Tetracyclic compounds for treating HIV infection

Abstract

The present disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making said compounds and pharmaceutical compositions. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection. (Formula (I))

Description

TETRACYCLIC COMPOUNDS FOR TREATING HIV INFECTION CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 980,857 filed on February 24, 2020, U.S. Provisional Application No. 63 / 036,268 filed June 8, 2020, and U.S. Provisional Application No. 63 / 128,670 filed December 21, 2020. FIELD

[0002] This disclosure relates generally to certain tetracyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions. BACKGROUND

[0003] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains may limit their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853–860; Richman, D. D. Nature (2001) 410:995–1001). Accordingly, there is a need for new agents that inhibit the replication of HIV.

[0004] A goal of antiretroviral therapy is to achieve viral suppression in the HIV infected patient. Current treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at https: / / files.aidsinfo.nih.gov / contentfiles / lyguidelines / AdultandAdolescentGL.pdf. Accessed February 20, 2020). In addition, decisions regarding the treatment of HIV infected patients are complicated when the patient requires treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the potential for drug interaction is a criterion for selection of a drug regimen. As such, there is a need for antiretroviral therapies having a decreased potential for drug interactions.

[0005] In addition, the HIV virus is known to mutate in infected subjects (Tang, et al. Drugs (2012) 72 (9) e1-e25). Because of the proclivity of the HIV virus to mutate, there is a need for anti-HIV drugs to be effective against a range of known HIV variants (Hurt, et al. HIV / AIDS) CID (2014) 58, 423-431).

[0006] For certain patients, for example, those with difficult or limited access to health care, adherence to daily oral treatment or prophylactic regimens can be challenging. Drugs that offer favorable pharmaceutical properties (for example, improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are amenable to less frequent administration and provide for better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the emergence of drug resistance. SUMMARY

[0007] In one aspect, provided herein is a compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is a H, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of <semantics>−C(O)NH−<annotation encoding="application / x-tex">-C(O)NH-< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] X is a bond or <semantics>−CR8aR8b<annotation encoding="application / x-tex">-CR^{8a}R^{8b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> ₽12a or –O–; or T and U together are sh sh • <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics>, <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics>, and <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> are independently H, <semantics>C1-6<annotation encoding="application / x-tex">C_{1\text{-}6}< / annotation>< / semantics>alkyl, <semantics>C1-6<annotation encoding="application / x-tex">C_{1\text{-}6}< / annotation>< / semantics>haloalkyl, <semantics>C3-<annotation encoding="application / x-tex">C_{3\text{-}}< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>; or Ci any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> or (iii) <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> and <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>; R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe; <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics>, <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics>, <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> are independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl; or any one of (i) <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, (ii) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, (iii) <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics> and <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, (iv) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, (v) <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics> and R5d, (vi) R8a and R8b, (vii) R9a and R9b, (viii) R9c and R9d, (ix) R9a and R9c, (x) R9b and R9d, (xi) <semantics>R8h<annotation encoding="application / x-tex">R^{8h}< / annotation>< / semantics> and one of <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, and <semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>, or (xii) one of <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> and one of <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, R4b, R5a, R5b, and R7 together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORc; CA each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; or any one of (i) R6a and R6b or (ii) R10a and R10b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe; R7 is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; CA WO 2021 / 173522 wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>; Rb is H, C1-4alkyl, C1-4haloalkyl or C3-6cycloalkyl; Rf is H, halo, C1-4alkyl, or C1-4haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl; <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>, each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - <semantics>NR2e<annotation encoding="application / x-tex">NR^{e}_{2}< / annotation>< / semantics>, or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>; each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0008] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In another embodiment, the disclosure provides a kit comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0010] In another embodiment, the disclosure provides a method of treating an HIV infection in a human having or at risk of having the infection, wherein the method comprises administering to the human a therapeutically effective amount of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or the pharmaceutical of the disclosure.

[0011] In another embodiment, the disclosure provides use of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for treating an HIV infection in a human having or at risk of having the infection.

[0012] In another aspect, the disclosure provides a compound of the disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for use in medical therapy.

[0013] In another embodiment, the disclosure provides use of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for use in treating an HIV infection.

[0014] In another aspect, the disclosure provides use of a compound of the disclosure, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the disclosure, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection. DETAILED DESCRIPTION

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. I. Definitions

[0016] Unless the context requires otherwise, throughout the present disclosure and claims, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, that is as "including, but not limited to". CA

[0017] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] "Amino" refers to the -NH2 radical.

[0019] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0020] "Oxo" refers to the =O substituent.

[0021] A prefix such as "Cu-v" or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, "C1-6alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0022] "Alkyl" refers to a straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms, which is saturated, having from one to twelve carbon atoms (C1-12alkyl), in certain embodiments one to eight carbon atoms (<semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics>alkyl) or one to six carbon atoms (<semantics>C1−8<annotation encoding="application / x-tex">C_{1-8}< / annotation>< / semantics> 6alkyl), or one to four carbon atoms (C1-4alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1- methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0023] "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,1 ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0024] "Aryl" or "aromatic ring" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used CA herein, aryl has 6 to 20 ring carbon atoms (i.e., <semantics>C6−20<annotation encoding="application / x-tex">C_{6-20}< / annotation>< / semantics> aryl), 6 to 12 carbon ring atoms (i.e., <semantics>C6−12<annotation encoding="application / x-tex">C_{6-12}< / annotation>< / semantics> aryl), or 6 to 10 carbon ring atoms (i.e., <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below.

[0025] "Cyano" or "carbonitrile" refers to the group -CN.

[0026] "Cycloalkyl" or "carbocyclic ring" refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., <semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics> cycloalkyl), 3 to 10 ring carbon atoms (i.e., <semantics>C3−12<annotation encoding="application / x-tex">C_{3-12}< / annotation>< / semantics> 10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Halocycloalkyl" refers to a cycloalkyl substituted with one or more halogens.

[0027] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.

[0028] "Haloalkyl" refers to an alkyl group, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0029] "Heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 5 to 20 ring atoms (5 to 20 membered heteroaromatic ring), 5 to 12 ring atoms (5 to 12 membered heteroaromatic ring), 5 to 10 ring atoms (5 to 10 membered heteroaromatic ring) or 5 to 6 ring atoms (5 to 6 membered heteroaromatic ring); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0030] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having from three to fifteen atoms wherein from one to six atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and attached to the rest of the molecule by a CA single bond. In certain embodiments, "heterocyclyl" has from three to ten atoms, wherein from one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or from three to seven atoms, wherein from one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen, carbon or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. As used herein, "heterocyclyl" or "heterocyclic ring" refers to rings that are saturated unless otherwise indicated, e.g., in some embodiments "heterocyclyl" or "heterocyclic ring" refers to rings that are saturated or partially saturated where specified. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0031] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I being isotopically-labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. In certain embodiments, these radiolabeled compounds are useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labeled compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0032] In certain embodiments, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.

[0033] Substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb can be prepared by techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0034] The methods, compositions, kits and articles of manufacture provided herein use or include compounds (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb) or pharmaceutically acceptable salts thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds increase resistance to metabolism, and thus are useful for increasing the half- life of compounds or pharmaceutically acceptable salts thereof, when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0035] The embodiments disclosed herein are also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0036] "Mammal" includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

[0037] "Optional" or "optionally" means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted and that the description includes both substituted heterocyclyl radicals and heterocyclyl radicals having no substitution.

[0038] "Pharmaceutically acceptable excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition and is compatible with the other ingredients of the formulation and suitable for use in humans or domestic animals without undue toxicity, irritation, allergic response, and the like.

[0039] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), ammonium and <semantics>NX4+<annotation encoding="application / x-tex">NX_4^+< / annotation>< / semantics> (wherein X is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl). Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts of organic carboxylic acids such as acetic, trifluoroacetic, adipic, ascorbic, aspartic, butyric, camphoric, cinnamic, citric, digluconic, glutamic, glycolic, glycerophosphoric, formic, hexanoic, benzoic, lactic, fumaric, tartaric, maleic, hydroxymaleic, malonic, malic, mandelic, isethionic, lactobionic, nicotinic, oxalic, pamoic, pectinic, phenylacetic, 3-phenylpropionic, pivalic, propionic, pyruvic, salicylic, stearic, sulfanilic, tartaric, undecanoic, and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, camphorsulfonic, mesitylenesulfonic, benzenesulfonic, p-toluenesulfonic acids, naphthalenesulfonic, and 2- naphthalenesulfonic; and inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, and sulfamic acids. Pharmaceutically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as <semantics>Na+<annotation encoding="application / x-tex">Na^+< / annotation>< / semantics> and <semantics>NX4+<annotation encoding="application / x-tex">NX_4^+< / annotation>< / semantics> (wherein X is independently selected from H or a <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl group).

[0040] For the rapeutic use, salts of active ingredients of the compounds disclosed herein will typically be pharmaceutically acceptable, i.e., they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of Formula I or another compound of the embodiments disclosed herein. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0041] Metal salts typically are prepared by reacting the metal hydroxide with a compound according to the embodiments disclosed herein. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0042] In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines. Finally, it is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form.

[0043] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable excipients.

[0044] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the embodiments disclosed herein, which when administered to a patient in need thereof, is sufficient to effect treatment of disease-states, conditions, or disorders disclosed herein. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician. The amount of a compound according to the embodiments disclosed herein which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination, or coincidentally, with the compounds of the embodiments disclosed herein, and the age, body weight, general health, sex and diet of the patient. Such a therapeutically effective amount can CA be determined by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0045] The terms "treating" and "treatment" as used herein are intended to mean the administration of a compound or composition according to the present embodiments disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and / or to reduce viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and / or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, and the administration of a compound or composition according to the present embodiments disclosed herein to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms "treating" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein before the exposure of the individual to the virus (also called pre-exposure prophylaxis or PrEP), to prevent HIV infection from taking hold if the individual is exposed to the virus and / or to keep the virus from establishing a permanent infection and / or to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood. The terms "treating" and "treatment" also encompass the administration of a compound or composition according to the present embodiments disclosed herein both before and after the exposure of the individual to the virus.

[0046] As used herein, the terms "preventing" and "prevention" refer to the administration of a compound, composition, or pharmaceutically salt according to the present disclosure pre- or post-exposure of the human to the virus but before the appearance of symptoms of the disease, and / or prior to the detection of the virus in the blood. The terms also refer to prevention of the appearance of symptoms of the disease and / or to prevent the virus from reaching detectible levels in the blood. The terms include both pre-exposure prophylaxis (PrEP), as well as post- exposure prophylaxis (PEP) and event driven or "on demand" prophylaxis. The terms also refer to prevention of perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms also refer to prevention of transmission of HIV through blood transfusion. CA

[0047] The term "antiviral agent" as used herein is intended to mean an agent (compound or biological) that is effective to inhibit the formation and / or replication of a virus in a human being, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and / or replication of a virus in a human being.

[0048] The term "inhibitor of HIV replication" as used herein is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in a host cell, whether in vitro, ex vivo or in vivo.

[0049] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0050] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, compounds disclosed herein may be in the form of a stereoisomer thereof.

[0051] "Partially unsaturated" refers to a cyclic group which contains at least one double bond but is not aromatic. П. Compounds

