JAK inhibitors

Abstract

Described herein are Janus kinase (JAK) inhibitors and methods of using JAK inhibitors to treat diseases, disorders, or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

[0001] Cross-Reference

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 845,119, filed May 8, 2019, and U.S. Provisional Application No. 62 / 884,588, filed August 8, 2019, both of which are incorporated by reference herein in their entireties. BACKGROUND

[0003] Janus kinases (JAKs) are a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-STAT pathway. The four members of the JAK family are Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), and have been shown to be critical components of cytokine-mediated actions. The key function of JAKs in cytokine signaling suggests that JAK inhibitors can be potential therapeutics for a variety of diseases, including autoimmune and inflammatory diseases. SUMMARY

[0004] In one aspect, provided herein is a compound of Formula (I’):

[0005]

[0006] wherein:

[0007] is phenyl or C2-C9heteroaryl ring;

[0008] X is C(R 11 ) or N;

[0009] L1is C1-C6alkyl or C1-C6heteroalkyl;

[0010] L2is a bond, C1-C6alkyl, or C1-C6heteroalkyl;

[0011] R1is C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0012] R2is -C(=O)OR6,

[0013] each R3is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0014] R4is hydrogen, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0015] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0016] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0017] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0018] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0019] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0020] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0021] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0022] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0023] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0024] R 13 is Ci-C6alkyl;

[0025] R 14 is -OH, -C(=O)H, or -C(=O)OR 15

[0026] R 15 is hydrogen or C1-C6alkyl;

[0027] n is 0, 1, 2, or 3;

[0028] p is 0, 1, or 2; and

[0029] q is 0, 1, or 2;

[0030] or a pharmaceutically acceptable salt or solvate thereof.

[0031] In another aspect, provided herein is a compound of Formula (I):

[0032]

[0033] wherein:

[0034] is phenyl or a C2-C9heteroaryl ring;

[0035] X is C(R 11 ) or N;

[0036] L1is C1-C6alkyl or C1-C6heteroalkyl;

[0037] L2is a bond, C1-C6alkyl, or C1-C6heteroalkyl;

[0038] R1is C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0039] R2is -C(=O)OR6or

[0040] each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0041] R4is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl;

[0042] ​each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci- C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, - NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0043] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0044] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0045] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0046] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0047] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0048] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0049] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0050] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0051] R 13 is Ci-C6alkyl;

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

[0053] p is 0, 1, or 2; and

[0054] q is 0, 1, or 2;

[0055] or a pharmaceutically acceptable salt or solvate thereof.

[0056] In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is phenyl. In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring. In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from pyrazolyl, pyrrolyl, and imidazolyl. In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is a bond. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C9alkyl, C3-C6cycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C3-C6cycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5, and C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C9alkyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0057] In some embodiments is a compound of Formula (II’):

[0058]

[0059] wherein:

[0060] is a C2-C9heteroaryl ring;

[0061] X is C(R 11 ) or N;

[0062] L1is a bond or C1-C6alkyl;

[0063] L2is C1-C6alkyl, C2-C9heteroaryl, or -C(H)(phenyl)-;

[0064] R2is -C(=O)OR6,

[0065] each R3is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0066] R4is hydrogen, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0067] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0068] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0069] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0070] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0071] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0072] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0073] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0074] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0075] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0076] R 13 It is a C1-C6 alkyl group;

[0077] R 14 It can be -OH, -C(=O)H or -C(=O)OR 15 ;

[0078] R 15 It is hydrogen or C1-C6 alkyl;

[0079] n is 0, 1, 2, or 3;

[0080] p is 0, 1, or 2; and

[0081] q is 0, 1, or 2;

[0082] Or its pharmaceutically acceptable salts or solvates.

[0083] In some implementations, the compound is of formula (II):

[0084]

[0085] in:

[0086] It is a C2-C9 heteroaryl ring;

[0087] X is C(R) 11 ) or N;

[0088] L1 is a bond or a C1-C6 alkyl group;

[0089] L2 is a C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-;

[0090] R2 is -C(=O)OR6 or

[0091] Each R3 is independently selected from halogens, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8 and -S(=O)2N(R7)2;

[0092] R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl;

[0093] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci- C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, - NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0094] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0095] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0096] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0097] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0098] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0099] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0100] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0101] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0102] R 13 is Ci-C6alkyl;

[0103] n is 0, 1, 2, or 3;

[0104] p is 0, 1, or 2; and

[0105] q is 0, 1, or 2;

[0106] or a pharmaceutically acceptable salt or solvate thereof.

[0107] In some embodiments is a compound of Formula (II’) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is pyrazolyl. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -C(H)(phenyl)-. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments is a compound of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl.

[0108] In some embodiments is a compound of Formula (I'), (I), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. In some embodiments is a compound of Formula (I'), (I), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-C6alkyl. In some embodiments is a compound of Formula (I'), (I), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen. In some embodiments is a compound of Formula (I'), (I), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is halogen. In some embodiments is a compound of Formula (I'), (I), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12C1-C6alkyl. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R7is independently selected from hydrogen and C1-C6alkyl. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C6alkyl. In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11 ) In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments is a compound of Formula (I’), (I), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0109] In another aspect, provided herein is a compound of Formula (Ia’):

[0110]

[0111] wherein:

[0112] L1is a bond or C1-C6alkyl;

[0113] L2is C1-C6alkyl;

[0114] R1is C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0115] R2is -C(=O)OR6,

[0116] each R5is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0117] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0118] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0119] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0120] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0121] each R9is independently selected from hydrogen and Ci-C6alkyl; and

[0122] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0123] R 13 is Ci-C6alkyl;

[0124] R 14 is -OH, -C(=0)H, or -C(=0)OR 15 ;

[0125] R 15 is hydrogen or Ci-C6alkyl;

[0126] p is 0, 1, or 2; and

[0127] q is 0, 1, or 2

[0128] or a pharmaceutically acceptable salt or solvate thereof.

[0129] In another aspect, provided herein is a compound of Formula (Ia):

[0130]

[0131] wherein:

[0132] L1is a bond or C1-C6alkyl;

[0133] L2is C1-C6alkyl;

[0134] R1is C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0135] R2is -C(=O)OR6or

[0136] each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0137] R6is hydrogen, C1-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl, or -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl;

[0138] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0139] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl;

[0140] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0141] each R9is independently selected from hydrogen and C1-C6alkyl; and

[0142] each R 10 is independently selected from hydrogen and C1-C6alkyl;

[0143] R 13 is C1-C6alkyl;

[0144] p is 0, 1, or 2; and

[0145] q is 0, 1, or 2

[0146] or a pharmaceutically acceptable salt or solvate thereof.

[0147] In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C9alkyl, C3-C6cycloalkyl, or C2-C9heteroaryl, wherein C1-C9alkyl, C3-C6cycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5, and C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-C9alkyl. In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0148] In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6is unsubstituted C1-C6alkyl. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments are compounds of Formula (I’), (I), (la’), (la), (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 15hydrogen. In some embodiments is a compound of Formula (I'), (I), (la'), (la), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments is a compound of Formula (I'), (I), (la'), (la), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (I'), (I), (la'), (la), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0149] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I'), (I), (la'), (la), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0150] 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 (I'), (I), (la'), (la), (II'), or (II), 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 individual a therapeutically effective amount of a compound of Formula (I'), (I), (la'), (la), (II'), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, an intestinal disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

[0151] Incorporation by Reference

[0152] 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

[0153] DEFINITIONS

[0154] In the context of the present disclosure, many terms will be used.

[0155] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information at an Internet location can come and go, but it is expected that the same information will be available at an equivalent location. Reference thereto evidences the availability of the information and public dissemination thereof.

[0156] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms such as "include", "includes," and "included" is not limiting.

[0157] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0158] Definitions of standard chemical terminology can be found in reference works, including but not limited to Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vol. A (2000) and Vol. B (2001), Plenum Press, New York. Conventional methods used in mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed.

[0159] Unless specifically defined otherwise, the nomenclature used herein for analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and their laboratory procedures and techniques is believed by the inventors to be of sufficient standing in the art. 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). For example, the techniques of

[0160] 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 as these can 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.

[0161] As used herein, C1-C x including C1-C2, C1-C3...C1-C x .C1-C x refers to the number of carbon atoms (excluding optional substituents) making up the moiety to which it designates.

[0162] An “alkyl” group refers to a straight or branched chain hydrocarbon chain radical consisting only of carbon and hydrogen atoms, having no unsaturation. In some embodiments, an “alkyl” group can have 1 to 6 carbon atoms (whenever it appears in the

[0163] “Alkoxy” refers to a “-O-alkyl” group, wherein alkyl is as defined herein.

[0164] The term “alkenyl” refers to a straight or branched chain hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. In some embodiments, an alkenyl group can have 2 to 6 carbons. An alkenyl group can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be monovalent or divalent (i.e., an alkenylene group).

[0165] The term“alkynyl” refers to straight-chain or branched hydrocarbon chain radicals, consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl include -CºCH, -CºCCH3, -CºCCH2CH3, and -CºCCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. An alkynyl group can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be monovalent or divalent (i.e., alkynylene).

[0166] “Amino” refers to a -NH2group.

[0167] The term“alkylamine” or“alkylamino” refers to a -N(alkyl)x group, where alkyl is as defined herein, and x is selected from x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups 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. x H y group, where alkyl is as defined herein, and x and y are selected from x = 1, y = 1 and x = 2, y = 0. When x = 2, the alkyl groups 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.

[0168] The term“aromatic” refers to a planar ring having a delocalized pi electron system containing 4n+2 pi electrons, where n is an integer. An aromatic ring can be formed from five, six, seven, eight, nine, or more than nine atoms. An aromatic group can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthyl) and heteroaryl groups (e.g., pyridyl, quinolyl).

[0169] As used herein, the term“aryl” refers to an aromatic ring in which each atom that constitutes the ring is a carbon atom. An aryl group can be formed from five, six, seven, eight, nine, or more than nine carbon atoms. An aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, an aryl group can be monovalent or divalent (i.e., arylene).

[0170] “Carboxyl” refers to -CO2H. In some embodiments, a carboxyl moiety can 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 as a carboxylic acid group. The carboxylic acid moiety of a compound having a carboxylic acid moiety can be interchanged with a carboxylic acid bioisostere and it has similar physical and / or biological properties compared to the carboxylic acid containing compound. For example, in one embodiment, a carboxylic acid bioisostere will ionize to about the same extent as a carboxylic acid group at physiological pH. Examples of bioisosteric replacements for carboxylic acids include, but are not limited to and the like.

