JAK inhibitors

Abstract

Described herein are Janus kinase (JAK) inhibitors and methods of utilizing the JAK inhibitors in the treatment of diseases, disorders, or conditions. Also described herein are pharmaceutical compositions containing such compounds.

Description

[Technical field]

[0001] cross reference 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 herein by reference. [Background technology]

[0002] Janus kinases (JAKs) are a family of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals through the JAK-STAT pathway. Four JAK family members, Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2), are recognized as key components of cytokine-mediated actions. The important function of JAKs in cytokine signaling has implicated JAK inhibitors as potential therapeutics for a variety of diseases, including autoimmune and inflammatory diseases. Summary of the Invention

[0003] In one aspect, provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt or solvate thereof:

[0004] [ka] During the ceremony,

[0005] [ka] is a phenyl or a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is C1-C6 alkyl or C1-C6 heteroalkyl; L2 is a single bond, C1-C6 alkyl, or C1-C6 heteroalkyl; R1 is a C3-C9 alkyl, a C3-C6 alkenyl, a C3-C6 alkynyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C3-C9 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6,

[0006] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0007] In another aspect, there is provided herein a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof:

[0008] [ka] During the ceremony,

[0009] [ka] is a phenyl or a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is C1-C6 alkyl or C1-C6 heteroalkyl; L2 is a single bond, C1-C6 alkyl, or C1-C6 heteroalkyl; R1 is a C3-C9 alkyl, a C3-C6 alkenyl, a C3-C6 alkynyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C3-C9 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6, or

[0010] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0011] In some embodiments,

[0012] [ka] is phenyl.

[0013] [ka] is a C2-C9 heteroaryl ring, or a pharma- ceutically acceptable salt or solvate thereof.

[0014] [ka] is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0015] [ka] is selected from pyrazolyl, pyrrolyl, and imidazolyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0016] [ka] but

[0017] [ka] In some embodiments, the compound of formula (I') or (I) is selected from:

[0018] [ka] but

[0019] [ka] In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, wherein L2 is C1-C6 alkyl. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, wherein L2 is a single bond. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, wherein L1 is C1-C6 alkyl. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C9 alkyl, C3-C6 cycloalkyl, or C2-C9 heteroaryl, where C3-C9 alkyl, C3-C6 cycloalkyl, or C2-C9 heteroaryl is optionally substituted with 1, 2, or 3 R5, and C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C3-C9 alkyl. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, there are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C2-C9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0020] In some embodiments, there is a compound of formula (II'), or a pharma- ceutically acceptable salt or solvate thereof:

[0021] [ka] During the ceremony,

[0022] [ka] is a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is -C(=O)OR6,

[0023] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0024] In some embodiments, there is a compound of formula (II) or a pharma- ceutically acceptable salt or solvate thereof:

[0025] [ka] During the ceremony,

[0026] [ka] is a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is -C(=O)OR6, or

[0027] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0028] In some embodiments,

[0029] [ka] is oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0030] [ka] In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrazolyl. In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -C(H)(phenyl)-. In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C2-C9 heteroaryl. In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond. In some embodiments, there are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl.

[0031] In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is hydrogen. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 alkyl ... 12 In some embodiments, R is a compound of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof.12 In some embodiments, R is a halogen atom. 12 In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is C1-C6 alkyl. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is 0. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where each R7 is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R3 is C1-C6 alkyl. In some embodiments, X is C(R 11 In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H). In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H). In some embodiments, there are compounds of formula (I'), (I), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is N.

[0032] In another aspect, provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt or solvate thereof:

[0033] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl; R1 is a C1-C9 alkyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C1-C9 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6,

[0034] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; p is 0, 1, or 2; and q is 0, 1, or 2.

[0035] In another aspect, provided herein is a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof:

[0036] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl; R1 is a C1-C9 alkyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C1-C9 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6, or

[0037] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 13 is C1-C6 alkyl, p is 0, 1, or 2; and q is 0, 1, or 2.