[0052] Disclosed herein are compounds of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is a H, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>heteroaryl is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of <semantics>−C(O)NH−<annotation encoding="application / x-tex">-C(O)NH-< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics>, <semantics>N−N<annotation encoding="application / x-tex">N-N< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . X is a bond or <semantics>−CR8aR8b<annotation encoding="application / x-tex">-CR^{8a}R^{8b}< / annotation>< / semantics>—; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] or –O–; or T and U together are R2a, R2b, R2c, R2d, R12a, and R12b are independently H, C1-6alkyl, C1-6haloalkyl, C3- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] n e [Image disponible dans le document PDF, Image available in the PDF document] any one of (i) R2a and R2b, (ii) R2c and R2d or (iii) R12a and R12b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORc; R3a and R3b are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic <semantics>Ci<annotation encoding="application / x-tex">C_i< / annotation>< / semantics> ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe, <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics>, <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics>, <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> are independently H, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl; or any one of (i) <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, (ii) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, (iii) <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics> and <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, (iv) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, (v) <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics> and <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, (vi) <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics> and <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics>, (vii) <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics> and <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, (viii) <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics> and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>, (ix) <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics> and <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, (x) <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics> and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>, (xi) <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics> and one of <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, and <semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>, or (xii) one of <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> and one of <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, R4b, R5a, R5b, and R7 together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe; each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; or any one of (i) R6a and R6b or (ii) R10a and R10b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORc; R' is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1- 6 6 6 6 6 6 6 6 6 6 10 6 6 10 6 10 6 10 to 10 membered aromatic ring or the 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORc; Rb is H, C1-4alkyl, C1-4haloalkyl or C3-6cycloalkyl; Rf is H, halo, C1-4alkyl, or C1-4haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>; each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - <semantics>NRe2<annotation encoding="application / x-tex">NR^{e_2}< / annotation>< / semantics>, or <semantics>−ORe1<annotation encoding="application / x-tex">-OR^{e_1}< / annotation>< / semantics>, each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3. 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0053] In some embodiments, of the compounds of Formula I, R1 is H, C6-10 aryl or C6-10 10heteroaryl, wherein the C6-10aryl or C6-10heteroaryl are optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, - O-C1-4alkyl, -O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of -C(O)NH-, <semantics>s′<annotation encoding="application / x-tex">^{\prime}_{s}< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] • [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] X is a bond or <semantics>−CR8aR8b<annotation encoding="application / x-tex">-CR^{8a}R^{8b}< / annotation>< / semantics>—, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . . . [Image disponible dans le document PDF, Image available in the PDF document] -O-; or T and U together are , R2a, R2b, R2c, R2d, R12a, and R12b are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] any one of (i) R2a and R2b, (ii) R2c and R2d or (iii) R12a and R12b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe; R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; R4a, R4b, R5a, R5b, R5c, R5d, R8a, R8b, R9a, R9b, R9c, and R9d are independently H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4 4alkylene–O–C1-4alkyl; each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; R7 is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>; <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is H, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl; <semantics>Rf<annotation encoding="application / x-tex">R^f< / annotation>< / semantics> is H, halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl; <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>. each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - <semantics>NR2e<annotation encoding="application / x-tex">NR^{e}_{2}< / annotation>< / semantics>, or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>; each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0054] In some embodiments, of the compounds of Formula I: <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is H, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl are optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of -C(O)NH-, \( \sigma_s \), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] X is a bond or -CR8aR8b-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] . . . [Image disponible dans le document PDF, Image available in the PDF document] –O−; or T and U together are R2a, R2b, R2c, R2d, R12a, and R12b are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O- <semantics>C(O)−NHRa<annotation encoding="application / x-tex">C(O)-NHR^{a}< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^{a})< / annotation>< / semantics>, or [Image disponible dans le document PDF, Image available in the PDF document] R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe; R4a, R4b, R5a, R5b, R5c, R5d, R8a, R8b, R9a, R9b, R9c, and R9d are independently H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4 4alkylene–O–C1-4alkyl; each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; R7 is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>; <semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics> is H, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl; <semantics>Rf<annotation encoding="application / x-tex">R^f< / annotation>< / semantics> is H, halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl; <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>. each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - <semantics>NR2e<annotation encoding="application / x-tex">NR^{e}_{2}< / annotation>< / semantics>, or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>; each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0055] In some embodiments, of the compounds of Formula I: <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is H, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl are optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of -C(O)NH-, \( \sigma_s \), [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] X is a bond or -CR8aR8b-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] -O-; or T and U together are , R2a, R2b, R2c, R2d, R12a, and R12b are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O- [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics>, <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics>, <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> are independently H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1- 4alkylene–O–C1-4alkyl; or any one of (i) <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, (ii) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, (iii) <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics> and <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, (iv) <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics> and <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, (v) <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics> and <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, (vi) <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics> and <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics>, (vii) <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics> and <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, (viii) <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics> and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>, (ix) <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics> and <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, (x) <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics> and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>, (xi) <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics> and one of <semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>, <semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>, <semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>, <semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>, and <semantics>R7<annotation encoding="application / x-tex">R^{7}< / annotation>< / semantics>, or (x) one of <semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>, <semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>, <semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>, and <semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics> and one of <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>, <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics>, R5a, R5b, and R7 together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe; each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; R7 is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; CA R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORc<annotation encoding="application / x-tex">-OR^{c}< / annotation>< / semantics> Rb is H, C1-4alkyl, C1-4haloalkyl or C3-6cycloalkyl; Rf is H, halo, C1-4alkyl, or C1-4haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl; <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>; each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - [Image disponible dans le document PDF, Image available in the PDF document] each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0056] In some embodiments, of the compounds of Formula I: <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is H, <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl are optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; Y is selected from the group consisting of <semantics>−C(O)NH−<annotation encoding="application / x-tex">-C(O)NH-< / annotation>< / semantics>, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] X is a bond or <semantics>−CR8aR8b<annotation encoding="application / x-tex">-CR^{8a}R^{8b}< / annotation>< / semantics>—. [Image disponible dans le document PDF, Image available in the PDF document] T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>; U is <semantics>−NR11<annotation encoding="application / x-tex">-NR^{11}< / annotation>< / semantics> <semantics>−CR12aR12b<annotation encoding="application / x-tex">-CR^{12a}R^{12b}< / annotation>< / semantics> <semantics>−CR12aR12b<annotation encoding="application / x-tex">-CR^{12a}R^{12b}< / annotation>< / semantics> <semantics>−CR12aR12b<annotation encoding="application / x-tex">-CR^{12a}R^{12b}< / annotation>< / semantics> [Image disponible dans le document PDF, Image available in the PDF document] -O-; or T and U together are <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics>, <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics>, and <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> are independently H, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>haloalkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics> 6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O- [Image disponible dans le document PDF, Image available in the PDF document] <semantics>−S(O)n−Ra−;<annotation encoding="application / x-tex">-S(O)_n-R^a-;< / annotation>< / semantics> R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl, R4a, R4b, R5a, R5b, R5c, R5d, R8a, R8b, R9b, R9c, and R9d are independently H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4 4alkylene–O–C1-4alkyl; each R6a, R6b, R10a, and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl; or any one of (i) R6a and R6b or (ii) R10a and R10b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe; R7 is H, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, C(O)Rc, or SO2Rc; R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S(O)n- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (ix) 6 to 10 membered aromatic ring, or (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>, Rb is H, C1-4alkyl, C1-4haloalkyl or C3-6cycloalkyl, <semantics>Rf<annotation encoding="application / x-tex">R^f< / annotation>< / semantics> is H, halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl; each Rc is independently, H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl; <semantics>C(O)Rd<annotation encoding="application / x-tex">C(O)R^d< / annotation>< / semantics>, or <semantics>−SO2Rd<annotation encoding="application / x-tex">-SO_2R^d< / annotation>< / semantics>; each Rd is independently C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, - <semantics>NR2e<annotation encoding="application / x-tex">NR^{e}_{2}< / annotation>< / semantics>, or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>; each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2.

[0057] In some embodiments, the compound of Formula I is a compound of Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ia.

[0058] In some embodiments, the compound of Formula I is a compound of Formula Ib: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ib.

[0059] In some embodiments for the compound of Formula I, Ia, or Ib, Y is selected from the [Image disponible dans le document PDF, Image available in the PDF document] CA [Image disponible dans le document PDF, Image available in the PDF document]

[0060] In some embodiments for the compounds of Formula I, Ia, or Ib, Y is . In [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] some embodiments, . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] embodiments, Y is . In some embodiments, Y is . In some embodiments, for the compounds of Formula I, Ia, or Ib, Y is –CONH–.

[0061] In some embodiments, the compound of Formula I is a compound of Formula II: [Image disponible dans le document PDF, Image available in the PDF document] Formula II.

[0062] In some embodiments, the compound of Formula I, Ia, or II is a compound of Formula IIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIa.

[0063] In some embodiments, the compound of Formula I, Ib, or II is a compound of Formula IIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIb.

[0064] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b or —CR2aR2b –CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−Ra<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-R^a< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe.

[0065] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b or —CR2aR2b –CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa−<annotation encoding="application / x-tex">-NHR^a-< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics> CA <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0066] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b or —CR2aR2b -CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−Ra<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-R^a< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0067] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b— or —CR2aR2b—CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−Re−Re−Re−Re−Re−Re−Re−Re−Re−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-R^e-R^e-R^e-R^e-R^e-R^e-R^e-R^e-R^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one to three <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0068] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b or —CR2aR2b –CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa−<annotation encoding="application / x-tex">-NHR^a-< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−<annotation encoding="application / x-tex">-NR^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring.

[0069] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b- or —CR2aR2b-CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NII(Ra)<annotation encoding="application / x-tex">-S(O)_n-NII(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or any one of (i) <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or (ii) <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics> and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> С together with the carbon atom to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>.

[0070] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b- or —CR2aR2b-CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−Ra<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-R^a< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or — CR2aR2b-CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1-6alkyl, C1. 6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -ORa, -O- <semantics>C(O)−NHRa<annotation encoding="application / x-tex">C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, or <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>−C(O)Ra<annotation encoding="application / x-tex">-C(O)R^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> CR2aR2b or —CR2aR2b –CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or - ORa. In some embodiments, T is -CR2aR2b- or --CR2aR2b-CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2ORa, or -ORa. In some embodiments, T is -CR2aR2b- or --CR2aR2b-CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, or cyano. In some embodiments, T is -CR2aR2b- or -CR2aR2b- CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl or C3-6halocycloalkyl. In some embodiments, T is -CR2aR2b- or --CR2aR2b- CR2cR2d; wherein each R2a, R2b, R2c, and R2d is independently H, C1-6alkyl, or C3-6cycloalkyl.

[0071] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – <semantics>CR2aR2b<annotation encoding="application / x-tex">CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>; wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa -ORa or - NHRa. In some embodiments, T is -CR2aR2b- or -CR2aR2b-CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or -ORa. In some embodiments, T is -CR2aR2b- or --CR2aR2b- CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, or halo. In some embodiments, T is -CR2aR2b- or -CR2aR2b- <semantics>CR2cR2d<annotation encoding="application / x-tex">CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H or halo. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics> <semantics>NH(Ra)−,−NRe−C(O)Ra−,−NRe−S(O)nRa−,−S(O)n−NH(Ra)−,−S(O)n−Ra−, or −O−C(O)−NHRa.<annotation encoding="application / x-tex">NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-S(O)_nR^a-, -S(O)_n-NH(R^a)-, -S(O)_n-R^a-, \text{ or } -O-C(O)-NHR^a.< / annotation>< / semantics> In some embodiments, T is -CR2aR2b- or --CR2aR2b-CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, ORa, NHRa, C(O) NH(Ra), NRe C(O)Ra, or NRe S(O)nRa. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H, –ORa, or –O–C(O)–NHRa. In some embodiments, T is –CR2aR2b– or — CR2aR2b-CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, -S(O)n-NH(Ra), or - <semantics>S(O)n−Ra<annotation encoding="application / x-tex">S(O)_n-R^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and R2d are independently H, halo, cyano, -NHRa- or -ORa. In some embodiments, T is - <semantics>CR2aR2b<annotation encoding="application / x-tex">CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H or <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> or <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>−CR2cR2d<annotation encoding="application / x-tex">-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently is H, halo, cyano, or -ORa. In some embodiments, T is -CR2aR2b- or --CR2aR2b- CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H or cyano.

[0072] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b – wherein, R2a and R2b together with the carbon to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>alkyl, <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>cycloloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>.

[0073] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b— wherein, R2a and R2b together with the carbon to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1- C6alkyl, C3-C6cycloloalkyl or -ORe.

[0074] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b – wherein, R2a and R2b together with the carbon to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1- C6alkyl, C3-C6cycloloalkyl or -ORe.

[0075] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – <semantics>CR2aR2b<annotation encoding="application / x-tex">CR^{2a}R^{2b}< / annotation>< / semantics> wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring. C /

[0076] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b— wherein, R2a and R2b together with the carbon to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-C6alkyl, C3-C6cycloloalkyl or -ORe.

[0077] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b— wherein, R2a and R2b together with the carbon to which they are attached form a 4 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 5 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-C6alkyl, C3-C6cycloloalkyl or -ORe.

[0078] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – <semantics>CR2aR2b<annotation encoding="application / x-tex">CR^{2a}R^{2b}< / annotation>< / semantics>— wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon to which they are attached form a 4 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S.

[0079] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b-, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6 6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -ORa or -NHRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or -ORa. In some embodiments, T is - CR2aR2b—, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6halocycloalkyl, or halo. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, C1-6alkyl, C3-6cycloalkyl, or halo. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H or halo. In some embodiments, T is -CR2aR2b-, wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics> <semantics>S(O)n−NH(Ra)−<annotation encoding="application / x-tex">S(O)_n-NH(R^a)-< / annotation>< / semantics>, <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b−<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-< / annotation>< / semantics>, wherein R2a and R2b are independently H, -ORa, -NHRa, -C(O)-NH(Ra), -NRe-C(O)Ra, or - NRe-S(O)nRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, -ORa, or -O-C(O)-NHRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein R2a and R2b are independently H, halo, cyano, -NHRa- or -ORa. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H or <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently is H, halo, cyano, or -ORa. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H or cyano. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are each H.

[0080] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b—; wherein each R2a and R2b is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O-C(O)-NHRa, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−C(O)Ra<annotation encoding="application / x-tex">-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−S(O)nRa<annotation encoding="application / x-tex">-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>; or R2a and R2b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>.

[0081] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b-; wherein each R2a and R2b is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O-C(O)-NHRa, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRc−C(O)Ra<annotation encoding="application / x-tex">-NR^{c}-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRc−S(O)nRa<annotation encoding="application / x-tex">-NR^{c}-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>; or R2a and R2b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe.

[0082] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b-; wherein each R2a and R2b is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O-C(O)-NHRa, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−C(O)Ra<annotation encoding="application / x-tex">-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−S(O)nRa<annotation encoding="application / x-tex">-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>−NH(Ra)<annotation encoding="application / x-tex">-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>−Ra<annotation encoding="application / x-tex">-R^{a}< / annotation>< / semantics>-, or R2a and R2b together with the carbon atom to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe.

[0083] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b—; wherein each R2a and R2b is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O-C(O)-NHRa, <semantics>−NIIRa<annotation encoding="application / x-tex">-NIIR^{a}< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-<semantics>NII(Ra)<annotation encoding="application / x-tex">NII(R^{a})< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_{n}R^{a}< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>NII(Ra)<annotation encoding="application / x-tex">NII(R^{a})< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^{a}< / annotation>< / semantics>-; or R2a and R2b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or ORe.

[0084] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T is – CR2aR2b—, wherein each R2a and R2b is independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, -ORa, -O-C(O)-NHRa, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−C(O)Ra<annotation encoding="application / x-tex">-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>−S(O)nRa<annotation encoding="application / x-tex">-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>; or R2a and R2b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring.

[0085] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T -CR2aR2b-, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, halo, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein R2a and R2b are independently H, halo, or -ORa, and each Ra is independently H or C1- 6alkyl. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, halo, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>-, wherein R2a and R2b are independently H, halo, or -ORa, and each Ra is independently H or methyl.

[0086] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T—CR2aR2b— CR2cR2d; wherein R2a, R2b, R2c, and R2d are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -ORa or -NHRa. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, C1. 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or - ORa. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, or halo. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, C1- 6alkyl, C3-6cycloalkyl or halo. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H or halo. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NR<annotation encoding="application / x-tex">-NR< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, T is — CR2aR2b-CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, -ORa, -NHRa, -C(O)- <semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^e-C(O)R^a< / annotation>< / semantics>, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b−CR2cR2d<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein R2a, R2b, R2c, and R2d are independently H, -ORa, or -O-C(O)-NHRa. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H, – <semantics>S(O)n<annotation encoding="application / x-tex">S(O)_n< / annotation>< / semantics> NH(Ra), or <semantics>S(O)n<annotation encoding="application / x-tex">S(O)_n< / annotation>< / semantics> Ra. In some embodiments, T is <semantics>CR2aR2b<annotation encoding="application / x-tex">CR^{2a}R^{2b}< / annotation>< / semantics> <semantics>CR2cR2d<annotation encoding="application / x-tex">CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, R2b, R2c, and R2d are independently H, halo, cyano, -NHRa- or -ORa. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently H or –NHRa. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein R2a, R2b, R2c, and R2d are independently is H, halo, cyano, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b−CR2cR2d<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and R2d are independently H or cyano. In some embodiments, T is —CR2aR2b—CR2cR2d, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are each H.