[0171] The term "cycloalkyl" refers to a monocyclic or polycyclic nonaromatic radical in which each atom (i.e., skeletal atom) that constitutes the ring is a carbon atom. Cycloalkyl groups can be saturated or partially unsaturated. Cycloalkyl groups can be fused with aromatic rings (in which case the cycloalkyl group is bonded through a nonaromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0172] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. "Heteroaromatic" or "heteroaryl" moieties containing N refer to aromatic groups in which at least one skeletal atom of the ring is a nitrogen atom.

[0173] "Heterocycloalkyl" or "heteroalicyclic" groups refer to cycloalkyl groups in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The group can be fused with an aryl or heteroaryl group. The term heteroalicyclic also includes all forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, a heterocycloalkyl group has from 2 to 10 carbon atoms in the ring. It will be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the total number of atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the skeletal atoms of the heterocycloalkyl ring) is different from the number of carbon atoms in the heterocycloalkyl group.

[0174] The term "halo" or "halogen" means fluoro, chloro, bromo, or iodo.

[0175] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens can be the same or can be different. Non-limiting examples of haloalkyl groups include -CH2C1, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0176] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups 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.

[0177] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal chain atoms are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or a combination thereof. The heteroatoms can be located anywhere on 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. Additionally, up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. In addition to the number of heteroatoms, a "heteroalkyl" can have 1 to 6 carbon atoms.

[0178] The term "bond" or "single bond" refers to a chemical bond between two atoms or, when the atoms connected by the bond are considered part of a larger substructure, a chemical bond between two moieties.

[0179] The term "moiety" refers to a particular segment or functional group of a molecule. A chemical moiety is typically a recognized chemical entity that is embedded in or appended to a molecule.

[0180] As used herein, the substituent "R" appearing alone and without a number designation refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0181] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0182] The term "optionally substituted" or "substituted" means that the referenced group can be substituted with one or more additional groups, which are each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6 alkyl alkyne, 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 protected derivatives thereof. For example, an optional substituent can be L s Rs wherein each L s is independently selected from a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=0)2NH-, -NHS(=0)2, -OC(O)NH-, -NHC(O)O-, -(Ci-C6alkyl)-, or -(C2-C6alkenyl)-; and each R s is independently selected from H, (Ci-C6alkyl), (C3-C8cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and Ci-C6heteroalkyl. Protecting groups that can form protecting derivatives of the above substituents can be found, for example, in the source cited above, Greene and Wuts.

[0183] 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.

[0184] The term "therapeutically effective amount" as used herein refers to an amount of a JAK inhibitor that, when administered to a mammal in need thereof, is effective to at least partially improve or at least partially prevent a condition associated with skin aging.

[0185] As used herein, the term "expression" includes the process of transcription into mRNA and translation into a peptide, polypeptide, or protein of a polynucleotide.

[0186] The term "modulate" includes a decrease or an increase in the activity or expression of a target molecule.

[0187] The term "activator" is used in this specification to mean any molecular species that results in activation of a specified receptor, whether it is the species itself that binds to the receptor, or a metabolite of the species that binds to the receptor when the species is locally administered. Thus, the activator can be a ligand for the receptor, or it can be an activator that is metabolized to a ligand for the receptor, i.e., a metabolite formed in the tissue and is the actual ligand.

[0188] The term "patient" or "mammal" refers to a human, non-human primate, dog, cat, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those of skill in the art recognize that a therapy that reduces the severity of a pathology in one mammalian species can be predictive of the effect of the therapy on another mammalian species.

[0189] The term "soft drug" as used herein refers to a drug substance and / or compound that is biologically active in a desired target tissue and is metabolized to a compound that is not active at the biological target after it has exerted its effect in the target tissue. In some embodiments, the soft drug has no targeted biological activity in the systemic circulation.

[0190] "Pharmaceutically acceptable salts" include both acid and base salt forms. Pharmaceutically acceptable salts of a compound described herein are intended to encompass any and all pharmaceutically suitable salt forms of the compound. Preferred pharmaceutically acceptable salts of a compound described herein are the pharmaceutically acceptable acid addition salts and the pharmaceutically acceptable base addition salts.

[0191] "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 such organic acids as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and

[0192] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic or organic base to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are formed with metals or amine bases, such as alkali and alkaline earth metal hydroxides and the like. 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 including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, propylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0193] As used herein, "treatment" or "treatment" or "palliation" or "amelioration" 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 prophylactic benefit. By "therapeutic benefit" is meant obtaining a complete or partial correction of a pathologic condition being treated. In addition, therapeutic benefit can also be achieved by eradicating or ameliorating one or more of the physiological symptoms associated with the pathologic condition such that an improvement is observed in the patient, even though the patient is still afflicted with the pathologic condition. For prophylactic benefit, the compositions are administered to a patient susceptible of developing a certain disease, or to a patient reporting one or more of the physiological symptoms associated with the disease, even though the patient has not yet been diagnosed with the disease.

[0194] JAK inhibitors

[0195] Cytokines are critical for host defense and immune regulation, but are also major players in the immune pathogenesis of autoimmune diseases. Based on structure, several major families of cytokines can be recognized. Two broad classes are the so-called type I and type II cytokine receptors. Type I receptors bind several interleukins (ILs), colony-stimulating factors, and hormones such as erythropoietin, prolactin, and growth hormone. Type II receptors bind interferons and IL-10-related cytokines. In contrast to other receptors whose intracellular domains encode kinase or other enzymatic activity domains, these receptors lack such elements. Instead, the cytoplasmic domains of type I and type II cytokine receptors associate with members of a specific family of kinases known as Janus kinases (JAKs), including JAK1, JAK2, JAK3, and TYK2. Cytokine receptors pair with different JAKs, which are activated upon cytokine binding. Because JAKs are phosphotransferases, they catalyze the transfer of phosphate from ATP to various substrates such as cytokine receptors. This modification allows the recruitment of various signal molecules, including members of the signal transducer and activator of transcription (STAT) family of DNA-binding proteins. STATs are another important JAK substrate. Phosphorylation of STATs promotes their nuclear accumulation and regulation of gene expression. Additionally, studies with knockout mice support a critical and specific role for JAK signaling by type I / II cytokines, but not other pathways. The critical function of JAKs in cytokine signaling suggests a therapeutic potential for JAK inhibitors.

[0196] The compounds of formula (I’), (I), (Ia’), (Ia), (Ib), (II’), (II), (IIa), (III), (IIIa), or (IV) described herein are JAK inhibitors. The compounds of formula (I’), (I), (Ia’), (Ia), (Ib), (II’), (II), (IIa), (III), (IIIa), or (IV) described herein and compositions comprising these compounds are useful for treating inflammatory or autoimmune diseases.

[0197] In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof:

[0198]

[0199] wherein:

[0200] is phenyl or C2-C9heteroaryl ring;

[0201] X is C(R 11 ) or N;

[0202] L1is C1-C6alkyl or C1-C6heteroalkyl;

[0203] L2is a bond, C1-C6alkyl, or C1-C6heteroalkyl;

[0204] R1is C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0205] R2is -C(=O)OR6,

[0206] each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0207] R4is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl;

[0208] each R5is independently selected from halogen, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0209] R6is hydrogen, C1-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl, or -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl;

[0210] each Y is independently selected from -CN, -OR9, -SR9, and -N(R9)2; 10

[0211] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl;

[0212] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0213] ​each R9is independently selected from hydrogen and Ci-C6alkyl;

[0214] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0215] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0216] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0217] R 13 is Ci-C6alkyl;

[0218] R 14 is -OH, -C(=0)H, or -C(=0)OR 15 ;

[0219] R 15 is hydrogen or Ci-C6alkyl;

[0220] n is 0, 1, 2, or 3;

[0221] p is 0, 1, or 2; and

[0222] q is 0, 1, or 2.

[0223] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0224]

[0225] wherein:

[0226] is phenyl or C2-C9heteroaryl ring;

[0227] X is C(R 11 ) or N;

[0228] L1is Ci-C6alkyl or Ci-C6heteroalkyl;

[0229] L2is a bond, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0230] R1is C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0231] R2is -C(=0)OR6or

[0232] each R3is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0233] R4is hydrogen, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0234] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0235] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0236] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0237] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0238] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0239] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0240] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0241] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0242] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0243] R 13C1-C6alkyl;

[0244] n is 0, 1, 2, or 3;

[0245] p is 0, 1, or 2; and

[0246] q is 0, 1, or 2.

[0247] In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11 ) In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0248] In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is phenyl.

[0249] In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein is

[0250] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6heteroalkyl.

[0251] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C9alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5.In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0252] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is a bond. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6heteroalkyl.

[0253] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is C1-C6alkyl optionally substituted with 1 or 2 Y. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2CH3. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2CH2CH3. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2H. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl-Y. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl-OR9. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl.

[0254] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is unsubstituted -C1-C6alkyl-C2-C9heterocycloalkyl.

[0255] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0256] and p is 1. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0257] In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments, provided herein is a compound of Formula (I’), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0258] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0259] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is halogen. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is C1-C6alkyl.

[0260] In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -CH3. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-C6heteroalkyl.

[0261] In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is halogen. In some embodiments is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I’), or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is -CH3.

[0262] In some embodiments, provided herein is a compound of Formula (Ia’), or a pharmaceutically acceptable salt or solvate thereof:

[0263]

[0264] wherein:

[0265] L1is a bond or C1-C6alkyl;

[0266] L2is C1-C6alkyl;

[0267] R1is C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0268] R2is -C(=O)OR6,

[0269] each R5is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0270] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0271] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0272] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0273] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0274] each R9is independently selected from hydrogen and Ci-C6alkyl; and

[0275] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0276] R 13 is Ci-C6alkyl;

[0277] R 14 is -OH, -C(=0)H, or -C(=0)OR 15 ;

[0278] R 15 is hydrogen or Ci-C6alkyl;

[0279] p is 0, 1, or 2; and

[0280] q is 0, 1, or 2.

[0281] In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0282]

[0283] wherein:

[0284] L1is a bond or C1-C6alkyl;

[0285] L2is C1-C6alkyl;

[0286] R1is C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C1-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0287] R2is -C(=O)OR6or

[0288] each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0289] R6is hydrogen, C1-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl, or -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl;

[0290] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0291] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl;

[0292] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0293] each R9is independently selected from hydrogen and C1-C6alkyl; and

[0294] each R 10 is independently selected from hydrogen and C1-C6alkyl;

[0295] R 13 is C1-C6alkyl;

[0296] n is 0, 1, 2, or 3;

[0297] p is 0, 1, or 2; and

[0298] q is 0, 1, or 2.

