TYK2 pseudokinase ligands

Abstract

Described herein are TYK2 pseudokinase ligands and methods of utilizing TYK2 pseudokinase ligands in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

WSGR Docket No. 55754-727.601TYK2 PSEUDOKINASE LIGANDSCROSS-REFERENCE

[0001] This application claims benefit of U. S. Provisional Patent Application No. 63 / 748,342 filed on January 22, 2025, which is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. The four JAK family members are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and Tyrosine kinase 2 (TYK2) and have been shown to be key components of cytokine-mediated effects. Unlike JAK1 deficient mice, TYK2 deficient mice are viable and the TYK2 deficiency has been shown to be protective in various models of autoimmunity.SUMMARY OF THE INVENTION

[0003] In one aspect, provided herein are compounds of Formula (T):R ‘5Formula (I’);wherein:W is CH orN;X is C(R2) or N;Y is C(R3) orN;Z is C(R4) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;R2, R3, and R4are independently selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C3- Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, C3-C6cycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, C3- Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio;WSGR Docket No. 55754-727.601Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORn, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 R7 groups;Re is selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, and -S(=O)2R12; each R7 is independently selected from halogen, hydroxy, -CN, -S(=O)2Rn, Ci-Cealkyl, -Ci- Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl, wherein Ci-Cealkyl, -Ci-Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, -Ci-Cealkyl-OH, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, Ce-Cioaryl, -C(=0)ORio, and -S(=0)2Rn; or two R7 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6- membered heterocycloalkyl ring;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce- Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; and R12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

[0004] In another aspect, provided herein are compounds of Formula (I):Formula (I);wherein:W is CH orN;X is C(R2) or N;Y is C(R3) orN;Z is C(R4) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;WSGR Docket No. 55754-727.601R2, R3, and R4are independently selected from hydrogen, halogen, -CN, C1-C6alkyl, C1- Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce- Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, C3- Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio;Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR11, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3- Cecycloalkyl;Re is selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, and -S(=O)2R12; each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce- Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; and R12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

[0005] In some embodiments is a compound of Formula (I’) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(R3). In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N. In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4). In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N. In some embodiments is a compound of Formula (F) or (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (la):WSGR Docket No. 55754-727.601Formula (la).

[0006] In another aspect, provided herein are compounds of Formula (II):Formula (II);wherein:W is CH orN;X is C(R2) or N;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci- Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, and -C(=0)ORio;R3aand R4aare independently selected from hydrogen and C1-C6alkyl; or R3aand R4aare combined to form a C3-C6cycloalkyl or C2-C9heterocycloalkyl ring;Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR11, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3- Cecycloalkyl;R6is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12; each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and phenyl;WSGR Docket No. 55754-727.601each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce- Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2; and R12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

[0007] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3aand R4aare combined to form a C3-C6cycloalkyl or C2-C9heterocycloalkyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3aand R4aare combined to form a C3-C6cycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3aand R4aare combined to form a C2-C9heterocycloalkyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3aand R4aare hydrogen.

[0008] In another aspect, provided herein are compounds of Formula (III):Formula (III);wherein:W is CH orN;X is C(R2) or N;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci- Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, and -C(=0)ORio;Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR11, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2,WSGR Docket No. 55754-727.601or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3- Cecycloalkyl;Re is selected from Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, and -S(=O)2R12; each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce- Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; and R12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

[0009] In some embodiments is a compound of Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, -ORn, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from:WSGR Docket No. 55754-727.601is a compound of Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2Ri2. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and R11 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)CH3. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0010] In another aspect described herein is a pharmaceutical composition comprising a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0011] In another aspect described herein is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient aWSGR Docket No. 55754-727.601therapeutically effective amount of a compound of Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from ulcerative colitis, psoriatic arthritis, Crohn’s disease, intestinal bowel disease, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and endotoxemia.

[0012] In another aspect described herein is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and frontotemporal dementia.INCORPORATION BY REFERENCE

[0013] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0014] In the context of this disclosure, a number of terms shall be utilized.

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0016] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singularWSGR Docket No. 55754-727.601forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0017] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0018] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0019] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification.

[0020] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0021] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. C1-Cxrefers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents).

[0022] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl groups may or may not include units of unsaturation. The alkyl moiety may be a “saturated alkyl” group, which means that it does not contain any units of unsaturation (i.e. a carbon-carbon double bond or a carboncarbon triple bond). The alkyl group may also be an “unsaturated alkyl” moiety, which means that it contains at least one unit of unsaturation. The alkyl moiety, whether saturated or unsaturated, may be branched or straight chain.WSGR Docket No. 55754-727.601

[0023] The “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “Ci-Cealkyl” or similar designations. By way of example only, “Ci-Cealkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group).

[0024] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.

[0025] The term “alkenyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C(R)=CR2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. Non-limiting examples of an alkenyl group include -CH=CH2, –C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2and –C(CH3)=CHCH3. The alkenyl moiety may be branched, straight chain, or cyclic (in which case, it would also be known as a “cycloalkenyl” group). Alkenyl groups may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0026] The term “alkynyl” refers to a type of alkyl group in which the first two atoms of the alkyl group form a triple bond. That is, an alkynyl group begins with the atoms –C≡C-R, wherein R refers to the remaining portions of the alkynyl group. Non-limiting examples of an alkynyl group include –C≡CH, –C≡CCH3, –C≡CCH2CH3and –C≡CCH2CH2CH3. The “R” portion of the alkynyl moiety may be branched, straight chain, or cyclic. An alkynyl group can have 2 to 6 carbons.Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0027] “Amino” refers to a -NH2 group.

[0028] The term “alkylamine” or “alkylamino” refers to the –N(alkyl)xHygroup, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to a -N(alkyl)2 group, where alkyl is as defined herein.

[0029] The term “aromatic” refers to a planar ring having a delocalized n-electron system containing 4n+2π electrons, where n is an integer. Aromatic rings can be formed from five, six,WSGR Docket No. 55754-727.601seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0030] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0031] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

[0032] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, or partially unsaturated. Cycloalkyls may be fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0033] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An A-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0034] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The radicals may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all ringWSGR Docket No. 55754-727.601forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).

[0035] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0036] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH2C1, -CF3, -CHF2, -CH₂CF₃, -CF₂CF₃, and the like.

[0037] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, -CH₂CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF₃, -OCHF₂, -OCH₂F, -OCH₂CF₃, -OCF₂CF₃, -OCF₂CF₂CF₃, -OCF(CH3)2, and the like.

[0038] The term “deuteroalkyl” refers to an alkyl group that is substituted with one or more deuteriums.

[0039] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH₂-O-CH₃, -CH₂-CH₂-O-CH₃, -CH₂-NH-CH₃, -CH₂-CH₂-NH-CH₃, -CH2-N(CH3)-CH₃, -CH₂-CH₂-NH-CH₃, -CH2-CH₂-N(CH3)-CH₃, -CH₂-S-CH₂-CH₃, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH₃, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH₂-NH-OCH₃ and -CH₂-O-Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms.

[0040] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure.

[0041] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0042] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.WSGR Docket No. 55754-727.601

[0043] " Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.

[0044] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-Cealkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituents may be LSRS, wherein each Lsis independently selected from a bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(Ci-C6alkyl)-, or -(C2-C6alkenyl)-; and each Rsis independently selected from among H, (Ci-Cealkyl), (C3-C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above.

[0045] As used herein, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0046] The term a “therapeutically effective amount” as used herein refers to the amount of a TYK2 pseudokinase ligand that, when administered to a mammal in need, is effective to at least partially ameliorate or to at least partially prevent conditions disclosed herein.

[0047] As used herein, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0048] The term “modulate” encompasses either a decrease or an increase in activity or expression depending on the target molecule.

[0049] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, regardless of whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is administered topically. Thus, the activator can be a ligand of the receptor or it can be an activator that is metabolized to the ligand of the receptor, i.e., a metabolite that is formed in tissue and is the actual ligand.

[0050] The term “patient” or “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of a pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.

[0051] The term “soft-drug” as used herein, refers to drug substance and / or a chemical compound that is biologically active in the desired target tissue and that is metabolized, after exerting its effectWSGR Docket No. 55754-727.601in the target tissue, to a compound that is inactive against the biological target. In some embodiments, the soft-drug has no target biological activity in systemic circulation.

[0052] " Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable base addition salts.

[0053] " Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S. M. et al., " Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0054] " Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines includingWSGR Docket No. 55754-727.601naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0055] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.TYK2 pseudokinase ligands

[0056] As a member of the JAK family of tyrosine kinases, TYK2 mediates the signaling of pro-inflammatory cytokines and therefore represents a target for treating various inflammatory and autoimmune diseases. The hallmark structural feature of the JAK family is the pseudokinase (JH2) domain immediately N-terminal to the catalytic domain (JH1). Although the JH2 domain shares the overall fold of atypical catalytic domain, a series of individual residue and conformational differences between the TYK2 JH1 and JH2 domains points to the lack of catalytic activity of the JH2 domain. The JH2 domains of the JAK family have been shown to regulate the function of the JH1 domains. The overall body of evidence is consistent with the TYK2 pseudokinase domain being auto-inhibitory, stabilizing the inactivated state of the kinase domain and that small molecule ligands can stabilize this auto-inhibitory conformation thereby preventing protein function in an allosteric manner (Moslin et al., Med. Chem. Commun., 2017, 700-712).

[0057] The compounds of Formula (I’), (I), (la), (II), or (III), described herein are TYK2 pseudokinase ligands. The compounds of Formula (F), (I), (la), (II), or (III), described herein, and compositions comprising these compounds, are useful for the treatment of an inflammatory or autoimmune disease.

[0058] In some embodiments, provided herein is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No. 55754-727.601Formula (I’);wherein:W is CH orN;X is C(R2) or N;Y is C(R3) orN;Z is C(R4) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;R2, R3, and R4are independently selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci- Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C3- Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, C3- Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio;R5is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 R7groups;R6is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12; each R7 is independently selected from halogen, hydroxy, -CN, -S(=O)2Rn, Ci-Cealkyl, -Ci- Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl, wherein Ci-Cealkyl, -Ci-Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Cs-Cecycloalkyl, C2- Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, -Ci-Cealkyl-OH, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, Ce-Cioaryl, -C(=0)ORio, and -S(=0)2Rn; or two R7 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6- membered heterocycloalkyl ring;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cs-Cecycloalkyl, and phenyl;WSGR Docket No. 55754-727.601each R11is independently selected from C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2; and R12is C1-C6alkyl or C1-C6haloalkyl.

[0059] In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(Rs). In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is CN. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -NH2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cedeuteroalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvateWSGR Docket No. 55754-727.601thereof, wherein R3 is -CF3. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCH2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cedeuteroalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCD2CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCD2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0060] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

[0061] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4). In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl,WSGR Docket No. 55754-727.601Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is CN. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cedeuteroalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCH2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cedeuteroalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCD2CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCD2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0062] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.WSGR Docket No. 55754-727.601

[0063] In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy optionally substituted with 1, 2, or 3 groups selected from hydroxy, C2-C9heterocycloalkyl, and -C(=0)ORio.In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and unsubstituted Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is CN. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cedeuteroalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments is a compound of Formula (F), or apharmaceutically acceptable salt or solvate thereof, wherein R2 is. In someWSGR Docket No. 55754-727.601embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvatethereof, wherein R2 is°. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 isCO2Me jn someembodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is'0 CO2Hjnsome embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cedeuteroalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCD2CD3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCD2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0064] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0065] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound ofWSGR Docket No. 55754-727.601Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is -CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0066] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is -WSGR Docket No. 55754-727.601CH3. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0067] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen and Ci-Cealkyl.

[0068] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-Cgheteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula(F), or a pharmaceutically acceptable salt or solvate thereof, wherein Riis C0H. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvateWSGR Docket No. 55754-727.601N-Nthereof, wherein Ri is °. In some embodiments is a compound of Formula (I’), or aN-NJNpharmaceutically acceptable salt or solvate thereof, wherein Ri isH

[0069] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof,or solvate thereof, wherein Ri is selected fromx,F,vF^SS ° II x JUT U A / XNA NF, H2N R,andI

[0070] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -ORn, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted C2-C9heteroaryl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is Ce-Cioaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-WSGR Docket No. 55754-727.601Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted phenyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -OCH3, -OCH2CH2OCH3,oII N N. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is hydrogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH2CH2OCH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvatethereof, wherein Rs is1. In some embodiments is a compound of Formula (F), or aCF2Hpharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvatethereof, wherein Rs is. In some embodiments is a compound of Formula (F), or aWSGR Docket No. 55754-727.601pharmaceutically acceptable salt or solvate thereof, wherein Rs is i. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt N-N7or solvate thereof, wherein Rs is1. In some embodiments is a compound of Formula (F), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is1In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (F), or a Npharmaceutically acceptable salt or solvate thereof, wherein Rs is i. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is i. In some embodiments is a compound of Formula (F), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isWSGR Docket No. 55754-727.601. In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt oor solvate thereof, wherein R5 is

[0071] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from Ci-Cealkyl, -ORn, Cs-Cecycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 R7 groups. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R7 groups. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl substituted with 1, 2, or 3 R7 groups. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl substituted with 1, 2, or 3 R7 groups, wherein C2-C9heteroaryl is selected from pyrazolyl, thiazolyl, oxazolyl, pyridyl, pyrmindinyl, and pyridazinyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl substituted with 1, 2, or 3 R7 groups, wherein C2-C9heteroaryl is pyrazolyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl substituted with 1 R7 group, wherein C2-C9heteroaryl is pyrazolyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is halogen. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CN. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is Cs-Cecycloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvateWSGR Docket No. 55754-727.601 / CF2H N-N N-Nthereof, wherein R5 is selected from hydrogen, -OCH3, -OCH2CH2OCH3,

[0072] In some embodiments is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2R12. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2R12. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cealkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cealkoxy. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkoxy.

[0073] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt °^O %o OX / O OX / ORvxS'ZF\ F, SZor solvate thereof, wherein Re is selected fromF

[0074] In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (F), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0075] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:WSGR Docket No. 55754-727.601Formula (I);wherein:W is CH orN;X is C(R2) orN;Y is C(R3) orN;Z is C(R4) orN;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, or C2-C9heteroaryl;R2, R3, and R4are independently selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, C3-C6cycloalkyl, C2-Cgheterocycloalkyl, and -C(=0)ORio;Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -ORn, C3-C6cycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, C3-C6cycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-C6cycloalkyl;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, C3-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, C3-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2; andR12 is C1-C6alkyl or C1-C6haloalkyl.