[0087] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, or IIb, T –CR2aR2b– CR2cR2d-; wherein R2a, R2b, R2c, and R2d are independently H, halo, or -ORa. In some embodiments, T is <semantics>−CR2aR2b−CR2cR2d<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-CR^{2c}R^{2d}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics>, <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics>, <semantics>R2c<annotation encoding="application / x-tex">R^{2c}< / annotation>< / semantics>, and <semantics>R2d<annotation encoding="application / x-tex">R^{2d}< / annotation>< / semantics> are independently H, halo, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl. In some embodiments, T is – CR2aR2b–CR2cR2d–, wherein R2a, R2b, R2c, and R2d are independently H, halo, or –ORa, and each Ra is independently H or C1-3 alkyl. In some embodiments, T is -CR2aR2b-CR2cR2d-, wherein R2a, R2b, R2c, and R2d are independently H, halo, or -ORa, and each Ra is independently H or methyl.

[0088] In some embodiments, the compound of Formula I or II is a compound of Formula III: [Image disponible dans le document PDF, Image available in the PDF document] Formula III. CF

[0089] In some embodiments, the compound of Formula I, Ia, II, or IIa is a compound of Formula IIIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIIa.

[0090] In some embodiments, the compound of Formula I, Ib, II, or IIb is a compound of Formula IIIb: [Image disponible dans le document PDF, Image available in the PDF document]

[0091] In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is <semantics>−NR11<annotation encoding="application / x-tex">-NR^{11}< / annotation>< / semantics>, <semantics>−CR12aR12b<annotation encoding="application / x-tex">-CR^{12a}R^{12b}< / annotation>< / semantics>, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>(O)-, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>(O)-, <semantics>−C<annotation encoding="application / x-tex">-C< / annotation>< / semantics>(O) -, or <semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>-. In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, U is -NR11, -CR12aR12b, -C(O) - or - O-. In some embodiments, U is -NR11, -CR12aR12b, or -O-. In some embodiments, U is -NR11 or –CR12aR12b. In some embodiments, U is –NR11.

[0092] In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, or IIIb, U is <semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>, <semantics>−S<annotation encoding="application / x-tex">-S< / annotation>< / semantics>, <semantics>−S(O)<annotation encoding="application / x-tex">-S(O)< / annotation>< / semantics>, or <semantics>−S(O)<annotation encoding="application / x-tex">-S(O)< / annotation>< / semantics>. In some embodiments, U is <semantics>−O<annotation encoding="application / x-tex">-O< / annotation>< / semantics> or <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>. In some embodiments, U is <semantics>−S−<annotation encoding="application / x-tex">-S-< / annotation>< / semantics>, <semantics>−S(O)−<annotation encoding="application / x-tex">-S(O)-< / annotation>< / semantics>, or <semantics>−S(O)2−<annotation encoding="application / x-tex">-S(O)_2-< / annotation>< / semantics>. In some embodiments, U is <semantics>−S−<annotation encoding="application / x-tex">-S-< / annotation>< / semantics>. In some embodiments, U is <semantics>−S(O)<annotation encoding="application / x-tex">-S(O)< / annotation>< / semantics> –. In some embodiments, U is <semantics>−S(O)2<annotation encoding="application / x-tex">-S(O)_2< / annotation>< / semantics> –. In some embodiments, U is – C(O)—. In some embodiments, U is –O—. C /

[0093] In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, R11 is H, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, -C(O)-Ra, -S-Ra, -S(O)- <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>S(O)2<annotation encoding="application / x-tex">S(O)_2< / annotation>< / semantics> <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>, <semantics>CH2<annotation encoding="application / x-tex">CH_2< / annotation>< / semantics> <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is H, <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> alkyl, <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> haloalkyl, <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>- C6cycloalkyl, or C3-C6halocycloalkyl. In some embodiments, R11 is H, C3-C6cycloalkyl, or C3- C6halocycloalkyl. In some embodiments, R11 is H, C1-C4 alkyl or C1-C4 haloalkyl. In some embodiments, R11 is H or C1-C4 alkyl. In some embodiments, R11 is C3-C6halocycloalkyl. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics>cycloalkyl. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> haloalkyl. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> alkyl. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is H. In some embodiments, <semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics> is <semantics>−C(O)−Ra<annotation encoding="application / x-tex">-C(O)-R^a< / annotation>< / semantics>, <semantics>−S−Ra<annotation encoding="application / x-tex">-S-R^a< / annotation>< / semantics>, <semantics>−S(O)−Ra<annotation encoding="application / x-tex">-S(O)-R^a< / annotation>< / semantics>, <semantics>−S(O)2−Ra<annotation encoding="application / x-tex">-S(O)_2-R^a< / annotation>< / semantics>, <semantics>−CH2−Ra<annotation encoding="application / x-tex">-CH_2-R^a< / annotation>< / semantics>.

[0094] In some embodiments, the compound of Formula I, II, or III has a Formula IV: [Image disponible dans le document PDF, Image available in the PDF document] Formula IV.

[0095] In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, or IV has a Formula IVa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IVa.

[0096] In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, or IV has a Formula IVb: [Image disponible dans le document PDF, Image available in the PDF document] Formula IVb.

[0097] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-C6alkyl, C3-C6cycloloalkyl or -ORe.

[0098] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>- C6alkyl, C3-C6cycloloalkyl or -ORe.

[0099] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>- C6alkyl, C3-C6cycloloalkyl or -ORe.

[0100] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring.

[0101] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-C6alkyl, C3-C6cycloloalkyl or ORe.

[0102] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 5 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-C6alkyl, C3-C6cycloloalkyl or -ORe.

[0103] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b together with the carbon to which they are attached form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S.

[0104] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6halocycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -ORa or -NHRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, - CH2Ra-, -CH2ORa, or -ORa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, C1-6alkyl, C3-6cycloalkyl, or halo. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H or halo. In some embodiments, T is -CR2aR2b-, wherein, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)n<annotation encoding="application / x-tex">-NR^e-S(O)_n< / annotation>< / semantics> <semantics>S(O)n−NH(Ra)−<annotation encoding="application / x-tex">S(O)_n-NH(R^a)-< / annotation>< / semantics>, <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b−<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-< / annotation>< / semantics>, wherein R2a and R2b are independently H, -ORa, -NHRa, -C(O)-NH(Ra), -NRe-C(O)Ra, or - NRe-S(O)nRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, -ORa, or -O-C(O)-NHRa. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently H, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>. In some embodiments, T is <semantics>−CR2aR2b−<annotation encoding="application / x-tex">-CR^{2a}R^{2b}-< / annotation>< / semantics>, wherein R2a and R2b are independently H, halo, cyano, -NHRa- or -ORa. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H or <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are independently is H, halo, cyano, or -ORa. In some embodiments, T is <semantics>−CR2aR2b<annotation encoding="application / x-tex">-CR^{2a}R^{2b}< / annotation>< / semantics>, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H or cyano. In some embodiments, T is -CR2aR2b-, wherein R2a and R2b are each H.

[0105] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R2a and R2b is independently II, C1-6alkyl, C3-6cycloalkyl, halo, cyano, – CA <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe.

[0106] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R2a and R2b is independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, – <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe.

[0107] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R2a and R2b is independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, – <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0108] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R2a and R2b is independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, – <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)<annotation encoding="application / x-tex">-O-C(O)< / annotation>< / semantics>-<semantics>NHRa<annotation encoding="application / x-tex">NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>- <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0109] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, each R2a and R2b is independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, – <semantics>CII2Ra<annotation encoding="application / x-tex">CII_2R^a< / annotation>< / semantics>, <semantics>−CII2ORa<annotation encoding="application / x-tex">-CII_2OR^a< / annotation>< / semantics>, <semantics>−CII2<annotation encoding="application / x-tex">-CII_2< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)<annotation encoding="application / x-tex">-O-C(O)< / annotation>< / semantics>-<semantics>NIIRa<annotation encoding="application / x-tex">NIIR^a< / annotation>< / semantics>, <semantics>−NIIRa<annotation encoding="application / x-tex">-NIIR^a< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-<semantics>NII(Ra)<annotation encoding="application / x-tex">NII(R^a)< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>- CA <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring.

[0110] In some embodiments for the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb, R12a and R12b are independently H, -ORa, or -O-C(O)-NHRa. In some embodiments, R12a and R12b are independently H, -NHRa, -C(O)-NH(Ra), -NRe-C(O)Ra, -NRe- <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>. In some embodiments, <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> and <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> are independently H, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics> Ra—. In some embodiments, R12a and R12b are independently H, halo, cyano, –NHRa— or –ORa. In some embodiments, R12a and R12b are independently H or –NHRa. In some embodiments, R12a and R12b are independently H, halo, cyano, or -ORa. In some embodiments, R12a and R12b are independently H or cyano. In some embodiments, R12a and R12b are independently H or -ORa. In some embodiments, R12a and R12b are independently H or -ORa, and Ra is C3-6cycloalkyl. In some embodiments, R12a and R12b are independently H or -ORa, and Ra is C1-4 haloalkyl. In some embodiments, R12a and R12b are independently H or –ORa, and Ra is C1-4alkyl optionally substituted with –O–C1-4alkyl.

[0111] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C1-6cycloloalkyl or -ORe.

[0112] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C1-6cycloloalkyl or –ORe.

[0113] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> cycloloalkyl or <semantics>−𝐎𝐑e<annotation encoding="application / x-tex">-\mathbf{OR}^e< / annotation>< / semantics>.

[0114] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C1-6cycloloalkyl.

[0115] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 5 membered carbocyclic ring or the 3 to 5 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C1-6cycloloalkyl.

[0116] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S.

[0117] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 to 5 membered carbocyclic ring, wherein the 3 to 5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C1-6cycloloalkyl.

[0118] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 5 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> cycloloalkyl.

[0119] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 to 5 membered carbocyclic ring.

[0120] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 to 5 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S.

[0121] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, or IVb, R12a and R12b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring.

[0122] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, each R2a, R2b, R12a, and R12b is independently H, halo, or -ORa. In some embodiments, each R2a, R2b, R12a, and R12b is independently H, halo, or -ORa and each Ra is independently H or C1-6alkyl. In some embodiments, each R2a, R2b, R12a, and R12b is independently H, halo, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics> and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics> alkyl. In some embodiments, each R2a, R2b, R12a, and R12b is independently H, halo, or -ORa and each Ra is independently H or methyl.

[0123] In some embodiments, the compound of Formula I or II has a Formula V: [Image disponible dans le document PDF, Image available in the PDF document] Formula V.

[0124] In some embodiments, the compound of Formula I, Ia, II, or IIa has a Formula Va: [Image disponible dans le document PDF, Image available in the PDF document] Formula Va.

[0125] In some embodiments, the compound of Formula I, Ib, II, or IIb has a Formula Vb: [Image disponible dans le document PDF, Image available in the PDF document]

[0126] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, – CH2Ra-, -CH2ORa, -ORa or -NHRa. In some embodiments, R2a and R12a are independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or -ORa. In some embodiments, R2a and R12a are independently H, C1-6alkyl, C3-6cycloalkyl, or halo. In some embodiments, R2a and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are independently H or halo. In some embodiments, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are independently H2 – <semantics>C(O)−NH(Ra)−,−NRc−C(O)Ra−,−NRc−S(O)nRa−,−S(O)n−NH(Ra)−,−S(O)n−Ra−,or−O−C(O)−<annotation encoding="application / x-tex">C(O)-NH(R^a)-, -NR^c-C(O)R^a-, -NR^c-S(O)_nR^a-, -S(O)_n-NH(R^a)-, -S(O)_n-R^a-, or -O-C(O)-< / annotation>< / semantics> NHRa. In some embodiments, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are independently H, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, -NRe-C(O)Ra, or -NRe-S(O)nRa. In some embodiments, R2a and R12a are independently H, - <semantics>ORa<annotation encoding="application / x-tex">OR^a< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are independently H, <semantics>−S(O)n−1<annotation encoding="application / x-tex">-S(O)_{n-1}< / annotation>< / semantics> NH(Ra), or -S(O)n-Ra-. In some embodiments, R2a and R12a are independently H, halo, cyano, - NHRa- or -ORa. In some embodiments, R2a and R12a are independently H or -NHRa. In some embodiments, R2a and R12a are independently is H, halo, cyano, or -ORa. In some embodiments, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are independently H or cyano. In some embodiments, <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> are each H.

[0127] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, – <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)<annotation encoding="application / x-tex">-O-C(O)< / annotation>< / semantics>-<semantics>NHRa<annotation encoding="application / x-tex">NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>- <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>-, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_{n}R^{a}< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^{a})< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^{a}< / annotation>< / semantics>-.

[0128] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6halocycloalkyl, halo, cyano, – <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>-, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)<annotation encoding="application / x-tex">-O-C(O)< / annotation>< / semantics>-<semantics>NHRa<annotation encoding="application / x-tex">NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>-, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>-, <semantics>−NRc<annotation encoding="application / x-tex">-NR^c< / annotation>< / semantics>- <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^{e}< / annotation>< / semantics>-<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_{n}R^{a}< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^{a})< / annotation>< / semantics>-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^{a}< / annotation>< / semantics>-.

[0129] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, - C [Image disponible dans le document PDF, Image available in the PDF document]

[0130] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, - <semantics>ORa<annotation encoding="application / x-tex">OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa−<annotation encoding="application / x-tex">-NHR^a-< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−S(O)n−<annotation encoding="application / x-tex">-S(O)_n-< / annotation>< / semantics> <semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>—, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>—<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>—.

[0131] In some embodiments, of the compound of Formula V, Va, and Vb, R2a and R12a are independently H, C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, -CH2-S(O)nRa-, - <semantics>ORa<annotation encoding="application / x-tex">OR^{a}< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^{a}< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^{e}-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^{e}-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_{n}< / annotation>< / semantics> <semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>—, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>—<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>—.