[0299] In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond.

[0300] In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-C9alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C9alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heterocycloalkyl.In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0301] In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-.

[0302] In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is C1-C6alkyl optionally substituted with 1 or 2 Y. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2CH3. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2CH2CH3. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2H. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl-Y. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -CO2C1-C6alkyl-OR9. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=O)OR6and R6is unsubstituted -C1-C6alkyl-C2-C9heterocycloalkyl.

[0303] In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (Ia’), or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (Ia') or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0304] In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments, provided herein is a compound of Formula (Ia'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0305] In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0306]

[0307] wherein:

[0308] L1is C1-C6alkyl;

[0309] L2is a bond or C1-C6alkyl;

[0310] R1is C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C1-C6alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0311] R2is -C(=O)OR6or

[0312] each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0313] R6is hydrogen, C1-C6alkyl, C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl, or -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl;

[0314] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl; and

[0315] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0316] R 13 is C1-C6alkyl;

[0317] p is 0, 1, or 2; and

[0318] q is 0, 1, or 2.

[0319] In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-.

[0320] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C6alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2.In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl. In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0321] In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is a bond. In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-.

[0322] In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C1-C6alkyl optionally substituted with 1 or 2 Y. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH3. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH2CH3. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02H. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted -C1-C6alkyl-C2-C9heterocycloalkyl.

[0323] In some embodiments, provided herein is a compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof:

[0324]

[0325] wherein:

[0326] is a C2-C9heteroaryl ring;

[0327] X is C(R 11 ) or N;

[0328] L1is a bond or C1-C6alkyl;

[0329] L2is C1-C6alkyl, C2-C9heteroaryl, or -C(H)(phenyl)-;

[0330] R2is -C(=O)OR6,

[0331] each R3is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0332] R4is hydrogen, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0333] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0334] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0335] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0336] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0337] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0338] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0339] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0340] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0341] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0342] R 13 is Ci-C6alkyl;

[0343] R 14 is -OH, -C(=0)H, or -C(=0)OR 15 ;

[0344] R 15 is hydrogen or Ci-C6alkyl;

[0345] n is 0, 1, 2, or 3;

[0346] p is 0, 1, or 2; and

[0347] q is 0, 1, or 2.

[0348] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0349]

[0350] wherein:

[0351] is a C2-C9heteroaryl ring;

[0352] X is C(R 11 ) or N;

[0353] L1is a bond or Ci-C6alkyl;

[0354] L2is Ci-C6alkyl, C2-C9heteroaryl, or -C(H)(phenyl)-;

[0355] R2is -C(=0)OR6or

[0356] each R3is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci- C6alkoxy, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, - C(=0)N(R7)2, -NR7C(=0)R8, -NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0357] R4is hydrogen, Ci-C6alkyl, or Ci-C6heteroalkyl;

[0358] each R5is independently selected from halogen, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci- C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=0)R8, -C(=0)OR7, -C(=0)N(R7)2, -NR7C(=0)R8, - NR7S(=0)2R8, -S(=0)2R8, and -S(=0)2N(R7)2;

[0359] R6is hydrogen, Ci-C6alkyl optionally substituted with 1 or 2 Y, C3-C6cycloalkyl optionally substituted with 1 or 2 Y, C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl, or -Ci-C6alkyl-C2-C9heterocycloalkyl optionally substituted with Ci-C6alkyl;

[0360] each Y is independently selected from -CN, -OR9, -SR9, and -N(R 10 )2;

[0361] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0362] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0363] each R9is independently selected from hydrogen and Ci-C6alkyl;

[0364] each R 10 is independently selected from hydrogen and Ci-C6alkyl;

[0365] R 11 is hydrogen or Ci-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0366] R 12 is hydrogen, halogen, or Ci-C6alkyl;

[0367] R 13 is Ci-C6alkyl;

[0368] n is 0, 1, 2, or 3;

[0369] p is 0, 1, or 2; and

[0370] q is 0, 1, or 2.

[0371] In some embodiments is a compound of Formula (II’) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11) In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0372] In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is pyrazolyl. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is pyrrolyl. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is imidazolyl. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein is

[0373] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2CH2-.

[0374] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is oxazolyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thiazolyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrazolyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thienyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrrolyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is imidazolyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyridyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -C(H)(phenyl)-.

[0375] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C1-C6alkyl optionally substituted with 1 or 2 Y. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH3. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH2CH3. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02H. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02C1-C6alkyl-Y. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02C1-C6alkyl-OR9. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted -C1-C6alkyl-C2-C9heterocycloalkyl.

[0376] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0377] In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments, provided herein are compounds of Formula (II'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0378] In some embodiments, provided herein is a compound of Formula (II’), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0379] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is halogen. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is C1-C6alkyl.

[0380] In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -CH3. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is C1-C6heteroalkyl.

[0381] In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is halogen. In some embodiments is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II’), or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is -CH3.

[0382] In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:

[0383]

[0384] wherein:

[0385] L1is a bond or C1-C6alkyl;

[0386] L2is C1-C6alkyl, C2-C9heteroaryl, or -C(H)(phenyl)-;

[0387] R2is -C(=O)OR6or

[0388] R3is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)2R8, and -S(=O)2N(R7)2;

[0389] R6is hydrogen, C1-C6alkyl, C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl, or -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl.

[0390] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl; and

[0391] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0392] R 13 is Ci-C6alkyl;

[0393] p is 0, 1, or 2; and

[0394] q is 0, 1, or 2.

[0395] In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2CH2-.

[0396] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is oxazolyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thiazolyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrazolyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thienyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrrolyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is imidazolyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyridyl. In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -C(H)(phenyl)-.

[0397] In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C1-C6alkyl optionally substituted with 1 or 2 Y. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH3. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02CH2CH3. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C02H. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is -C1-C6alkyl-C2-C9heterocycloalkyl optionally substituted with C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -C(=0)OR6and R6is unsubstituted -C1-C6alkyl-C2-C9heterocycloalkyl.

[0398] In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1 and q is 2. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0399] In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, and -S(=O)2R8. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -C(=O)R8, and -S(=O)2R8. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-C6alkyl and C1-C6heteroalkyl. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C6alkyl. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is selected from C1-C6haloalkyl. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C6heteroalkyl. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is -C(=O)R8. In some embodiments, provided herein are compounds of Formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is -S(=O)2R8.

[0400] In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0401]

[0402] wherein:

[0403] is phenyl or C2-C9heteroaryl ring;

[0404] X is C(R 11 ) or N;

[0405] L1is C1-C6alkyl or C1-C6heteroalkyl;

[0406] L2is a bond, C1-C6alkyl, or C1-C6heteroalkyl;

[0407] R1is C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein C3-C9alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0408] R2is

[0409] each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0410] R4is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl;

[0411] each R5is independently selected from halogen, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0412] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl;

[0413] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0414] R 11 is hydrogen or C1-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0415] R 12 is hydrogen, halogen, or C1-C6alkyl;

[0416] R 13 is C1-C6alkyl;

[0417] R14 is -OH, -C(=O)H, or -C(=O)OR 15 ;

[0418] R 15 is hydrogen or C1-C6alkyl;

[0419] n is 0, 1, 2, or 3;

[0420] p is 0, 1, or 2; and

[0421] q is 0, 1, or 2.

[0422] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11 ). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0423] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is phenyl.

[0424] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9heteroaryl ring selected from In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments, the present application provides a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein is

[0425] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6heteroalkyl.

[0426] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C9alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heterocycloalkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2.In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0427] In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is a bond. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6heteroalkyl.

[0428] In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein are compounds of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0429] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0430] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0431] In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 2. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 3. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 or 2 and each R3 is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 heteroalkyl groups, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 or 2 and each R3 is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 heteroalkyl groups, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 or 2 and each R3 is independently selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR7, and -N(R7)2. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 or 2 and each R3 is independently selected from halogens and C1-C6 alkyl groups. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 and R3 is selected from halogens, C1-C6 alkyl groups, C1-C6 haloalkyl groups, -OR7, and -N(R7)2. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 and R3 is selected from halogens and C1-C6 alkyl groups. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 and R3 is a halogen. In some embodiments, this document provides a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein n is 1 and R3 is a C1-C6 alkyl group.

[0432] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -CH3. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is Ci-C6heteroalkyl.

[0433] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is halogen. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is -CH3.

[0434] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof:

[0435]

[0436] wherein:

[0437] L1is a bond or Ci-C6alkyl;

[0438] L2is Ci-C6alkyl;

[0439] R1is Ci-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl, wherein Ci-C9alkyl, C3-C6cycloalkyl, C2-C9heterocycloalkyl, or C2-C9heteroaryl is optionally substituted with 1, 2, or 3 R5;

[0440] R2is

[0441] each R5is independently selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0442] each R7is independently selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, Ci-C6haloalkyl, and Ci-C6heteroalkyl;

[0443] each R8is independently selected from Ci-C6alkyl, C2-C6alkenyl, Ci-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0444] R 13 is Ci-C6alkyl;

[0445] R 14 is -OH, -C(=0)H, or -C(=0)OR 15 ;

[0446] R 15 is hydrogen or Ci-C6alkyl;

[0447] p is 0, 1, or 2; and

[0448] q is 0, 1, or 2.

[0449] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond.

[0450] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C1-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C9alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C1-C9alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C9alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C3-C6cycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C3-C6cycloalkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heterocycloalkyl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heterocycloalkyl.In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is C2-C9heteroaryl optionally substituted with 1, 2, or 3 R5, wherein each R5is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is unsubstituted C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein C2-C9heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0451] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-.

[0452] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0453] In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments, provided herein is a compound of Formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0454] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof:

[0455]

[0456] wherein:

[0457] is a C2-C9heteroaryl ring;

[0458] X is C(R 11 ) or N;

[0459] L1is a bond or C1-C6alkyl;

[0460] L2is C1-C6alkyl, C2-C9heteroaryl, or -C(H)(phenyl)-;

[0461] R2is

[0462] each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0463] R4is hydrogen, C1-C6alkyl, or C1-C6heteroalkyl;

[0464] each R5is independently selected from halogen, oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2;

[0465] each R7is independently selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C1-C6haloalkyl, and C1-C6heteroalkyl;

[0466] each R8is independently selected from C1-C6alkyl, C2-C6alkenyl, C1-C6heteroalkyl, C3-C6cycloalkyl, and C2-C9heterocycloalkyl;

[0467] R 11 is hydrogen or C1-C6alkyl optionally substituted with 1, 2, or 3 R5;

[0468] R 12 is hydrogen, halogen, or C1-C6alkyl;

[0469] R 13 is C1-C6alkyl;

[0470] R 14 is -OH, -C(=O)H, or -C(=O)OR 15 ;

[0471] R 15 is hydrogen or C1-C6alkyl;

[0472] n is 0, 1, 2, or 3;

[0473] p is 0, 1, or 2; and

[0474] q is 0, 1, or 2.