[0076] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(R3). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from hydrogen, halogen,WSGR Docket No. 55754-727.601-CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-Cgheteroaryl, wherein Ci-Cealkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0077] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

[0078] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-Cgheteroaryl, wherein Ci-Cealkyl, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionallyWSGR Docket No. 55754-727.601substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0079] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

[0080] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-Cgheteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio. In someWSGR Docket No. 55754-727.601embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy optionally substituted with 1, 2, or 3 groups selected from hydroxy, C2-Cgheterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and unsubstituted Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is CN. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein R2 is— '. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvatethereof, wherein R2 is0. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is'0CO2Me jn someembodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 isCO2H jn someembodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-WSGR Docket No. 55754-727.601Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0081] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0082] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, C1-C6alkoxy, and -N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0083] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn. In some embodiments is a compound of Formula (I),WSGR Docket No. 55754-727.601or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is -CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0084] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)N(R10)2 and each R10 is independently selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)N(R10)2 and each R10 is independently selected from hydrogen, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)N(R10)2 and each R10 is independently selected from hydrogen and C1-C6alkyl.WSGR Docket No. 55754-727.601

[0085] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, wherein Ri is C °H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri N-NisC °H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable N-NN *salt or solvate thereof, wherein Ri isH

[0086] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,or solvate thereof, wherein Ri is selected fromx, F,, VF^sS O n nI H A / N HF, H2N R,andI

[0087] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, -OR11, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, C6-C10aryl, and C2-C9heteroaryl, wherein C6-C10aryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceuticallyWSGR Docket No. 55754-727.601acceptable salt or solvate thereof, wherein R5 is C2-C9heteroaryl optionally substituted with 1 or 2 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C2-C9heteroaryl optionally substituted with 1 group selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is unsubstituted C2-C9heteroaryl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C6-C10aryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1 or 2 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1 group selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with C1-C6alkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is unsubstituted phenyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, -OCH3, -OCH2CH2OCH3,1and1. In some embodiments is a compound of Formula (I), or a pharmaceuticallyN-NHacceptable salt or solvate thereof, wherein Rs is 1. In some embodiments is a compound of N-N7Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is 1. In someWSGR Docket No. 55754-727.601embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate CF3N-N / / Athereof, wherein R5 is. In some embodiments is a compound of Formula (I), or a CD3N-N / / A pharmaceutically acceptable salt or solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5zPMBN- N' / / Ais. In some embodiments is a compound of Formula (I), or a pharmaceutically / SOzCHaN-N / / Aacceptable salt or solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 isDy* OHN-N. In some embodiments is a compound of Formula (I), or a pharmaceuticallyN-N / C°2E* / / Aacceptable salt or solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is

[0088] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from C1-C6haloalkyl and -S(=O)2R12. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -S(=O)2R12. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -S(=O)2R12 and R12 is C1-C6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -S(=O)2CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is -S(=O)2R12 and R12 is C1-C6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptableWSGR Docket No. 55754-727.601salt or solvate thereof, wherein R6 is C1-C6haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is C1-C6alkoxy. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is C1-C6haloalkoxy.

[0089] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, andF

[0090] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0091] In some embodiments, provided herein is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof:WFormula (la);wherein:W is CH orN;X is C(R2) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;R2 is selected from hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, and -C(=O)OR10;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;WSGR Docket No. 55754-727.601R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each R11 is independently selected from C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2; andR12 is C1-C6alkyl or C1-C6haloalkyl.

[0092] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-C9heterocycloalkyl, and C2-Cgheteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen and Ci-Cealkoxy optionally substituted with 1, 2, or 3 groups selected from hydroxy, C2-Cgheterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from hydrogen and unsubstituted Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is CN. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CF3. In some embodiments is a compound of Formula (la), or aWSGR Docket No. 55754-727.601pharmaceutically acceptable salt or solvate thereof, wherein R2 is. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvatethereof, wherein R2 is0. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 isCO2Me jn someembodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is'0 CO2Hjnsome embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0093] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0094] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, C1-C6alkoxy, and -N(R10)2. In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(=O)R11 and R11 is C1-C6alkylWSGR Docket No. 55754-727.601optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is -CH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0095] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is -CH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceuticallyWSGR Docket No. 55754-727.601acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0096] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)N(RIO)2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)N(RIO)2 and each Rio is independently selected from hydrogen and Ci-Cealkyl.

[0097] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-Cgheteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula(la), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is0. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate N-Nthereof, wherein Ri is0. In some embodiments is a compound of Formula (la), or aN-Npharmaceutically acceptable salt or solvate thereof, wherein Ri isHWSGR Docket No. 55754-727.601

[0098] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof,or solvate thereof, wherein Ri is selected fromx,F,,v

[0099] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -ORn, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted C2-C9heteroaryl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is Ce-Cioaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceuticallyWSGR Docket No. 55754-727.601acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted phenyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -OCH3, -OCH2CH2OCH3,|, i, i, i, and i. In some embodiments is a compound ot Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is hydrogen. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH2CH2OCH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate N-N7thereof, wherein Rs is1. In some embodiments is a compound of Formula (la), or aCF2HN-NVpharmaceutically acceptable salt or solvate thereof, wherein Rs is 1. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvateN-Nythereof, wherein Rs is1. In some embodiments is a compound of Formula (la), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isWSGR Docket No. 55754-727.601,N=^o. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt N-NZor solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (la), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is1In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isQ|. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is V '. In some embodiments is a compound of Formula (la), or a N^Npharmaceutically acceptable salt or solvate thereof, wherein Rs is ■' ' in some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isN^N. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptablesalt or solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (la),0or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Rsis i. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptablesalt or solvate thereof, wherein Rs is "iWSGR Docket No. 55754-727.601

[0100] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2Ri2. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2R12. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cealkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cealkoxy. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkoxy.

[0101] In some embodiments is a compound of Formula (la), or a pharmaceutically °K / OOzp Oxo, SS I acceptable salt or solvate thereof, wherein Re is selected from, 1

[0102] In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0103] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II);wherein:W is CH orN;X is C(R2) orN;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;WSGR Docket No. 55754-727.601R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=O)ORio;R3a and R4a are independently selected from hydrogen and Ci-Cealkyl; or R3a and R4a are combined to form a Cs-Cecycloalkyl or C2-C9heterocycloalkyl ring;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; andR12 is Ci-Cealkyl or Ci-Cehaloalkyl.

[0104] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are independently selected from hydrogen and Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is hydrogen and R4a are Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a is hydrogen and R4a are -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are independently selected from Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are -CH3.

[0105] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a Cs-Cecycloalkyl or C2-Cgheterocycloalkyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a C3-WSGR Docket No. 55754-727.601Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a cyclopropyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a cyclobutyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a cyclopentyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a cyclohexyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form a C2-C9heterocycloalkyl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3a and R4a are combined to form an oxetane ring.

[0106] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-Cgheterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=O)ORio. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy optionally substituted with 1, 2, or 3 groups selected from hydroxy, C2-Cgheterocycloalkyl, and -C(=O)ORio. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and unsubstituted Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is CN. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkyl. In someWSGR Docket No. 55754-727.601embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein R2 is— '. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvatethereof, wherein R2 is0. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is'0CO2Me jn someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 isCO2H jn someembodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0107] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0108] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy,WSGR Docket No. 55754-727.601Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0109] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is -CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1,WSGR Docket No. 55754-727.6012, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0110] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen and Ci-Cealkyl.

[0111] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is°. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate N-Nthereof, wherein Ri is°. In some embodiments is a compound of Formula (II), or aN-NN *pharmaceutically acceptable salt or solvate thereof, wherein Ri isHWSGR Docket No. 55754-727.601

[0112] In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt or solvate thereof, wherein Ri is selected from

[0113] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -ORn, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted C2-C9heteroaryl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is Ce-Cioaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of FormulaWSGR Docket No. 55754-727.601(II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionally substituted with Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted phenyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is hydrogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is -OCH2CH2OCH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate N-N7thereof, wherein Rs is1. In some embodiments is a compound of Formula (II), or aCF2HN-NVpharmaceutically acceptable salt or solvate thereof, wherein Rs is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvateN-Nythereof, wherein Rs is1. In some embodiments is a compound of Formula (II), or a,N=\pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isWSGR Docket No. 55754-727.601,N=^o. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt N-NZor solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is1In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs isQ|. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is V '. In some embodiments is a compound of Formula (II), or a N^Npharmaceutically acceptable salt or solvate thereof, wherein Rs is ■' ' in some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (II), or aQpharmaceutically acceptable salt or solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is'i'w. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs isWSGR Docket No. 55754-727.601

[0114] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2Ri2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2R12. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cealkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cealkoxy. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkoxy.

[0115] In some embodiments is a compound of Formula (II), or a pharmaceutically °K / OOzp Oxo, SS I acceptable salt or solvate thereof, wherein Re is selected from, 1 %oFx FFF,F, and F

[0116] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0117] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:wherein:W is CH orN;X is C(R2) orN;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;WSGR Docket No. 55754-727.601R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=O)ORio;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; andR12 is Ci-Cealkyl or Ci-Cehaloalkyl.

[0118] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, C2-Cgheterocycloalkyl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, C2-C9heterocycloalkyl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy optionally substituted with 1, 2, or 3 groups selected from hydroxy, C2-Cgheterocycloalkyl, and -C(=0)ORio. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and unsubstituted Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2WSGR Docket No. 55754-727.601is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is CN. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein R2 is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvatethereof, wherein R2 is0. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 isCO2Me jn someembodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is'0 CO2Hjnsome embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cehaloalkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

[0119] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0120] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-WSGR Docket No. 55754-727.601Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N(RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0121] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cehaloalkyl, Ci-Cealkoxy, -ORio, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-Cealkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkoxy, and -N(RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Ci-CealkylWSGR Docket No. 55754-727.601optionally substituted with 1, 2, or 3 groups selected from halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2RII and Rn is unsubstituted Ci-Cealkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is -CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, Ci-Cealkyl, Ci-Cehaloalkyl, and Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=O)2Rn and Rn is Cs-Cecycloalkyl optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, and Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -S(=0)2Rn and Rn is unsubstituted Cs-Cecycloalkyl.

[0122] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen, Ci-Cealkyl, and Ci-Cehaloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)N(RIO)2 and each Rio is independently selected from hydrogen and Ci-Cealkyl.

[0123] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl ring. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is C2-C9heteroaryl selected from imidazolyl, pyrazolyl, oxadiazolyl, and triazolyl. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is. In someWSGR Docket No. 55754-727.601embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate N-Nthereof, wherein Ri is O ° --. In some embodiments is a compound of Formula (III), or aN-NN *pharmaceutically acceptable salt or solvate thereof, wherein Ri isH

[0124] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable o °salt or solvate thereof, wherein Ri is selected fromx,F,vF, H2NH, and I

[0125] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -ORn, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce-Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is C2-C9heteroaryl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is unsubstituted C2-C9heteroaryl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is Ce-Cioaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is phenyl optionallyWSGR Docket No. 55754-727.601substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1 or 2 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and C3-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1 group selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is unsubstituted phenyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, -OCH3, -OCH2CH2OCH3, / CF2HN-N N-Ni~, and 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OCH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OCH2CH2OCH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate N-N / / ?thereof, wherein R5 is. In some embodiments is a compound of Formula (III), or a CF2HN-N / / \ pharmaceutically acceptable salt or solvate thereof, wherein R5 is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvateN-Nu >thereof, wherein R5 is. In some embodiments is a compound of Formula (III), or aWSGR Docket No. 55754-727.601,N=\spharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt N-N7or solvate thereof, wherein Rs is1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof, wherein Rs is1In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable saltor solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (III), or a Npharmaceutically acceptable salt or solvate thereof, wherein Rs is i. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptablesalt or solvate thereof, wherein Rs is i. In some embodiments is a compound of Formula (III),or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is '. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein RsWSGR Docket No. 55754-727.601xo0is i. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptablesalt or solvate thereof, wherein Rs is

[0126] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2Ri2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2R12. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cealkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2 and R12 is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cealkoxy. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkoxy.

[0127] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable Oxo ° / / ° Ox / o OX / OF'VS / F\ / F Isalt or solvate thereof, wherein Re is selected from,1,F,, \ FF,F, andF

[0128] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

[0129] In some embodiments, provided herein is a compound selected from:WSGR Docket No. 55754-727.601

[0130] In some embodiments, provided herein is a compound selected from:WSGR Docket No. 55754-727.601WSGR Docket No. 55754-727.601

[0131] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.Further Forms of Compounds Disclosed HereinIsomers

[0132] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.Labeled compounds

[0133] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the factWSGR Docket No. 55754-727.601that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as2H,3H,13C,14C,15N,17O,18O,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certainisotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i. e.,3H and carbon-14, z.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, z.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.

[0134] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0135] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0136] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.Solvates

[0137] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.WSGR Docket No. 55754-727.601

[0138] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Synthesis of Compounds

[0139] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary.

[0140] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

[0141] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4thEd., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rdEd., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. As a guide the following synthetic methods may be utilized.Use of Protecting Groups

[0142] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the finalWSGR Docket No. 55754-727.601product, in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. It is preferred that each protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.

[0143] Protective groups can be removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as t-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.

[0144] Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or they may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates.

[0145] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd°-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.

[0146] Typically blocking / protecting groups may be selected from:WSGR Docket No. 55754-727.601(H3C)3C^ MeEtallylt-butylCbz Boc acetyl

[0147] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure).Methods of Treatment and Prevention

[0148] In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from ulcerative colitis, psoriatic arthritis, Crohn’s disease, intestinal bowel disease, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and endotoxemia. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is rheumatoid arthritis. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, whereinWSGR Docket No. 55754-727.601the disease is psoriasis. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is systemic lupus erythematosus. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is intestinal bowel disease. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is Crohn’s disease. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is ulcerative colitis. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is psoriatic arthritis. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is type 1 diabetes. In some embodiments is a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is endotoxemia.

[0149] In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is selected from Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and frontotemporal dementia. In some embodiments is a method of treating a neurological orWSGR Docket No. 55754-727.601neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is Alzheimer’s disease. In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is Parkinson’s disease. In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is multiple sclerosis. In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is amyotrophic lateral sclerosis. In some embodiments is a method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound Formula (F), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the neurological or neurodegenerative disease is frontotemporal dementia.Pharmaceutical compositions and methods of administration

[0150] TYK2 pseudokinase ligands described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of TYK2 pseudokinase ligands as described herein can be in any pharmacological form including a therapeutically effective amount of a TYK2 pseudokinase ligand alone or in combination with a pharmaceutically acceptable carrier.

[0151] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).WSGR Docket No. 55754-727.601

[0152] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[0153] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I’), (I), (la), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0154] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), (I), (Ia), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0155] In certain embodiments, the compound as described herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic smallWSGR Docket No. 55754-727.601molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.

[0156] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), or aerosol administration.

[0157] Exemplary pharmaceutical compositions are used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which includes one or more of a disclosed compound, as an active ingredient, in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.

[0158] In some embodiments, TYK2 pseudokinase ligands described herein are administered to subjects in a biologically compatible form suitable for topical administration to treat or prevent dermal diseases, disorders or conditions. By “biologically compatible form suitable for topical administration” is meant a form of the TYK2 pseudokinase ligand to be administered in which any toxic effects are outweighed by the therapeutic effects of the inhibitor. Administration of TYK2 pseudokinase ligands as described herein can be in any pharmacological form including a therapeutically effective amount of a TYK2 pseudokinase ligand alone or in combination with a pharmaceutically acceptable carrier.

[0159] Topical administration of a TYK2 pseudokinase ligand may be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term “a semisolid composition” is meant an ointment, cream, salve, jelly, or other pharmaceutical composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.

[0160] Dermal or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer such as DMSO to increase the absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. Patches may provide a variety of dosing systems including a reservoir system or a monolithic system, respectively. The reservoir design may, for example, have four layers: the adhesive layer that directly contacts the skin, the control membrane, which controls the diffusion of drug molecules, the reservoir of drug molecules, and a water-resistant backing. Such aWSGR Docket No. 55754-727.601design delivers uniform amounts of the drug over a specified time period, the rate of delivery has to be less than the saturation limit of different types of skin. The monolithic design, for example, typically has only three layers: the adhesive layer, a polymer matrix containing the compound, and a water-proof backing. This design brings a saturating amount of drug to the skin. Thereby, delivery is controlled by the skin. As the drug amount decreases in the patch to below the saturating level, the delivery rate falls.

[0161] In one embodiment, the topical composition may, for example, take the form of hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example with polyethyleneglycol (PEG) as the carrier, like the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, optionally with added liposomes. Suitable permeation accelerators (entraining agents) include sulfoxide derivatives such as dimethylsulfoxide (DMSO) or decylmethylsulfoxide (decyl-MSO) and transcutol (diethyleneglycolmonoethylether) or cyclodextrin; as well as pyrrolidones, for example 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or the biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and the fatty acid esters thereof; urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3 -diphenylurea; terpenes, for example D-limonene, menthone, a-terpinol, carvol, limonene oxide, or 1,8-cineol.

