a bond. In some embodiments of compounds of formulas (Va-5a), (Va-5b) or (Va-5c), Y ³ is N and Y ² is CR ¹⁰ . In other embodiments of compounds of formulas (Va-5a), (Va-5b) or (Va-5c), Y ³ is N and Y ² is CH. In other embodiments of compounds of formulas (Va-5a), (Va-5b) or (Va-5c), Y ³ and Y ² are CH. In other embodiments of compounds of formula (Va-5a), (Va-5b) or (Va-5c), Y ³ is CH and Y ² is N. In some embodiments of compounds of formulas (Va-5a), (Va-5b) or (Va-5c), R ⁹ is a R ^c ; or R ^d ; or R ^e ; or R ¹⁵ ; or R ¹⁶ ; or R ¹⁷ ; or R ¹⁹ ; or R ²⁰ group.

[0176] In a 28th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va) have subformula (Va-6):

The variables, R ³ , R ⁴ , R ⁵ , R ¹⁰ , L ² , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ or Y ⁸ in formula (Va-6) are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V) or (Va). In some instances of compounds of formula (Va-6), R ⁵ is H. In other instances of compounds of formula (Va-6), R ¹ is H. In other instances of compounds of formulas (Va-6), L ² is a bond. In still other instances of compounds of formulas (Va-6), R ¹⁰ is H. In other instances of compounds of formulas (Va-6), Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are CH, each of which is optionally substituted with from (i) a R ⁹ group; or (ii) a R ^c substituent; or (iii) a R ^d substituent; or (iv) a R ¹⁵ substituent; or (v) a R ¹⁶ substituent; or (vi) a R ¹⁷ substituent; or (vii) a R ¹⁸ substituent; (viii) a R ¹⁹ substituent; or (ix) a R ²⁰ substituent selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , - NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH-, EtNHS0 ₂ -, PhNHS0 ₂ -, CH ₃ S0 ₂ NH-, EtS0 ₂ NH-, PhS0 ₂ NH-, CH ₃ S0 ₂ , EtS0 ₂ , PhS0 ₂ -, 4-morpholinyl, EtOC(0)NH-,

CH ₃ OC(0)NH-, EtNHC(0)NH-, CH ₃ NHC(0)NH-, EtOC(0)0- or CH ₃ OC(0)0-, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2- azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ ,

CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In some embodiments of compounds of formulas (Va-1), (Va-2) or (Va-3), R ¹ , R ⁵ and R ¹⁰ are H; L ² is a bond; and Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are CH, each of which is optionally substituted with from (i) a R ⁹ group; or (ii) a R ^c substituent; or (iii) a R ^d substituent; or (iv) a R ¹⁵ substituent; or (v) a R ¹⁶ substituent; or (vi) a R ¹⁷ substituent; or (vii) a R ¹⁸ substituent; (viii) a R ¹⁹ substituent; or (ix) a R ²⁰ substituent selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , - NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH-, EtNHS0 ₂ -, PhNHS0 ₂ -, CH ₃ S0 ₂ NH-, EtS0 ₂ NH-, PhS0 ₂ NH-, CH ₃ S0 ₂ , EtS0 ₂ , PhS0 ₂ -, 4-morpholinyl, EtOC(0)NH-,

CH ₃ OC(0)NH-, EtNHC(0)NH-, CH ₃ NHC(0)NH-, EtOC(0)0- or CH ₃ OC(0)0-, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, -OH, - NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . 0177] In a 29th group of embodiments of the disclosure, compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va) or (Va-6) have subformulas (Va-6a), (Va-6b), (Va-6c) or (Va-6d):

(Va-6a) (Va-6b)

(Va-6c) (Va-6d)

The variables, R ³ , R ⁴ and R ⁹ in formulas (Va-6a), (Va-6b), (Va-6c) or (Va-6d) are as defined in any of the embodiments of compounds of formulas (Γ), (I), (II), (III), (V), (V), (Va) or (Va-6). The subscript p is 0, 1, 2 or 3. In some embodiments of compounds of formulas (Va-6a), (Va-6b), (Va-6c) or (Va-6d), R ⁹ is R ²⁰ .