[0132] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W1 is a bond or -CR4aR4b-R4a; wherein R4b and R4b are independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl; or R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe. In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W1 is a bond or <semantics>−CR4aR4b−R4a<annotation encoding="application / x-tex">-CR^{4a}R^{4b}-R^{4a}< / annotation>< / semantics>, wherein <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics> are independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl. In some embodiments, W1 is a bond or <semantics>−CR4aR4b−R4a<annotation encoding="application / x-tex">-CR^{4a}R^{4b}-R^{4a}< / annotation>< / semantics>, wherein <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics> are independently H, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics> alkyl, halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl, or cyano. In some embodiments, W1 is a bond or -CR4aR4b-R4a, wherein R4a and R4b are independently H, C1-C6 alkyl, halo, or cyano. In some embodiments, W1 is a bond or -CR4aR4b- R4a, wherein R4a and R4b are independently H, halo, or C1-C4 alkyl. In some embodiments, W1 is a bond or <semantics>−CR4aR4b−R4a<annotation encoding="application / x-tex">-CR^{4a}R^{4b}-R^{4a}< / annotation>< / semantics>, wherein <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics> are independently H, fluoro, chloro, or <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> alkyl. In some embodiments, W1 is a bond or -CR4aR4b-R4a, wherein R4a and R4b are independently H or cyano. In some embodiments, W1 is a bond or -CR4aR4b-R4a, wherein R4a and R4b are independently H or C1-4haloalkyl.

[0133] In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to C / 7 membered heterocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, W1 is a bond or -CR4aR4b-R4a, wherein R4a and R4b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring.

[0134] In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three <semantics>RA3<annotation encoding="application / x-tex">R^{A3}< / annotation>< / semantics>, wherein each <semantics>RA3<annotation encoding="application / x-tex">R^{A3}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, or C3-6cycloalkyl.

[0135] In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W1 is -CR4aR4b-, wherein R4b and R4b are independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl; or R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic С ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe. In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W1 is CR4aR4b, wherein R4a and R4b are independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, -O-C1-4alkyl, or C1- 4alkylene-O-C1-4alkyl. In some embodiments W1 is-CR4aR4b-, wherein R4a and R4b are independently H, C1-C6 alkyl, halo, C1-4haloalkyl, or cyano. In some embodiments, W1 is – CR4aR4b-, wherein R4a and R4b are independently H, C1-C6 alkyl, halo, or cyano. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b are independently H, halo, or C1- C4 alkyl. In some embodiments, W1 is a bond or -CR4aR4b-, wherein R4a and R4b are independently H, fluoro, chloro, or C1-C4 alkyl. In some embodiments, W1 is a bond or – CR4aR4b-, wherein R4a and R4b are independently H or cyano. In some embodiments, W1 is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>, wherein <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics> are independently H or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl.

[0136] In some embodiments, W1 is -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe. In some embodiments, W1 is-CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three <semantics>RA3<annotation encoding="application / x-tex">R^{A3}< / annotation>< / semantics>, wherein each <semantics>RA3<annotation encoding="application / x-tex">R^{A3}< / annotation>< / semantics> is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, W1 is -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3- 6cycloalkyl. In some embodiments, W1 is -CR4aR4b-, wherein R4a and R4b together with the carbon atom to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, W1 is–CR4aR4b–, wherein R4a and R4b together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, C O, and S. In some embodiments, <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>, wherein <semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics> and <semantics>R4b<annotation encoding="application / x-tex">R^{4b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring. In some embodiments, W1 is CR4aR4b, wherein R4a and R4b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl.

[0137] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W1 is a bond.

[0138] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W2 is -CR5aR5b-.

[0139] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, W2 is -CR6a=CR6b-, wherein R6a and R6b is independently H, halo, C1- 4haloalkyl, or C1-6alkyl. In some embodiments, W2 is -CR6a=CR6b-, wherein each R6a and R6b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently halo or C1-4alkyl.

[0140] In some embodiments, W2 is -CR6a=CR6b-, wherein each R6a and R6b together with the carbon atoms to which each is attached form (i) a 6 to 10 membered aromatic ring, or (ii) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 6 to 10 membered aromatic ring or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four <semantics>RA4<annotation encoding="application / x-tex">R^{A4}< / annotation>< / semantics>, wherein each <semantics>RA4<annotation encoding="application / x-tex">R^{A4}< / annotation>< / semantics> is independently halo or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl.

[0141] In some embodiments, W2 is -CR6a=CR6b-, wherein each R6a and R6b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring or (ii) a 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, wherein the 5 to 10 membered carbocyclic ring or the 5 to 10 membered heterocyclic ring, is optionally substituted with one to four <semantics>RA4<annotation encoding="application / x-tex">R^{A4}< / annotation>< / semantics>, wherein each <semantics>RA4<annotation encoding="application / x-tex">R^{A4}< / annotation>< / semantics> is independently halo or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl.

[0142] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, X is a bond. In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, X is CR8aR8b.

[0143] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is <semantics>−CR9aR9b<annotation encoding="application / x-tex">-CR^{9a}R^{9b}< / annotation>< / semantics>.

[0144] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, Z is -CR10a=CR10b-, wherein each R10a and R10b is independently H, halo, C1-4haloalkyl, or C1-6alkyl. In some embodiments, Z is -CR10a=CR10b-, wherein each R10a and R10b together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring, (ii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, (iii) a 6 to 10 membered aromatic ring, or (iv) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each <semantics>RA4<annotation encoding="application / x-tex">R^{A4}< / annotation>< / semantics> is independently halo, oxo, cyano, or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> alkyl. In some embodiments, Z is - <semantics>CR10a=CR10b<annotation encoding="application / x-tex">CR^{10a}=CR^{10b}< / annotation>< / semantics>-, wherein each <semantics>R10a<annotation encoding="application / x-tex">R^{10a}< / annotation>< / semantics> and <semantics>R10b<annotation encoding="application / x-tex">R^{10b}< / annotation>< / semantics> together with the carbon atoms to which each is attached form (i) a 6 to 10 membered aromatic ring, or (ii) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O and S, wherein the 6 to 10 membered aromatic ring or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently halo or C1-4alkyl. In some embodiments, Z is - <semantics>CR10a=CR10b<annotation encoding="application / x-tex">CR^{10a}=CR^{10b}< / annotation>< / semantics>-, wherein each <semantics>R10a<annotation encoding="application / x-tex">R^{10a}< / annotation>< / semantics> and <semantics>R10b<annotation encoding="application / x-tex">R^{10b}< / annotation>< / semantics> together with the carbon atoms to which each is attached form (i) a 5 to 10 membered carbocyclic ring or (ii) a 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, wherein the 5 to 10 membered carbocyclic ring or the 5 to 10 membered heterocyclic ring, is optionally substituted with one to four RA4, wherein each RA4 is independently halo or C1-4alkyl.

[0145] In some embodiments, the compound of Formula I, II, III, or IV has a Formula VI: [Image disponible dans le document PDF, Image available in the PDF document] Formula VI; wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa−<annotation encoding="application / x-tex">-NHR^a-< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)−<annotation encoding="application / x-tex">-C(O)-NH(R^a)-< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra−<annotation encoding="application / x-tex">-NR^e-C(O)R^a-< / annotation>< / semantics>, <semantics>−NRe−<annotation encoding="application / x-tex">-NR^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>-, <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-NH(<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>)-, or <semantics>−S(O)n<annotation encoding="application / x-tex">-S(O)_n< / annotation>< / semantics>-<semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>-; or two R2 on same carbon atom, together with the carbon atom to which they both are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe.

[0146] In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV, or IVa has a Formula VIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIa; wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, or C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−Ra−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-R^a-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>S(O)n<annotation encoding="application / x-tex">S(O)_n< / annotation>< / semantics> <semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>, or <semantics>S(O)n<annotation encoding="application / x-tex">S(O)_n< / annotation>< / semantics> <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>; or two R2 on same carbon atom, together with the carbon atom to which they both are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – <semantics>ORe<annotation encoding="application / x-tex">OR^e< / annotation>< / semantics>.

[0147] In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV, or IVb has a Formula VIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIb; wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - <semantics>CH2−S(O)nRa−,−ORa,−O−C(O)−NHRa,−NHRa−,−C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−<annotation encoding="application / x-tex">CH_2-S(O)_nR^a-, -OR^a, -O-C(O)-NHR^a, -NHR^a-, -C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>; or two R2 on same carbon atom, together with the carbon atom to which they both are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe.

[0148] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>, <semantics>−SO2<annotation encoding="application / x-tex">-SO_2< / annotation>< / semantics>, <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>, <semantics>−CR3cR3d<annotation encoding="application / x-tex">-CR^{3c}R^{3d}< / annotation>< / semantics>, or С <semantics>−N(Ra)<annotation encoding="application / x-tex">-N(R^a)< / annotation>< / semantics>—. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>—, <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>—, <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>—<semantics>CR3cR3d<annotation encoding="application / x-tex">CR^{3c}R^{3d}< / annotation>< / semantics>—, or <semantics>−SO2<annotation encoding="application / x-tex">-SO_2< / annotation>< / semantics>. In some embodiments, L is -CR3aR3b-, -C(O)- or -CR3aR3b-CR3cR3d-. In some embodiments, L is - CR3aR3b or CR3aR3b CR3cR3d. In some embodiments, L is C(O). In some embodiments, L is <semantics>−SO2<annotation encoding="application / x-tex">-SO_2< / annotation>< / semantics>. In some embodiments, L is <semantics>−CR3aR3b−CR3cR3d<annotation encoding="application / x-tex">-CR^{3a}R^{3b}-CR^{3c}R^{3d}< / annotation>< / semantics>. In some embodiments, L is <semantics>−N(Ra)<annotation encoding="application / x-tex">-N(R^a)< / annotation>< / semantics>. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>-.

[0149] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-6 4haloalkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl; or any one of (i) <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics> and <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics> or (ii) <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics> and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1- 6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-3alkyl, C1-4haloalkyl, or -O-C1-3alkyl. In some embodiments, <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and R3d are each H.

[0150] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics> or <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics> <semantics>−CR3cR3d<annotation encoding="application / x-tex">-CR^{3c}R^{3d}< / annotation>< / semantics> , wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, C. R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe. In some embodiments, L is -CR3aR3b- or -CR3aR3b-CR3cR3d-, wherein R3a, R3b, R3c, and R3d are independently H, C1- 6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics> or <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics> <semantics>−CR3cR3d<annotation encoding="application / x-tex">-CR^{3c}R^{3d}< / annotation>< / semantics> -, wherein R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one or two <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, L is –CR3aR3b– or –CR3aR3b–CR3cR3d–, wherein R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, L is -CR3aR3b- or - CR3aR3b–CR3cR3d–, wherein R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-3alkyl, C1-3 3haloalkyl, or -O-C1-3alkyl. In some embodiments, L is -CR3aR3b- or -CR3aR3b-CR3cR3d-, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are each H.

[0151] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is <semantics>−CR3aR3b−CR3cR3d<annotation encoding="application / x-tex">-CR^{3a}R^{3b}-CR^{3c}R^{3d}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>. In some embodiments, L is -CR3aR3b-CR3cR3d-, wherein R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1. 4haloalkyl, or O C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, L is <semantics>−CR3aR3b−CR3cR3d<annotation encoding="application / x-tex">-CR^{3a}R^{3b}-CR^{3c}R^{3d}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, L is -CR3aR3b-CR3cR3d-, wherein R3a, R3b, R3c, and R3d are independently H, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>haloalkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl; or any one of (i) <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics> and <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics> or (ii) <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics> and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, L is -CR3aR3b-CR3cR3d-, wherein R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R3a, R3b, R3c, and R3d are independently H, C1-3alkyl, C1-3haloalkyl, or -O-C1-3alkyl. In some embodiments, L is <semantics>−CR3aR3b−CR3cR3d<annotation encoding="application / x-tex">-CR^{3a}R^{3b}-CR^{3c}R^{3d}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>alkyl. In some embodiments, L is <semantics>−CR3aR3b−CR3cR3d<annotation encoding="application / x-tex">-CR^{3a}R^{3b}-CR^{3c}R^{3d}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics>, <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics>, <semantics>R3c<annotation encoding="application / x-tex">R^{3c}< / annotation>< / semantics>, and <semantics>R3d<annotation encoding="application / x-tex">R^{3d}< / annotation>< / semantics> are each H.

[0152] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, or VIb, L is -CR3aR3b-, wherein R3a and R3b are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics>, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe. In some embodiments, L is -CR3aR3b-, wherein R3a and R3b are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is ( independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl. In some embodiments, L is – CR3aR3b-, wherein R3a and R3b are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one or two RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, L is –CR3aR3b–, wherein R3a and R3b are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics> and <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics> are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, L is -CR3aR3b-, wherein R3a and R3b are independently H, C1-3alkyl, C1-3haloalkyl, or -O-C1-3alkyl. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics> and <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics> are independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>alkyl. In some embodiments, L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>, wherein <semantics>R3a<annotation encoding="application / x-tex">R^{3a}< / annotation>< / semantics> and <semantics>R3b<annotation encoding="application / x-tex">R^{3b}< / annotation>< / semantics> are each II.

[0153] In some embodiments, the compound of Formula I, II, III, IV, or VI, has a Formula VII: [Image disponible dans le document PDF, Image available in the PDF document] Formula VII.

[0154] In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, or VIa, has a Formula VIIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIa. CA

[0155] In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, or VIb, has a Formula VIIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIb.

[0156] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, and VIIb, R1 is a H, C6-10aryl or C6-10heteroaryl, wherein the <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl or <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> heteroaryl are optionally substituted with one to four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, - O-C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl.

[0157] In some embodiments, R1 is H, phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3- 6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, or -O-C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or -O-C1-4alkyl. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with one, two, three, or four halogens. In some embodiments, R1 is phenyl, pyridyl, pyridazine, CA pyrazine, or pyrimidine substituted with two or three halogens. In some embodiments, R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with two or three halogens selected from chloro and fluoro.

[0158] In some embodiments, R1 is H, phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is phenyl or pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R1 is phenyl or pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, or -O-C1-4alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is phenyl or pyridyl, optionally substituted with one, two, three, or four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently halo or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is phenyl or pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or -O-C1. 4alkyl. In some embodiments, R1 is phenyl or pyridyl substituted with one, two, three, or four halogens. In some embodiments, R1 is phenyl or pyridyl substituted with two or three halogens. In some embodiments, R1 is phenyl or pyridyl substituted with two or three halogens selected from chloro and fluoro.