[0162] Ointments, pastes, creams and gels also can contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, and talc, or mixtures thereof. Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used for making aerosol pharmaceuticals. In general, such methods comprise pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can additionally contain customary propellants, such a chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0163] The carrier can also contain other pharmaceutically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation. The anti-skin aging compositions can also further comprise antioxidants, sun screens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[0164] In some embodiments for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumWSGR Docket No. 55754-727.601phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition is readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0165] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, docusate sodium, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the compositions comprise buffering agents. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0166] In some embodiments, a tablet is made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. In some embodiments, molded tablets are made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0167] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions,WSGR Docket No. 55754-727.601microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage forms contain inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0168] In some embodiments, suspensions, in addition to the subject composition, contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0169] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. In some embodiments, sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0170] Compositions and compounds disclosed herein alternatively are administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, sonic nebulizers are used because they minimize exposing the agent to shear, which results in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0171] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which are reconstituted into sterile injectable solutions or dispersions just prior to use, which, in some embodiments, contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.WSGR Docket No. 55754-727.601

[0172] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0173] The dose of the composition comprising at least one compound described herein differs, depending upon the patient's (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors.

[0174] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0175] Dose administration can be repeated depending upon the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0176] It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the TYK2 pseudokinase ligand and the particular therapeutic effect to be achieved and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. The specific dose can be readily calculated by one of ordinary skill in the art, e.g., according to the approximate body weight or body surface area of the patient or the volume of body space to be occupied. The dose will also be calculated dependent upon the particular route of administration selected. Further refinement of the calculations necessary to determine the appropriate dosage for treatment is routinely made by those of ordinary skill in the art. Such calculations can be made without undue experimentation by one skilled in the art in lightWSGR Docket No. 55754-727.601of the TYK2 pseudokinase ligand activities disclosed herein in assay preparations of target cells. Exact dosages are determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by a practitioner, in the light of the relevant circumstances including the condition or conditions to be treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration.

[0177] Toxicity and therapeutic efficacy of such TYK2 pseudokinase ligands can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, for determining the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50 / ED50. TYK2 pseudokinase ligands that exhibit large therapeutic indices are preferred. While TYK2 pseudokinase ligands that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such inhibitors to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0178] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such TYK2 pseudokinase ligands lies preferably within a range of circulating concentrations that include the ED50with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any TYK2 pseudokinase ligand used in a method described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50(i.e., the concentration of TYK2 pseudokinase ligand that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.EXAMPLES

[0179] The following examples are offered for purposes of illustration and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by references for all legal purposes to be served thereby. The starting materials and reagents used for the synthesis of the compounds described herein may be synthesized or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.WSGR Docket No. 55754-727.601

[0180] Standard abbreviations and acronyms as defined in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreviations and acronyms used herein are as follows:AcOH acetic acidDCM dichloromethaneDMF dimethylformamideDMP Dess-Martin periodinanedppf (diphenylphosphino)ferroceneEtOAc ethyl acetateEtOH ethanoleq equivalentHBTU N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphatehr hourLC-MS liquid chromatography-mass spectrometryMeOH methanolTEA triethylamineRT room temperatureExample 1: Synthesis of N-(4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (1)NaSMe Oxone DMF / 100 °C Pd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3Compound 1

[0181] 6 -Chloro-lH-pyrrolo[2,3-b]pyridine (500 mg, 1.0 eq) in DMF (20 mL) was degassed with bubbling N2 gas for lOmin. To the solution was added sodium methanethiolate (460 mg, 2.0 eq). The resulting mixture was heated at 100°C for 15hr. The mixture was poured in ice-water 100 mL, extracted with ethyl acetate (2x100 mL). The combined organic phase was washed with water 2x50 mL and brine, and concentrated in vacuo. The residue was purified on a 40 g silica-gel column to afford 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (360 mg, yield 72%).

[0182] A mixture of 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (105 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (138 mg, 1.0 eq), Pd2(dba)3 (30 mg, 0.05 eq), XantaPhos (41 mg, 0.11 eq), Zn(OAc)2 (71 mg, 0.6 eq), and K2CO3 (176 mg, 2.0 eq) in dry dioxane (8 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 16hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (80 mL), and washed with brine.WSGR Docket No. 55754-727.601The crude mixture was purified on a silica-gel column (12 g) to afford N-(4-(6-(methylthio)-lH-pyrrolo[2, 3-b]pyri din- l-yl)pyri din-2 -yl)acetamide (96 mg, yield 50%).

[0183] To a solution of N-(4-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (60 mg, 1.0 eq) in 15 mL MeOH and 15 mL CH3CN was added a solution of Oxone (375 mg, 3.0 eq) in water 8 mL at RT and the mixture was stirred at RT for 4 hr. The reaction was quenched with saturated NaHCO3and extracted with DCM (2 x 60 mL). The combined organic phase was washed with brine. The mixture was purified on a 4 g silica-gel column to afford N-(4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 1) (22 mg, yield 33%). LCMS: 331.2 (M+H)+.Example 2: Synthesis of N-(6-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyrimidin-4-yl)acetamide (2)Compound 2

[0184] 6-Bromopyrimidin-4-amine (580 mg) in AC2O (10 mL) was heated at 158°C in microwave reactor for 3hr. The mixture was cooled and the excess AC2O was removed in vacuo, the residue was suspended in 30 mL toluene, and concentrated. The residue was suspended in ethyl acetate (20 mL) and filtered. The mother liquid was concentrated in vacuo to afford N-(6-bromopyrimidin-4-yl)acetamide (570 mg) which was used without further purification.

[0185] A mixture of N-(6-bromopyrimidin-4-yl)acetamide (158 mg, 1.0 eq), 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (120 mg, 1.0 eq), Pd2(dba)3 (34 mg, 0.05 eq), XantaPhos (47 mg, 0.11 eq), Zn(OAc)2 (80 mg, 0.6 eq), and K2CO3 (202 mg, 2.0 eq) in dry dioxane (10 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 16hr in a sealed-tube. The mixture was cooled, diluted with acetate (100 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to afford N-(6-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyrimidin-4-yl)acetamide (108 mg, yield 49%).

[0186] To a solution of N-(6-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyrimidin-4-yl)acetamide (62 mg, 1.0 eq) in 20 mL MeOH and 50 mL CH3CN was added a solution of Oxone (385 mg, 3.0 eq) in water 15 mL at RT and the mixture was stirred at RT for 14hr. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x60 mL). The combined organic phase was washed with brine. The mixture was purified on a 12 g silica-gel column to afford N-(6-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyrimidin-4-yl)acetamide (Compound 2) (41 mg, yield 59%). LCMS: 332.2 (M+H)+.WSGR Docket No. 55754-727.601Example 3: Synthesis of N-(5-methyl-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (3)Br S' AC2O S'Oxone ° O O o V, N Pd2(dba)3I XantaPhos / Zn(OAc)21 K2CO3 A, H / — N ' HZHCompound 3

[0187] A mixture of 4-bromo-5-methylpyridin-2-amine (680 mg) in AC2O (5 mL) was heated at 75°C in sealed-tube for 15hr. The mixture was cooled and the excess AC2O was removed in vacuo. The residue was dissolved in DCM (40 mL) washed with saturated NaHCO3and brine to afford solid N-(4-bromo-5-methylpyridin-2-yl)acetamide (650 mg), which was used without purification.

[0188] A mixture of N-(4-bromo-5-methylpyridin-2-yl)acetamide (168 mg, 1.0 eq), 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (120 mg, 1.0 eq), Pd2(dba)3 (34 mg, 0.05 eq), XantaPhos (47 mg, 0.11 eq), Zn(OAc)2 (80 mg, 0.6 eq), and K2CO3 (202 mg, 2.0 eq) in dry dioxane (10 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 16hr in a sealed-tube. The reaction was cooled, diluted with acetate (100 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to afford N-(5-methyl-4-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (102 mg, yield 44%).

[0189] To a solution of N-(5-methyl-4-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (12 mg, 1.0 eq) in 5 mL MeOH and 3 mL CH3CN was added a solution of Oxone (72 mg, 3.0 eq) in water (15 mL) at RT. The mixture was stirred at RT for Ihr. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x20 mL). The combined organic phase was washed with brine. The mixture was purified on a 4 g silica-gel column to afford N-(5-methyl-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 3) (3 mg, yield 22%). LCMS: 345.2 (M+H)+.Example 4: Synthesis of N-(4-(6-(methylsulfonyl)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yi) (4)s. NaSMe N N > H Oxone fj DMF / 90 °CsPd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3N H NHCompound 4

[0190] A mixture of 6-chloro-lH-pyrazolo[3,4-b]pyridine (120 mg, 1.0 eq) in dry DMF (3 mL) was degassed with bubbling N2 gas for 5min. NaSMe (110 mg, 2.0 eq) was added and the mixture was heated at 90°C overnight. The mixture was cooled, diluted with ethyl acetate (40 mL), washed with H2O (3x15 mL) and brine. The organic phase was dried over Na2SC>4 and concentrated inWSGR Docket No. 55754-727.601vacuo. The residue was suspended in ethyl acetate (~3 mL) and stirred at RT for lOmins. A solid was collected by filtration to afford 6-(methylthio)-lH-pyrazolo[3,4-b]pyridine (73 mg, yield 56%).

[0191] A mixture of 6-(methylthio)-lH-pyrazolo[3,4-b]pyridine (73 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (95 mg, 1.0 eq), Pd2(dba)3 (21 mg, 0.05 eq), XantaPhos (29 mg, 0.11 eq), Zn(OAc)2 (50 mg, 0.6 eq), and K2CO3 (125 mg, 2.0 eq) in dry dioxane (6 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 15hr in a sealed-tube. The reaction was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to afford N-(4-(6-(methylthio)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yl)acetamide (81 mg, yield 61%).

[0192] To a solution of N-(4-(6-(methylthio)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yl)acetamide (50 mg, 1.0 eq) in 10 mL MeOH and 10 mL CH3CN was added a solution of Oxone (310 mg, 3.0 eq) in water (10 mL) at RT. The mixture was stirred at RT for 2hr. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x20 mL). The combined organic phase was washed with brine. The mixture was purified on a 4 g silica-gel column to afford N-(4-(6-(methylsulfonyl)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 4) (22 mg, yield 39%). LCMS: 332.4 (M+H)+.Example 5: Synthesis of N-(4-(6-(methylsulfonyl)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yl)acetamide (5)NaBH3CN Oxone Pd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3Compund 5

[0193] To a solution of 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (164 mg, 1.0 eq) in AcOH (10 ml) was added NaBH3CN (157 mg, 2.5 eq) at 0°C. The reaction mixture was stirred at room temperature for 4 hours. Water (20 mL) was added to the reaction mixture and the reaction mixture pH was adjusted to 9-10 by adding saturated aqueous NaOH. The mixture was extracted with EtOAc (2x30 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel to give 6-(methylthio)-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine (77 mg, yield 46%).

[0194] A mixture of 6-(methylthio)-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine (77 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (100 mg, 1.0 eq), Pd2(dba)3 (22 mg, 0.05 eq), XantaPhos (30 mg, 0.11 eq), Zn(OAc)2 (51 mg, 0.6 eq), and K2CO3 (130 mg, 2.0 eq) in dry dioxane (8 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 15hr in a sealed-tube. The reaction was cooled, diluted with DCM (50 mL), washed with water and brine.WSGR Docket No. 55754-727.601The crude mixture was purified on a silica-gel column (12 g) to afford N-(4-(6-(methylthio)-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (83 mg, yield 57%).

[0195] To a solution of N-(4-(6-(methylthio)-2,3-dihydro-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (52 mg, 1.0 eq) in 15 mL MeOH and 10 mL CH3CN was added a solution of Oxone (320 mg, 3.0 eq) in water 5 mL at RT and the mixture was stirred at RT for 30mins. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x20 mL). The combined organic phase was washed with brine. The mixture was purified on a 12 g silica-gel column to afford N-(4-(6-(methylsulfonyl)-lH-pyrazolo[3,4-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 5) (30 mg, yield 52%). LCMS: 333.8 (M+H)+.Example 6: Synthesis of N-(4-(6'-(methylsulfonyl)spiro [cyclopropane-1, 3'-pyrrolo [2,3-b]pyridin]-l'(2'H)-yl)pyridin-2-yl)acetamide (6)Compound 6

[0196] To a solution of 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (0.98 g, 1.0 eq) in ACN (90 ml) was added solution of Oxone (12.3 g, 3.0 eq) in water (90 mL). The reaction mixture was stirred at room temperature for 4 hours and then quenched with sat. NaHCO3. The reaction mixture was extracted with DCM (3x60 mL). The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo and the residue was collected by filtration to give 6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (710 mg, yield 60%).

[0197] To a solution of 6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (700 mg, 3.6 mmol) in tertbutyl alcohol (40 ml) was added PyHBr3 (4 g) in portions. The reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was diluted with EtOAc. The organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The solvent was concentrated in vacuo and the solid was collected by filtration to give 3,3-dibromo-6-(m ethyl sulfonyl)- 1, 3 -dihydro-2H-pyrrolo[2, 3 -b]pyridin-2-one (602 mg, yield 45%).

[0198] To a solution of 3,3-dibromo-6-(methylsulfonyl)-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (600 mg, 1.6 mmol) in a mixture of acetic acid (5 mL) and acetonitrile (10 mL) was added zinc dust (1.3 g). The mixture was stirred for 2 hours at room temperature. The solid was filtered from the mixture and the solvent was evaporated in vacuo. The residue was slurried in ethyl acetate. The ethyl acetate solution containing insoluble solid was passed through a short column of silica gel.WSGR Docket No. 55754-727.601The collected ethyl acetate solution was evaporated to give 6-(m ethyl sulfonyl)- 1, 3 -dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (320 mg, yield 93%) which was used without purification.

[0199] To a solution of 6-(methylsulfonyl)-l,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (320 mg, 1.5 mmol) in DMF (5 ml) was added (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (886 mg, 2 mmol), Zn(OTf)2 (550 mg, 1.5mmol) and DBU (684 mg, 4.5 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The reaction was quenched with sat. aq. NH4CI and extracted with EtOAc (3 x 20 mL). The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. The solvent was removed, and the solid was collected by filtration to give 6'-(methylsulfonyl)spiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridin]-2'(TH)-one (270 mg, yield 75%) which was used without purification.

[0200] To a solution of 6'-(methylsulfonyl)spiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridin]-2'(l'H)-one (150 mg, 0.63 mmol) in anhydrous THF (5 mL) was added DIBAL in THF (4 ml, 4 mmol) at 0°C under N2. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with IN NaOH and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the solid was collected by filtration to give 6'-(methylsulfonyl)-l',2'-dihydrospiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridine] (73 mg, yield 51%).

[0201] A mixture of 6'-(methylsulfonyl)-l',2'-dihydrospiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridine] (73 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (70 mg, 1.0 eq), Pd2(dba)3 (15 mg, 0.05 eq), XantaPhos (21 mg, 0.11 eq), Zn(OAc)2 (36 mg, 0.6 eq), and K2CO3 (90 mg, 2.0 eq) in dry dioxane (8 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 100°C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to afford N-(4-(6'-(methylsulfonyl)spiro[cyclopropane-l,3'-pyrrolo[2,3-b]pyridin]-l'(2'H)-yl)pyridin-2-yl)acetamide (Compound 6) (55 mg, yield 47%). LCMS: 359.4 (M+H)+.Example 7: Synthesis of N-(4-(3-chloro-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (7)ciCompound 7

[0202] To a solution of N-(4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (15 mg, 1.0 eq) in DCM (5 mL) and THF (2 mL) was added NCS (7 mg, 1.2 eq) at RT. The resulting mixture was stirred at RT for 1.5hr. The solvent was removed in vacuo and the crude mixture was purified on a silica-gel column to give N-(4-(3-chloro-6-(methylsulfonyl)-lH-WSGR Docket No. 55754-727.601pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 7) (9 mg, yield 50%). LCMS: 365.0 (M+H)+.Example 8: Synthesis of N-(4-(3-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (8)NBS

[0203] To a solution of N-(4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (30 mg, 1.0 eq) in DCM (5 mL) and THF (4 mL) was added NBS (17.8 mg, 1.1 eq) at RT. The resulting mixture was stirred at RT for 3hr. The solvent was removed in vacuo and the crude mixture was purified on a silica-gel column to give N-(4-(3-bromo-6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- l-yl)pyri din-2 -yl)acetamide (21 mg, yield 56%).