[0038] In some embodiments, there are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, in which L1 is C1-C6 alkyl. In some embodiments, there are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C1-C9 alkyl, C3-C6 cycloalkyl, or C2-C9 heteroaryl, where C1-C9 alkyl, C3-C6 cycloalkyl, or C2-C9 heteroaryl is optionally substituted with 1, 2, or 3 R5, and C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. In some embodiments, there are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, there are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C1-C9 alkyl. In some embodiments, there are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, there is a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R1 is an unsubstituted C2-C9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0039] In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, in which R2 is -C(=O)OR6. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, in which R2 is unsubstituted C1-C6 alkyl. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, in which R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R6 is -C1-C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R6 is hydrogen. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is

[0040] [ka] In some embodiments, R2 is a compound of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof.

[0041] [ka] In some embodiments, R is a compound of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof. 14 In some embodiments, R is -OH, or a pharma- ceutically acceptable salt or solvate thereof.14 In some embodiments, R is -C(=O)H, or a pharma- ceutically acceptable salt or solvate thereof. 14 -C(=O)OR 15 In some embodiments, R is a compound of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof. 15 is hydrogen. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where q is 0. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where p is 1. In some embodiments, there are compounds of formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is

[0042] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0043] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

[0044] In another aspect, described herein is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (II'), or (II), or a pharma- ceutically acceptable salt or solvate thereof, the disease being selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

[0045] Citation by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0046] definition In the context of this disclosure, a number of terms shall be utilized.

[0047] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood to belong to the subject matter specified in the invention. In the event of multiple definitions of terms herein, the definitions in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in databases such as GenBank) cited herein are incorporated by reference. When reference is made to a URL or other identifier or address, it is understood that such identifiers may change and that particular information on the Internet may come and go, but that equivalent information may be found by an Internet search. Reference thereto acknowledges the availability and public dissemination of such information.

[0048] It is to be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to be limiting of the invention as defined by the claims. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless otherwise clearly stated from the context. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including" is open-ended, as are other forms such as "include," "includes," "included," and the like.

[0049] The section headings used herein are for organizational purposes only and should not be construed as limiting the particular subject matter described.

[0050] Definitions of standard chemical terms can be found in references including, but not limited to, Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise specified, conventional methods are mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology.

[0051] Unless specific definitions are given, the nomenclature adopted in connection with analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry described herein, and the procedures and techniques for testing them, are art-recognized. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be performed as commonly accomplished in the art, for example, using kits per manufacturer's specifications, or as described herein. The techniques and procedures described above can generally be performed by conventional methods and as described in various general and more specific references cited and discussed throughout this specification.

[0052] It is understood that the methods and compositions described herein are not limited to the particular methods, protocols, cell lines, constructs, and reagents described herein, and as such may vary. It is also 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, and compositions described herein.

[0053] As used herein, C1-C x is C1-C2, C1-C3...C1-C x Includes: C1-C xrefers to the number of carbon atoms that make up the moiety it designates (excluding any substituents).

[0054] An "alkyl" group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms and containing no unsaturation. In some embodiments, an "alkyl" group may have 1-6 carbon atoms (wherever this term appears herein, numerical ranges such as "1-6" refer to each integer within the given range, e.g., "1-6 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 6 carbon atoms, but this definition also encompasses occurrences of the term "alkyl" when no numerical range is specified). The alkyl group of the compounds described herein may be designated as "C1-C6 alkyl" or a similar designation. By way of example only, "C1-C6 alkyl" indicates that there are 1-6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, alkyl groups can be monoradicals or diradicals (alkylene groups).

[0055] "Alkoxy" refers to the group "-O-alkyl", where alkyl is as defined herein.

[0056] The term "alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and 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, -C(CH3)=CHCH3. In some embodiments, an alkenyl group may have 2-6 carbons. Alkenyl groups may be substituted or unsubstituted. Depending on the structure, an alkenyl group may be a monoradical or a diradical (an alkenylene group).