[0159] In some embodiments, of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, or VIIb, R1 is H or a C6-10aryl, wherein the C6-10 10 aryl is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1- 6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4 4alkyl. In some embodiments, R1 is H or phenyl, wherein the phenyl is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3. 6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is phenyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, - <semantics>O−C3−6<annotation encoding="application / x-tex">O-C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl<semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is phenyl, optionally substituted with one, two, three, or four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, <semantics>C1−1<annotation encoding="application / x-tex">C_{1-1}< / annotation>< / semantics>haloalkyl, or <semantics>−O−C1−1<annotation encoding="application / x-tex">-O-C_{1-1}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is phenyl, optionally substituted with С one, two, three, or four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is phenyl, optionally substituted with one, two, three, or four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently halo or <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^{1}< / annotation>< / semantics> is phenyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or –O–C1-4alkyl. In some embodiments, R1 is phenyl substituted with one, two, three, or four halogens. In some embodiments, R1 is phenyl substituted with two or three halogens. In some embodiments, R1 is phenyl substituted with two or three halogens selected from chloro and fluoro. [Image disponible dans le document PDF, Image available in the PDF document]

[0160] In some embodiments, R1 is selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 2 , , , and . In some embodiments, R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] , , and <semantics>⋅<annotation encoding="application / x-tex">\cdot< / annotation>< / semantics> In some embodiments, <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is selected from the group [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] consisting of , , and

[0161] In some embodiments, R1 is pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, - O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, R1 is pyridyl, optionally substituted with one, two, three, or four RAI, wherein each RAI is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, R1 is pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, or –O–C1-4alkyl. In some embodiments, R1 is pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or C1-4alkyl. In some embodiments, R1 is pyridyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, <semantics>ℝ1<annotation encoding="application / x-tex">\mathbb{R}^1< / annotation>< / semantics> is pyridyl substituted with one, CA two, three, or four halogens. In some embodiments, R1 is pyridyl substituted with two or three halogens. In some embodiments, R1 is pyridyl substituted with two or three halogens selected from chloro and fluoro.

[0162] In some embodiments, the compound of Formula I, II, III, IV, VI, or VII, has a Formula VIII: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIII; wherein p is 2 or 3.

[0163] In some embodiments, the compound of Formula I, Ia, II, IIa, III, IIIa, IV, IVa, VI, VIa, VII, or VIIa, has a Formula VIIIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIIa; wherein p is 2 or 3.

[0164] In some embodiments, the compound of Formula I, Ib, II, IIb, III, IIIb, IV, IVb, VI, VIb, VII, or VIIb, has a Formula VIIIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIIb; wherein p is 2 or 3.

[0165] In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa, IIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, each RAl is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3- 6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, each RA1 is independently halo, C1-4 6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1. 4alkyl. In some embodiments, each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3. 6cycloalkyl, cyano, -O-C1-4alkyl, -O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, each RA1 is independently halo, C1-4alkyl, or -O-C1-4alkyl. In some embodiments, each RA1 is independently halo, C1-4alkyl, cyano, or –O–C1-4alkyl. In some embodiments, each RA1 is independently halo, cyano, or C1-4alkyl. In some embodiments, each RA1 is independently halo or C1-4alkyl. In some embodiments, each RA1 is independently halo, cyano, or -O-C1-4alkyl. In some embodiments, each RA1 is independently halo or -O-C1-4alkyl. In some embodiments, each RA1 is independently a halogen. In some embodiments, each RA1 is independently chloro or fluoro.

[0166] In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa, IIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, – O-C1-4alkyl, or C1-4alkylene-O-C1-4alkyl. In some embodiments, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, C1-C6 alkyl, halo, or cyano. In some embodiments, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, halo, or C1-C4 alkyl. In some С embodiments, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, fluoro, chloro, or C1-C4 alkyl. In some embodiments, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H or cyano. In some embodiments, R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H or C1-4haloalkyl.

[0167] In some embodiments, for the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, C3- 6cycloalkyl or -ORe. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or (ii) 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring, wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a 4 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 4 to 7 membered heterocyclic ring is optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, or <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a (i) 3 to 7 membered carbocyclic ring or a (ii) 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, any one of (i) R4a and R4b, (ii) R5a and C R5b, (iii) R8a and R8b, or (iv) R9a and R9b together with the carbon atom to which they are attached form a 3 to 7 membered carbocyclic ring. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments R5a and R5b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R8a and R8b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R9a and R9b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring optionally substituted with one to three RA3, wherein each RA3 is independently oxo, halo, cyano, C1-6alkyl, or C3-6cycloalkyl. In some embodiments, R4a and R4b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments R5a and R5b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, <semantics>R8a<annotation encoding="application / x-tex">R^{8a}< / annotation>< / semantics> and <semantics>R8b<annotation encoding="application / x-tex">R^{8b}< / annotation>< / semantics> together with the carbon atom to which they are attached form a 3 membered carbocyclic ring. In some embodiments, R9a and R9b together with the carbon atom to which they are attached form a 3 membered carbocyclic ring.

[0168] In some embodiments, for the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0169] In some embodiments, for the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, - <semantics>CH2ORa<annotation encoding="application / x-tex">CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)−<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)-< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>; or two <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> on same carbon atom together with the carbon atom to which they both are attached form a 3 to 7 membered carbocyclic ring wherein the 3 to 7 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or -ORe.

[0170] In some embodiments, for the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, - <semantics>CH2ORa<annotation encoding="application / x-tex">CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)−<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)-< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>; or <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> or two <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> on same carbon atom together with the carbon atom to which they both are attached form a 3-5 membered carbocyclic ring wherein the 3-5 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or – ORe.

[0171] In some embodiments, for the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, - <semantics>CH2ORa<annotation encoding="application / x-tex">CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>-<semantics>−C(O)Ra<annotation encoding="application / x-tex">-C(O)R^a< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)−<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)-< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>; or two <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> on same carbon atom together with the carbon atom to which they both are attached form a 3 membered carbocyclic ring, wherein the 3 membered carbocyclic ring is optionally substituted with one to three RA2, wherein each <semantics>RA2<annotation encoding="application / x-tex">R^{A2}< / annotation>< / semantics> is independently oxo, halo, cyano, <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^{e}< / annotation>< / semantics>.

[0172] In some embodiments, for the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIb, each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, - <semantics>CH2ORa<annotation encoding="application / x-tex">CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRc−C(O)Ra<annotation encoding="application / x-tex">-NR^c-C(O)R^a< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa−<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a-< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)−<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)-< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>; or two <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> on same carbon atom together with the carbon atom to which they both are attached form a 3 membered carbocyclic ring.

[0173] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, - CH2ORa, –ORa or –NHRa. In some embodiments, each R2 is independently C1-6alkyl, C3- 6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or -ORa. In some embodiments, each R2 is independently C1-6alkyl, C3-6cycloalkyl, or halo. In some embodiments, each R2 is independently halo. In some embodiments, each R2 is independently -C(O)-NH(Ra)-, -NRe-C(O)Ra-, -NRe- <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^e-C(O)R^a< / annotation>< / semantics>, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. In some embodiments, each R2 is independently -ORa, or -O-C(O)-NHRa. In some embodiments, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>. In some embodiments, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo, cyano, -NHRa- or -ORa. In some embodiments, each R2 is -NHRa. In some embodiments, each R2 is independently is halo, cyano, or -ORa. In some embodiments, each R2 is cyano. In some embodiments, each R2 is independently –ORa. In some embodiments, each R2 is independently –ORa and each Ra is independently C3-C6 cycloalkyl optionally substituted CA optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl. In some embodiments, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>; wherein each Ra is independently C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, -O-C1-C4 alkyl. In some embodiments, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>; wherein each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl optionally substituted with a -O-C1-4alkyl or halo. In some embodiments, each R2 is independently –ORa; wherein each Ra is independently C1-C6 alkyl optionally substituted with a <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl.

[0174] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl, halo, cyano, – CH2Ra-, -CH2ORa, -ORa or -NHRa. In some embodiments, m is 2 and each R2 is independently C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, or -ORa. In some embodiments, m is 2 and each R2 is independently C1-6alkyl, C3-6cycloalkyl, or halo. In some embodiments, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo. In some embodiments, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently – <semantics>C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−S(O)nRa−,−S(O)n−NH(Ra)−,−S(O)n−Ra−,or−O−C(O)−<annotation encoding="application / x-tex">C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-S(O)_nR^a-, -S(O)_n-NH(R^a)-, -S(O)_n-R^a-, or -O-C(O)-< / annotation>< / semantics> NHRa. In some embodiments, m is 2 and each R2 is independently–ORa, –NHRa, –C(O)– <semantics>NH(Ra)<annotation encoding="application / x-tex">NH(R^a)< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^e-C(O)R^a< / annotation>< / semantics>, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. In some embodiments, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently–ORa, or –O–C(O)–NHRa. In some embodiments, m is 2 and each R2 is independently <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>. In some embodiments, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo, cyano, -NHRa- or -ORa. In some embodiments, m is 2 and each R2 is independently –NHRa. In some embodiments, m is 2 and each R2 is independently is halo, cyano, or -ORa. In some embodiments, m is 2 and each R2 is cyano. In some embodiments, m is 2 and each R2 is independently a halo. In some embodiments, m is 2 and each R2 is independently –ORa. In some embodiments, m is 2 and each R2 is independently –ORa and each Ra is independently C3-C6 cycloalkyl optionally substituted optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and -O-C1- C4alkyl. In some embodiments, m is 2 and each R2 is independently –ORa; wherein each Ra is independently C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, -O-C1-C4 alkyl. In some embodiments, m is 2 and each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>; wherein each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl optionally substituted with a -O-C1-4alkyl or halo. In some embodiments, each m is 2 and R2 is independently –ORa; wherein each Ra is independently C1-C6 alkyl optionally substituted with a <semantics>−O−C14<annotation encoding="application / x-tex">-O-C_{14}< / annotation>< / semantics>alkyl. C.

[0175] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 1 and R2 is C1-6alkyl, C3-6cycloalkyl, halo, cyano, -CH2Ra-, -CH2ORa, - ORa or NHRa. In some embodiments, m is 1 and R2 is C1-6alkyl, C3-6cycloalkyl, halo, cyano, <semantics>CH2Ra<annotation encoding="application / x-tex">CH_2R^a< / annotation>< / semantics>, <semantics>−CH2ORa<annotation encoding="application / x-tex">-CH_2OR^a< / annotation>< / semantics>, or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl, <semantics>C3−6<annotation encoding="application / x-tex">C_{3-6}< / annotation>< / semantics>cycloalkyl, or halo. In some embodiments, m is 1 and R2 is halo. In some embodiments, m is 1 and R2 is – <semantics>C(O)−NH(Ra)−,−NRe−C(O)Ra−,−NRe−S(O)nRa−,−S(O)n−NH(Ra)−,−S(O)n−Ra−, or −O−C(O)−<annotation encoding="application / x-tex">C(O)-NH(R^a)-, -NR^e-C(O)R^a-, -NR^e-S(O)_nR^a-, -S(O)_n-NH(R^a)-, -S(O)_n-R^a-, \text{ or } -O-C(O)-< / annotation>< / semantics> NHRa. In some embodiments, m is 1 and R2 is -ORa, -NHRa, -C(O)-NH(Ra), -NRe-C(O)Ra, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>. In some embodiments, m is 1 and R2 is halo, cyano, -NHRa- or -ORa. In some embodiments, m is 1 and R2 is -NHRa. In some embodiments, m is 1 and R2 is halo, cyano, or -ORa. In some embodiments, m is 1 and R2 is cyano. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is halo. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is – <semantics>ORa<annotation encoding="application / x-tex">OR^a< / annotation>< / semantics>. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics> and <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is <semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> cycloalkyl optionally substituted optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl. In some embodiments, m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>−OR3<annotation encoding="application / x-tex">-OR^3< / annotation>< / semantics>; wherein Ra is C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl. In some embodiments, m is 1 and <semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics> is <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>; wherein <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl optionally substituted with a <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics> alkyl or halo. In some embodiments, each m is 1 and <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>; wherein each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl optionally substituted with a <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl.

[0176] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 1 or 2, each R2 is independently halo or -ORa, and each Ra is independently H or <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C6<annotation encoding="application / x-tex">C_6< / annotation>< / semantics> alkyl. In some embodiments, m is 1 or 2, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each Ra is independently H or C1-C3 alkyl. In some embodiments, m is 1 or 2, each R2 is independently halo or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is independently H or methyl. In some embodiments, m is 1 or 2, each R2 is independently halo or -ORa, and each Ra is H. In some embodiments, m is 1 or 2, each R2 is independently halo or -ORa, and each Ra is methyl.

[0177] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 1, R2 is halo or –ORa, and Ra is H or C1-C6 alkyl. In some embodiments, m is 1, R2 is halo or –ORa, and Ra is H or C1-C3 alkyl. In some embodiments, m is 1, R2 is halo or – ORa, and Ra is H or methyl. In some embodiments, m is 1, R2 is halo or -ORa, and Ra is H. In some embodiments, m is 1, R2 is halo or –ORa, and Ra is methyl. CA

[0178] In some embodiments, the compounds of Formula VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa or VIIIb, m is 2, each R2 is independently halo or -ORa, and each Ra is independently H or C1-C6 alkyl. In some embodiments, m is 2, each R2 is independently halo or ORa, and each Ra is independently H or <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C3<annotation encoding="application / x-tex">C_3< / annotation>< / semantics> alkyl. In some embodiments, m is 2, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo or -ORa, and each Ra is independently H or methyl. In some embodiments, m is 2, each R2 is independently halo or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is H. In some embodiments, m is 2, each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently halo or <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, and each <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is methyl.

[0179] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Rais independently H, C1-6alkyl, or C3-6cycloalkyl; wherein the C1-6alkyl or C3-6cycloloalkyl is optionally substituted with 0 to 4 substituents independently selected from the group consisting of halo, cyano, <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, 6 to 10 membered aromatic ring, and 5 to 10 membered heteroaromatic ring containing 1 or 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C1-6cycloloalkyl or –ORe.

[0180] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Rais independently H, C1-C6 alkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl, 5 to 10 membered carbocyclic ring, and 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from N, O and S.

[0181] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Rais independently H, C1-C4 alkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and -O-C1-C4 alkyl.

[0182] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Ra is independently C3-C6 cycloalkyl optionally substituted optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and <semantics>−O−C1<annotation encoding="application / x-tex">-O-C_1< / annotation>< / semantics>- C4alkyl.

[0183] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Ra is independently C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl.