[0204] A mixture of N-(4-(3-bromo-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2-yl)acetamide (20 mg, 1.0 eq), (l-methyl-lH-pyrazol-4-yl)boronic acid (8 mg, 1.3 eq), PdCl2 dppf (3.6 mg, 0.1 eq) and CS2CO3 (32 mg, 2.0 eq) in dioxane (3 mL) and water (1 mL) was degassed with N2 for 5mins. The mixture was heated at 100°C for 14hr under N2. The reaction mixture was cooled, diluted with ethyl acetate (30 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column to give N-(4-(3-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 8) (12 mg, yield 60%). LCMS: 411.1 (M+H)+.Example 9: Synthesis of N-(4-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (9)Br\N-N1N TABF Oxone Pd2(dba)31 XantaPhos Zn(OAc)2 / K2CO3Compound 9WSGR Docket No. 55754-727.601

[0205] To a solution of 4-bromo-6-chloro-lH-pyrrolo[2,3-b]pyridine (600 mg, 1.0 eq) in dry THF (20 mL) in 0°C was added NaH (60% in mineral oil, 160 mg, 1.5 eq). The mixture was stirred at RT for 30mins then SEMC1 (90%, 720 mg) in THF (2 mL) was added dropwise. The resulting mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3and extracted with DCM (2x50 mL). The combined organic phase was dried over Na2SO4. The crude mixture was purified in silica-gel column (24 g) to afford 4-bromo-6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (905 mg, yield 96%).

[0206] A mixture of 4-bromo-6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (150 mg, 1.0 eq), (l-methyl-lH-pyrazol-4-yl)boronic acid (52 mg, 1.0 eq), PdCl2 dppf (25 mg, 0.08 eq) and CS2CO3 (270 mg, 2.0 eq) in dioxane (8 mL) and water (2 mL) was degassed with N2 for 5mins. The reaction mixture was heated at 85°C for 8hr under N2. The mixture was diluted with ethyl acetate (50 mL) and washed with water and brine. The crude mixture was purified on a silica-gel column to give 6-chloro-4-(l-methyl-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (123 mg, yield 82%).

[0207] A solution of 6-chloro-4-(l-methyl-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (120 mg, 1.0 eq) in dry DMF (4 mL) was degassed with N2 gas for 5mins, then NaSMe (28 mg, 1.2 eq) was added. The resulting mixture was heated at 110°C for 15hr. The reaction was cooled, diluted with ethyl acetate (50 mL), and washed with water (3x20 mL) and brine. The crude mixture was purified on a silica-gel column to give 4-(1 -methyl- lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2, 3-b]pyridine (97 mg, yield 78%).

[0208] 4-(l-Methyl-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (78 mg) in IN TBAF in THF (4 mL) was heated at 70°C for 5hr. The mixture was diluted with ethyl acetate (50 mL) and washed with water (3x20 mL). The crude mixture was purified on a silica-gel column to give 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (42 mg, yield 83%).

[0209] To a solution of 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (42 mg, 1.0 eq) in MeOH (15 mL) and CH3CN (10 mL) was added a solution of Oxone (320 mg, 3.0 eq) in water (8 mL). The mixture was stirred at RT for 8hr. The reaction was quenched with saturated NaHCO3 and extracted with DCM (3x40 mL). The crude mixture was purified on a silica-gel column to afford 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (29 mg, yield 60%).

[0210] A mixture of 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (20 mg, 1.0 eq), Pd2(dba)3 (8.5 mg, 0.1 eq), XantaPhos (11 mg, 0.21 eq), Zn(OAc)2 (10 mg, 0.6 eq), and K2CO3 (25 mg, 2.0 eq) in dry dioxaneWSGR Docket No. 55754-727.601(5 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to give N-(4-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 9) (12 mg, yield 37%). LCMS: 411.5 (M+H)+.

[0211] Compounds 10-21 were prepared by similar procedures as described in Example 9.MSCompound Structure Name[M+H]+N-(4-(4-(2-methyl-2H- 1,2,3- triazol-4-yl)-6-(methylsulfonyl)- 10 412.41 H-pyrrolo [2,3 -b] pyridin- 1 - yl)pyridin-2-yl)acetamideN! z_ \ / zi N-(4-(6-(methylsulfonyl)-4- (pyridin-4-yl)-lH-pyrrolo[2,3- 11 408.5 b]pyridin- 1 -yl)pyridin-2- ° XZ' Mz° / zV Noyl)acetamideo / xZ N7HQN-(4-(6-(methylsulfonyl)-4- (pyridin-3 -yl) - 1 H-pyrrolo [2,3 - 12 N N 408.2 b]pyridin- 1 -yl)pyridin-2- yl)acetamideZ'N H^NN-(4-(6-(methylsulfonyl)-4- (pyrimidin-5 -yl)- IH-pyrrolo [2,3 - 13 1 N23 N 409.2 b]pyridin- 1 -yl)pyridin-2- yl)acetamide / N7HN [f^XNN-(4-(6-(methylsulfonyl)-4- (pyrimidin-2-yl)- IH-pyrrolo [2,3 - 14 409.3 NN. b]pyridin- 1 -yl)pyridin-2- yl)acetamideZ ~N7HWSGR Docket No. 55754-727.601N-(4-(6-(methylsulfonyl)-4- (pyridazin-4-yl) - 1 H-pyrrolo [2,3- 15 409.4 b]pyridin- 1 -yl)pyridin-2- yl)acetamide° / <.Wz N-(4-(4-(2-methyloxazol-5-yl)- 6-(methylsulfonyl)- 1H- 16 M V°2 / 4_ 412.4 pyrrolo[2,3-b]pyridin-l- 1 z yl)pyridin-2-yl)acetamide,N=\VsN-(4-(6-(methylsulfonyl)-4- (thiazol-5 -yl)- 1 H-pyrrolo [2,3- 17 11 N 3 N 414.3 b]pyridin- 1 -yl)pyridin-2- 1 z yl)acetamide• \ / -~fy\ o ) (? —7if \ J.xN HF— F\ z° - o / (Z N-N A N-(4-(4-(l -(difluoromethyl) - 1 H- pyrazol-4-yl)-6- 18 Ju (methylsulfonyl)- 1H- 447.5 N 3 N pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamide7 / N HM N-(4-(4-(3-methoxyphenyl)-6- J (methylsulfonyl)- 1H- 19 u 437.2 N 3 N pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamide•\ / N7HO""00 N-(4-(4-(4-methoxyphenyl)-6- (methylsulfonyl)- 1H- 20 JE ND 437.1 pyrrolo[2,3-b]pyridin-l- Nyl)pyridin-2-yl)acetamide'\ / N7H0WSGR Docket No. 55754-727.601Example 10: Synthesis of N-(4-(4-methoxy-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (22)

[0212] A solution of 4,6-dichloro-lH-pyrrolo[2,3-b]pyridine (450 mg, 1.0 eq) in dry NMP (10 mL) was degassed with N2 for 5 mins. NaSMe (845 mg, 5.0 eq) was added. The mixture was heated at 120°C for 18hr. The mixture was cooled to RT and Mel (1.4 g, 4.0 eq) was added. The mixture was stirred at RT for lOmins, then diluted with ethyl acetate (100 mL). The mixture was washed with water (3x40 mL) and brine. The crude mixture was purified on prep-HPLC to give 4.6-bis(methylthio)-lH-pyrrolo[2,3-b]pyridine (257 mg, yield 51%).

[0213] To a solution of 4,6-bis(methylthio)-lH-pyrrolo[2,3-b]pyridine (250 mg, 1.0 eq) in MeOH (25 mL) and CH3CN (25 mL) was added a solution of Oxone (4.5 g, 6.0 eq) in water (20 mL). The mixture was stirred at RT for 15hr. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x50 mL). The crude mixture was purified on a silica-gel column to afford 4.6-bis(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (101 mg, yield 31%).

[0214] To a solution of 4,6-bis(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (50 mg) in dry MeOH (1 mL) was added 2N NaOMe in MeOH (1 mL). The mixture was heated at 80°C in a sealed-tube for 4hr. The mixture was cooled, diluted with ethyl acetate (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column to give 4-methoxy-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (32 mg, yield 79%).

[0215] A mixture of 4-methoxy-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (20 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (19 mg, 1.0 eq), Pd2(dba)3(8 mg, 0.1 eq), XantaPhos (11 mg,WSGR Docket No. 55754-727.6010.21 eq), Zn(OAc)2 (9.7 mg, 0.6 eq), and K2CO3 (24 mg, 2.0 eq) in dry dioxane (5 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(4-methoxy-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 22) (9 mg, yield 28%). LCMS: 361.4 (M+H)+.Example 11: Synthesis of N-(4-(4-(2-methoxyethoxy)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (23)Pd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3Compound 23

[0216] To 2-methoxyethan-l-ol (dry, 2 mL) was added sodium (45 mg). The mixture was stirred at RT for Ihr to form a clear solution, then 4,6-bis(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (50 mg) was added and heated at 80°C for 3hr. The reaction mixture was cooled, diluted with ethyl acetate, and washed with water and brine. The crude mixture was purified on a silica-gel to give 4-(2-methoxyethoxy)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, yield 51%).

[0217] A mixture of 4-(2-methoxyethoxy)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (20 mg, 1.0 eq), Pd2(dba)3(8 mg, 0.1 eq), XantaPhos (11 mg, 0.21 eq), Zn(OAc)2 (10 mg, 0.6 eq), and K2CO3 (25 mg, 2.0 eq) in dry dioxane (6 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(4-(2-methoxyethoxy)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 23) (11 mg, yield 29%). LCMS: 405.2 (M+H)+.Example 12: Synthesis of N-(4-(6-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (24)WSGR Docket No. 55754-727.601Compound 24

[0218] To a solution of 4-bromo-6-chloro-lH-pyrrolo[2,3-b]pyridine (250 mg, 1.0 eq) in dry DMF (10 mL) was added NaH (60% in mineral oil, 65 mg, 1.5 eq). The mixture was stirred at RT for 30min under N2, then cooled with ice-water. A solution of TosCl (250 mg, 1.2 eq) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at RT overnight. The reaction was diluted with ethyl acetate (100 mL) and then washed with water (3x50 mL) and brine. The crude mixture was purified on a silica-gel column to give 4-bromo-6-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridine (385 mg, yield 92%).

[0219] To a solution of 4-bromo-6-chloro-l-tosyl-lH-pyrrolo[2,3-b]pyridine (1.15 g, 1.0 eq) in dioxane (15 mL) was added water (4 mL), (l-methyl-lH-pyrazol-4-yl)boronic acid (380 mg, 1.0 eq), PdC12(dtbpf) (195 mg, 0.1 eq) and NaHCO3(840 mg, 1.5 eq). The mixture was degassed with N2 and heated at 85 °C under N2 overnight. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by flash chromatography on silica gel to give 6-chloro-4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (875 mg, yield 76%).

[0220] To a solution of 6-chloro-4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (580 mg, 1.0 eq) in dioxane (10 mL) was added tributyl(l -ethoxy vinyl)stannane (0.72 g, 1.3 eq) and PdC12(PPh3)2 (105 mg, 0.1 eq). The mixture was degassed and stirred at 100°C under N2 overnight. The mixture was cooled to room temperature. IN HC1 (5 mL) was added, and the mixture was stirred for 2 hours. The mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel to give l-(4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-6-yl)ethan-l-one (512 mg, yield 86%).

[0221] To a solution of l-(4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridin-6-yl)ethan-l-one (120 mg, 1.0 eq) in dry 1,2-di chloroethane was added DAST (500 mg, 10 eq) at RT. The mixture was heated at 80°C in a sealed-tube for 40hr. The reaction was cooled, diluted with DCM, and quenched with saturated NaHCO3at 0°C. The crude mixture was purified on silica-gelWSGR Docket No. 55754-727.601to give 6-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (34 mg, yield 27%).

[0222] To a mixture of 6-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-l-tosyl-lH-pyrrolo[2,3-b]pyridine (27 mg, 1.0 eq) in MeOH (6 mL) was added K2CO3 (33 mg, 3.0 eq). The mixture was heated at 70°C for 2.5hr. The mixture was diluted with DCM (50 mL) washed with water. The crude mixture was purified on a silica-gel column to afford 6-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine (17 mg, yield 81%).

[0223] A mixture of 6-(1,1-difluoroethyl)-4-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (17 mg, 1.0 eq), N-(4-bromopyri din-2 -yl)acetamide (15 mg, 1.1 eq), Pd2(dba)3(4 mg, 0.06 eq), XantaPhos (5 mg, 0.12 eq), Zn(OAc)2 (8 mg, 0.6 eq), and K2CO3 (20 mg, 2.0 eq) in dry dioxane (3 mL) was heated at 105 °C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(6-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 24) (15 mg, yield 58%). LCMS: 397.2 (M+H)+.Example 13: Synthesis of N-(4-(4-cyano-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (25)Compound 25

[0224] A solution of 6-chloro-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (150 mg, 1.0 eq) in dry DMF (4 mL) was degassed with N2 then added NaSMe (120 mg, 2.0 eq). The mixture was heated at 90°C for 6hr. The mixture was diluted with ethyl acetate and washed with water (3x10 mL). The crude mixture was purified on a silica-gel column to give 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (61 mg, yield 32%).

[0225] A mixture of 6-(methylthio)-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (52 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (60 mg, 1.1 eq), Pd2(dba)3 (15 mg, 0.06 eq), XantaPhos (20 mg, 0.12 eq), Zn(OAc)2 (31 mg, 0.6 eq), and K2CO3 (76 mg, 2.0 eq) in dry dioxane (4 mL) was heated at 105°C (oil-bath) for 18hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(4-cyano-6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (23 mg, yield 26%).WSGR Docket No. 55754-727.601

[0226] To a solution of N-(4-(4-cyano-6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (23 mg, 1.0 eq) in MeOH (15 mL) and CH3CN (15 mL) was added a solution of Oxone (155 mg, 3.0 eq) in water (8 mL). The resulting mixture was stirred at RT for 15hr. The reaction was quenched with saturated NaHCO3 and extracted with DCM (3x50 mL). The crude mixture was purified on a silica-gel column to afford N-(4-(4-cyano-6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- l-yl)pyri din-2 -yl)acetamide (Compound 25) (15 mg, yield 60%). LCMS: 356.4 (M+H)+.Example 14: Synthesis of N-(4-(4-(l-methyl-lH-pyrazol-4-yl)-2-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (26) / N-NB(OH)2Oxone Pd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3Compound 26

[0227] A mixture of 4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.0 eq), (1-methyl-lH-pyrazol-4-yl)boronic acid (145 mg, 1.2 eq), PdCl2 dppf (60 mg, 0.08 eq) and CS2CO3 (650 mg, 2.0 eq) in dioxane (15 mL) and water (3 mL) was degassed with N2 for 5mins and heated at 85°C for 8hr under N2. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column to give 4-(l-methyl-lH-pyrazol-4-yl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (167 mg, yield 68%).

[0228] A mixture of 4-(l-methyl-lH-pyrazol-4-yl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (46 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (41 mg, 1.1 eq), Pd2(dba)3 (11 mg, 0.06 eq), XantaPhos (13 mg, 0.12 eq), Zn(OAc)2 (21 mg, 0.6 eq), and K2CO3 (52 mg, 2.0 eq) in dry dioxane (4 mL) was heated at 105 °C (oil-bath) for 18hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(4-(l -methyl- IH-pyrazol -4-yl)-2-(methylthio)-7H-pyrrolo[2, 3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (53 mg, yield 74%).