[0178] In some embodiments of compounds of any of formulas (Va), (Va-1), (Va-2), (Va-3), (Va-la), (Va-2a), (Va-3a), (Va-la-1), (Va-2a- l), (Va- lb), (Va-2b), (Va-3b), (Va-lb- 1), (Va-2b- l), (Va-6), (Va- 6a), (Va-6b), (Va-6c) or (Va-6d), wherein the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is optionally substituted with from (i) 1-3 R ⁹ groups; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1-3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents; (viii) 1-3 R ¹⁹ substituents; or (ix) 1-3 R ²⁰ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 1 -azetidinyl, 2-azetidinyl, 3-azetidinyl, 2-oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ -, (CH ₃ ) ₂ S(0) ₂ NH-, EtNHS0 ₂ -, PhNHS0 ₂ -, CH ₃ S0 ₂ NH-, EtS0 ₂ NH-, PhS0 ₂ NH-, CH ₃ S0 ₂ , EtS0 ₂ , PhS0 ₂ -, 4-morpholinyl,

EtOC(0)NH-, CH ₃ OC(0)NH-, EtNHC(0)NH-, CH ₃ NHC(0)NH-, EtOC(0)0- or CH ₃ OC(0)0-, wherein each of R ⁹ , R ^c , R ^d , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ or R ²⁰ substituent is further optionally substituted with from 1-3 R ¹⁹ substituents independently selected from -CN, F, CI, I, -OCH ₃ , Ci_ ₆ alkyl, cyclopropyl, 2- oxetanyl, 3-oxetanyl, -OH, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CH ₂ F, -CHF ₂ , CF ₃ , -OCF ₃ , -OCHF ₂ , -OCH ₂ F, CH ₃ C(0)-, CH ₃ C(0)0-, CH ₃ OC(0)-, CH ₃ NHC(0)-, CH ₃ C(0)NH-, (CH ₃ ) ₂ NC(0)-, (CH ₃ ) ₂ NS(0) ₂ - ,(CH ₃ ) ₂ S(0) ₂ NH- or CH ₃ S0 ₂ . In some instances, the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is an optionally substituted benzene ring. In other instances, the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is an optionally substituted pyridine ring, wherein Y ⁴ is N; or Y ⁵ is N or Y ⁶ is N. In other instances, the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is an optionally substituted pyrimidine ring, wherein Y ⁴ and Y ⁶ are N; or Y ⁴ and Y ⁸ are N; or Y ⁵ and Y ⁷ are N. In other instances, the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is an optionally substituted pyrazine ring, wherein Y ⁴ and Y ⁷ are N. In other instances, the aromatic ring containing Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ is an optionally substituted pyridazine ring, wherein Y ⁴ and Y ⁵ are N; or Y ⁵ and Y ⁶ are N. In some embodiments, the optional substituents for the benzene, pyridine, pyrimidine, pyrazine or pyridazine rings are (i) 1-3 R ⁹ groups; or (ii) 1-3 R ^c substituents; or (iii) 1-3 R ^d substituents; or (iv) 1-3 R ¹⁵ substituents; or (v) 1-3 R ¹⁶ substituents; or (vi) 1- 3 R ¹⁷ substituents; or (vii) 1-3 R ¹⁸ substituents; (viii) 1-3 R ¹⁹ substituents; or (ix) 1-3 R ²⁰ substituents.