[0184] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Rais independently <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl optionally substituted with a <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl or halo.

[0185] In some embodiments, of the compounds of Formula I, Ia, Ib, II, IIa, IIIb, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Rais independently a 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from N, O, and S, a 6 to 10 membered aromatic ring, or a 5 to 10 membered heteroaromatic ring containing 1 or 3 heteroatoms selected from N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA4, wherein each RA4 is independently oxo, halo, cyano, C1-6alkyl, C1-6 6cycloloalkyl or –ORe.

[0186] In some embodiments of the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, and VIIIb, each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3-6cycloalkyl is optionally substituted by a halo or a cyano. In some embodiments, each Re is independently H, C1-4alkyl or C3-6cycloalkyl. In some embodiments, each Re is independently H or C1-4alkyl wherein the C1-4alkyl is optionally substituted by a halo or a cyano. In some embodiments, each Re is independently H or C3-6cycloalkyl wherein each C3-6cycloalkyl is optionally substituted by a halo or a cyano. In some embodiments, each Re is independently H or C1-4alkyl. In some embodiments, each Re is independently H or C3-6cycloalkyl. In some embodiments, each Re is H. In some embodiments, each Re is independently C1-4alkyl. In some embodiments, each Re is independently C3-6cycloalkyl.

[0187] In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIIb, p is 2 or 3 and each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1. 4alkyl, O C3-6cycloalkyl or C1-4alkyl O C1-4alkyl. In some embodiments, p is 2 or 3 and each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, p is 2 or 3 and each RA1 is independently halo, C1-4alkyl, or -O-C1-4alkyl. In some embodiments, p is 2 or 3 and each <semantics>ℝAl<annotation encoding="application / x-tex">\mathbb{R}^{Al}< / annotation>< / semantics> is independently halo or <semantics>ℂ1−4<annotation encoding="application / x-tex">\mathbb{C}_{1-4}< / annotation>< / semantics> alkyl. In some embodiments, p is 2 or 3 each RA1 is independently halo or -O-C1-4alkyl. In some embodiments, p is 2 or 3 and each RA1 is independently a halogen. In some embodiments, p is 2 or 3 and each RA1 is independently selected from chloro and fluoro.

[0188] In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIIb, p is 2 and each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, - O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, p is 2 and each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or –O–C1-4alkyl. In some embodiments, p is 2 and each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently halo, <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, p is 2 and each RA1 is independently halo or C1-4alkyl. In some embodiments, p is 2 and each RA1 is independently halo or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, p is 2 and each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently a halogen. In some embodiments, p is 2 and each RA1 is independently selected from chloro and fluoro.

[0189] In some embodiments, for the compounds of Formula VIII, VIIIa, and VIIIb, p is 3 and each RA1 is independently halo, C1-6alkyl, C1-4haloalkyl, C3-6cycloalkyl, cyano, -O-C1-4alkyl, - O-C3-6cycloalkyl or C1-4alkyl-O-C1-4alkyl. In some embodiments, p is 3 and each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. In some embodiments, p is 3 and each RA1 is independently halo, C1-4alkyl, or -O-C1-4alkyl. In some embodiments, p is 3 and each RA1 is independently halo or C1-4alkyl. In some embodiments, p is 3 and each RA1 is independently halo or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. In some embodiments, p is 3 and each RA1 is independently a halogen. In some embodiments, p is 3 and each RA1 is independently selected from chloro and fluoro.

[0190] In some embodiments of the compounds of Formula IV, IVa, or IVb: [Image disponible dans le document PDF, Image available in the PDF document] Formula IV [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Formula IVb <semantics>Xis−CR8aR8b<annotation encoding="application / x-tex">X is -CR^{8a}R^{8b}< / annotation>< / semantics>-; <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>-; <semantics>W2<annotation encoding="application / x-tex">W^2< / annotation>< / semantics> is <semantics>−CR5aR5b<annotation encoding="application / x-tex">-CR^{5a}R^{5b}< / annotation>< / semantics> or <semantics>−CR6a<annotation encoding="application / x-tex">-CR^{6a}< / annotation>< / semantics> <semantics>=CR6b<annotation encoding="application / x-tex">= CR^{6b}< / annotation>< / semantics> -; <semantics>Z<annotation encoding="application / x-tex">Z< / annotation>< / semantics> is <semantics>−CR9aR9b<annotation encoding="application / x-tex">-CR^{9a}R^{9b}< / annotation>< / semantics>—; L is <semantics>−CH2−<annotation encoding="application / x-tex">-CH_2-< / annotation>< / semantics>; R2a, R2b, R12a, and R12b are independently H, C1-6alkyl, halo, -ORa-, or -CH2ORa; Ra is H or C1-6alkyl; R4a, R4b, R5a, R5b, R8a, R8b, R9a, R9b are independently H, hydroxyl, C1-6alkyl, or – <semantics>O−C1−4<annotation encoding="application / x-tex">O-C_{1-4}< / annotation>< / semantics>alkyl; both R6a and R6b are H; and <semantics>R1<annotation encoding="application / x-tex">R^1< / annotation>< / semantics> is <semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics> aryl optionally substituted with one to four <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics>, wherein each <semantics>RA1<annotation encoding="application / x-tex">R^{A1}< / annotation>< / semantics> is independently fluoro or chloro.

[0191] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, is a compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] e salt thereof.

[0192] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, is a compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] CA [Image disponible dans le document PDF, Image available in the PDF document] pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb, is a compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] , CA [Image disponible dans le document PDF, Image available in the PDF document] - - - ereof. Ш. Compositions and Kits

[0194] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. The compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0195] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0196] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more <semantics>(e.g.,one,two,three,four,oneortwo,onetothree,oronetofour)<annotation encoding="application / x-tex">(e.g., one, two, three, four, one or two, one to three, or one to four)< / annotation>< / semantics> additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more <semantics>(e.g.,one,two,three,four,oneortwo,onetothree,oronetofour)<annotation encoding="application / x-tex">(e.g., one, two, three, four, one or two, one to three, or one to four)< / annotation>< / semantics> additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0197] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical compositions may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0198] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0199] Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (such as a compound provided herein) is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0200] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof. The pharmaceutical compositions can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents; or any combinations thereof.

[0201] The pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient (such as a compound provided herein) after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems С and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0202] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0203] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0204] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized <semantics>Ci<annotation encoding="application / x-tex">C_{i}< / annotation>< / semantics> solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0205] In one aspect, provided herein are kits that comprise a compound provided herein, (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIIb, VIII, VIIIa, or VIIIb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0206] In some embodiments, the kits further comprise one or more (e.g., ...