[0229] To a solution of N-(4-(4-(l-methyl-lH-pyrazol-4-yl)-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (53 mg, 1.0 eq) in MeOH (20 mL) and CH3CN (20 mL) was added a solution of Oxone (240 mg, 2.8 eq) in water (10 mL). The resulting mixture was stirred at RT for 18hr. The reaction was quenched with saturated NaHCO3 and extracted with DCM (3x50 mL). The crude mixture was purified on a silica-gel column to afford N-(4-(4-(l-methyl-lH-pyrazol-4-yl)-2-(methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (Compound 26) (16 mg, yield 28%). LCMS: 412.5 (M+H)+.WSGR Docket No. 55754-727.601Example 15: Synthesis of N-(4-(2-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (27)ci / N-N \ N-N DASTPd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3Compound 27

[0230] To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 1.0 eq) in dry DMF (10 mL) was added NaH (60% in mineral oil, 80 mg, 1.5 eq) at 0°C. The mixture was stirred at 0°C for 30min under N2, then a solution of TosCl (330 mg, 1.3 eq) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at RT overnight. The reaction was diluted with ethyl acetate (100 mL) and washed with water (3x50 mL) and brine. The crude mixture was purified on a silica-gel column to 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, yield 88%).

[0231] To a solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (400 mg, 1.0 eq) in dioxane (10 mL) was added water (2 mL), (l-methyl-lH-pyrazol-4-yl)boronic acid (150 mg, 1.0 eq), PdC12(dtbpf) (86 mg, 0.1 eq) and NaHCO3(250 mg, 2.0 eq). The mixture was degassed with N2 and heated at 70°C under N2 overnight. The mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give 2-chloro-4-(l-methyl-lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (303 mg, yield 67%).

[0232] To a solution of 2-chloro-4-(l-methyl-lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (300 mg, 1.0 eq) in dioxane (6 mL) was added tributyl(l -ethoxy vinyl)stannane (365 mg, 1.3 eq) and PdC12(PPh3)2 (54 mg, 0.1 eq). The mixture was degassed and stirred at 100°C under N2 overnight. The mixture was cooled to room temperature, IN HC1 (4 mL) was added, and the mixture was stirred for 2 hours. The mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give l-(4-(l -methyl- lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)ethan-l-one (275 mg, yield 90%).

[0233] To a solution of l-(4-(l-methyl-lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)ethan-l-one (100 mg, 1.0 eq) in dry 1,2-di chloroethane (2 mL) was added DAST (200 mg, 5 eq)WSGR Docket No. 55754-727.601at RT. The mixture was heated at 50°C in a sealed-tube for 15hr. The reaction mixture was cooled, diluted with DCM, and quenched with saturated NaHCO3at 0°C. The crude mixture was purified on silica-gel to give 2-(l,l-difluoroethyl)-4-(l -methyl- lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2, 3-d]pyrimidine (93 mg, yield 88%).

[0234] To a mixture of 2-(l, l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 1.0 eq) in MeOH (5 mL) was added K2CO3 (90 mg, 3.0 eq). The mixture was stirred at RT for 4hr. The mixture was diluted with DCM (50 mL) and washed with water. The crude mixture was purified on a silica-gel column to afford 2-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (48 mg, yield 85%).

[0235] A mixture of 2-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine (46 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (38 mg, 1.1 eq), Pd2(dba)3(10 mg, 0.06 eq), XantaPhos (12 mg, 0.12 eq), Zn(OAc)2 (20 mg, 0.6 eq), and K2CO3 (50 mg, 2.0 eq) in dry dioxane (5 mL) was heated at 105°C (oil-bath) for 17hr in a sealed-tube. The reaction mixture was diluted with DCM (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(2-(l,l-difluoroethyl)-4-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-2-yl)acetamide (Compound 27) (48 mg, yield 69%). LCMS: 398.3 (M+H)+.Example 16: Synthesis of N-(4-(7-(l-methyl-lH-pyrazol-4-yl)-5-(methylsulfonyl)pyrazolo[l,5-a] pyrimidin-3-yl)pyridin-2-yl)acetamide (28)Compound 28

[0236] A mixture of 3-bromo-5,7-dichloropyrazolo[l,5-a]pyrimidine (300 mg, 1.0 eq), (1-methyl-lH-pyrazol-4-yl)boronic acid (145 mg, 1.0 eq), Pd(PPh3)4 (65 mg, 0.05 eq) and Na2CO3 (238 mg, 2.0 eq) in THF (15 mL) and water (3 mL) was degassed with N2 and stirred at RT under N2 for 18hr. The mixture was diluted with EtOAc, washed with brine, and dried over anhydrous Na2SC>4. The solvent was removed and the residue was purified by flash chromatography on silica gel to give 3-bromo-5-chloro-7-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrimidine (190 mg, yield 54%).WSGR Docket No. 55754-727.601

[0237] A solution of 3-bromo-5-chloro-7-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrimidine (156 mg, 1.0 eq) in dry NMP (3 mL) was degassed with N2 then NaSMe (55 mg, 1.5 eq) was added. The mixture was heated at 100°C for Ihr. The mixture was diluted with ethyl acetate and washed with water (3x10 mL). The crude mixture was purified on a silica-gel column to give 3-bromo-7-(l-methyl-lH-pyrazol-4-yl)-5-(methylthio)pyrazolo[l,5-a]pyrimidine (73 mg, yield 45%).

[0238] A mixture of 3-bromo-7-(l-methyl-lH-pyrazol-4-yl)-5-(methylthio)pyrazolo[l,5-a]pyrimidine (11 mg, 1.0 eq), (2-aminopyridin-4-yl)boronic acid (10 mg, 2.0 eq), PdCl2 dppf (3 mg, 0.1 eq) and CS2CO3 (22 mg, 2.0 eq) in dioxane (2 mL) and water (0.5 mL) was degassed with N2 for 5mins and heated at 105°C for 8hr under N2. The reaction was diluted with ethyl acetate (50 mL) and washed with water and brine. The crude mixture was dissolved in DCM (2 mL) and AC2O (30 mg) was added. The resulting mixture was heated at 50°C for 6hr in a sealed tube. The solvent was removed and the residue was purified on 4 g silica-gel to give N-(4-(7-(l-methyl-lH-pyrazol-4-yl)-5-(methylthio)pyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl)acetamide (6.5 mg).

[0239] To a solution of N-(4-(7-(l-methyl-lH-pyrazol-4-yl)-5-(methylthio)pyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl)acetamide (6.5 mg, 1.0 eq) in MeOH (4 mL) and CH3CN (3 mL) was added a solution of Oxone (25 mg, 2.5 eq) in water (3 mL). The resulting mixture was stirred at RT for 18hr. The reaction was quenched with saturated NaHCO3 and extracted with DCM (3x50 mL). The crude mixture was purified on a silica-gel column to afford N-(4-(7-(l -methyl- lH-pyrazol-4-yl)-5-(methylsulfonyl)pyrazolo[l,5-a]pyrimidin-3-yl)pyridin-2-yl)acetamide (Compound 28) (1.2 mg, yield 17%). LCMS: 412.4 (M+H)+.Example 17: Synthesis of N-(4-(6-(difluoromethoxy)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (29)mCPBAPd2(dba)3 / XantaPhos Zn(OAc)2 / K2CO3

[0240] To a solution of 4-bromo-lH-pyrrolo[2,3-b]pyridine (3 g, 1.0 eq) in ethyl acetate (120 mL) was added mCPBA (70%, 4.5 g, 1.2 eq) in portions at 0°C. The mixture was stirred at 0°C forWSGR Docket No. 55754-727.6011 hr then RT 2hr. The precipitated solid was collected by filtration and washed with ethyl acetate (2x10 mL) to give 4-bromo-lH-pyrrolo[2,3-b]pyridine 7-oxide (2.45 g, yield 75%).

[0241] A solution of 4-bromo-lH-pyrrolo[2,3-b]pyridine 7-oxide (500 mg) in AC2O (8 mL) was heated at 148°C in microwave reactor for 3hr. The mixture was concentrated in vacuo. The residue was purified on a silica-gel column to give l-acetyl-4-bromo-lH-pyrrolo[2,3-b]pyridin-6-yl acetate (350 mg, yield 50%).

[0242] A mixture of l-acetyl-4-bromo-lH-pyrrolo[2,3-b]pyridin-6-yl acetate (150 mg, 1.0 eq), (l-methyl-lH-pyrazol-4-yl)boronic acid (83 mg, 1.3 eq), PdCl2 dppf (25 mg, 0.06 eq) and CS2CO3 (820 mg, 5.0 eq) in dioxane (15 mL) and water (5 mL) was degassed with N2 for 5mins and heated at 100°C for 18hr under N2. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The crude mixture was dissolved in DCM (2 mL) and AC2O (30 mg) was added. The resulting mixture was heated at 50°C for 6hr in a sealed tube. The solvent was removed and the residue was purified on 4 g silica-gel to give 4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-6-ol (62 mg, yield 57%).

[0243] To a suspension solution of 4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-6-ol (62 mg, 1.0 eq) in CH3CN (8 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (62 mg, 1.2 eq) at RT. The mixture was stirred at RT for 5mins, then Na2CO3 (77 mg, 2.5 eq) was added in portions. The resulting mixture was stirred at RT for 2hr. The mixture was diluted with ethyl acetate (40 mL) and washed with saturated NaHCO3. The crude mixture was purified on a silica-gel column to give 6-(difluoromethoxy)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine (11 mg, yield 14%).

[0244] A mixture of 6-(difluoromethoxy)-4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrrolo[2, 3-b]pyridine (9.5 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (8 mg, 1 eq), Pd2(dba)3 (2 mg, 0.06 eq), XantaPhos (3 mg, 0.12 eq), Zn(OAc)2 (4 mg, 0.6 eq), and K2CO3 (10 mg, 2.0 eq) in dry dioxane (3 mL) was heated at 110°C (oil-bath) for 17hr in a sealed-tube. The reaction was diluted with DCM (40 mL) and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(6-(difluoromethoxy)-4-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 29) (9 mg, yield 64%). LCMS: 399.4 (M+H)+.Example 18: Synthesis of N-(4-(6-(methylsulfonyl)-4-morpholino-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (30)WSGR Docket No. 55754-727.601

[0245] To a solution of 4,6-dichloro-lH-pyrrolo[2,3-b]pyridine (1 g, 1.0 eq) in dry DMF (20 mL) in 0°C was added NaH (60% in mineral oil, 215 mg, 1.5 eq). The mixture was stirred at RT for 30mins then SEMC1 (90%, 1.28 g, 1.3 eq) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3and extracted with DCM (2x50 mL). The combined organic phase was dried over Na2SC>4. The crude mixture was purified on a silica-gel column (24 g) to afford 4,6-dichloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (1.56 g, yield 92%).

[0246] To a solution of 4,6-dichloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (200 mg) in NMP (2 mL) was added morphine (300 mg). The solution was heated to 115°C for 3 hours. The mixture was cooled, diluted with EtOAc, washed with water (3 times), brine and dried over anhydrous Na2SC>4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give 4-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (80 mg, yield 35%).

[0247] To a degassed solution of 4-(6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (80 mg, 1.0 eq) in NMP (2 mL) was added NaSMe (42 mg, 2.0 eq) under nitrogen. The solution was heated to 120°C overnight. The mixture was diluted with EtOAc, washed with water (3x20 mL) and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel to give 4-(6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (60 mg, yield 71%).

[0248] To a solution of 4-(6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (60 mg) in THF (1 mL) was added TBAF in THF (1 mL, Immol). The solution was heated to 70°C overnight. The mixture was diluted with EtOAc, washed with water (3 times) and brine, and dried over anhydrous Na2SO4. The solvent was removed and residue was purified by flash chromatography on silica gel to give 4-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (40 mg, yield 100%).WSGR Docket No. 55754-727.601

[0249] A mixture of 4-(6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-4-yl)morpholine (43 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (37 mg, 1.1 eq), Pd2(dba)3(10 mg, 0.06 eq), XantaPhos (12 mg, 0.12 eq), Zn(OAc)2 (19 mg, 0.6 eq), and K2CO3 (50 mg, 2.0 eq) in dry dioxane (6 mL) was heated at 105 °C (oil-bath) for 18hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (40 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(4-(6-(methylthio)-4-morpholino-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (56 mg, yield 84%).

[0250] To a solution of N-(4-(6-(methylthio)-4-morpholino-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (56 mg, 1.0 eq) in MeOH (20 mL) and CH3CN (20 mL) was added a solution of Oxone (240 mg, 2.8 eq) in water (10 mL). The resulting mixture was stirred at RT for 2hr. The reaction was quenched with saturated NaHCO3 and extracted with DCM (3x50 mL). The crude mixture was purified on a silica-gel column to afford N-(4-(6-(methylsulfonyl)-4-morpholino-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 30) (36 mg, yield 53%). LCMS: 416.3 (M+H)+.Example 19: Synthesis of N-(5-ethoxy-4-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (31)Compound 31

[0251] To a solution of 5-fluoropicolinic acid (2.1 g, 15 mmol) in THF (50 mL) was added LDA (30 ml of IM in THF, 30 mmol) at -78°C under N2. The mixture was stirred at -40°C for 1 hour and cooled to -78°C. 1,2-Dibromotetrachloroethane (5 g, 15.3 mmol) in THF (20 mL) was added at -78°C, and the mixture was stirred at -78°C to -30°C for 2 hours. The reaction was quenched by addition of aqueous solution of citric acid, and the mixture was saturated with NaCl. The mixture was extracted with EtOAc (3 times). The combined organic phase was dried over anhydrous Na2SC>4. The crude mixture was purified on prep-HPLC to give 4-bromo-5-fluoropicolinic acid (1.5 g, yield 39%).

[0252] A mixture of 4-bromo-5-fluoropicolinic acid (300 mg) and 2N NaOEt in EtOH (10 mL) was heated at 80°C for 8hr. The reaction mixture was poured into ice-water and adjusted pH ~4 byWSGR Docket No. 55754-727.601adding 6N HC1. The mixture was extracted with ethyl acetate (3x50 mL) to give 4-bromo-5-ethoxypicolinic acid (296 mg, yield 88%) which was used without purification.

[0253] To a mixture of 4-bromo-5-ethoxypicolinic acid (200 mg, 1.0 eq) in toluene (10 ml) was added DPP A (440 mg, 2.0 eq) and TEA (300 mg, 4 eq). After stirring at room temperature for 30 minutes, tert-butyl alcohol (2 mL) and BOC2O (654 mg, 4 eq) were added. The mixture was stirred at 90°C for 3 hours. The mixture was cooled, diluted with EtOAc, washed with NaHCO3and brine, and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified on a silica-gel column to give tert-butyl (4-bromo-5-ethoxypyridin-2-yl)carbamate (131 mg, yield 51%).

[0254] To a solution of tert-butyl (4-bromo-5-ethoxypyridin-2-yl)carbamate (61 mg) in DCM (2 mL) was added 4N HC1 in dioxane (1 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in DCM (1 mL). TEA (0.3 mL) and AC2O (0.3 mL) were added and the mixture was stirred at 50°C for 5 hours. The solvent was removed and the residue was purified on a silica-gel column to give N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (30 mg, yield 61%).