[0179] In some embodiments of compounds of any of formulas (Ilia), (Illb), (IIIc), (Hid), (Hid), (Hie), (IIIa- 1), (IIIa-2), (IIIa-3), (IIIa-4), (IIIa-5), (IIIa-6), (IIIa-7), (IIIa-8), (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb-5), (IIIc-1), (IIIc-2), (IIIc-3), (IIIc-4), (IIIc-5), (IIId-1), (IIId-2), (IIId-3), (IIId-4), (IIId-5), (IIIe-1), (IIIe-2), (IIIe-3), (IIIe-4), (IIIe-5), (IVa), (IVa-1), (IVa-2), (IVa-3), (IVa-4), (IVa-5), (IVa-6), (IVa-7), (IVa-8), (IVa-9), (IVa- 10), (IVa- la), (IVa-2a), (IVa-3a), (IVa-4a), (IVa-5a), (IVa-6a), (IVa-7a), (IVa-8a), (IVa-9a), (IVa- lOa), (IVa-lb), (IVa-2b), (IVa-5b), (IVa-6b), (IVb), (IVb- 1), (IVb-2), (IVb-3), (IVb-4), (IVb-5), (IVb-6), (IVb-7), (IVb-8), (IVc), (IVc-1), (IVc-2), (IVc-3), (IVc-4), (IVc-5), (IVd), (IVd- 1), (IVd-2), (IVd-3), (IVd-4), (IVd-5), (IVe), (IVe-1), (IVe-2), (IVe-3), (IVe-4), (IVe-5), (V), (V), (Va), (Va-1), (Va-2), (Va-3), (Va-la), (Va-2a), (Va-3a), (Va-la-1), (Va-2a- l), (Va- lb), (Va-2b), (Va-3b), (Va- lb-1), (Va-2b-l), (Va-6), (Va-6a), (Va-6b), (Va-6c) or (Va-6d), R ³ and R ⁴ are each independently selected from H, Ci_ ₆ alkyl, halogen, CN, cyclopropyl, CN-CH ₂ -, phenyl, cyclopropylmethyl, Ci_ ₆ alkoxy, Ci_ ₆ haloalkyl, Ci_ ₆ haloalkoxy or R ^s . In other instances, R ³ and R ⁴ are each independently selected from H, -CH ₃ , -CD ₃ , -C ₆ D ₅ , -CF ₃ , -CHF ₂ , -CH ₂ F, -OCF ₃ , -OCHF ₂ , -OCH ₂ F halogen, CN, cyclopropyl, CN- CH ₂ -, phenyl, cyclopropylmethyl or -OCH ₃ . In yet other instances, R ³ and R ⁴ are each independently H, F, CI, Br, NH ₂ C(0)-, CH ₃ , CD ₃ , Et, cyclopropyl, CN, CH ₂ CH ₂ - or CH ₃ C(0)NH-. In other instances, R ³ and R ⁴ are D. In other instances, R ³ and R ⁴ are Ci_ ₆ alkyl. In other instances, R ³ and R ⁴ are Ci_ ₄ alkoxy.

[0180] In some embodiments, the disclosure provides any of the compounds set forth in Table 1, or pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers thereof. In certain embodiments, the disclosure provides the above selected compounds and pharmaceutically acceptable salts thereof. In certain embodiments, the disclosure provides any of compounds P-2001 to P-2273 and P-2274 to P-2307 as described herein or pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers thereof. In certain embodiments, the disclosure provides any of the compounds described in formulas (Γ), (I'a), (I), (ΙΙ),(ΙΙΙ), (IV), or any of the subformulas as described herein, any of the compounds described in the examples and any of the compounds described herein, or pharmaceutically acceptable salts, hydrates, solvates, tautomers or isomers thereof.

[0181] In some embodiments, the disclosure provides a compound selected from: (2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol (P-2001),

(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)metha none (P-2002),

N-(3-carbamoylphenyl)-2-phenyl-lH-pyrrolo[2,3-b]pyridine- 5-carboxamide (P-2003),

2- phenyl-N-(lH-pyrazol-3-yl)-lH-pyrrolo[2,3-b]pyridine-5-carbo xamide (P-2004),

4-bromo-N-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyr azole-5-carboxamide, (P-2005), ethyl 3-[(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)carbamoylamino]propanoate, (P-2006),

3.4- dimethyl-N-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyraz ole-5-carboxamide (P-2007),

4- methyl-3-phenyl-N-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-l H-pyrazole-5-carboxamide, (P- 2008),

3- cyclopropyl-N-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-py razole-5-carboxamide,(P-2009),

5- fluoro-N-(2-phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-indazole-3-carboxamide (P-2010), N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide (P-201 1),

3-fluoro-N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide (P-2012),

3.5- dimethyl-N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carboxamide (P-2013), N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide (P-2014),

N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-carboxamide (P-2015),

3-methyl-N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide (P-2016),

4,5-dimethyl-N-(2 -phenyl- lH-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carboxamide (P-2017), N-(2-phenyl-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-4-sul fonamide (P-2018),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-3-methy l- lH-pyrazole-5-carboxamide (P- 2019),

N3-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]benzene - l,3-dicarboxamide (P-2020),

3- (cyanomethyl)-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin -5-yl]benzamide (P-2021),

2- chloro-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]- 6-methyl-benzamide (P-2022),

4- chloro-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]- 3-methyl-lH-pyrazole-5-carboxamide (P-2023),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-3,4-dim ethyl- lH-pyrazole-5-carboxamide(P- 2024),