[0475] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11 ) In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N.

[0476] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is a C2-C9 heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is pyrazolyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is pyrrolyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is imidazolyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is selected from In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein is

[0477] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is a bond. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2-. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is -CH2CH2CH2-.

[0478] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2-. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2-. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -CH2CH2CH2-. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is C2-C9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is oxazolyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thiazolyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrazolyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is thienyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyrrolyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is imidazolyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is pyridyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein L2is -C(H)(phenyl)-.

[0479] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0480] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is and p is 1. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 0. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is p is 1, and q is 2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -OH. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)H. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 . In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 14 is -C(=O)OR 15 and R 15 is hydrogen.

[0481] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0482] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, -OR7, -N(R7)2, -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3is independently selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen, C1-C6alkyl, C1-C6haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is selected from halogen and C1-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is halogen. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R3is C1-C6alkyl.

[0483] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is -CH3. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is Ci-C6heteroalkyl.

[0484] In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is hydrogen. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is halogen. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is Ci-C6alkyl. In some embodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 12 is -CH3.

[0485] In some embodiments, provided herein is a compound selected from:

[0486]

[0487]

[0488]

[0489]

[0490] or a pharmaceutically acceptable salt or solvate thereof.

[0491] In some embodiments, provided herein is a compound selected from:

[0492] or a pharmaceutically acceptable salt or solvate thereof.

[0493] In some embodiments, provided herein is a compound selected from:

[0494] or a pharmaceutically acceptable salt or solvate thereof.

[0495] In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 50 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 100 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 250 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 500 nM. 50 In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 50 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 100 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 250 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 500 nM. 50 In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 50 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 100 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 250 nM. In some embodiments, the compounds provided herein have an IC50in the JAK / TYK2 assay of about or less than 500 nM. 50 In another embodiment, the compounds provided herein selectively inhibit JAK1 relative to JAK2, JAK3, and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK2 relative to JAK1, JAK3, and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK3 relative to JAK1, JAK2, and TYK2. In another embodiment, the compounds provided herein selectively inhibit TYK2 relative to JAK1, JAK2, and JAK3. In another embodiment, the compounds provided herein selectively inhibit JAK1 and JAK2 relative to JAK3 and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK1 and JAK3 relative to JAK2 and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK1 and TYK2 relative to JAK2 and JAK3. In another embodiment, the compounds provided herein selectively inhibit JAK2 and JAK3 relative to JAK1 and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK2 and TYK2 relative to JAK1 and JAK3. In another embodiment, the compounds provided herein selectively inhibit JAK3 and TYK2 relative to JAK1 and JAK2. In another embodiment, the compounds provided herein selectively inhibit JAK1, JAK2, and JAK3 relative to TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK1, JAK2, and TYK2 relative to JAK3. In another embodiment, the compounds provided herein selectively inhibit JAK1, JAK3, and TYK2 relative to JAK2. In another embodiment, the compounds provided herein selectively inhibit JAK1, JAK2, and JAK3 relative to TYK2.

[0496] Any combination of the groups described above for each variable is contemplated herein. Throughout the specification, groups and substituents thereof can be chosen by one of skill in the art to provide stable moieties and compounds.

[0497] In some embodiments, the therapeutic agent (e.g., a compound of Formula (I’), (I), (Ia’), (Ia), (Ib), (II’), (II), (IIa), (III), (IIIa), or (IV)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any of the compounds described above are suitable for any of the methods or compositions described herein.

[0498] Other forms of the compounds disclosed herein

[0499] Isomers

[0500] Further, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and mixtures thereof. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the general formulae described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from single preparation steps, combinations, or interconversions are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by resolution of a racemic mixture by chiral chromatography. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by separating the racemic mixture of the compound by reacting the racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, isolating the non-racemic mixture of diastereomers, and recovering the optically pure enantiomer of the compound. In some embodiments, isolable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, 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 on solubility differences. In some embodiments, the optically pure enantiomer is recovered along with the resolving agent by any practical means that does not cause racemization.

[0501] Labeled Compounds

[0502] In some embodiments, the compounds described herein exist in isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds in the form of a pharmaceutical composition. Accordingly, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, l5 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. The compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, containing the above-mentioned isotopes and / or other isotopes of other atoms are within the scope of the present application. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3 H, and 14 C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e.,, 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, are prepared by any suitable method.

[0503] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0504] Pharmaceutically Acceptable Salts

[0505] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0506] In some embodiments, the compounds described herein have an acidic or basic group and, therefore, react with any base, such as some inorganic or organic bases, and with any acid, such as 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

[0507] Solvates

[0508] In some embodiments, the compounds described herein exist as solvates. In some embodiments, the methods of treating a disease are by administering such solvates. Further described herein are methods of treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0509] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and in some embodiments, solvates are formed during 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 an alcohol. Solvates of the compounds described herein are conveniently prepared or formed in the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures employing organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Additionally, 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 purposes of the compounds and methods provided herein.

[0510] Synthesis of compounds

[0511] In some embodiments, the synthesis of the compounds described herein is achieved using means described in the chemical literature, using the methods described herein, or by a combination thereof. Additionally, the solvents, temperatures, and other reaction conditions presented herein can be varied.

[0512] In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0513] In further embodiments, the compounds described herein and other related compounds having different substituents are synthesized using techniques and materials described herein and techniques and materials recognized in the art, such as those described 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 Supplemental (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 Fourth Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry Fourth Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis Third Edition (Wiley 1999) (all of which are incorporated by reference for such disclosure). The general methods for preparing the compounds disclosed herein can be found in reactions, and these reactions can be adapted to use appropriate reagents and conditions in order to incorporate the various moieties found in the general formulas provided herein. As a guide, the following synthetic methods can be used.

[0514] Use of protecting groups

[0515] In the reactions described, it can be necessary to protect reactive functional groups, for example, hydroxyl, amino, imino, thio, or carboxyl groups, where these are desired in the final product, to avoid unnecessary reaction with other functional groups. Protecting groups are used to block some or all of the reactive moieties and prevent these groups from participating in a chemical reaction until the protecting group is removed. Preferably, each protecting group can be removed by different means. Protecting groups that are cleaved under completely different reaction conditions satisfy the need for differential removal.

[0516] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl are acid labile and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected with Cbz groups, which can be removed by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxyl reactive moieties can 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 carbamates, or carbamates that are stable to both acid and base but can be removed by hydrolysis.

[0517] Carboxylic acid and hydroxyl reactive moieties can be blocked with hydrolytically removable protecting groups such as benzyl, while amine groups capable of hydrogen bonding with acids can be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties can be protected by conversion to mono-ester compounds as exemplified herein, which includes conversion to alkyl esters, or can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amines can be blocked with fluoride labile silyl carbamates.

[0518] Allyl blocking groups are useful in the presence of acid and base protecting groups because they are stable and can be removed subsequently by metal or pi-acid catalysts. For example, in the presence of acid labile t-butyl carbamates or base labile amine protecting groups of acetic acid, an allyl blocked carboxylic acid can be deprotected by Pd 0 catalyzed reaction. Another form of a protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group is available for reaction.

[0519] In general, blocking / protecting groups can be selected from the group consisting of:

[0520]

[0521] Other protecting groups, as well as detailed descriptions of applicable techniques for their creation and removal, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated by reference for such disclosure.

[0522] Methods of treatment and prevention

[0523] 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, an intestinal disease, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis. 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is multiple sclerosis.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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is lupus. 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is enteropathy. 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), 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 of Formula (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is ankylosing spondylitis.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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is vitiligo. 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 (I’), (I), (la’), (la), (lb), (II’), (II), (Ila), (III), (Ilia), or (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is atopic dermatitis.

[0524] Pharmaceutical compositions and methods of administration

[0525] The JAK inhibitors described herein are administered to a subject in a biologically compatible form suitable for administration to treat or prevent a disease, disorder, or condition. Administration of the JAK inhibitors as described herein can be in any pharmacological form, including a therapeutically effective amount of the JAK inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0526] In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also herein a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), which is selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0527] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0528] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I’), (I), (Ia’), (Ia), (Ib), (II’), (II), (IIa), (III), (IIIa), or (IV), 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 (Ib), 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 (IIa), or a pharmaceutically acceptable salt or solvate thereof.

[0529] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I’), (I), (Ia’), (Ia), (Ib), (II’), (II), (IIa), (III), (IIIa), or (IV), 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 (Ib), 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 (IIa), or a pharmaceutically acceptable salt or solvate thereof.

[0530] In certain embodiments, a 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 small organic molecules, such as, for example, contaminating intermediates or byproducts produced in one or more steps of a synthetic process.

[0531] These formulations include those suitable for oral, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0532] Exemplary pharmaceutical compositions are in the form of a pharmaceutical preparation, for example, in solid, semi-solid, or liquid form, which contains one or more of the disclosed compounds as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. In some embodiments, the active ingredient is compounded with a carrier that can take a wide variety of forms depending on the form of preparation desired. For example, in some embodiments, the pharmaceutical compositions include those suitable for oral, rectal, topical, or parenteral administration, although the most suitable form of administration will depend on the particular groups of patients to be treated. In some embodiments, the compositions take the form of preparations suitable for extended release or sustained release of the active ingredient. Typically, the pharmaceutical compositions are compounded in unit dosage form for ease of administration and uniformity of dosage. In some embodiments, the compositions are in unit dosage form such as tablets, pills, capsules, powders, suppositories, solutions, suspensions, and any form suitable for the application.

[0533] In some embodiments, the JAK inhibitors described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. By "biologically compatible form suitable for topical administration" is meant a form of the JAK inhibitor to be administered in which the therapeutic effects of the inhibitor outweigh any toxic effects. Administration of the JAK inhibitors as described herein can be in any pharmacological form, including a therapeutically effective amount of the JAK inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0534] Topical administration of the JAK inhibitors can be presented in the form of an aerosol, a semi-solid pharmaceutical composition, a powder, or a solution. By the term "semi-solid composition" is meant an ointment, cream, salve, jelly, or other pharmaceutical composition having a consistency that is substantially similar to that suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy by 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.