[0255] A mixture of 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (20 mg, 1.0 eq), N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (19 mg, 1.0 eq), Pd2(dba)3(10 mg, 0.15 eq), XantaPhos (12.7 mg, 0.3 eq), Zn(OAc)2 (8 mg, 0.6 eq), and K2CO3 (20 mg, 2.0 eq) in dry dioxane (4 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 120°C (oil-bath) for 14hr in a sealed-tube. The reaction was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(5-ethoxy-4-(4-(l -methyl- lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 31) (11 mg, yield 34%). LCMS: 455.2 (M+H)+.Example 20: Synthesis of N-(5-fluoro-4-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (32)Compound 32

[0256] To a mixture of 4-bromo-5-fluoropicolinic acid (220 mg, 1.0 eq) in toluene (10 mL) was added DPP A (550 mg, 2.0 eq) and TEA (400 mg, 4 eq). After stirring at room temperature for 30 minutes, tert-butyl alcohol (2 mL) and BOC2O (880 mg, 4 eq) were added. The mixture was stirred at 90°C for 3 hours. The mixture was cooled, diluted with EtOAc, washed with NaHCO3and brine,WSGR Docket No. 55754-727.601and dried over anhydrous Na2SC>4. The solvent was removed in vacuo and the residue was purified on a silica-gel column to give tert-butyl (4-bromo-5-fluoropyri din-2 -yl)carbamate (61 mg, yield 21%).

[0257] To a solution of tert-butyl (4-bromo-5-fluoropyridin-2-yl)carbamate (61 mg) in DCM (2 mL) was added 4N HC1 in dioxane (1 mL). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in DCM (1 mL). TEA (0.3 mL) and AC2O (0.3 mL) were added and the mixture was stirred at 50°C for 5 hours. The solvent was removed in vacuo and the residue was purified on a silica-gel column to give N-(4-bromo-5-fluoropyridin-2-yl)acetamide (30 mg, yield 61%).

[0258] A mixture of 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (20 mg, 1.0 eq), N-(4-bromo-5-fluoropyridin-2-yl)acetamide (17 mg, 1.0 eq), Pd2(dba)3(10 mg, 0.15 eq), XantaPhos (12.7 mg, 0.3 eq), Zn(OAc)2 (8 mg, 0.6 eq), and K2CO3 (20 mg, 2.0 eq) in dry dioxane (4 mL) was degassed with bubbling N2 gas for 5min. The resulting mixture was heated at 120°C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(5-fluoro-4-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2 -yl)acetamide (Compound 32) (14 mg, yield 45%). LCMS: 429.3 (M+H)+.Example 21: Synthesis of N-(6-(4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyrimidin-4-yl)acetamide (33)Compound 33

[0259] A mixture of 4-(l-methyl-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (20 mg, 1.0 eq), N-(6-bromopyrimidin-4-yl)acetamide (16 mg, 1.0 eq), Pd2(dba)3(10 mg, 0.15 eq), XantaPhos (12.7 mg, 0.3 eq), Zn(OAc)2 (8 mg, 0.6 eq), and K2CO3 (20 mg, 2.0 eq) in dry dioxane (4 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 120°C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (40 mL) and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(6-(4-(1 -methyl- lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3 -b]pyridin-l -yl)pyrimidin-4-yl)acetamide (Compound 33) (12 mg, yield 41%). LCMS: 412.3 (M+H)+.Example 22: Synthesis of N-(5-ethoxy-4-(4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (34)WSGR Docket No. 55754-727.601Oxone Pd2(dba)3 / XantaPhos / Zn(OAc)2 / K2CO3

[0260] A mixture of 4-bromo-6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (152 mg, 1.0 eq), l-(methyl-d3)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (116 mg, 1.0 eq), PdCl2 dppf (16 mg, 0.05 eq), and CS2CO3 (271 mg, 2.0 eq) in dioxane (8 mL) and water (2 mL) was degassed with N2 for 5mins and heated at 85°C for 8hr under N2. The reaction mixture was cooled, diluted with ethyl acetate (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column to give 6-chloro-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (109 mg, yield 70%).

[0261] A solution of 6-chloro-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (100 mg, 1.0 eq) in dry DMF (4 mL) was degassed with N2 gas for 5mins, then NaSMe (26 mg, 1.2 eq) was added. The resulting mixture was heated at 110°C for 15hr. The reaction was cooled, diluted with ethyl acetate (50 mL), and washed with water (3x20 mL) and brine. The crude mixture was purified on a silica-gel column to give 4-(1 -(methyl -d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (92 mg, yield 89%).

[0262] 4-(l -(Methyl -d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (92 mg) in IN TBAF in THF (4 mL) was heated at 70°C for 5hr. The mixture was cooled, diluted with ethyl acetate (50 mL), and washed with water (3x20 mL). The crude mixture was purified on a silica-gel column to give 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (47 mg, yield 79%).

[0263] To a solution of 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (47 mg, 1.0 eq) in MeOH (10 mL) and CH3CN (10 mL) was added a solution of Oxone (350 mg, 3.0 eq) in water (8 mL). The mixture was stirred at RT for 8hr. The reaction was quenched with saturated NaHCO3 and extracted with DCMWSGR Docket No. 55754-727.601(3x40 mL). The crude mixture was purified on a silica-gel column to afford 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, yield 47%).

[0264] A mixture of 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, 1.0 eq), N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (24 mg, 1.0 eq), Pd2(dba)3(13 mg, 0.15 eq), XantaPhos (17 mg, 0.31 eq), Zn(OAc)2 (11 mg, 0.6 eq), and K2CO3 (26 mg, 2.0 eq) in dry dioxane (5 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at O / *110°C (oil-bath) for 14hr in \ 0—. a sealed-tube. The reaction mixture was cooled, diluted with DCM (50 mL), and washed with water V a°ndz / \ iz brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(5-ethoxy-4-(4-(l-(meth YVvyl z-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3- 0 ^b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 34) (22 mg, yield 53%). LCMS: 458.5 (M+H)+.

[0265] Compounds 35-37 were prepared by similar procedures as described in Example 22.MSCompound Structure Name[M+H]+N-(4-(4-( 1 -cyclopropyl- 1H- pyrazol-4-yl)-6- 35 (methylsulfonyl)-lH- 481.2 pyrrolo[2,3 -b]pyridin- 1 -y 1) -5 - % ethoxypyridin-2-yl)acetamide\ zO —vf wO / 'N-(5-ethoxy-4-(6- (methylsulfonyl)-4-(pyridin-3- 36 452.4 yl) - 1 H-pyrrolo [2,3 -b]pyridin- 1 - yl)pyridin-2-yl)acetamide0 N-(5-ethoxy-4-(6- (methylsulfonyl)-4-phenyl- 1H- 37 N N - / 451.4 pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamide°"° o bA z ~N / N7HExample 23: Synthesis of N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (38)WSGR Docket No. 55754-727.601Br tert-Butyl nitrile CuBr2Pd2(dba)31 XantaPhos H H Zn(OAc)2 / K2CO3Compound 38

[0266] To a solution of N-(4-amino-5-ethoxypyridin-2-yl)acetamide (1 g, 1.0 eq) in CH3CN (30 mL) was added tert-butyl nitrile (750 mg, 1.4 eq) dropwise at RT. The mixture was stirred at RT for lOmins after addition of tert-butyl nitrile, then CuBn (1.8 g, 1.5 eq) was added into reaction mixture. The resulting mixture was heated at 68°C (oil-bath) for Ihr. The solvent was removed in vacuo. The residue was suspended into water (50 mL) and concentrated NH4OH (10 mL) was added. The mixture was stirred at RT for 20mins and extracted with ethyl acetate (2x100 mL). The crude product was purified on a silica-gel column to give N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (1.01 g, yield 77%).

[0267] A mixture of 6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (30 mg, 1.0 eq), N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (40 mg, 1.0 eq), Pd2(dba)3(21 mg, 0.15 eq), XantaPhos (29 mg, 0.32 eq), Zn(OAc)2 (17 mg, 0.6 eq), and K2CO3 (43 mg, 2.0 eq) in dry dioxane (5 mL) was degassed with bubbling N2 gas for 5min. The mixture was heated at 120°C (oil-bath) for 14hr in a sealed-tube. The reaction mixture was cooled, diluted with DCM (50 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (4 g) to give N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 38) (17 mg, yield 30%). LCMS: 375.2 (M+H)+.Example 24: Synthesis of N-(5-(2-methoxyethoxy)-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (39)Compound 39

[0268] To a solution of 6-chl oro-4-iodopyri din-3 -ol (100 mg, 1.0 eq) in dry THF (4 mL) was added NaH (60%, 16 mg, 1.55 eq) at 0°C under N2. The mixture was stirred at 0°C for 5 min then RT 15min. To the mixture was added l-bromo-2-methoxy ethane (71 mg in 1 mL THF, 1.3 eq) dropwise. The resulting mixture was stirred at 50°C for Ihr. The reaction was quenched with ice-WSGR Docket No. 55754-727.601water, and extracted with ethyl acetate (2x25 mL). The crude mixture was purified on a 4g silica-gel column to afford 2-chloro-4-iodo-5-(2 -methoxyethoxy )pyridine (110 mg, yield 89%).

[0269] 2 -Chloro-4-iodo-5-(2-methoxyethoxy)pyridine (60 mg, 1.0 eq), 6-(m ethyl sulfonyl)- 1H-pyrrolo[2,3-b]pyridine (38 mg, 1.0 eq), Pd2(dba)3(35 mg, 0.2 eq), XantaPhos (44 mg, 0.4 eq), Zn(OAc)2 (21 mg, 0.6 eq) and K2CO3 (53 mg, 2.0 eq) were combined in dry dioxane (8 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed-tube for 40hrs The crude mixture was diluted with DCM (80 mL) washed with brine and the crude mixture was purified on a 12 g silica-gel column to give l-(2-chloro-5-(2-methoxyethoxy)pyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (32 mg, yield 44%).

[0270] l-(2-Chloro-5-(2-methoxyethoxy)pyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, 1.0 eq), Pd(OAc)2 (1.5 mg, 0.1 eq), Binap (8.6 mg, 0.21 eq), acetamide (5 mg, 1.3 eq) and CS2CO3 (43 mg, 2.0 eq) were combined in dry dioxane (6 mL). The mixture was degassed with bubbling N2 gas for 5min. The resulting mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction was diluted with DCM (50 mL), washed with water and brine. The crude mixture was purified on silica-gel column (4 g) to give N-(5-(2-methoxyethoxy)-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 39) (15 mg, yield 57%). LCMS: 405.5 (M+H)+.

[0271] Compounds 40 and 41 were prepared by similar procedures as described in Example 24.MSCompound Structure Name[M+H]+HO p N-(5-(cyclopropylmethoxy)-4-N N\ Z0^ (6-(methylsulfonyl)- 1H- 40 401.3 pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamideZ-N7Hno N-(4-(6-(methylsulfonyl)-lH- pyrrolo[2,3 -b]pyridin- 1 -y 1) -5 -(2- 41 460.5 morpholinoethoxy)pyridin-2- yl)acetamide / -~N7HExample 25: Synthesis of N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)propionamide (42)oCS2CO3Pd(OAc)2 / Binap Compound 42WSGR Docket No. 55754-727.601

[0272] To a solution of 6-chl oro-4-iodopyri din-3 -ol (100 mg, 1.0 eq) in dry DMF (2 mL) was added CS2CO3 (190 mg, 1.5 eq) at RT under N2. The mixture was stirred at RT 15min. To the mixture was added iodoethane (80 mg, 1.3 eq) dropwise. The resulting mixture was stirred at RT for 2hr. The reaction was quenched with ice-water and extracted with ethyl acetate (2x25 mL), the combined organic phase was washed with water (3x10 mL) and brine. The crude mixture was purified on a 4g silica-gel column to afford 2-chloro-5-ethoxy-4-iodopyridine (101 mg, yield 91%).

[0273] 2 -Chloro-4-iodo-5-(2-methoxyethoxy)pyridine (65 mg, 1.0 eq), 6-(m ethyl sulfonyl)- 1H-pyrrolo[2,3-b]pyridine (45 mg, 1.0 eq), Pd2(dba)3(42 mg, 0.2 eq), XantaPhos (53 mg, 0.4 eq), Zn(OAc)2 (25 mg, 0.6 eq) and K2CO3 (63 mg, 2.0 eq) were combined in dry dioxane (8 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed-tube for 40 hrs. The crude mixture was diluted with DCM (80 mL) washed with brine and the crude mixture was purified on a 12g silica-gel column to give l-(2-chloro-5-ethoxypyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (33 mg, yield 41%).

[0274] l-(2-Chloro-5-ethoxypyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (24 mg, l. Oeq), Pd(OAc)2 (1.6 mg, 0.1 eq), Binap (8.8 mg, 0.21 eq), propionamide (6 mg, 1.3 eq) and CS2CO3 (44 mg, 2.0 eq) were combined in dry dioxane (6 mL). The mixture was degassed with bubbling N2 gas for 5min. The resulting mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction was diluted with DCM (50 mL), washed with water and brine. The crude mixture was purified on silica-gel column (4g) to give N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- l-yl)pyri din-2 -yl)propionamide (Compound 42) (13 mg, yield 50%).LCMS: 389.3 (M+H)+.Example 26: Synthesis of N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)-2,2-difluoroacetamide (43)1)4 N HCICS2CO3 Pd(OAc)2 / Binap Et3N / DCMCompound 43

[0275] l-(2-Chloro-5-ethoxypyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (30 mg, l. Oeq), Pd(OAc)2 (2 mg, 0.1 eq), Binap (10.8 mg, 0.21 eq), tert-butyl carbamate (12 mg, 1.2 eq) and CS2CO3 (55 mg, 2.0 eq) were combined in dry dioxane (6 mL). The mixture was degassed with bubbling N2 gas for 5min. The resulting mixture was heated at 110°C (oil-bath) for 14hr in a sealed-tube. The reaction was diluted with DCM (50 mL), washed with water and brine. The crude mixture was purified on silica-gel column (4g) to give tert-butyl (5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)carbamate (17 mg, yield 46%).WSGR Docket No. 55754-727.601

[0276] tert-butyl (5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)carbamate (15 mg) in DCM (2 mL) was added 4N HC1 (1 mL), the mixture was stirred at RT for 2hrs. LC / MS analysis showed that the reaction went completely. The solvent was removed in high vacuo and the residue was suspended in DCM (4 mL). To the mixture was added Et3N (O.lmL) to form clear solution, then 2,2-difluoroacetic anhydride (30 mg, 5.0 eq) was added and the resulting mixture was heated at 50°C for 3hrs. The reaction was diluted with DCM (40 mL), washed with saturated NaHCO3and purified on a 4g silica-gel column to give N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)-2,2-difluoroacetamide (Compound 43) (6 mg, yield 42%). LCMS: 411.4 (M+H)+.Example 27: Synthesis of N-(5-ethoxy-4-(4-methyl-6-(methylsulfonyl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (44)Compound 44

[0277] To a solution of 6-chloro-4-methyl-lH-pyrrolo[2,3-b]pyridine (200 mg, 1.0 eq) in dry DMF (8 mL) in 0°C was added NaH (60% in mineral oil, 72 mg, 1.5 eq). The mixture was stirred at RT for 30mins then SEMC1 (90%, 289 mg, 1.3 eq) in DMF (ImL) was added dropwise. The resulting mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3and extracted with DCM (2x50 mL). The combined organic phase was dried over Na2SO4. The crude mixture was purified on a silica-gel column (12g) to afford 6-chloro-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (272 mg, yield 76%).

[0278] To a degassed solution of 6-chloro-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (100 mg, 1.0 eq) in NMP (2 mL) was added NaSMe (47 mg, 2.0 eq) under nitrogen, and the solution was heated to 120°C overnight. The mixture was diluted with EtOAc, washed with water (3x20 mL), brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by flash chromatography on silica gel to give 4-methyl-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (78 mg, yield 75%).

[0279] 4-Methyl-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (78 mg) in IN TABF (3 mL, 12.0 eq) was heated at 80°C for 6hrs. The mixture was diluted withWSGR Docket No. 55754-727.601acetate and washed with water and brine, the crude was purified on 4g silica-gel column to give 4-methyl-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (37 mg, yield 82%).