3- cyano-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]be nzamide (P-2025),

3-acetamido-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridi n-5-yl]benzamide (P-2026),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-2H-i ndazole-4-carboxamide (P-2027),

3-ethyl-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5- yl]-4-methyl- lH-pyrazole-5-carboxamide (P-2028),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-4-methy l- lH-pyrazole-3-carboxamide (P- 2029),

2-ethyl-N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl] pyrazole-3-sulfonamide (P-2030), 5-methyl-N- [2- [ 1 -(mo^holine-4-carbony

yl]-lH-pyrazole-3-carboxamide (P-2031),

3,4-dimethyl-N-(lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazole-5 -carboxamide (P-2032),

N-[l-(benzenesulfonyl)-2-[l-(mo^holine-4-carbonyl)-3,6-dihyd ro-2H-pyridin-4-yl]pyrrolo[2,3- b]pyridin-5-yl]-3,4-dimethyl-lH-pyrazole-5-carboxamide (P-2033),

3,4-dimethyl-N-[2-[l-(mo^holine-4-carbonyl)-3,6-dihydro-2H-p yridin-4-yl]-lH-pyrrolo[2,3- b]pyridin-5-yl]-lH-pyrazole-5-carboxamide (P-2034),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-lH-l,2, 4-triazole-5-carboxamide (P-2035),

4-chloro-3-methyl-N-[2-[l-(mo^holine-4-carbonyl)-3,6-dihy dro-2H-pyridin-4-yl]-lH-pyrrolo[2,3- b]pyridin-5-yl]-lH-pyrazole-5-carboxamide (P-2036),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-5-methy l-2H-triazole-4-carboxamide (P-2037),

N-[2-(l,3-dimethylpyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin- 5-yl]-3,4-dimethyl- lH-pyrazole-5- carboxamide (P-2038),

4-chloro-N-[2-[l-(cyclopropanecarbonyl)-3,6-dihydro-2H-pyrid in-4-yl]- lH-pyrrolo[2,3-b]pyridin-5- yl]-5-methyl-lH-pyrazole-3-carboxamide (P-2039),

3,4-dimethyl-N-(3-methyl-lH-pyrazolo[3,4-b]pyridin-5-yl)- lH-pyrazole-5-carboxamide (P-2040),

N-[3-(4-fluorophenyl)-lH-pyrazolo[3,4-b]pyridin-5-yl]-3,4 -dimethyl-lH-pyrazole-5-carboxamide (P- 2041),

N-[2-[l-(cyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]- lH-pyrrolo[2,3-b]pyridin-5-yl]-5- methyl-lH-pyrazole-3-carboxamide (P-2042),

N-[2-[l-(cyclopropanecarbonyl)-3,6-dihydro-2H-pyridin-4-yl]- lH-pyrrolo[2,3-b]pyridin-5-yl]-4,5- dimethyl- lH-pyrazole-3-carboxamide (P-2043),

N-(2-anilinopyrimidin-5-yl)-3,4-dimethyl-lH-pyrazole-5-carbo xamide (P-2044), N-(6-anilino-3-pyridyl)-3,4-dimethyl- lH-pyrazole-5-carboxamide (P-2045), N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-lH-inda zole-3-carboxamide (P-2046),

N-[2-(4-fluorophenyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]-4,5, 6,7-tetrahydro-lH-indazole-3-carboxamide (P-2047),

3,4-dimethyl-N-[2-[l-(4-piperidyl)pyrazol-4-yl]-lH-pyrrolo[2 ,3-b]pyridin-5-yl]- lH-pyrazole-5- carboxamide (P-2048),

N-(2-chloro-lH-pyrrolo[2,3-b]pyridin-5-yl)-3,4-dimethyl- lH-pyrazole-5-carboxamide (P-2049), N-[2-[3-(ethylsulfamoyl)anilino]pyrimidin-5-yl]-3,4-dimethyl - lH-pyrazole-5-carboxamide (P-2050),

3,4-dimethyl-N-[2-(3-mo^holinoanilino)pyrimidin-5-yl]-lH- pyrazole-5-carboxamide (P-2051),

3,4-dimethyl-N-[2-[3-(propylsulfonylamino)anilino]pyrimid in-5-yl]-lH-pyrazole-5-carboxamide (P-

2052) ,

N-[2-[3-(benzenesulfonamido)anilino]pyrm (P-