[0057] The term "alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms and containing at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -C≡CCH2CH2CH3. In some embodiments, alkynyl groups can have 2-6 carbons. Alkynyl groups can be substituted or unsubstituted. Alkynyl groups can be monoradicals or diradicals (alkynylene groups) depending on the structure.

[0058] "Amino" refers to the group -NH2.

[0059] The term "alkylamine" or "alkylamino" refers to -N(alkyl) x H y "Dialkylamino" refers to the -N(alkyl)2 group, where alkyl is as defined herein, and x and y are selected from the group: x=1, y=1, and x=2, y=0. When x=2, the alkyl groups together with the nitrogen to which they are attached can optionally form a cyclic ring system. "Dialkylamino" refers to the -N(alkyl)2 group, where alkyl is as defined herein.

[0060] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. Aromatic rings can be formed from 5, 6, 7, 8, 9, or more atoms. Aromatics can be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0061] As used herein, the term "aryl" refers to an aromatic ring in which the atoms forming the ring are each carbon atoms. The aryl ring can be formed by 5, 6, 7, 8, 9, or more carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (arylene group).

[0062] "Carboxy" refers to -CO2H. In some embodiments, the carboxy moiety may be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties as a carboxylic acid group. A compound with a carboxylic acid moiety may have a carboxylic acid moiety replaced with a carboxylic acid bioisostere and has similar physical and / or biological properties compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere ionizes to approximately the same extent as a carboxylic acid group at physiological pH. Examples of carboxylic acid bioisosteres include, but are not limited to, the following:

[0063] [ka]

[0064] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, where each of the atoms forming the ring (skeletal atoms) are carbon atoms. Cycloalkyls may be saturated or partially unsaturated. Cycloalkyls may be fused to an aromatic ring (in which case the cycloalkyl is attached via a non-aromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms.

[0065] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0066] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The radical may be fused to an aryl or heteroaryl. The term "heteroalicyclic" further includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, a heterocycloalkyl has 2-10 carbons in the ring. It is understood that the number of carbon atoms in a heterocycloalkyl, when referring to the number of carbon atoms in a heterocycloalkyl, is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (skeletal atoms of the heterocycloalkyl ring).

[0067] The term "halo" or alternatively "halogen" means fluoro, chloro, bromo, and iodo.

[0068] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, which can be the same or different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0069] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl 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.

[0070] The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatoms may be located at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-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, -CHO-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl" may have from 1 to 6 carbon atoms.

[0071] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms joined by the single bond are considered to be part of a larger substructure.

[0072] The term "moiety" refers to a specific area or functional group of a molecule. A chemical moiety is often recognized as a chemical entity that is embedded in or appended to a molecule.

[0073] As used herein, the substituent "R" occurring alone and without a number designation refers to a substituent selected from among alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded via a ring carbon), and heterocycloalkyl.

[0074] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs and examples when it does not occur.

[0075] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C1-C6 alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-substituted amino groups (e.g., -NH2, -NHR, -N(R)2), and protected derivatives thereof. As an example, an optional substituent is L s R s Each L may be s is independently selected from a single bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O)2-, -NH-, -NHC(O)-, -C(O)NH-, S(=O)2NH-, -NHS(=O)2, -OC(O)NH-, -NHC(O)O-, -(C1-C6 alkyl)-, or -(C3-C6 alkynyl)-; sis independently selected from H, (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6 heteroalkyl. Protecting groups that may form the protective derivatives of the above substituents can be found in sources such as Greene and Wuts, above.

[0076] 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.

[0077] As used herein, the term "therapeutically effective amount" refers to an amount of a JAK inhibitor that is effective to at least partially ameliorate or at least partially prevent a disease associated with skin aging when administered to a mammal in need thereof.

[0078] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide, or protein.

[0079] The term "modulate" includes either a decrease or an increase in activity or expression in response to a target molecule.