[0280] To a solution of 4-methyl-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (37 mg, 1.0 eq) in CH3CN (10 mL) was added a solution of Oxone (385 mg, 3.0 eq) in H2O (4 mL). The resulting mixture was stirred at RT for 6hrs, the reaction was quenched with saturated NaHCCL and extracted with DCM (3x30 mL). The crude mixture was purified on a silica-gel column to give 4-methyl-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (26 mg, yield 60%).

[0281] 4-Methyl-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (25 mg, 1.0 eq), N-(4-bromo-5-ethoxypyridin-2-yl)acetamide (32 mg, 1.0 eq), Pd2(dba)3(11 mg, O.leq), XantPhos (15 mg, 0.21 eq), Zn(OAc)2 (14 mg, 0.6 eq), and K2CO3 (34 mg, 2.0 eq) were combined in dry dioxane (5 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed-tube for 18 hrs. The crude mixture was diluted with DCM (80 mL) washed with brine and the crude mixture was purified on a 4 g silica-gel column to N-(5-ethoxy-4-(4-methyl-6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- 1 -yl)pyri din-2 -yl)acetamide (Compound 44) (12 mg, yield 25%). LCMS: 389.4 (M+H)+.Example 28: Synthesis of N-(4-(3-amino-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)-5-ethoxypyridin-2-yl)acetamide (45)KNO3 / HNO3Compound 38

[0282] To a solution of N-(5-ethoxy-4-(6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (27 mg, 1.0 eq) in H2SO4 (98%, 1.2 mL) was added KNO3 (8 mg, 1.1 eq) at 0°C. The resulting mixture was stirred at 0°C for 30mins. To the reaction mixture was added ice water (~10 mL), then adjusted pH -9 by adding NaOH (4N) at 0°C. The mixture was extracted with mixture solvent (DCM:iPrOH = 10:1) (2x25 mL). The combined organic layer was washed with brine and dried over Na2SC>4. The solvent was concentrated in vacuo to afford N-(5-ethoxy-4-(6-(methylsulfonyl)-3-nitro-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (25 mg, yield 89%), which was used without further purification.

[0283] To N-(5-ethoxy-4-(6-(methylsulfonyl)-3-nitro-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2-yl)acetamide (25 mg) suspended in EtOH (20 mL) was added Fe powder (10 mg) and the mixture was heated at 85°C. To the reaction mixture was added saturated NH4CI (~0.5 mL) dropwise in Imin. The resulting mixture was heated at 85°C for 20 mins. The mixture was filtered through celite pad and washed celite pad with MeOH (2x1 OmL). The mixture was concentrated in vacuo.WSGR Docket No. 55754-727.601The residue was dissolved in DCM (50 mL) and MeOH (5 mL), dried over Na2SC>4 and concentrated again. The mixture was purified on a silica-gel column to give N-(4-(3-amino-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)-5-ethoxypyridin-2-yl)acetamide (Compound 45) (10 mg, yield 43%). LCMS: 390.3 (M+H)+.Example 29: Synthesis of N-(5-ethoxy-4-(3-fluoro-6-(methylsulfonyl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (46)Compound 46

[0284] To a solution 3-fluoro-lH-pyrrolo[2,3-b]pyridine (0.5 g, 3.7 mmol) in EtOAc (60 mL) was slowly added m-CPBA (0.92 g, 4.4 mmol) at 0°C. The mixture was warmed to r.t. and stirred for 5 hours. The precipitate was filtered and washed with EtOAc. The solid was stirred in EtOAc and filtered to give 3-fluoro-lH-pyrrolo[2,3-b]pyridine 7-oxide (330 mg, yield 59%).

[0285] To a solution of 3-fluoro-lH-pyrrolo[2,3-b]pyridine 7-oxide (700 mg, 4.6 mmol) and bis(trimethylsilyl)amine (0.89 g, 5.5 mmol) in THF (30 mL) was slowly added methyl chloroformate (0.87 g, 9.2 mmol) at 0°C under N2. The mixture was stirred at room temperature for 2 hours and diluted with EtOAc (30 mL). The mixture was washed with saturated NaHCO3and brine, and dried over Na2SO4. The solvent was evaporated and the solid was collected by filtration to give methyl 6-chloro-3-fluoro-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (400 mg, yield 38%).

[0286] To a solution of methyl 6-chloro-3-fluoro-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (390 mg, 1.7 mmol) in anhydrous toluene (20 mL) was added (4-methoxyphenyl)methanethiol (385 mg, 2.5 mmol), pd2(dba)3 (91 mg, 0.1 mmol), Xantphos (58 mg, 0.1 mmol) and DIEA (1 ml). The mixture was degassed and stirred at 115°C under N2 overnight. The mixture was cooled, diluted with EtOAc, washed with brine, and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by flash chromatography on silica gel to give methyl 3-fluoro-6-((4-methoxybenzyl)thio)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (0.6 g, yield 95%).WSGR Docket No. 55754-727.601

[0287] To a solution of methyl 3-fluoro-6-((4-methoxybenzyl)thio)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (300mg, 0.85 mmol) in TFA (6 mL) was added trifluoromethanesulfonic acid (127 mg, 0.85 mmol). The mixture was stirred at 60°C for 1 hour and evaporated. The residue was diluted with ACN (10 mL), CS2CO3 (0.65 g, 2 mmol) was added followed by Mel (0.28 g, 2 mmol). The mixture was stirred at room temperature for 1 hour and diluted with EtOAc. The mixture was washed with brine and dried over anhydrous Na2SO4. The solvent was removed. The residue was purified by flash chromatography on silica gel to give l-(3-fluoro-6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)ethan-l-one (0.16 g, yield 78%).

[0288] To a solution of l-(3-fluoro-6-(methylthio)-lH-pyrrolo[2,3-b]pyridin-l-yl)ethan-l-one (160 mg, 0.66 mmol) in THF (5 mL) was added aqueous NaOH (IN, 1 mL, 1 mmol). The mixture was stirred at room temperature for 2 hours and diluted with EtOAc. The mixture was washed with brine and dried over anhydrous Na2SO4. The solvent was removed. The residue was purified by flash chromatography on silica gel to give 3-fluoro-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (85 mg, yield 66%).

[0289] To a solution of 3-fluoro-6-(methylthio)-lH-pyrrolo[2,3-b]pyridine (80 mg, 0.44 mmol) in ACN (15 mL) was added solution of oxone (0.93 g, 1.5 mmol) in water (10 mL). The reaction mixture was stirred at room temperature for 6 hours. Sat. NaHCO3 in water was added to the reaction mixture to adjust pH ~ 7. The reaction mixture was extracted with DCM (3x20 mL). The organic layer was washed with brine and dried over anhydrous Na2SC>4. The solvent was removed, and the solid was collected by filtration to give 3-fluoro-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (80 mg, yield 85%).

[0290] 3-Fluoro-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (35 mg, 1.0 eq), N-( 4-bromo-5-ethoxypyridin-2-yl)acetamide (42 mg, 1.0 eq), Pd2(dba)3(15 mg, 0.1 eq), XantPhos (19 mg, 0.2 eq), Zn(OAc)2 (18 mg, 0.6 eq), and K2CO3 (45 mg, 2.0 eq) were combined in dry dioxane (5 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed tube for 18 hrs. The crude mixture was diluted with DCM (60 mL) washed with brine and the crude mixture was purified on ISCO (4 g silica-gel column) to give N-(5-ethoxy-4-(3-fluoro-6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- 1 -yl)pyri din-2 -yl)acetamide (Compound 46) (26 mg, yield 41%). LCMS: 393.6 (M+H)+.Example 30: Synthesis of N-(5-ethoxy-4-(3-fluoro-6-(methylsulfonyl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (47)WSGR Docket No. 55754-727.601Pd2(dba)3 / XantPhos Zn(OAc)2 / K2CO3

[0291] 4 -Bromo-6-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (150 mg, 1.0 eq), (l-(methyl-d3)-lH-pyrazol-4-yl)boronic acid (54 mg, 1.0 eq), PdC12(dppf) (25 mg, 0.08 eq) and CS2CO3 (270 mg, 2.0 eq) were combined in dioxane (8 mL) and water (2 mL). The mixture was degassed with N2 for 5mins and heated at 85°C for 8hr under N2. The reaction was diluted with ethyl acetate (50 mL) and washed with water and brine. The crude mixture was purified on a silica-gel column to afford 6-chloro-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (128 mg, yield 83%).

[0292] A solution of 6-chloro-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (122 mg, 1.0 eq) in dry DMF (4 mL) was degassed with N2 gas for 5 mins, then NaSMe (28 mg, 1.2 eq). The resulting mixture was heated at 110°C for 15hrs. The reaction was cooled, diluted with ethyl acetate (50 mL), washed with water (3x20mL) and brine. The crude mixture was purified on silica-gel column to afford 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (99 mg, yield 78%).

[0293] To a solution of 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylthio)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (90 mg) in CH3CN (10 mL) was added a solution of oxone (440 mg, 3.0 eq) in water (5 mL). The resulting mixture was stirred at RT for 8hrs. The reaction was quenched with saturated NaHCO3and extracted with DCM (3x40 mL). The crude mixture was purified on a silica-gel column to afford 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (68 mg, yield 70%).

[0294] 4-(l -(Methyl -d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-l -((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[2,3-b]pyridine (68 mg) in TBAF (4 mL, 1N in THF) was heated at 70°C for 5hrs. The mixture was diluted with ethyl acetate (50 mL), washed withWSGR Docket No. 55754-727.601water (3x20 mL). The crude mixture was purified on a silica-gel column to give 4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (40 mg, yield 86%).

[0295] 4-(l-(Methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (40 mg, 1.0 eq), N-(4-bromopyridin-2-yl)acetamide (31 mg, 1.0 eq), Pd2(dba)3(13 mg, 0.1 eq), XantPhos (16 mg, 0.2 eq), Zn(OAc)2 (16 mg, 0.6 eq), and K2CO3 (40 mg, 2.0 eq) were combined in dry dioxane (5 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed tube for 18hrs. The ° / c*rude mixture was cooled, diluted with DCM (60 mL), and washed with brine. The crude mixture was purified on ISCO (4 g silica-gel column) to give N-(4-(4-(l-(methyl- >°d3)-lH-pyrazol-4-yl)-6-(methylsul IZf \ Ionyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide z(Compound 47) (32 mg, yield 55%). LCMS: 414.5 (M+H)+.

[0296] Compounds 48-51 were prepared by similar procedures as described in Example 30.MSCompound Structure Name[M+H]+1 z N-(4-(4-(5,6-dihydro-4H- / >■- pyrrolo[l,2-b]pyrazol-3-yl)-6- 48 J \ _ \ / ZI (methylsulfonyl)- 1H- 437.2 Jzpyrrolo[2,3-b]pyridin-l- \ / O — yl)pyridin-2-yl)acetamideo c'o / xN-(4-(3 -methyl-4-( 1 -methyl- 1H- pyrazol-4-yl)-6- 49 (methylsulfonyl)- 1H- 425.1 pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamideF3CN-NzN-(4-(6-(methylsulfonyl)-4-( 1 - (trifluoromethyl)- lH-pyrazol-4- 50 465.4 N yl) - 1 H-pyrrolo [2,3 -b]pyridin- 1 - O' '° A-x yl)pyridin-2-yl)acetamide0 p7HPMBsN-NZ VjN-(4-(4-(l-(4-methoxybenzyl)- lH-pyrazol-4-yl)-6- 51 (methylsulfonyl)- 1H- 517.3 'X' N N pyrrolo[2,3-b]pyridin-l- O' '°yl)pyridin-2-yl)acetamide°, 0Z N7HWSGR Docket No. 55754-727.601Example 31: Synthesis of N-(4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (52)PMBsN-N HN-NTFA / AnisoleCompound 51 Compound 52

[0297] To a solution of N-(4-(4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2, 3-b]pyri din- 1 -yl)pyri din-2 -yl)acetamide (Compound 51) (80 mg) in TFA (2 mL) was added anisole (10 mg). The resulting mixture was heated at 85°C for 5hr in a sealed tube. TFA was removed in vacuo. The residue was suspended in water (1 mL) and the pH was adjusted to pH = 8 by adding saturated NaHCO3. The white solid was collected with filtration, and washed with DI water (3x5 mL). The white solid was suspended in DCM (4 mL) and sonicated for 2mins and filtered to afford N-(4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 52) (50 mg, yield 82%) as a white solid. LCMS: 397.4 (M+H)+.Example 32: Synthesis of N-(4-(6-(methylsulfonyl)-4-(l-(methylsulfonyl)-lH-pyrazol-4-yl)- IH-pyrrolo [2,3-b] pyridin-l-yl)pyridin-2-yl)acetamide (53)HN-NCH3S02ClCompound 52

[0298] N-(4-(6-(Methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2-yl)acetamide (Compound 52) (10 mg, 1.0 eq) was suspended in DCM (5 mL). To the solution was added DIEA (16 mg, 5.0 eq) and methanesulfonyl chloride (9 mg, 3.0 eq) at 0°C. The resulting mixture was stirred at 0°C for 10 minutes. The crude mixture was purified on a silica-gel column (4 g), washed with DCM (~40 mL) and then ethyl acetate to give N-(4-(6-(methylsulfonyl)-4-(l-(methylsulfonyl)-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 53) (4 mg, yield 33%). LCMS: 475.3 (M+H)+.WSGR Docket No. 55754-727.601Example 33: Synthesis of N-(4-(4-(l-(2-hydroxyethyl-l,l,2,2-d4)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (54)

[0299] To a solution of N-(4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2 -yl)acetamide (Compound 52) (20 mg, 1.0 eq) in DMF (1.5 mL) was added CS2CO3 (25 mg, 1.5 eq). The mixture was stirred at RT for 30mins. 2-Bromoethan-l,l,2,2-d4-l-ol (10 mg, 1.5 eq) was added and the resulting mixture was stirred at RT for 15hrs. The mixture was directly purified on HPLC to afford N-(4-(4-(l-(2-hydroxyethyl-l,l,2,2-d4)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 54) (12 mg, yield 54%). LCMS: 445.7 (M+H)+.Example 34: Synthesis of ethyl 2-(4-(l-(2-acetamidopyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl)acetate (55)

[0300] To a solution of N-(4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyri din-2 -yl)acetamide (Compound 52) (27 mg, 1.0 eq) in DMF (2 mL) was added CS2CO3 (50 mg, 2.0 eq). The mixture was stirred at RT for 5mins. Bromo acetate (15 mg, 1.3 eq) was added and the resulting mixture was stirred at RT for 2hrs. The mixture was diluted with ethyl acetate (40 mL), washed with water (3x20 mL) and brine. The crude mixture was purified on ISCO (silica-gel column 4 g) to give ethyl 2-(4-(l-(2-acetamidopyridin-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-pyrazol-l-yl)acetate (Compound 55) (18 mg, yield 54%). LCMS: 483.4 (M+H)+.WSGR Docket No. 55754-727.601Example 35: Synthesis of N-(5-(methoxy-d3)-4-(4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (56)D3CCS2CO3 Pd(OAc)2 / Binap

[0301] 4-(l -(Methyl -d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (108 mg, 1.0 eq), 2-chloro-4-iodo-5-(methoxy-d3)pyridine (150 mg, 1.5 eq), Pd2(dba)3(82 mg, 0.25 eq), XantPhos (105 mg, 0.5 eq), Zn(OAc)2 (40 mg, 0.6 eq) and K2CO3 (150 mg, 3.0 eq) were combined in dry dioxane (12 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oilbath) in a sealed tube for 16 hrs. Additional 2-chloro-4-iodo-5-(methoxy-d3)pyridine (50 mg) was added and the reaction was heated at 120 °C for 15hr. The crude mixture was cooled, diluted with DCM (80 mL), and washed with brine. The crude mixture was purified on ISCO (12 g silica-gel column) to give l-(2-chloro-5-(methoxy-d3)pyridin-4-yl)-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (140 mg, yield 85%).