[0535] Skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide absorption enhancers, such as DMSO, to increase absorption of the compounds. Patches can include those that control the rate of drug delivery to the skin. Patches can provide a variety of drug delivery systems, including reservoir systems or monolithic systems, respectively. For example, a reservoir design can have four layers: an adhesive layer that directly contacts the skin, a control membrane that controls diffusion of the drug molecules, a reservoir of the drug molecules, and a water-resistant backing. Such a design delivers a uniform amount of drug over a specified period of time, and the rate of delivery must be less than the saturation limit for different types of skin. For example, a monolithic design typically has only three layers: an adhesive layer, a polymer matrix containing the compound, and a water-resistant backing. This design brings the skin to a saturation amount of drug. Thus, the delivery is controlled by the skin. When the amount of drug in the patch decreases below the saturation level, the rate of delivery decreases.

[0536] In one embodiment, the topical composition can, for example, take the form of a polyacrylic acid or polyacrylamide-based hydrogel; as an ointment, for example with polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, in particular a water-in-oil or oil-in-water microemulsion, optionally with the addition of liposomes. Suitable penetration accelerators (entrainers) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decylmethyl sulfoxide (decyl-MSO) and dioxyglycols (diethylene glycol monoethyl ether) or cyclodextrins; and pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and fatty acid esters thereof; urea derivatives, such as dodecyl urea, 1,3-bis-dodecyl urea and 1,3-diphenyl urea; and terpenes, such as D-limonene, menthone, a-terpineol, carvyl ketone, limonene oxide or 1,8-eucalyptol.

[0537] Ointments, pastes, creams and gels can also contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid and talc, or mixtures thereof. Powders and sprays can also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. The solution of nanocrystalline antimicrobial metal can be converted into an aerosol or spray by any known means conventionally used in the art for the preparation of aerosol medicaments. Typically, such a process involves pressurizing or providing pressurized means to a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. The spray can additionally contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0538] The carrier can further comprise other pharmaceutically acceptable excipients for altering or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, dissolution rate, or odor of the formulation. The anti- skin aging compositions can further comprise antioxidants, sunscreens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[0539] In some embodiments, for preparing a solid composition such as a tablet, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, magnesium stearate, sodium chloride, dicalcium phosphate, 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 nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed essentially uniformly in the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0540] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the compositions of the present application are 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 carboxymethylcellulose, hydroxypropylmethylcellulose, 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 sodium lauryl sulfate, cetostearyl alcohol, and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as 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 also contain buffering agents. 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.

[0541] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared with an excipient such as a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or crosscarmellose sodium), a surface active or dispersing agent. In some embodiments, molded tablets are made by molding an mixture of the composition of the present application with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, are optionally scored or prepared with coatings and shells, like enteric coatings and other coatings.

[0542] 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, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the composition of the present application, the liquid dosage forms can in some embodiments contain inert diluents commonly used in the art, such as 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, circuline and mixtures thereof.

[0543] In some embodiments, suspensions contain, in addition to the composition of the present application, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0544] In some embodiments, powders and sprays contain, in addition to the composition of the present application, 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.

[0545] Alternatively, the compositions and compounds disclosed herein are administered by aerosol. This is achieved by preparing an aqueous aerosol, liposome preparation, or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic nebulizers are used as they minimize the exposure of the medicament to shear forces which result in the degradation of the compounds contained in the compositions of the present invention. Generally, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compositions of the present invention with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular composition targeted, but generally include non-ionic surfactants (Tweens, Pluronics or polyethylene glycols), nontoxic excipients, such as sugars or mannitol, oleic acids, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. The aerosols are generally prepared from isotonic solutions.

[0546] Pharmaceutical compositions suitable for parenteral administration include one or more compositions of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use, which in some embodiments contain anti-oxidants, buffers, bacteriostats, solutes which render the formulation isotonic to the possible

[0547] Examples of suitable aqueous and nonaqueous carriers which can be 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 can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

[0548] The dosage of the compositions comprising at least one compound described herein varies depending on the condition, i.e., the stage of the disease, the general state of the patient, the age, and other factors, of the patient (e.g., human).

[0549] The pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dosage and suitable duration and frequency of administration will depend on factors such 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. Generally, the appropriate dosage and treatment regimen provide the compositions in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduction in severity of symptoms). Optimal dosages are typically determined using experimental models and / or clinical trials. In some embodiments, the optimal dosage depends on the body mass, weight, or blood volume of the patient.

[0550] Oral dosages generally will be in the range of about 1.0 mg to about 1000 mg, one to four or more times per day.

[0551] Dose administration can be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0552] 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 JAK inhibitor and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compound for the treatment of sensitivity in individuals. A person of ordinary skill in the art could readily determine the appropriate dosages using, for example, the patient's approximate body weight or body surface area or the volume of body space to be occupied. The dosages will also depend on the particular route of administration selected. The determination of the appropriate dosage for treatment is routinely refined by the ordinarily skilled artisan further refining the calculations necessary to determine the dosages suitable for treatment. Such calculations can be made by the skilled artisan based on the activity of the JAK inhibitors disclosed herein in target cell assay preparations without undue experimentation. The exact dosage will be determined in accordance with standard dose-response studies. It will be appreciated that the amount of composition actually administered will be determined by a physician, 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.

[0553] Toxicity and therapeutic efficacy of such JAK inhibitors can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (fatal dose 50% of the population) and the ED 50 (dose effective 50% of the population) in standard pharmaceutical procedures. The dose ratio between toxic and therapeutic effect is the therapy index and can be expressed as the ratio LD 50 / ED 50 A JAK inhibitor that exhibits large therapy indices is preferred. While JAK inhibitors that exhibit toxic side effects can be used, it is desirable to design delivery systems that target such inhibitors to the affected tissue site in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

[0554] 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 JAK inhibitors lies preferably within a range of dosages that include the ED 50and have no or little toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized. For any JAK inhibitor used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the JAK inhibitor 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 can be measured, for example, by high pressure liquid chromatography. 50 (ie, the concentration of the JAK inhibitor that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high pressure liquid chromatography.

[0555] Examples

[0556] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All documents cited in these examples and throughout the specification are incorporated herein by reference for all purposes. The starting materials and reagents used to synthesize the compounds described herein can be synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0557] The standard abbreviations and shorthand used in J. Org. Chem. 2007 72(1): 23A-24A are used herein. Other abbreviations and shorthand used herein are as follows:

[0558]

[0559] General synthetic schemes:

[0560]

[0561] General procedure

[0562] To a solution of 2 (1.0 eq) in DMF was added Cs2CO3(2.5 eq). The mixture was stirred at room temperature under N2for 5 minutes. Then 1 (1.5 eq) was added to the reaction mixture. The resulting mixture was heated at 50 °C to 90 °C to provide 3.

[0563] 3 (1.0 eq) and 4 (HC1 salt, 1.4 eq) were combined in anhydrous EtOH. The mixture was heated in a sealed tube at 120 °C for 20 hours to 48 hours to provide 5.

[0564] Example A: Synthesis of Intermediate 1

[0565]

[0566] Dissolve the alcohol in DCM and pyridine (5 eq). To this solution, add MsCI (1.5 eq) or TsCI (1.5 eq) at 0 °C. Stir the reaction mixture at room temperature for 2 hours to give 1.

[0567] Example B: Synthesis of intermediates 4-a, 4-b, 4-c, 4-d, 4-e

[0568]

[0569] Synthesis of 4-a

[0570] To a solution of 4-nitro pyrazole (1.13 g, 1.0 eq) in anhydrous DMF (15 mL) was added Cs2C03(8.13 g, 2.5 eq). The mixture was stirred at room temperature under N2for 30 min, then bromoacetate (2 g, 1.2 eq) was added to the reaction. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with 50 mL ethyl acetate and 10 mL hexanes. The inorganics were removed by filtration. The filtrate was washed with 3 x 30 mL water and brine. The crude was purified on ISCO silica gel to give 6 as a white solid (1.65 g, 83% yield).

[0571] To a solution of intermediate 6 (1.65 g) in ethyl acetate (40 mL) was added Pd / C (10% palladium on carbon, 165 mg). The mixture was hydrogenated at 30 psi for 2 hr. The catalyst was removed by filtration. To the acetate solution was added 2N HC1 in ether (10 mL) and stirred at room temperature for 5 min. The solvent was removed in vacuo to give 4-a as a HC1 salt.

[0572] 4-c, 4-d and 4-e were prepared in a similar manner as described for 4-a.

[0573] Synthesis of Intermediate 4-b

[0574] NaH (60% in mineral oil, 0.48 g, 1.0 eq) was suspended in anhydrous THF (15 mL) at 0 °C under N2. A solution of 3-amino pyrazole (1.0 g, 1.0 eq) in anhydrous THF (5 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 30 min. Bromoacetate (2.0 g, 1.0 eq) was added dropwise. The resulting mixture was stirred at 0 °C for 1 hr, then at room temperature overnight. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give an oil, which was directly purified on an ISCO silica gel column to give 7 (0.28 g). 7 was treated with 2N HC1 in ether to give 4-b as a HC1 salt.

[0575] Example 1: Synthesis of ethyl 2-(4-((7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)acetate (8)

[0576]

[0577] To a solution of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (2) (100 mg, 1.0 eq) in DMF (5 mL) was added Cs2CO3(530 mg, 2.5 eq). The mixture was stirred at room temperature under N2for 5 min. To the reaction mixture was added 3-(bromomethyl)pentane (162 mg, 1.5 eq). The resulting mixture was heated at 50 °C overnight. The reaction mixture was diluted with 30 mL ethyl acetate and 10 mL hexanes, washed with 3 x 20 mL water and 30 mL brine. The crude mixture was purified on an ISCO silica gel column to give 2-chloro-7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidine (3) (139 mg, 90% yield) as an oil.

[0578] To a solution of 2-chloro-7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidine (3) (100 mg, 1.0 eq) and 4-a (122 mg, 1.4 eq) in anhydrous EtOH (4 mL) was added. The resulting mixture was heated in a sealed tube at 120 °C for 28 h. The solvent was removed in vacuo, the residue was dissolved in 30 mL ethyl acetate and washed with saturated NaHCO3. The crude mixture was purified on an ISCO silica gel column to give ethyl 2-(4-((7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate (8) (75 mg, 48% yield). MS: 371.6 [M+H] + .