[0080] The term "activator" is used herein to denote a molecular species that results in activation of the indicated receptor, whether the species itself binds to the receptor or a metabolite of this species binds to the receptor upon local administration of the species. The activator may thus be a ligand of the receptor or an activator that is metabolized to a ligand of the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

[0081] The term "patient" or "mammal" refers to a human, non-human primate, dog, cat, cow, sheep, pig, mouse, or other veterinary or laboratory mammal. One of skill in the art recognizes that a therapeutic agent that reduces the severity of a disease state in one species of mammal is predictive of the effectiveness of that therapeutic agent in another mammalian species.

[0082] The term "soft-drug," as used herein, refers to drugs and / or chemical compounds that are biologically active in a desired target tissue and that are metabolized to compounds that are inactive against the biological target after exerting their effect on the target tissue. In some embodiments, the soft-drug has no target biological activity in the systemic circulation.

[0083] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to include all pharmaceutically appropriate salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0084] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanediol (alkanediol) acids, aromatic acids, aliphatic sulfonic acids, aromatic sulfonic acids, and the like, as well as salts with, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base with a sufficient amount of the desired acid to produce the salt.

[0085] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharma-ceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, 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, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0086] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including but not limited to therapeutic benefit and / or preventive benefit. "Therapeutic benefit" refers to eradication or reduction of the underlying disease being treated. Moreover, therapeutic benefit is achieved by eradication or reduction of one or more of the physiological symptoms associated with the underlying disease, such that the patient observes improvement even though the patient still suffers from the underlying disease. For preventive benefit, the composition is administered to a patient at risk of developing a particular disease or who reports one or more of the physiological symptoms of the disease, even if the disease has not been diagnosed.

[0087] JAK inhibitors Cytokines are important for host defense and immune regulation, but also play a major role in the immunopathogenesis of autoimmune diseases. Based on structure, different major families of cytokines can be recognized. The two main classes are the so-called type I and type II cytokine receptors. Type I receptors bind various 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 kinases or other enzymatically active domains, the above receptors lack such elements. Instead, the cytoplasmic domains of type I and type II cytokine receptors bind members of a specific kinase family known as Janus kinases (JAKs), which include JAK1, JAK2, JAK3, and TYK2. Cytokine receptors pair with different JAKs, which are activated upon cytokine binding. As 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 signaling 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. In addition, studies with knockout mice support a critical and specific role for JAK signaling by type I / II cytokines but not other pathways. The important function of JAKs in cytokine signaling suggests the therapeutic potential of JAK inhibitors.

[0088] 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, or compositions comprising these compounds, are useful for treating inflammatory or autoimmune diseases.

[0089] In some embodiments, provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt or solvate thereof:

[0090] [ka] During the ceremony,

[0091] [ka] is a phenyl or a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is C1-C6 alkyl or C1-C6 heteroalkyl; L2 is a single bond, C1-C6 alkyl, or C1-C6 heteroalkyl; R1 is a C3-C9 alkyl, a C3-C6 alkenyl, a C3-C6 alkynyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C3-C9 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6,

[0092] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0093] In some embodiments, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof:

[0094] [ka] During the ceremony,

[0095] [ka] is a phenyl or a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is C1-C6 alkyl or C1-C6 heteroalkyl; L2 is a single bond, C1-C6 alkyl, or C1-C6 heteroalkyl; R1 is a C3-C9 alkyl, a C3-C6 alkenyl, a C3-C6 alkynyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C3-C9 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6, or

[0096] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0097] In some embodiments, X is C(R 11 In some embodiments, there are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H)alkyl. In some embodiments, there are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H)alkyl. In some embodiments, there are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where X is N.

[0098] In some embodiments,

[0099] [ka] is phenyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0100] In some embodiments,

[0101] [ka] is a C2-C9 heteroaryl ring, or a pharma- ceutically acceptable salt or solvate thereof.