[0302] l-(2-Chloro-5-(methoxy-d3)pyridin-4-yl)-4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (140 mg, 1.0 eq), Pd(OAc)2 (11 mg, 0.15 eq), Binap (62 mg, 0.3 eq), acetamide (39 mg, 2 eq) and CS2CO3 (215 mg, 2.0 eq) were combined in dry dioxane (15 mL). The mixture was degassed with bubbling N2 gas for 5min. The resulting mixture was heated at 120°C (oil-bath) for 15hrs in a sealed tube. The reaction was cooled, diluted with DCM (80 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to give N-(5-(methoxy-d3)-4-(4-(l-(methyl-d3)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 56) (131 mg, yield 89%). LCMS: 447.4 (M+H)+.

[0303] Compounds 57-62 were prepared by similar procedures as described in Example 35.MSCompound Structure Name[M+H]+D3C,N-NA ftN-(5-(ethoxy-d5)-4-(3-methyl-4- ( 1 -(methyl -d3)- lH-pyrazol-4- 57 yl)-6-(methylsulfonyl)-lH- 477.26"S'bN IV / O'CD2CD3pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamide7HWSGR Docket No. 55754-727.601N-(4-(4-(5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl)-6- (methylsulfonyl)-lH- 58 486.6 pyrrolo[2,3 -b]pyridin- 1 -y 1) -5 - (ethoxy-d5)pyridin-2- yl)acetamideQ / ,J1« z\o o _,zN-(5-(ethoxy-d5)-4-(4-(l- vo / / \\ / Z \5; (methyl-d3)-lH-pyrazol-4-yl)-6- 59IZ\ 1 (methylsulfonyl)- 1H- 463.5 / z _ pyrrolo[2,3-b]pyridin-l- o 1 yl)pyridin-2-yl)acetamideoo wN-N^H \ _ / N-(4-(4-(5,6-dihydro-4H- pyrrolo[l,2-b]pyrazol-3-yl)-3- methyl-6-(methylsulfonyl)-lH- 60 CO co coI Q Q 500.6 dAbNV / 0~CD2M C o O O pyrrolo[2,3 -b]pyridin- 1 -y 1) -5 - CM CM D QCDo3(ethoxy-d5)pyridin-2- l 1 1 O o O1 0 o O o yl)acetamide / N7H_ \ / ZI\zAV i N-(5 -(ethoxy- 1, 1 -d2)-4-(4-( 1 - \zoo oo''Q □ CO' (methyl-d3)-lH-pyrazol-4-yl)-6- 61 o / o o / / ' (methylsulfonyl)- 1H- 460.3 pyrrolo[2,3-b]pyridin-l- yl)pyridin-2-yl)acetamideN-(5-(methoxy-d3)-4-(6- (methylsulfonyl)-4-( 1 - 62 (trifluoromethyl)- lH-pyrazol-4- 498.5 yl) - 1 H-pyrrolo [2,3 -b]pyridin- 1 - yl)pyridin-2-yl)acetamideExample 36: Synthesis of N-(5-(ethoxy-d5)-4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (63)WSGR Docket No. 55754-727.601CS2CO3 Pd(OAc)2 / Binap

[0304] 4-(l-(4-Methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (200 mg, 1.0 eq), 2-chloro-5-(ethoxy-d5)-4-iodopyridine (230 mg, 1.5 eq), Pd2(dba)3(96 mg, 0.2 eq), XantPhos (122 mg, 0.4 eq), Zn(OAc)2 (60 mg, 0.6 eq) and K2CO3 (180 mg, 2.5 eq) were combined in dry dioxane (20 mL) then degassed with N2 for 5 min. The mixture was heated at 120°C (oil-bath) in a sealed tube for 15hrs. Additional 2-chloro-5-(ethoxy-d5)-4-iodopyridine (100 mg), Pd2(dba)3(30 mg), and XantPhos (40 mg) were added and the reaction was heated at 120°C for 20hrs. The crude mixture was cooled, diluted with DCM (100 mL), and washed with brine. The crude mixture was purified on ISCO (12 g silica-gel column) to give l-(2-chloro-5-(ethoxy-d5)pyridin-4-yl)-4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (236 mg, yield 83%).

[0305] l-(2-Chloro-5-(ethoxy-d5)pyridin-4-yl)-4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridine (236 mg, 1.0 eq), Pd(OAc)2 (15 mg, 0.15 eq), Binap (87 mg, 0.32 eq), acetamide (51 mg, 2 eq), and CS2CO3 (285 mg, 2.0 eq) were combined in dry dioxane (15 mL). The mixture was degassed with bubbling N2 gas for 5mins. The resulting mixture was heated at 120°C (oil-bath) for 18hrs in a sealed tube. The reaction was cooled, diluted with DCM (100 mL), and washed with water and brine. The crude mixture was purified on a silica-gel column (12 g) to give N-(5-(ethoxy-d5)-4-(4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (212 mg, yield 86%).

[0306] To a solution of N-(5-(ethoxy-d5)-4-(4-(l-(4-methoxybenzyl)-lH-pyrazol-4-yl)-6-(methylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (212 mg) in TFA (5 mL) was added anisole (0.5 mL). The mixture was heated at 80°C in a sealed tube for 6hrs. TFA was removed in vacuo and the residue was suspended in DI water (5 mL). The mixture was adjusted to pH >8 by adding saturated NaHCO3and stirred at RT for lOmins. The solid was collected by filtration and washed with DI water (3x5 mL) to afford a white solid which was suspended in DCMWSGR Docket No. 55754-727.601(lOmL) and sonicated for 2mins. The solid was filtered and washed with DCM (2x5 mL) to afford N-(5-(ethoxy-d5)-4-(6-(methylsulfonyl)-4-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-l-yl)pyridin-2-yl)acetamide (Compound 63) (128 mg, yield 76%). LCMS: 446.5 (M+H)+.Example 37: Stimulation Assay in primary human lymphocytes; IFNa induced JAK1 / TYK2 Stimulated STAT1 Phosphorylation AssayCompound and Cytokine treatment

[0307] Aliquot 2.4xl05of healthy human PBMCs in to wells of 96-well plate. Added 10 pL of (10X cone.) of different concentrations of compounds to all wells except controls (unstained and unstimulated) and mixed with the help of 100 uL multichannel. Added 10 uL of RPMI media in controls. For dilution of compounds and dilution range, see table below. Incubated on water bath or CO2 incubator for 1 hour at 37°C. Added 10 pL of (10X cone.) of IFNa) (final cone. 100 ng / mL of IFNa) to each well except unstimulated and unstained controls and incubated further for 15 minutes at 37°C.Lysis and Fixation

[0308] Added 1 mL of prewarmed IX Fix / Lyse solution and mixed it properly using 1000 pL multichannel. Incubated further on water bath at 37°C for 10 minutes (which includes time of addition). Centrifuged at 800 x g for 5 minutes at 4°C; removed supernatant and added ImL of IX PBS. Centrifuged at 800 x g for 5 minutes at 4°C, removed supernatant. Washed one more time with ImL of PBS (optional) and moved to permeabilization step.Permeabilization

[0309] Disrupted the pellet by gentle tapping and resuspending in 1000 pL of BD Phosflow Perm Buffer III and incubated plate on ice for 30 minutes. Centrifuged plate at 800 x g for 5 minutes at 4°C. Washed two more times with 1000 pL of BD Pharmingen Stain Buffer.Antibody treatment

[0310] Disrupted the pellet by gentle tapping. Resuspended pellets in 100 uL of Stain Buffer and add 5 pL of 5 uL of p STAT 1 PE in all wells except unstained control and mixed properly using 200 pL multichannel. Incubated overnight at 4°C. Added 900 pL of wash buffer and centrifuged at 800xg for 3 minutes at 4°C. Washed one more time with 1000 pL of BD Pharmingen Stain Buffer. Finally resuspended the pellet in 150-200 uL of BD Pharmingen Stain Buffer. Transferred the cells to 96-well v-bottom plate and acquired the cells in Beckman Coulter CytExpert. Acquiring cells in Flow Cytometer: Kept the threshold value to 250 and cell concentration should not exceed 100-500 cells / pL. Acquired at least 5,000-10,000 cells.Preparation of Reagents

[0311] RPMI 1640 Complete Medium: RPMI 1640 media + 10% FBS.WSGR Docket No. 55754-727.601

[0312] Cytokine dilution: IFNa Stock at 200 ug / mL. Diluted IFNa stock 1:200 by adding 5 uL of stock into the 1000 uL of 100 ng / mL Kept it on ice until used.

[0313] Lyse / Fix buffer preparation: Diluted 5X Lyse / Fix buffer to IX using MQ water and kept at 37°C until used.

[0314] BD Phosflow perm buffer III: Kept on ice / fridge.Compound dilutionFinal10XSample concentration, Dilutionconcentration, nMnM2 pL of 10 mM compound + 198 pL of cRPMI 1 10,000100,000 media2 3333.3 33,333 60 pL of A + 120 pL of cRPMI media 3 1111.1 11,111 60 pL of B + 120 pL of cRPMI media 4 370.4 3,704 60 pL of C + 120 pL of cRPMI media 5 123.5 1,235 60 pL of D + 120 pL of cRPMI media 6 41.2 412 60 pL of E + 120 pL of cRPMI media 7 13.7 137 60 pL of F + 120 pL of cRPMI media 8 4.6 46 60 pL of G + 120 pL of cRPMI media 9 0 0 2 pL of DMSO + 198 pL of cRPMI media

[0315] IC50 values are shown in the table below.Compound IFN-a / JaklTyk2 Compound IFN-a / JaklTyk2 Compound IFN-a / JaklTyk2IC50 IC50 IC50 1 B 2 B 3 C4 C 5 C 6 B7 C 8 B 9 A10 A 11 A 12 A13 A 14 B 15 C16 C 17 A 18 A19 A 20 A 21 A22 B 23 B 24 A25 C 26 A 27 B28 A 29 C 30 B31 A 32 B 33 A34 A 35 A 36 AWSGR Docket No. 55754-727.60137 A 38 A 39 B40 B 41 B 42 C43 A 44 B 45 A46 A 47 A 48 A49 A 50 A 51 A52 A 53 A 54 A55 A 56 A 57 A58 A 59 A 60 A61 A 62 A 63 AA: IC50 <200 nM; B: IC50 >200 nM and < 1 pM; C: IC50 >1 pM and < 3 pM

[0316] The examples and embodiments described herein are for illustrative purposes only and in some embodiments, various modifications or changes are to be included within the purview of disclosure and scope of the appended claims.

Claims

WSGR Docket No. 55754-727.601CLAIMSWHAT IS CLAIMED IS:

1. A compound having the structure of Formula (I’):Formula (I’);wherein:W is CH orN;X is C(R2) orN;Y is C(R3) orN;Z is C(R4) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;R2, R3, and R4are independently selected from hydrogen, halogen, -CN, -N(RIO)2, Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Ci-Cehaloalkoxy, C3-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cedeuteroalkyl, Ci-Cealkoxy, Ci-Cedeuteroalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio;Rs is selected from hydrogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, -OR11, Cs-Cecycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-Cgheterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 R7 groups;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each R7 is independently selected from halogen, hydroxy, -CN, -S(=O)2Rn, Ci-Cealkyl, -Ci-Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl, wherein Ci-Cealkyl, -Ci-Cealkyl-Ce-Cioaryl, Ci-Cedeuteroalkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, -Ci-Cealkyl-OH, Ci-Cedeuteroalkyl, Ci-Cehaloalkyl, Ci-WSGR Docket No. 55754-727.601Cealkoxy, Cs-Cecycloalkyl, Ce-Cioaryl, -C(=0)ORio, and -S(=O)2Rn; or two R7 are combined to form a 4-, 5-, or 6-membered cycloalkyl ring or a 4-, 5-, or 6-membered heterocycloalkyl ring; each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; andR12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

2. A compound having the structure of Formula (I):WFormula (I);wherein:W is CH orN;X is C(R2) orN;Y is C(R3) orN;Z is C(R4) orN;R1is -C(=O)R11, -C(=O)N(R10)2, -S(=O)2R11, or C2-C9heteroaryl;R2, R3, and R4are independently selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-Cgheterocycloalkyl, and -C(=0)ORio;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;WSGR Docket No. 55754-727.601R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each R11 is independently selected from C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, -OR10, and -N(R10)2; andRI2is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is C(Rs).

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cealkoxy, and Ci-Cehaloalkoxy.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein Y is N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(R4).

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci- Cealkoxy, and Ci-Cehaloalkoxy.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is N.

9. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (la):‘5R6N NFormula (la).

10. A compound having the structure of Formula (II):WSGR Docket No. 55754-727.601Formula (II);wherein:W is CH orN;X is C(R2) orN;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;R2 is selected from hydrogen, halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Ci-Cehaloalkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, and -C(=0)ORio;R3a and R4a are independently selected from hydrogen and Ci-Cealkyl; or R3a and R4a are combined to form a Cs-Cecycloalkyl or C2-C9heterocycloalkyl ring;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; andR12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein Rsa and R4a are combined to form a Cs-Cecycloalkyl or C2-C9heterocycloalkyl ring.WSGR Docket No. 55754-727.60112. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein Rja and R4a are combined to form a Cs-Cecycloalkyl ring.

13. The compound of claim 10 or claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein Rja and R4a are combined to form a C2-C9heterocycloalkyl ring.

14. The compound of claim 10, or a pharmaceutically acceptable salt or solvate thereof, wherein Rsa and R4a are hydrogen.

15. A compound having the structure of Formula (III):wherein:W is CH orN;X is C(R2) orN;Ri is -C(=O)Rn, -C(=0)N(RIO)2, -S(=O)2RII, and C2-C9heteroaryl;R2 is selected from hydrogen, halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C6cycloalkyl, C2-C9heterocycloalkyl, and -C(=O)OR10;R5 is selected from hydrogen, -CN, C1-C6alkyl, C1-C6haloalkyl, -OR11, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, C6-C10aryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, and C3-C6cycloalkyl;R6 is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and -S(=O)2R12;each Rio is independently selected from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C3-Cecycloalkyl, and phenyl;each Rn is independently selected from Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ci-Cealkyl, Cs-Cecycloalkyl, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, hydroxy, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, -OR10, and -N(RIO)2; andWSGR Docket No. 55754-727.601R12 is Ci-Cealkyl or Ci-Cehaloalkyl;or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein Rs is selected from hydrogen, -ORn, C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl, wherein C2-C9heterocycloalkyl, Ce-Cioaryl, and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci- Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from hydrogen, Ce-Cioaryl, and C2-C9heteroaryl, wherein Ce- Cioaryl and C2-C9heteroaryl are optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C2-C9heteroaryl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is phenyl optionally substituted with 1, 2, or 3 groups selected from halogen, -CN, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cealkoxy, and Cs-Cecycloalkyl.

20. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is selected from:hydrogen, -OCH3, -OCH2CH2OCH3, 121. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein Re is selected from Ci-Cehaloalkyl and -S(=O)2R12.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2Ri2.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2R12 and R12 is Ci-Cealkyl.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein Re is -S(=O)2CH3.WSGR Docket No. 55754-727.60125. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein Re is Ci-Cehaloalkyl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=O)Rn and Rn is Ci-Cealkyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein Ri is -C(=0)CH3.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R2).

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is selected from hydrogen and Ci-Cealkoxy.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-Cealkoxy.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OCH2CH3.

33. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

34. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein W is CH.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein W is N.

37. A compound selected from:WSGR Docket No. 55754-727.60138. A compound selected from:WSGR Docket No. 55754-727.60139. A pharmaceutical composition comprising a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.WSGR Docket No. 55754-727.60140. A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof.

41. The method of claim 40, wherein the disease is selected from ulcerative colitis, psoriatic arthritis, Crohn’s disease, intestinal bowel disease, psoriasis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and endotoxemia.

42. A method of treating a neurological or neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof.

43. The method of claim 42, wherein the disease is selected from Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and frontotemporal dementia.

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