[0579] Example 2: Synthesis of 2-(4-((7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetic acid (9)

[0580]

[0581] To a solution of 8 (20 mg, 1.0 eq) in THF (2 mL) and MeOH (2 mL) was added a solution of LiOH.H2O (2.3 mg) in water (1.5 mL). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was treated with 1 N HC1 to pH 5 to give 2-(4-((7-(2-ethylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid (9) (14 mg, yield 78%). MS: 343.1 [M+H] + .

[0582] Compound 10-33 was prepared by an analogous procedure described in Example 1 or Example 2.

[0583]

[0584]

[0585]

[0586]

[0587] Example 3: Synthesis of Ethyl 2-(4-((7-(((1s,3s)-adamantan-1-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate (34)

[0588]

[0589] To a solution of 1-(hydroxymethyl)adamantane (150 mg, 1.0 eq) and DIEA (350 mg, 3.0 eq) in DCM (15 mL) was added MsCl (155 mg, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min, then at room temperature for 2 h. The reaction mixture was quenched with saturated NaHC03. The organic phase was washed with 1 N HC1 and brine, dried over Na2S04, and concentrated to give adamantane methanesulfonate (34) (216 mg, yield 98%) which was used without further purification.

[0590] Adamantane methanesulfonate (34) (200 mg, 1.5 eq), 2 (84 mg. 1.0 eq) and Cs2C03(670 mg, 2.5 eq) were combined in anhydrous DMF (12 mL). The mixture was heated at 90 °C under N2for 15 h. Workup and purification on silica gel gave adamantane 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (35) (163 mg, yield 66%).

[0591] Combine adamantane 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (35) (150 mg, 1.0 eq) and 4-a (155 mg, 1.5 eq) in anhydrous EtOH (8 mL). Heat the resulting mixture in a sealed tube at 120 °C for 20 h. Remove the solvent in vacuo. Dissolve the residue in 30 mL ethyl acetate and wash with saturated NaHC03. Purify the crude mixture on an ISCO silica gel column to give ethyl 2-(4-((7-(((1s,3s)-adamantane-1-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetate (36) (112 mg, 52% yield). MS: 435.6 [M+H] + .

[0592] Compounds 35-52 were prepared by an analogous procedure as described in Example 3 or Example 2.

[0593]

[0594]

[0595]

[0596] Example 4: Synthesis of 7-(cyclohexylmethyl)-N-(1-methyl-1H-pyrazol-4-yl)-7H- pyrrolo[2,3-d]pyrimidin-2-amine (54)

[0597]

[0598] Combine 2 (60 mg, 1.0 eq), (bromomethyl)cyclohexane (104 mg, 1.5 eq), and Cs2C03(318 mg, 2.5 eq) in anhydrous DMF (10 mL). Heat the mixture at 50 °C under N2for 15 h. Purify on silica gel to give 2-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (90 mg, 92% yield).

[0599] Combine 2-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (90 mg, 1.0 eq) and 4 (72 mg, 1.5 eq) in anhydrous EtOH (5 mL). Heat the resulting mixture in a sealed tube at 120 °C for 20 h. Remove the solvent in vacuo. Dissolve the residue in 30 mL ethyl acetate and wash with saturated NaHC03. Purify the crude mixture on an ISCO silica gel column to give 7-(cyclohexylmethyl)-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (54) (60 mg, 54% yield). MS: 311.5 [M+H]+ .

[0600] Compounds 55-58 were prepared by an analogous procedure as described in Example 4.

[0601]

[0602]

[0603] Example 5: Synthesis of ethyl 2-(4-((5-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate (60)

[0604]

[0605] To a solution of 2-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (100 mg, 1.0 eq) in anhydrous THF (8 mL) was added N-chlorosuccinimide (64 mg, 1.2 eq) at 0 °C. The resulting mixture was stirred at room temperature for 18 h. The crude mixture was purified on ISCO to give 2,5-dichloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (59) (82 mg, 73% yield).

[0606] A mixture of 2,5-dichloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (59) (40 mg, 1.0 eq) and 4-a (43 mg, 1.5 eq) in anhydrous EtOH (3 mL) was combined. The resulting mixture was heated in a microwave reactor at 140 °C for 2 h. The solvent was removed in vacuo. The residue was dissolved in 30 mL of ethyl acetate and washed with saturated NaHCO3. The crude mixture was purified on an ISCO silica gel column to give ethyl 2-(4-((5-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate (60) (22 mg, 38% yield). MS: 417.1 [M+H] + .

[0607] Example 6: Synthesis of ethyl 2-(4-((7-(2-(hydroxymethyl)butyl)-7H-pyrrolo[2,3-d]pyrimidin-2- yl)amino)-1H-pyrazol-1-yl)acetate (65)

[0608]

[0609] To a suspension of NaH (60%, 170 mg, 1.0 eq) in anhydrous THF (10 mL) was added 2-ethylpropane-1,3-diol (500 mg, 1.0 eq) in anhydrous THF (10 mL) dropwise. The mixture was stirred at room temperature for 1 h. To the reaction was added tert-butyldimethylsilyl chloride (640 mg, 1.0 eq). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column to give 2-(((tert-butyldimethylsilyl)oxy)methyl)butan-1-ol (61) (995 mg, 95% yield).

[0610] To a solution of 2-(((tert-butyldimethylsilyl)oxy)methyl)butan-1-ol (61) (500 mg, 1.0 eq) in DCM (15 mL) was added DIEA (3.0 eq) followed by TsCl (660 mg, 1.5 eq). The mixture was stirred at room temperature overnight. The mixture was washed with 1 N HC1 and brine. The crude product was purified on a silica gel column to give 2-(((tert-butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (546 mg, 64% yield).

[0611] 2-(((tert-butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (200 mg, 1.5 eq), 2 (55 mg, 1.0 eq), and Cs2C03(300 mg, 2.5 eq) were combined in anhydrous DMF (8 mL). The mixture was heated at 80 °C under N2for 15 h. Workup and purification on silica gel gave 7-(2-(((tert-butyldimethylsilyl)oxy)methyl)butyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (63) (99 mg, 78% yield).

[0612] To a solution of 7-(2-(((tert-butyldimethylsilyl)oxy)methyl)butyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (63) (99 mg) in THF (5 mL) was added a solution of TABF (1 N in THF, 2.8 mL, 10 eq). The mixture was stirred at room temperature for 3 h. The reaction was diluted with 30 mL of ethyl acetate, washed with saturated NH4C1 and brine, and concentrated. The residue was purified on a silica gel column to give 2-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)butan-1-ol (64) (60 mg, 90% yield).

[0613] Combine 2-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)butan-1-ol (64) (60 mg, 1.0 eq) and 4-a (73 mg, 1.4 eq) in anhydrous EtOH (3 mL). Heat the resulting mixture in a microwave reactor at 140 °C for 2 h. Remove the solvent in vacuo, dissolve the residue in 30 mL ethyl acetate and wash with saturated NaHC03. Purify the crude mixture on an ISCO silica gel column to give ethyl 2-(4-((7-(2-(hydroxymethyl)butyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetate (65) (57 mg, 61% yield). MS: 387.4 [M+H] + .

[0614] Example 7: Synthesis of ethyl 2-(4-((7-(2-(cyanomethyl)butyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetate (70)

[0615]

[0616] Combine 2-(((tert-butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (500 mg, 1.0 eq), KCN (175 mg, 2.0 eq) and (Bu)4N + CN - (20 mg) in anhydrous CH3CN (30 mL). Heat the resulting mixture in a sealed tube at 90 °C for 24 h. Remove CH3CN in vacuo and purify the residue directly on a silica gel column to give 3-(((tert-butyldimethylsilyl)oxy)methyl)pentanenitrile (66) (210 mg, 69% yield).

[0617] Treat 3-(((tert-butyldimethylsilyl)oxy)methyl)pentanenitrile (66) (210 mg) in THF (10 mL) with 1 N TABF (10 eq) at room temperature for 3 h. Purify the crude mixture on a silica gel column to give 3-(hydroxymethyl)pentanenitrile (67) (74 mg, 70% yield).

[0618] To a solution of 3-(hydroxymethyl)pentanenitrile (67) (70 mg, 1.0 eq) in DCM (5 mL) add DIEA (2.5 eq). Cool the mixture in an ice water bath. Add MSCl (1.5 eq) dropwise. Stir the resulting mixture at 0 °C for 1 h. Quench the reaction with 1 N HC1. Purify the crude mixture on a silica gel column to give 2-(cyanomethyl)butyl methanesulfonate (68) (109 mg, 92% yield).

[0619] Combine 2-(cyanomethyl)butyl methanesulfonate (68) (108 mg, 1.2 eq), 2 (98 mg. 1.0 eq) and Cs2CO3(390 mg, 2.5 eq) in anhydrous DMF (8 mL). Heat the mixture at 80 °C under N2for 15 h. Purify on silica gel to give 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- yl)methyl)pentanenitrile (69) (87 mg, 74% yield).

[0620] Combine 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pentanenitrile (69) (70 mg, 1.0 eq) and 4-a (87 mg, 1.5 eq) in anhydrous EtOH (5 mL). Heat the resulting mixture in a microwave reactor at 140 °C for 2 h. Remove the solvent under vacuum. Dissolve the residue in ethyl acetate (30 mL) and wash with saturated NaHCO3. Purify the crude mixture on an ISCO silica gel column to give ethyl 2-(4-((7-(2-(cyanomethyl)butyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H- pyrazol-1-yl)acetate (70) (71 mg, 66% yield).

[0621] Example 8: Synthesis of 3-(4-((7-((S)-2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one (82), (R)-3-(4- ((7-((S)-2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1- yl)dihydrofuran-2(3H)-one (82a) and (S)-3-(4-((7-((S)-2-ethyl-3-methylbutyl)-7H- pyrrolo[2,3-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one (82b)

[0622]

[0623] To a stirred solution of 4-nitro-lH-pyrazole 71 (65 g, 0.57 mol) in DMF (650 mL) under inert atmosphere was added potassium carbonate (1.58 g, 1.15 mol) and 3-bromodihydrofuran-2(3H)-one 72 (93.76 g, 0.57 mol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (2 L) and n-hexane (650 mL). The reaction mixture was filtered and washed with EtOAc (800 mL). The organic extract was washed with water (3 x 1 L) and brine (1 L). The organic solution was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was washed with 3% EtOAc / hexane (500 mL) to obtain a solid. The solid was dried under vacuum to get 3-(4-nitro-lH-pyrazol-l-yl)dihydrofuran-2(3H)-one 73 (80 g, 70%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.38 (s, 1H), 5.66 (t, J = 9.7 Hz, 1H), 4.59 - 4.54 (m, 1H), 4.46 - 4.38 (m, 1H), 3.05 - 2.59 (m, 2H).