Claims

<pat:ClaimStatement>CLAIMS< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. A compound of Formula I: [Image disponible dans le document PDF, Image available in the PDF document] Formula I or a pharmaceutically acceptable salt thereof, wherein R1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with one to four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or –O–C1-4alkyl; [Image disponible dans le document PDF, Image available in the PDF document] Y is selected from the group consisting of –C(O)NH– and [Image disponible dans le document PDF, Image available in the PDF document] <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond or <semantics>−CR4aR4b<annotation encoding="application / x-tex">-CR^{4a}R^{4b}< / annotation>< / semantics>—; <semantics>W2<annotation encoding="application / x-tex">W^2< / annotation>< / semantics> is <semantics>−CR5aR5b<annotation encoding="application / x-tex">-CR^{5a}R^{5b}< / annotation>< / semantics> or <semantics>−CR6a=CR6b−<annotation encoding="application / x-tex">-CR^{6a}=CR^{6b}-< / annotation>< / semantics>; [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] R2a, R2b, R12a, and R12b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6 6halocycloalkyl, halo, cyano, -CH2Ra, -CH2ORa, -CH2-S(O)nRa, -ORa, -O-C(O)-NHRa, - <semantics>NHRa<annotation encoding="application / x-tex">NHR^{a}< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^{a})< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^{e}-C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^{e}-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>; R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl; or any one of (i) R3a and R3b or (ii) R3c and R3d together with the carbon atom to which they are attached form (i) a 3 to 7 membered carbocyclic ring or (ii) a 3 to 7 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, wherein the 3 to 7 membered carbocyclic ring or the 3 to 7 membered heterocyclic ring is optionally substituted with one to three RA2, wherein each RA2 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe; R4a, R4b, R5a, R5b, R8a, R8b, R9a, and R9b are independently H, C1-6alkyl hydroxyl, or -O- C1-4alkyl; each R6a and R6b is independently H or C1-6alkyl; each Ra is independently (i) H, (ii) C1-6alkyl, (iii) C3-6cycloalkyl, (iv) a 5 to 10 membered carbocyclic ring, (v) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from the group consisting of N, O, and S, (vi) a 6 to 10 membered aromatic ring, or (vii) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; wherein the C1-6alkyl, C3-6cycloalkyl, 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring or 5 to 10 membered heteroaromatic ring is optionally substituted with 0 to 4 substituents independently selected from the group consisting of (i) oxo (ii) halo, (iii) cyano, (iv) -O-C1-4alkyl, (v) C1-6alkyl, (vi) -ORe (vii) 3 to 10 membered carbocyclic ring, (viii) 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from the group consisting of N, O, and S, (ix) 6 to 10 membered aromatic ring, and (x) a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S; wherein the 3 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, 6 to 10 membered aromatic ring, or 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or –ORe; each Re is independently H, C1-4alkyl or C3-6cycloalkyl wherein each C1-4alkyl or C3- 6cycloalkyl is optionally substituted by a halo or a cyano; and each n is 0, 1, or 2. The compound of claim 1, or the pharmaceutically acceptable salt thereof, wherein: R3a, R3b, R3c, and R3d are independently H, C1-6alkyl, C1-4haloalkyl, or -O-C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. The compound of claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula Ia: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ia. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. The compound of claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula Ib: [Image disponible dans le document PDF, Image available in the PDF document] Formula Ib. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The compound of any one of claims 1-4, or the pharmaceutically acceptable salt thereof, [Image disponible dans le document PDF, Image available in the PDF document] wherein Y is • < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The compound of claim 1 or 2, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula II: [Image disponible dans le document PDF, Image available in the PDF document] Formula II. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The compound of any one of claims 1-3, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. The compound of any one of claims 1, 2 and 4, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula IIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula IIb. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6halocycloalkyl, halo, cyano, -CH2Ra, -CH2ORa, -ORa or -NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. The compound of any one of claims 1-9, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3- 6halocycloalkyl, halo, cyano, -CH2Ra, -CH2ORa, or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The compound of any one of claims 1-10, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The compound of any one of claims 1-11, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, or -ORa; and wherein each Ra in <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> or <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> is independently H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. The compound of any one of claims 1-12, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, or -ORa; and wherein each Ra in <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> or <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> is independently H or <semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The compound of any one of claims 1-13, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, or -ORa; and wherein each Ra in <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> or <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> is independently H or methyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The compound of any one of claims 1-10, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, C1-6alkyl, C1-6haloalkyl, C3- 6cycloalkyl, C3-6halocycloalkyl, or halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. The compound of any one of claims 1-10, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, C1-6alkyl, C3-6cycloalkyl, or halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17< / pat:ClaimNumber> <pat:ClaimText>17. The compound of any one of claims 1-16, or the pharmaceutically acceptable salt thereof, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H or halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18< / pat:ClaimNumber> <pat:ClaimText>18. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe−C(O)Ra<annotation encoding="application / x-tex">-NR^e-C(O)R^a< / annotation>< / semantics>, <semantics>−NRe−<annotation encoding="application / x-tex">-NR^e-< / annotation>< / semantics> <semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>, or <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19< / pat:ClaimNumber> <pat:ClaimText>19. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, -ORa, -NHRa, -C(O)-NH(Ra), -NRe-C(O)Ra, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20< / pat:ClaimNumber> <pat:ClaimText>20. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, –ORa, or –O–C(O)–NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00021"> <pat:ClaimNumber>21< / pat:ClaimNumber> <pat:ClaimText>21. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein <semantics>R2a<annotation encoding="application / x-tex">R^{2a}< / annotation>< / semantics> and <semantics>R2b<annotation encoding="application / x-tex">R^{2b}< / annotation>< / semantics> are independently H, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_n-R^a< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00022"> <pat:ClaimNumber>22< / pat:ClaimNumber> <pat:ClaimText>22. The compound of any one of claims 1-8, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, cyano, –NHRa, or –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00023"> <pat:ClaimNumber>23< / pat:ClaimNumber> <pat:ClaimText>23. The compound of any one of claims 1-8 and 22, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H or –NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00024"> <pat:ClaimNumber>24< / pat:ClaimNumber> <pat:ClaimText>24. The compound of any one of claims 1-10, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H, halo, cyano, or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00025"> <pat:ClaimNumber>25< / pat:ClaimNumber> <pat:ClaimText>25. The compound of any one of claims 1-10 and 24, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H or cyano. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00026"> <pat:ClaimNumber>26< / pat:ClaimNumber> <pat:ClaimText>26. The compound of any one of claims 1-10 and 24, or the pharmaceutically acceptable salt thereof, wherein R2a and R2b are independently H or –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00027"> <pat:ClaimNumber>27< / pat:ClaimNumber> <pat:ClaimText>27. The compound of any one of claims 1-11, 18-24 and 26, or the pharmaceutically acceptable salt thereof, wherein Ra is independently H, C1-6alkyl, or C3-6cycloalkyl; wherein each C1-6alkyl or C3-6cycloalkyl is optionally substituted with 0 to 4 substituents independently selected from the group consisting of halo, cyano, -O-C1-4alkyl, a 5 to 10 membered carbocyclic ring, a 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatom selected from the group consisting of N, O, and S, a 6 to 10 membered aromatic ring, and a 5 to 10 membered heteroaromatic ring containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein the 5 to 10 membered carbocyclic ring, 5 to 10 membered heterocyclic ring, the 6 to 10 membered aromatic ring, or the 5 to 10 membered heteroaromatic ring is optionally substituted with one to four RA5, wherein each RA5 is independently oxo, halo, cyano, C1-6alkyl, C3-6cycloalkyl or <semantics>−ORe<annotation encoding="application / x-tex">-OR^e< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00028"> <pat:ClaimNumber>28< / pat:ClaimNumber> <pat:ClaimText>28. The compound of any one of claims 1-11, 18-24, 26 and 27, or the pharmaceutically acceptable salt thereof, wherein each Ra is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, –O–C1-C4 alkyl, 5 to 10 membered carbocyclic ring, and 5 to 10 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00029"> <pat:ClaimNumber>29< / pat:ClaimNumber> <pat:ClaimText>29. The compound of any one of claims 1-11, 18-24, and 26-28, or the pharmaceutically acceptable salt thereof, wherein Ra is H, C1-C4 alkyl, or C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00030"> <pat:ClaimNumber>30< / pat:ClaimNumber> <pat:ClaimText>30. The compound of any one of claims 1-11, 18-24, and 26-29, or the pharmaceutically acceptable salt thereof, wherein Ra is C3-C6 cycloalkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and –O– C1-C4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00031"> <pat:ClaimNumber>31< / pat:ClaimNumber> <pat:ClaimText>31. The compound of any one of claims 1-11, 18-24 and 26-28, or the pharmaceutically acceptable salt thereof, wherein Ra is C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and -O- <semantics>C1<annotation encoding="application / x-tex">C_1< / annotation>< / semantics>-<semantics>C4<annotation encoding="application / x-tex">C_4< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00032"> <pat:ClaimNumber>32< / pat:ClaimNumber> <pat:ClaimText>32. The compound of any one of claims 1-11, 18-24 and 26-28, or the pharmaceutically acceptable salt thereof, wherein Ra is C1-6alkyl optionally substituted with a –O–C1-4alkyl or halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00033"> <pat:ClaimNumber>33< / pat:ClaimNumber> <pat:ClaimText>33. The compound of any one of claims 1-10, or the pharmaceutically acceptable salt thereof, wherein: L is <semantics>−CH2−<annotation encoding="application / x-tex">-CH_2-< / annotation>< / semantics>; R2a, R2b, R12a, and R12b are independently H, C1-6alkyl, halo, –ORa, or –CH2ORa; <semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics> is H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl; and each RA1 is independently fluoro or chloro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00034"> <pat:ClaimNumber>34< / pat:ClaimNumber> <pat:ClaimText>34. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H, –ORa, or –O–C(O)–NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00035"> <pat:ClaimNumber>35< / pat:ClaimNumber> <pat:ClaimText>35. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H, -NHRa, -C(O)-NH(Ra), -NRe- <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics>–<semantics>S(O)nRa<annotation encoding="application / x-tex">S(O)_nR^a< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00036"> <pat:ClaimNumber>36< / pat:ClaimNumber> <pat:ClaimText>36. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> and <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> are independently H, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics>, or <semantics>−S(O)n−Ra−<annotation encoding="application / x-tex">-S(O)_n-R^a-< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00037"> <pat:ClaimNumber>37< / pat:ClaimNumber> <pat:ClaimText>37. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H, halo, cyano, -NHRa- or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00038"> <pat:ClaimNumber>38< / pat:ClaimNumber> <pat:ClaimText>38. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00039"> <pat:ClaimNumber>39< / pat:ClaimNumber> <pat:ClaimText>39. The compound of any one of claims 1-32, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H, halo, cyano, or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00040"> <pat:ClaimNumber>40< / pat:ClaimNumber> <pat:ClaimText>40. The compound of any one of claims 1-32 and 39, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or cyano. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00041"> <pat:ClaimNumber>41< / pat:ClaimNumber> <pat:ClaimText>41. The compound of any one of claims 1-32 and 39, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00042"> <pat:ClaimNumber>42< / pat:ClaimNumber> <pat:ClaimText>42. The compound of any one of claims 1-29, 39, and 41, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa; and wherein each Ra in <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> or <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> is H or <semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00043"> <pat:ClaimNumber>43< / pat:ClaimNumber> <pat:ClaimText>43. The compound of any one of claims 1-29, 39, 41, and 42, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa; and wherein each Ra in R12a or R12b is H or C1-3alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00044"> <pat:ClaimNumber>44< / pat:ClaimNumber> <pat:ClaimText>44. The compound of any one of claims 1-29, 39, and 41-43, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa; and wherein each Ra in R12a or R12b is H or methyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00045"> <pat:ClaimNumber>45< / pat:ClaimNumber> <pat:ClaimText>45. The compound of any one of claims 1-30, 39, and 41, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa, and Ra in R12a or R12b is C3-6cycloalkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00046"> <pat:ClaimNumber>46< / pat:ClaimNumber> <pat:ClaimText>46. The compound of any one of claims 1-29, 31, 32, 39, and 41, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa, and Ra in <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> or <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics> haloalkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00047"> <pat:ClaimNumber>47< / pat:ClaimNumber> <pat:ClaimText>47. The compound of any one of claims 1-29, 31, 32, 39, and 41, or the pharmaceutically acceptable salt thereof, wherein R12a and R12b are independently H or –ORa, and Ra in <semantics>R12a<annotation encoding="application / x-tex">R^{12a}< / annotation>< / semantics> or <semantics>R12b<annotation encoding="application / x-tex">R^{12b}< / annotation>< / semantics> is <semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>alkyl optionally substituted with <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00048"> <pat:ClaimNumber>48< / pat:ClaimNumber> <pat:ClaimText>48. The compound of any one of claims 1-47, or the pharmaceutically acceptable salt thereof, wherein <semantics>W1<annotation encoding="application / x-tex">W^1< / annotation>< / semantics> is a bond. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00049"> <pat:ClaimNumber>49< / pat:ClaimNumber> <pat:ClaimText>49. The compound of any one of claims 1-47, or the pharmaceutically acceptable salt thereof, wherein W1 is -CR4aR4b-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00050"> <pat:ClaimNumber>50< / pat:ClaimNumber> <pat:ClaimText>50. The compound of any one of claims 1-49, or the pharmaceutically acceptable salt thereof, wherein W2 is –CR5aR5b–. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00051"> <pat:ClaimNumber>51< / pat:ClaimNumber> <pat:ClaimText>51. The compound of any one of claims 1-49, or the pharmaceutically acceptable salt thereof, wherein W2 is –CR6a=CR6b–; wherein R6a and R6b are independently H or C1- 6alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00052"> <pat:ClaimNumber>52< / pat:ClaimNumber> <pat:ClaimText>52. The compound of any one of claims 1-51, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1- 4alkyl, C1-4haloalkyl, or –O–C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00053"> <pat:ClaimNumber>53< / pat:ClaimNumber> <pat:ClaimText>53. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00054"> <pat:ClaimNumber>54< / pat:ClaimNumber> <pat:ClaimText>54. The compound of any one of claims 1-53, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00055"> <pat:ClaimNumber>55< / pat:ClaimNumber> <pat:ClaimText>55. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00056"> <pat:ClaimNumber>56< / pat:ClaimNumber> <pat:ClaimText>56. The compound of any one of claims 1-52 and 55, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00057"> <pat:ClaimNumber>57< / pat:ClaimNumber> <pat:ClaimText>57. The compound of any one of claims 1-52 and 56, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00058"> <pat:ClaimNumber>58< / pat:ClaimNumber> <pat:ClaimText>58. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or –O–C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00059"> <pat:ClaimNumber>59< / pat:ClaimNumber> <pat:ClaimText>59. The compound of any one of claims 1-52 and 58, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00060"> <pat:ClaimNumber>60< / pat:ClaimNumber> <pat:ClaimText>60. The compound of any one of claims 1-52, 58, and 59, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00061"> <pat:ClaimNumber>61< / pat:ClaimNumber> <pat:ClaimText>61. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00062"> <pat:ClaimNumber>62< / pat:ClaimNumber> <pat:ClaimText>62. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00063"> <pat:ClaimNumber>63< / pat:ClaimNumber> <pat:ClaimText>63. The compound of any one of claims 1-52, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00064"> <pat:ClaimNumber>64< / pat:ClaimNumber> <pat:ClaimText>64. The compound of any one of claims 1-63, wherein L is <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00065"> <pat:ClaimNumber>65< / pat:ClaimNumber> <pat:ClaimText>65. The compound of any one of claims 1-63, wherein L is -SO2-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00066"> <pat:ClaimNumber>66< / pat:ClaimNumber> <pat:ClaimText>66. The compound of any one of claims 1-63, wherein L is -CH2-CH2-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00067"> <pat:ClaimNumber>67< / pat:ClaimNumber> <pat:ClaimText>67. The compound of any one of claims 1-63, wherein L is <semantics>−N(Ra)<annotation encoding="application / x-tex">-N(R^a)< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00068"> <pat:ClaimNumber>68< / pat:ClaimNumber> <pat:ClaimText>68. The compound of any one of claims 1-63, wherein L is -CR3aR3b-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00069"> <pat:ClaimNumber>69< / pat:ClaimNumber> <pat:ClaimText>69. The compound of any one of claims 1, 2 and 6, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VI: [Image disponible dans le document PDF, Image available in the PDF document] wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, or C3-6cycloalkyl, halo, cyano, -CH2Ra, - [Image disponible dans le document PDF, Image available in the PDF document] <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^{e}-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00070"> <pat:ClaimNumber>70< / pat:ClaimNumber> <pat:ClaimText>70. The compound of any one of claims 1-3 and 7, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIa: [Image disponible dans le document PDF, Image available in the PDF document] wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, or C3-6cycloalkyl, halo, cyano, -CH2Ra, - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00071"> <pat:ClaimNumber>71< / pat:ClaimNumber> <pat:ClaimText>71. The compound of any one of claims 1, 2, 4 and 8, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIb; wherein m is 0, 1, 2, 3, or 4; and each R2 is independently C1-6alkyl, or C3-6cycloalkyl, halo, cyano, -CH2Ra, - <semantics>CH2ORa<annotation encoding="application / x-tex">CH_2OR^a< / annotation>< / semantics>, <semantics>−CH2−S(O)nRa<annotation encoding="application / x-tex">-CH_2-S(O)_nR^a< / annotation>< / semantics>, <semantics>−ORa<annotation encoding="application / x-tex">-OR^a< / annotation>< / semantics>, <semantics>−O−C(O)−NHRa<annotation encoding="application / x-tex">-O-C(O)-NHR^a< / annotation>< / semantics>, <semantics>−NHRa<annotation encoding="application / x-tex">-NHR^a< / annotation>< / semantics>, <semantics>−C(O)−NH(Ra)<annotation encoding="application / x-tex">-C(O)-NH(R^a)< / annotation>< / semantics>, <semantics>−NRe<annotation encoding="application / x-tex">-NR^e< / annotation>< / semantics> <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^{a}< / annotation>< / semantics>, <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^{e}-S(O)_{n}R^{a}< / annotation>< / semantics>, <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_{n}-NH(R^{a})< / annotation>< / semantics>, or <semantics>−S(O)n−Ra<annotation encoding="application / x-tex">-S(O)_{n}-R^{a}< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00072"> <pat:ClaimNumber>72< / pat:ClaimNumber> <pat:ClaimText>72. The compound of any one of claims 69-71, wherein L is <semantics>−C(O)<annotation encoding="application / x-tex">-C(O)< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00073"> <pat:ClaimNumber>73< / pat:ClaimNumber> <pat:ClaimText>73. The compound of any one of claims 69-71, wherein L is <semantics>−SO2<annotation encoding="application / x-tex">-SO_2< / annotation>< / semantics>-. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00074"> <pat:ClaimNumber>74< / pat:ClaimNumber> <pat:ClaimText>74. The compound of any one of claims 69-71, wherein L is <semantics>−CH2−CH2−<annotation encoding="application / x-tex">-CH_2-CH_2-< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00075"> <pat:ClaimNumber>75< / pat:ClaimNumber> <pat:ClaimText>75. The compound of any one of claims 69-71, wherein L is <semantics>−N(Ra)<annotation encoding="application / x-tex">-N(R^a)< / annotation>< / semantics>—. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00076"> <pat:ClaimNumber>76< / pat:ClaimNumber> <pat:ClaimText>76. The compound of any one of claims 69-71, wherein L is <semantics>−CR3aR3b<annotation encoding="application / x-tex">-CR^{3a}R^{3b}< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00077"> <pat:ClaimNumber>77< / pat:ClaimNumber> <pat:ClaimText>77. The compound of any one of claims 1, 2, 6 and 69, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VII: [Image disponible dans le document PDF, Image available in the PDF document] Formula VII. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00078"> <pat:ClaimNumber>78< / pat:ClaimNumber> <pat:ClaimText>78. The compound of any one of claims 1-3, 7 and 70, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00079"> <pat:ClaimNumber>79< / pat:ClaimNumber> <pat:ClaimText>79. The compound of any one of claims 1, 2, 4, 8 and 71, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIb. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00080"> <pat:ClaimNumber>80< / pat:ClaimNumber> <pat:ClaimText>80. The compound of any one of claims 69-79, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1- 4alkyl, C1-4haloalkyl, or –O–C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00081"> <pat:ClaimNumber>81< / pat:ClaimNumber> <pat:ClaimText>81. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00082"> <pat:ClaimNumber>82< / pat:ClaimNumber> <pat:ClaimText>82. The compound of any one of claims 69-81, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00083"> <pat:ClaimNumber>83< / pat:ClaimNumber> <pat:ClaimText>83. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00084"> <pat:ClaimNumber>84< / pat:ClaimNumber> <pat:ClaimText>84. The compound of any one of claims 69-80 and 83, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00085"> <pat:ClaimNumber>85< / pat:ClaimNumber> <pat:ClaimText>85. The compound of any one of claims 69-80 and 84, or the pharmaceutically acceptable salt thereof, wherein R1 is pyridyl, wherein the pyridyl is substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00086"> <pat:ClaimNumber>86< / pat:ClaimNumber> <pat:ClaimText>86. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl, optionally substituted with one, two, three, or four RA1, wherein each RA1 is independently halo, C1-4alkyl, C1-4haloalkyl, or -O-C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00087"> <pat:ClaimNumber>87< / pat:ClaimNumber> <pat:ClaimText>87. The compound of any one of claims 69-80 and 86, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with one, two, three, or four halogens. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00088"> <pat:ClaimNumber>88< / pat:ClaimNumber> <pat:ClaimText>88. The compound of any one of claims 69-80, 86, and 87, or the pharmaceutically acceptable salt thereof, wherein R1 is phenyl substituted with two or three halogens selected from the group consisting of chloro and fluoro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00089"> <pat:ClaimNumber>89< / pat:ClaimNumber> <pat:ClaimText>89. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00090"> <pat:ClaimNumber>90< / pat:ClaimNumber> <pat:ClaimText>90. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00091"> <pat:ClaimNumber>91< / pat:ClaimNumber> <pat:ClaimText>91. The compound of any one of claims 69-80, or the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] • < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00092"> <pat:ClaimNumber>92< / pat:ClaimNumber> <pat:ClaimText>92. The compound of claim 77, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIII: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIII; wherein p is 2 or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00093"> <pat:ClaimNumber>93< / pat:ClaimNumber> <pat:ClaimText>93. The compound of claim 78, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIIIa: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIIa; wherein p is 2 or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00094"> <pat:ClaimNumber>94< / pat:ClaimNumber> <pat:ClaimText>94. The compound of claim 79, or the pharmaceutically acceptable salt thereof, wherein the compound has a Formula VIIIb: [Image disponible dans le document PDF, Image available in the PDF document] Formula VIIIb; wherein p is 2 or 3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00095"> <pat:ClaimNumber>95< / pat:ClaimNumber> <pat:ClaimText>95. The compound of any one of claims 92-94, wherein p is 3, and each RA1 is independently a halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00096"> <pat:ClaimNumber>96< / pat:ClaimNumber> <pat:ClaimText>96. The compound of any one of claims 92-94, wherein p is 2, and each RA1 is independently a halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00097"> <pat:ClaimNumber>97< / pat:ClaimNumber> <pat:ClaimText>97. The compound of any one of claims 92-96 wherein each RA1 is independently a fluoro or a chloro. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00098"> <pat:ClaimNumber>98< / pat:ClaimNumber> <pat:ClaimText>98. The compound of any one of claims 69-97, wherein m is 0, 1, or 2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00099"> <pat:ClaimNumber>99< / pat:ClaimNumber> <pat:ClaimText>99. The compound of any one of claims 69-97, wherein m is 0. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00100"> <pat:ClaimNumber>100< / pat:ClaimNumber> <pat:ClaimText>100. The compound of any one of claims 69-97, wherein m is 1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00101"> <pat:ClaimNumber>101< / pat:ClaimNumber> <pat:ClaimText>101. The compound of any one of claims 69-97, wherein m is 2. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00102"> <pat:ClaimNumber>102< / pat:ClaimNumber> <pat:ClaimText>102. The compound of any one of claims 69-98, 100 and 101, wherein each R2 is independently –ORa or –O–C(O)–NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00103"> <pat:ClaimNumber>103< / pat:ClaimNumber> <pat:ClaimText>103. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently –NHRa, –C(O)–NH(Ra), –NRe– <semantics>C(O)Ra<annotation encoding="application / x-tex">C(O)R^a< / annotation>< / semantics>, or <semantics>−NRe−S(O)nRa<annotation encoding="application / x-tex">-NR^e-S(O)_nR^a< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00104"> <pat:ClaimNumber>104< / pat:ClaimNumber> <pat:ClaimText>104. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each <semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics> is independently <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics> or <semantics>−S(O)n−NH(Ra)<annotation encoding="application / x-tex">-S(O)_n-NH(R^a)< / annotation>< / semantics> Ra—. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00105"> <pat:ClaimNumber>105< / pat:ClaimNumber> <pat:ClaimText>105. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo, cyano, -NHRa, or -ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00106"> <pat:ClaimNumber>106< / pat:ClaimNumber> <pat:ClaimText>106. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently –NHRa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00107"> <pat:ClaimNumber>107< / pat:ClaimNumber> <pat:ClaimText>107. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo, cyano, or –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00108"> <pat:ClaimNumber>108< / pat:ClaimNumber> <pat:ClaimText>108. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo or cyano. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00109"> <pat:ClaimNumber>109< / pat:ClaimNumber> <pat:ClaimText>109. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein R2 is halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00110"> <pat:ClaimNumber>110< / pat:ClaimNumber> <pat:ClaimText>110. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein R2 is cyano. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00111"> <pat:ClaimNumber>111< / pat:ClaimNumber> <pat:ClaimText>111. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo or –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00112"> <pat:ClaimNumber>112< / pat:ClaimNumber> <pat:ClaimText>112. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo or -ORa; wherein each Ra is independently H or C1-C6 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00113"> <pat:ClaimNumber>113< / pat:ClaimNumber> <pat:ClaimText>113. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo or -ORa; wherein each Ra is independently H or C1-C3 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00114"> <pat:ClaimNumber>114< / pat:ClaimNumber> <pat:ClaimText>114. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently halo or –ORa; wherein each Ra is independently H or methyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00115"> <pat:ClaimNumber>115< / pat:ClaimNumber> <pat:ClaimText>115. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein each R2 is independently –ORa. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00116"> <pat:ClaimNumber>116< / pat:ClaimNumber> <pat:ClaimText>116. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein R2 is –ORa and Ra is C3-C6 cycloalkyl optionally substituted optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and -O-C1-C4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00117"> <pat:ClaimNumber>117< / pat:ClaimNumber> <pat:ClaimText>117. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein R2 is –ORa; wherein Ra is C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from the group consisting of halo, cyano, and <semantics>−O−C1−C4<annotation encoding="application / x-tex">-O-C_1-C_4< / annotation>< / semantics> alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00118"> <pat:ClaimNumber>118< / pat:ClaimNumber> <pat:ClaimText>118. The compound of any one of claims 69-98, 100 and 101, or the pharmaceutically acceptable salt thereof, wherein R2 is –ORa; wherein Ra is C1-C6 alkyl optionally substituted with a <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl or halo. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00119"> <pat:ClaimNumber>119< / pat:ClaimNumber> <pat:ClaimText>119. The compound of any one of claims 69-98, 100 and 101 and 118, or the pharmaceutically acceptable salt thereof, wherein R2 is –ORa; wherein Ra is C1-C6 alkyl optionally substituted with a –O–C1-4alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00120"> <pat:ClaimNumber>120< / pat:ClaimNumber> <pat:ClaimText>120. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, C1-C6 alkyl, or <semantics>−O−C1−4<annotation encoding="application / x-tex">-O-C_{1-4}< / annotation>< / semantics>alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00121"> <pat:ClaimNumber>121< / pat:ClaimNumber> <pat:ClaimText>121. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H or C1- C6 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00122"> <pat:ClaimNumber>122< / pat:ClaimNumber> <pat:ClaimText>122. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H or C1- C4 alkyl. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00123"> <pat:ClaimNumber>123< / pat:ClaimNumber> <pat:ClaimText>123. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each H. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00124"> <pat:ClaimNumber>124< / pat:ClaimNumber> <pat:ClaimText>124. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H or - <semantics>CH3<annotation encoding="application / x-tex">CH_3< / annotation>< / semantics>. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00125"> <pat:ClaimNumber>125< / pat:ClaimNumber> <pat:ClaimText>125. The compound of any one of claims 1-119, or the pharmaceutically acceptable salt thereof, wherein R4a, R4b, R5a, R5b, R8a, R8b, R9a and R9b are each independently H, -CH3, or -OCH3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00126"> <pat:ClaimNumber>126< / pat:ClaimNumber> <pat:ClaimText>126. A compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00127"> <pat:ClaimNumber>127< / pat:ClaimNumber> <pat:ClaimText>127. A compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] CA 3166480 [Image disponible dans le document PDF, Image available in the PDF document] pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00128"> <pat:ClaimNumber>128< / pat:ClaimNumber> <pat:ClaimText>128. A compound selected from the group consisting of: [Image disponible dans le document PDF, Image available in the PDF document] , , [Image disponible dans le document PDF, Image available in the PDF document] reof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00129"> <pat:ClaimNumber>129< / pat:ClaimNumber> <pat:ClaimText>129. A pharmaceutical composition comprising a compound of any one of claims 1-128, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00130"> <pat:ClaimNumber>130< / pat:ClaimNumber> <pat:ClaimText>130. The pharmaceutical composition of claim 129, further comprising one, two, three, or four additional therapeutic agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00131"> <pat:ClaimNumber>131< / pat:ClaimNumber> <pat:ClaimText>131. The pharmaceutical composition of claim 130, wherein the additional therapeutic agent or agents are anti-HIV agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00132"> <pat:ClaimNumber>132< / pat:ClaimNumber> <pat:ClaimText>132. The pharmaceutical composition of claim 130 or 131, wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, nucleoside reverse transcriptase translocation inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00133"> <pat:ClaimNumber>133< / pat:ClaimNumber> <pat:ClaimText>133. The pharmaceutical composition of any one of claims 130-132, wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00134"> <pat:ClaimNumber>134< / pat:ClaimNumber> <pat:ClaimText>134. The pharmaceutical composition of any one of claims 130-133, wherein the additional therapeutic agent or agents comprise lenacapavir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00135"> <pat:ClaimNumber>135< / pat:ClaimNumber> <pat:ClaimText>135. The pharmaceutical composition of any one of claims 130-132, wherein the additional therapeutic agent or agents comprise a nucleoside reverse transcriptase translocation inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00136"> <pat:ClaimNumber>136< / pat:ClaimNumber> <pat:ClaimText>136. The pharmaceutical composition of any one of claims 130-132 and 135, wherein the additional therapeutic agent or agents comprise islatravir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00137"> <pat:ClaimNumber>137< / pat:ClaimNumber> <pat:ClaimText>137. The pharmaceutical composition of any one of claims 130-132, wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor and a nucleoside reverse transcriptase translocation inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00138"> <pat:ClaimNumber>138< / pat:ClaimNumber> <pat:ClaimText>138. The pharmaceutical composition of any one of claims 130-132 and 137, wherein the additional therapeutic agent or agents comprise lenacapavir and islatravir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00139"> <pat:ClaimNumber>139< / pat:ClaimNumber> <pat:ClaimText>139. The pharmaceutical composition of any one of claims 130-132, wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N- <semantics>((S)−1−(3−(4−chloro−3−(methylsulfonamido)−1−(2,2,2−trifluoroethyl)−1H−indazol−7−yl)−6−(3−(4−chloro−3−(methylsulfonamido)−1−(2,2,2−trifluoroethyl)−1H−indazol−7−yl)−6−(3−(3−(3−(3−(3−(3−(3−(3−(3−(3−(3−(3−(3−<annotation encoding="application / x-tex">((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-(3-(3-(3-(3-(3-(3-(3-(3-(3-(3-(3-(3-< / annotation>< / semantics> methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2- ((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH- cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00140"> <pat:ClaimNumber>140< / pat:ClaimNumber> <pat:ClaimText>140. The pharmaceutical composition of any one of claims 129-139, wherein the pharmaceutical composition is for oral or parenteral administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00141"> <pat:ClaimNumber>141< / pat:ClaimNumber> <pat:ClaimText>141. A kit comprising a compound of any one of claims 1-128, or a pharmaceutically acceptable salt thereof, and instructions for use. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00142"> <pat:ClaimNumber>142< / pat:ClaimNumber> <pat:ClaimText>142. The kit of claim 141, further comprising one, two, three, or four additional therapeutic agent or agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00143"> <pat:ClaimNumber>143< / pat:ClaimNumber> <pat:ClaimText>143. The kit of claim 142, wherein the additional therapeutic agent or agents are anti-HIV agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00144"> <pat:ClaimNumber>144< / pat:ClaimNumber> <pat:ClaimText>144. The kit of claim 142 or 143, wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00145"> <pat:ClaimNumber>145< / pat:ClaimNumber> <pat:ClaimText>145. The kit of any one of claims 142-144, wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3- (methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3- (methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)- 5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[1,2- cpyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00146"> <pat:ClaimNumber>146< / pat:ClaimNumber> <pat:ClaimText>146. Use of a compound as defined in any one of claims 1-128, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 129-140, for treating an HIV infection in a human having or at risk of having the infection. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00147"> <pat:ClaimNumber>147< / pat:ClaimNumber> <pat:ClaimText>147. The use of claim 146, wherein said compound or pharmaceutical composition is for administration to the human of an effective amount of one, two, three, or four additional therapeutic agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00148"> <pat:ClaimNumber>148< / pat:ClaimNumber> <pat:ClaimText>148. The use of claim 147, wherein the additional therapeutic agent or agents are anti-HIV agents. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00149"> <pat:ClaimNumber>149< / pat:ClaimNumber> <pat:ClaimText>149. The use of claim 147 or 148, wherein the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, nucleoside reverse transcriptase translocation inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00150"> <pat:ClaimNumber>150< / pat:ClaimNumber> <pat:ClaimText>150. The use of any one of claims 147-149, wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor or a nucleoside reverse transcriptase translocation inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00151"> <pat:ClaimNumber>151< / pat:ClaimNumber> <pat:ClaimText>151. The use of any one of claims 147-149, wherein the additional therapeutic agent or agents comprise lenacapavir and islatravir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00152"> <pat:ClaimNumber>152< / pat:ClaimNumber> <pat:ClaimText>152. The use of any one of claims 147-150, wherein the additional therapeutic agent or agents comprise a HIV capsid inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00153"> <pat:ClaimNumber>153< / pat:ClaimNumber> <pat:ClaimText>153. The use of any one of claims 147-150 and 152, wherein the additional therapeutic agent or agents comprise lenacapavir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00154"> <pat:ClaimNumber>154< / pat:ClaimNumber> <pat:ClaimText>154. The use of any one of claims 147-150, wherein the additional therapeutic agent or agents comprise a nucleoside reverse transcriptase translocation inhibitor. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00155"> <pat:ClaimNumber>155< / pat:ClaimNumber> <pat:ClaimText>155. The use of any one of claims 147-150 and 154, wherein the additional therapeutic agent or agents comprise islatravir. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00156"> <pat:ClaimNumber>156< / pat:ClaimNumber> <pat:ClaimText>156. The use of any one of claims 147-149, wherein the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3- (methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3- (methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5- difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2- c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00157"> <pat:ClaimNumber>157< / pat:ClaimNumber> <pat:ClaimText>157. The use of any one of claim 147-156, wherein the administration is oral, intravenous, subcutaneous, or intramuscular. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00158"> <pat:ClaimNumber>158< / pat:ClaimNumber> <pat:ClaimText>158. A compound of any one of claims 1-128, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 129-140, for use in medical therapy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00159"> <pat:ClaimNumber>159< / pat:ClaimNumber> <pat:ClaimText>159. A compound of any one of claims 1-128, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 129-140, for use in treating an HIV infection. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00160"> <pat:ClaimNumber>160< / pat:ClaimNumber> <pat:ClaimText>160. Use of a compound as defined in any one of claims 1-128, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 129-140, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having the infection. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>