[0102] [ka] is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0103] [ka] is a C2-C9 heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0104] [ka] but,

[0105] [ka] In some embodiments, the C2-C9 heteroaryl ring is selected from the group consisting of:

[0106] [ka] but

[0107] [ka] In some embodiments, the compound of formula (I') or (I) is:

[0108] [ka] but

[0109] [ka] In some embodiments, the compound of formula (I') or (I) is:

[0110] [ka] but

[0111] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0112] In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 heteroalkyl.

[0113] In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C9 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2.In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C2-C9 heteroaryl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, wherein C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0114] In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is a single bond. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-. In some embodiments, provided herein are compounds of Formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein L2 is C1-C6 heteroalkyl.

[0115] In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C1-C6 alkyl optionally substituted with one or two Y. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH3. In some embodiments, provided herein are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2CH2CH3. In some embodiments, provided herein are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2H. In some embodiments, provided herein are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-Y. In some embodiments, provided herein are compounds of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-OR9. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted C2-C9 heterocycloalkyl.In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is -C1-C6 alkyl-C2-C9 heterocycloalkyl, optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted -C1-C6 alkyl-C2-C9 heterocycloalkyl.

[0116] In some embodiments, the present disclosure provides that R

[0117] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0118] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0119] [ka] and p is 1 and q is 0. In some embodiments, provided herein is a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0120] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0121] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0122] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0123] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0124] In some embodiments, the present disclosure provides that R

[0125] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound of formula (I'), wherein R2 is

[0126] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0127] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (I'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0128] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt solvate thereof, wherein R 14 Provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14 Provided herein is a compound of formula (I'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -C(=O)H. 14 -C(=O)OR 15 or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound of formula (I'), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen; or a pharma- ceutically acceptable salt or solvate thereof.

[0129] In some embodiments, provided herein are compounds of Formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0.

[0130] In some embodiments, provided herein are compounds of Formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, provided herein are compounds of Formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, provided herein are compounds of Formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, where n is 3. In some embodiments, the present specification provides a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 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. In some embodiments, the present specification provides a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 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. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 or 2, and each R3 is independently selected from halogen and C1-C6 alkyl.In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is halogen. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is C1-C6 alkyl.

[0131] In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R4 is hydrogen. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R4 is -CH3. In some embodiments, provided herein are compounds of formula (I') or (I), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 heteroalkyl.

[0132] In some embodiments, R 12 In some embodiments, R is a compound of formula (I') or (I), or a pharma- ceutically acceptable salt or solvate thereof. 12 In some embodiments, R is a halogen. 12is C1-C6 alkyl. 12 is -CH3, or a pharma- ceutically acceptable salt or solvate thereof.

[0133] In some embodiments, provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt or solvate thereof:

[0134] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl; R1 is a C1-C9 alkyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C1-C9 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6,

[0135] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; p is 0, 1, or 2; and q is 0, 1, or 2.

[0136] In some embodiments, provided herein is a compound of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof:

[0137] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl; R1 is a C1-C9 alkyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C1-C9 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6, or

[0138] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 13 is C1-C6 alkyl, n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0139] In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond.

[0140] In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C1-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C1-C9 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C9 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, where each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C6 cycloalkyl.In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, where each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, where each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, where each R5 is independently selected from halogen and C1-C6 alkyl.In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C2-C9 heteroaryl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0141] In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2CH2CH2-.

[0142] In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C1-C6 alkyl optionally substituted with one or two Y. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH3. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2CH2CH3. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2H. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-Y. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-OR9. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted C2-C9 heterocycloalkyl.In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is -C1-C6 alkyl-C2-C9 heterocycloalkyl, optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ia') or (Ia), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted -C1-C6 alkyl-C2-C9 heterocycloalkyl.