[0624] To a stirred solution of 3-(4-nitro-lH-pyrazol-l-yl)dihydrofuran-2(3H)-one 73 (110 g, 558.37 mol) in EtOAc (1.1 L) under inert atmosphere was added 10% Pd / C (22 g, 50% wet) at room temperature. The reaction mixture was stirred under hydrogen atmosphere (55 psi) at room temperature for 12 h. The reaction mixture was filtered through a pad of Celite, washed with CH2Cl2(2 x 100 mL), and concentrated under reduced pressure. To the above amine in CH2Cl2(1.23 L) was added HC1 (492 mL, 2.0 N in Et20) at 0 °C. The reaction mixture was stirred for 10 min, then hexane (1.64 L) was added. The mixture was stirred for 20 min. The precipitated solid was filtered and dried under high vacuum to get 3-(4-amino-lH-pyrazol-l-yl)dihydrofuran-2(3H)-one hydrochloride 74 (82 g) as a light brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.14 (s, 1H), 7.01 (s, 1H), 5.27 (t, J = 9.5 Hz, 1H), 4.50 - 4.45 (m, 1H), 4.37 - 4.12 (m, 1H), 3.91 (br s, 2H), 2.68 - 2.58 (m, 2H).

[0625] To a stirred solution of (S)-4-benzyl oxazolidin-2-one 75 (300 g, 1.69 mol) in CH2Cl2(2.1 L) under inert atmosphere was added 4-dimethylaminopyridine (20.6 g, 0.16 mol), triethylamine (256.7 g, 2.54 mol) followed by a solution of 3-methylbutanoyl chloride (224.4 g, 1.86 mol) in CH2Cl2(900 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (2 L) and extracted with CH2Cl2(2 x 1 L). The combined organic extracts were washed with saturated sodium bicarbonate solution (1.0 L), water (1.0 L), 2.0 N aqueous HC1 (1 L) and brine (1 L). The organic solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in n-hexane (1.5 L), cooled to 0 °C and stirred for 1 h to get a solid. The solid was filtered and dried under vacuum to get (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 76 as off-white solid (402 g, 1.54 mol, 91%). 1 H NMR (500 MHz, DMSO-d6) d 7.37 - 7.16 (m, 5H), 4.74 - 4.57 (m, 1H), 4.32 (t, J = 8.7 Hz, 1H), 4.17 (dd, J = 8.7, 2.9 Hz, 1H), 3.06 - 2.98 (m, 1H), 2.96 - 2.89 (m, 1H), 2.82 - 2.73 (m, 1H), 2.69 - 2.58 (m, 1H), 2.13 - 2.07 (m, 1H), 0.98 - 0.92 (m, 6H).

[0626] To a stirred solution of LiHMDS (1.724 mL, 1.14 mol) in THF (2.1 L) under an inert atmosphere was added (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 76 (300 g, 1.14 mol) in THF (900 mL) portionwise over a period of 20 min at -78 °C. The mixture was stirred for 1.5 h. lodoe thane (712.6 g, 4.59 mol) was added at -78 °C. The reaction mixture was stirred at -78 °C for 2 h and then at ~ -5 °C for 4 h. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with saturated ammonium chloride solution (3 L) and extracted with EtOAc (2 x 1 L). The combined organic extracts were washed with 1.0 M aqueous HC1 (500 mL) and saturated sodium bicarbonate solution (500 mL). The organic solution was dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 2% EtOAc / hexanes) to give (S)-4-benzyl-3-((S)-2-ethyl-3-methylbutanoyl)oxazolidin-2-one 77 (120 g, 36%) as a colorless oil. 1 H NMR (500 MHz, DMSO-d6) δ 7.34 - 7.18 (m, 5H), 4.72 - 4.68 (m, 1H), 4.30 (t, J = 8.4 Hz, 1H), 4.15 (dd, J = 8.7, 2.7 Hz, 1H), 3.54 - 3.50 (m, 1H), 3.05 (dd, J = 13.4, 3.4 Hz, 1H), 2.91 - 2.86 (m, 1H), 1.98 - 1.72 (m, 1H), 1.69 - 1.51 (m, 2H), 0.89 - 0.79 (m, 9H).

[0627] To a stirred solution of (S)-4-benzyl-3-((S)-2-ethyl-3-methylbutanoyl)oxazolidin-2-one 77 (98 g, 0.33 mol) in THF (1.5 L) and water (400 mL) under an inert atmosphere was added 30% aqueous H2O2 (225 mL) and lithium hydroxide monohydrate (28 g, 0.67 mol) in 200 mL water at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with 2.0 M aqueous Na2S03solution (800 mL) at 0 °C and the volatiles were evaporated under reduced pressure. The residue was basified with 2.0 M aqueous NaOH to pH ~ 12-13 and extracted with EtOAc (2 x 500 mL). The combined organic extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give (S)-2-ethyl-3-methylbutanoic acid 78 (44 g, crude) as a light yellow solid. 1HNMR (400 MHz, CDC13) δ 11.23-10.31 (m, 1H), 2.12-2.00 (m, 1H), 1.93-1.78 (m, 1H), 1.68-1.55 (m, 2H), 0.99-0.90 (m, 9H).

[0628] To a stirred solution of (S)-2-ethyl-3-methylbutanoic acid 78 (44 g, 0.33 mol) in THF (1.5 L) under an inert atmosphere at 0 °C was added lithium aluminum hydride (1.01 L, 1.01 mol, 1.0 M in THF). The reaction mixture was stirred for 16 h. The reaction mixture was diluted with 2.0 N aqueous HC1 solution to pH ~ 1 and extracted with CH2Cl2(2 x 1 L). The combined organic extracts were dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford (S)-2-ethyl-3-methylbutan-1-ol 79 (38 g, crude) as a colorless syrup, which was used in the next step without further purification. 1 H NMR (500 MHz, CDC13) δ 3.66-3.54 (m, 2H), 1.88-1.76 (m, 1H), 1.47-1.37 (m, 1H), 1.32-1.20 (m, 3H), 0.94-0.88 (m, 9H).

[0629] To a stirred solution of (S)-2-ethyl-3-methylbutan-1-ol 79 (38 g, 0.32 mol) in CH2Cl2(400 mL) under an inert atmosphere at 0 °C was added diisopropylethylamine (126.77 g, 0.98 mol) and methanesulfonyl chloride (56 g, 0.50 mol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 1.0 N HC1 solution (2 x 300 mL) and extracted with CH2Cl2(2 x 1 L). The combined organic extracts were washed with saturated sodium bicarbonate solution (1 L), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to afford (S)-2-ethyl-3-methylbutyl methanesulfonate 80 (63 g, crude) as a light yellow syrup.

[0630] To a stirred solution of (S)-2-ethyl-3-methylbutyl methanesulfonate 80 (63 g, 0.32 mol) in DMF (1.3 L) was added cesium carbonate (263 g, 0.81 mol) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (49.68 g 0.32 mol) at room temperature under inert atmosphere. The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 x 500 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 10% EtOAc / hexane) to afford (S)-2-chloro-7-(2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine 81 (52 g, 64%) as colorless oil. 1 H NMR (400 MHz, CDC13) δ 8.77 (s, 1H), 7.19 (d, J = 3.7 Hz, 1H), 6.56 (d, J = 3.5 Hz, 1H), 4.24 - 4.07 (m, 2H), 1.82 - 1.71 (m, 1H), 1.44 - 1.28 (m, 1H), 1.44 - 1.27 (m, 1H), 1.23 - 1.13 (m, 1H), 0.96 - 0.92 (m, 6H), 0.87 (t, J = 7.5 Hz, 3H).

[0631] To a stirred solution of (S)-2-chloro-7-(2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3- d]pyrimidine 81 (10 g, 39.84 mmol) in acetonitrile (100 mL) was added 3-(4-amino- 1H-pyrazol-1-yl)dihydrofuran-2(3H)-one hydrochloride 74 (12.13 g, 59.76 mmol) and sodium iodide (593 mg, 3.98 mmol) at room temperature under inert atmosphere. The reaction mixture was heated to 130 °C and stirred in a sealed tube for 18 h. The reaction mixture was cooled to room temperature and evaporated to remove volatiles under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 60% EtOH / hexane) to afford 3-(4-((7-((S)-2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- 1H-pyrazol-1-yl)dihydrofuran-2(3H)-one 82 (6.0 g, 40%) as off-white solid. 1HNMR(400MHz,DMSO-d6)δ9.24(s,1H),8.61(s,1H),8.10(s,1H),7.71(s,1H),7.18(d,J=3 .5Hz,1H),6.40(d,J=3.5Hz,1H),5.45(t,J=9.5Hz,1H),4.55-4.50(m,1H),4.43-4.30(m,1 H),4.16-3.99(m,2H),2.78-2.67(m,2H),1.83-1.79(m,1H),1.65-1.60(m,1H),1.35-1.22 (m,1H),1.21-1.06(m,1H),0.90(t,J=7.2Hz,6H),0.82(t,J=7.4Hz,3H); LCMS:383.3(M+H) + .

[0632] 40g of 82 was purified by chiral HPLC to yield 15g of 82a and 15g of 82b.

[0633] 82a: 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.61(s,1H),8.10(s,1H),7.71(s,1H),7.18(d,J=3. 5Hz,1H),6.40(d,J=3.5Hz,1H),5.45(t,J=9.5Hz,1H),4.55-4.50(m,1H),4.43-4.30(m,1H ),4.16-3.99(m,2H),2.78-2.67(m,2H),1.83-1.79(m,1H),1.65-1.60(m,1H),1.35-1.22 (m,1H),1.21-1.06(m,1H),0.90(t,J=7.2Hz,6H),0.82(t,J=7.4Hz,3H); LCMS:383.3(M+H) + Chiral HPLC (purity): 100% (column; Chiralpak IC-3 (150X4.6mm, 3.5μm); RT 16.49min; mobile phase: n-heptane; EtOAc; MTBE (60:35:5); flow rate: 0.7mL / min).

[0634] 82b: 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 7.18 (d, J = 3.5 Hz, 1H), 6.40 (d, J = 3.5 Hz, 1H), 5.45 (t, J = 9.5 Hz, 1H), 4.55-4.50 (m, 1H), 4.43-4.30 (m, 1H), 4.16-3.99 (m, 2H), 2.78-2.67 (m, 2H), 1.83-1.79 (m, 1H), 1.65-1.60 (m, 1H), 1.35-1.22 (m, 1H), 1.21-1.06 (m, 1H), 0.90 (t, J = 7.2 Hz, 6H), 0.82 (t, J = 7.4 Hz, 3H); LCMS: 383.3 (M+H) + Chiral HPLC (purity): 100%: (Column; Chiralpak IC-3 (150 X 4.6 mm, 3.5 pm); RT 19.03 min; mobile phase: n-Heptane; EtOAc; MTBE (60:35:5); flow rate: 0.7 mL / min).

[0635] Compounds 83-147 were prepared by procedures analogous to those described in the preceding examples.

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648] Example 9: JAK / TYK2 assay

[0649] A 10 mM stock solution of test compound in DMSO or 1 mM stock solution of control compound (tofacitinib, ruxolitinib or staurosporine) in DMSO was diluted to 0.4 mM in DMSO. A 3-fold serial dilution was then performed in DMSO to generate 10 different compound concentrations. The assay was performed in 384 well white plates. 0.5 uL of the 40x compound DMSO solution at different concentrations was mixed with 10 uL of 2x enzyme prepared in reaction buffer (20 mM HEPES, 10 mM MgCl2, 0.01% Tween, 1 mM DTT, pH 7.5). 10 uL of 2x substrate mix prepared in reaction buffer was then added to initiate the reaction. A brief spin was performed to settle all solutions to the bottom of the plate. The final concentration of test compound in the reaction mixture was 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52 and 0.51 nM. The concentration of control compounds was ten-fold lower. The enzymatic reaction was performed at 25 °C for 1-2 hours. 10 uL of Kinase Glo Reagents was added to stop the reaction and generate a luminescent signal which was measured using Envision. The luminescent signal is inversely correlated with the kinase activity. Reaction mixtures without enzyme served as negative controls. Mixtures without any compound were positive controls. The final concentrations of enzyme and substrate as well as the incubation time are summarized in the table below.

[0650]

[0651]

[0652] EC 50 Values are shown in the table below.

[0653]

[0654]

[0655] A: IC 50 <100 nM; B: IC 50 > 100 nM and < 1 uM; C: IC 50 > 1 uM and < 10

[0656] uM; D: IC 50 > 10 uM; NT = not tested

[0657] Example 10: JAK1 / JAK3: IL-2 stimulated STAT5 phosphorylation in PBMCs

[0658] Assay

[0659] Human PBMCs: (Precision Biomedicine)

[0660] Thaw according to instructions. Thaw frozen PBMCs in a 37°C water bath. Transfer cell suspension into 9 mL of pre-warmed complete medium (RPMI + 10% FBS + L-Glu + Pen / Strep). Centrifuge at 400 x g for 5 minutes and wash cells with 10 mL of complete medium. Resuspend pellet to obtain a cell count of 3 x 10 6

[0661] Compound and Cytokine Treatment

[0662] Seeding of cells: According to the plate layout, seed cells at 80 uL / well into 96 deep well. Add 10 pL (10X concentration) of different concentrations of compounds to all wells except control (unstimulated) and mix with 200 uL multichannel pipette. In control add 10 uL of complete RPMI medium with same % DMSO. See appendix for dilution and dilution range of compounds. Incubate for 1 hour at 37°C in a 5% CO2 incubator. Add 10 pL (10X concentration) of IL-2 (final concentration 50 ng / mL) to each well except unstimulated and unstained control and further incubate for 20 minutes at 37°C water bath.

[0663] Fixation

[0664] Add 900 pL of pre-warmed 1X Fixation / lysis solution (Appendix) and mix appropriately using 1000 pL multichannel pipette; further incubate for 10 minutes on a 37°C water bath. Centrifuge at 800 x g for 5 minutes, remove 900 uL supernatant and add 1000 pL of freshly prepared wash buffer or 1x PBS. Centrifuge at 800 x g for 5 minutes, remove 900 uL supernatant and resuspend pellet in remaining buffer.

[0665] Permeabilization

[0666] Break up the pellet by gently tapping, add 1000 pL of ice-cold BD Phosflow Perm Buffer III and further incubate on ice for 30 minutes. Centrifuge at 800 x g for 5 minutes. Wash twice with 1000 pL of BD Staining Buffer, remove 100 uL of supernatant after the last wash.

[0667] Antibody Treatment

[0668] ​Break up the pellet by gently tapping. Add 100 uL stain buffer and 5 uL pSTAT5_Alex488 (pY701) to all appropriate wells and mix appropriately using a 200 uL multi-channel pipette. Incubate the plate overnight at 40 °C. Add 900 uL BD stain buffer and centrifuge at 800 x g for 5 minutes. Wash once more with 1000 uL buffer. Finally resuspend the pellet in 300 uL BD stain buffer. Transfer the cells to a 96-well V-bottom plate and acquire the cells in a Beckman Coulter Cytoflex. Acquire the cells in the flow cytometer: keep threshold at 250. Obtain at least 8,000-10,000 cells.

[0669] Preparation of Reagents

[0670] RPMI 1640 complete media: RPMI 1640 media + 10% FBS.

[0671] Cytokine dilutions: 1) IL-2 stock at 100 ug / mL. Prepare 0.5 ug / mL dilution by adding 5 uL stock to 995 uL cRPMI. Keep on ice until use.

[0672] Lysis / fixation buffer preparation: Dilute 5X lysis / fixation buffer to 1X using MQ water and keep at 37 °C until use.

[0673] BD Phosflow perm buffer III: Keep on ice / refrigerator.

[0674] Compound Dilution

[0675]

[0676] Example 11: Co-stimulation experiments in lysed whole blood; JAK2: GM-CSF stimulated STAT5 phosphorylation and JAK1 / TYK2 stimulated STAT1 phosphorylation experiments

[0677] Human Blood Lysis Using Abeam's RBC Lysis Buffer

[0678] Dilute RBC lysis buffer to 1X in distilled water. Add 2 mL blood to 38 mL 1X RBC-lysis buffer. Incubate at room temperature in the dark for 15 minutes. Spin at 300 g for 5 minutes to collect pellet. Re-lyse if necessary. Resuspend pellet in 5 mL cRPMI.

[0679] Compound and Cytokine Treatment

[0680] Add 80 μΐ of lysed human blood to the wells of a 96 deep well plate. Add 10 μΐ (10X concentration) of different concentrations of compounds to all wells except controls (unstained and unstimulated) and mix with the help of a 100 uL multichannel. Add 10 uL of RPMI medium in the controls. See Appendix for dilution and dilution range of compounds. Incubate for 1 hour at 37°C in a water bath or CO2 incubator. Add 10 μΐ (10X concentration) of cytokine mix (GM-CSF and IFNa) (final concentration of 10 ng / mL GM-CSF and 100 ng / mL IFNa) to each well except unstimulated and unstained controls and further incubate for 20 minutes at 37°C in a water bath.

[0681] RBC Lysis and Fixation

[0682] Add 900 μΐ of pre-warmed 1X Fixation / lysis solution (Appendix) and mix appropriately using a 1000 μΐ multichannel, further incubate for 10 minutes at 37°C in a water bath (including addition time). Centrifuge at 800 x g for 5 minutes at 40°C; remove 900 uL of supernatant and add 900 μΐ of 1X PBS. Centrifuge at 800 x g for 5 minutes at 40°C, remove 900 μΐ of supernatant. Wash once more with 900 μΐ of PBS (optional) and then resuspend the pellet in 100 uL of PBS.

[0683] Permeabilization

[0684] Resuspend by gently tapping the pellet in 1000 μΐ of BD Phosflow Perm Buffer III and incubate the plate on ice for 30 minutes. Centrifuge the plate at 800 x g for 5 minutes at 40°C. Wash twice more with 1000 μΐ of BD Pharmingen Staining Buffer.

[0685] Antibody Treatment

[0686] Break up the pellet by gently tapping. Resuspend the pellet in 100 uL staining buffer and add 5 uL pSTAT5_AF488 Ab and 5uL pSTAT1_PE in all wells except the unstained control and mix well using 200 ul multi-channel and incubate overnight at 40C. Add 900 uL wash buffer and centrifuge at 1800 rpm for 3 minutes at 40C. Wash once more with 1000 uL BD Pharmingen staining buffer. Finally resuspend the pellet in 300 uL BD Pharmingen staining buffer. Transfer the cells to a 96 well V-bottom plate and acquire the cells in a Beckman Coulter CytExpert. Acquire the cells in a flow cytometer: keep the threshold at 250 and the cell concentration should not exceed 100-500 cells / uL. Obtain at least 5,000-10,000 cells.

[0687] Preparation of Reagents

[0688] RPMI 1640 complete media: RPMI 1640 media + 10% FBS.

[0689] Cytokine dilutions: 1) 100 ug / mL GM-CSF stock. Prepare a 1 ug / mL intermediate dilution by adding 2 uL stock to 198 uL cRPMI. Further dilute to 100 ng / mL by adding 100 uL intermediate stock to 900 uL cRPMI. 2) 200 ug / mL IFNa stock. Dilute the IFNa stock 1:200 by adding 5 uL stock to 1000 uL of the above 100 ng / mL GM-CSF working stock to make a combined working stock (10x) of 1000 ng / mL IFNa and 100 ng / mL GM-CSF. Keep on ice until use.

[0690] Lysis / fixation buffer preparation: Dilute 5X lysis / fixation buffer to 1X using MQ water and keep at 37C until use.

[0691] BD Phosflow perm buffer III: Keep on ice / icebox.

[0692] Compound Dilution

[0693]

[0694] The examples and embodiments described herein are for illustrative purposes only and, in some embodiments, the scope and range of the present disclosure and the appended claims will include modifications or alterations to the embodiments described herein.

Claims

1. Compound of formula (I'): in: for X is C(R) 11 ); L1 is a C1-C6 alkyl group; L2 is a C1-C6 alkyl group; R1 is an unsubstituted C3-C9 alkyl group; R² is -C(=O)OR6; R4 is hydrogen; R6 is an unsubstituted C1-C6 alkyl group; R 11 It is hydrogen; R 12 It is hydrogen; and n is 0; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:

9. A pharmaceutical composition comprising a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. Use of any compound of claims 1-8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating inflammatory or autoimmune diseases in patients in need.

11. The use according to claim 10, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, enteropathy, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

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