[0143] In some embodiments, the present disclosure provides that R

[0144] [ka] In some embodiments, the present invention provides a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0145] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0146] [ka] and p is 1 and q is 0. In some embodiments, provided herein is a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0147] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0148] [ka] In some embodiments, the present invention provides a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0149] [ka] In some embodiments, the present invention provides a compound of formula (Ia') or (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0150] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0151] In some embodiments, the present disclosure provides that R

[0152] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound of formula (Ia'), wherein R2 is

[0153] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0154] [ka] and p is 1 and q is 0. In some embodiments, provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0155] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt solvate thereof, wherein R 14 Provided herein is a compound of formula (Ia'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14 Provided herein are compounds of formula (Ia'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -C(=O)H. 14 -C(=O)OR 15 or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, provided herein is a compound of formula (Ia'), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen; or a pharma- ceutically acceptable salt or solvate thereof.

[0156] In some embodiments, provided herein is a compound of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof:

[0157] [ka] During the ceremony, L1 is C1-C6 alkyl; L2 is a single bond or C1-C6 alkyl; R1 is C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl, where C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is -C(=O)OR6, or

[0158] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R6 is hydrogen, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; R 13 is C1-C6 alkyl, p is 0, 1, or 2; and q is 0, 1, or 2.

[0159] In some embodiments, provided herein are compounds of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof, wherein L1 is -CH2-. In some embodiments, provided herein are compounds of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof, wherein L1 is -CH2CH2-.

[0160] In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C1-C6 alkyl, optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl, optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, where each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2.In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C2-C9 heteroaryl. In some embodiments, provided herein is a compound of formula (Ib), or a pharma- ceutically acceptable salt or solvate thereof, wherein C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0161] In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where L2 is a single bond. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-.

[0162] In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C1-C6 alkyl optionally substituted with one or two Y. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH3. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH2CH3. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2H. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (Ib), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, the present specification provides a compound of formula (Ib), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is -C(=O)OR6 and R6 is unsubstituted -C1-C6 alkyl-C2-C9 heterocycloalkyl.

[0163] In some embodiments, provided herein is a compound of formula (II'), or a pharma- ceutically acceptable salt or solvate thereof:

[0164] [ka] During the ceremony,

[0165] [ka] is a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is -C(=O)OR6,

[0166] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0167] In some embodiments, provided herein is a compound of formula (II), or a pharma- ceutically acceptable salt or solvate thereof:

[0168] [ka] During the ceremony,

[0169] [ka] is a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is -C(=O)OR6, or

[0170] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; R6 is hydrogen, C1-C6 alkyl optionally substituted with one or two Y, C3-C6 cycloalkyl optionally substituted with one or two Y, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; Each Y is independently -CN, -OR9, -SR9, and -N(R 10 )2 is selected, each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; each R9 is independently selected from hydrogen and C1-C6 alkyl; Each R 10 is independently selected from hydrogen and C1-C6 alkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0171] In some embodiments, X is C(R 11In some embodiments, there are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H)alkyl. In some embodiments, there are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is C(H)alkyl. In some embodiments, there are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where X is N.

[0172] In some embodiments,

[0173] [ka] is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0174] [ka] is a C2-C9 heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0175] [ka] is pyrazolyl.

[0176] [ka] is pyrrolyl.

[0177] [ka] is imidazolyl.

[0178] [ka] but,

[0179] [ka] In some embodiments, the compound of formula (II') or (II) is selected from:

[0180] [ka] but

[0181] [ka] In some embodiments, the compound is of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof.

[0182] [ka] but

[0183] [ka] In some embodiments, the compound is of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof.

[0184] [ka] but

[0185] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0186] In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2CH2-.

[0187] In some embodiments, provided herein are compounds of formula (II') or (I), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C2-C9 heteroaryl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridinyl. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is oxazolyl.In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is thiazolyl.In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrazolyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is thienyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrrolyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is imidazolyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyridinyl. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, Wherein L2 is -C(H)(phenyl)-.

[0188] In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C1-C6 alkyl, optionally substituted with one or two Y. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH3. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2CH2CH3. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2H. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-Y. In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where R2 is -CO2C1-C6 alkyl-OR9. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted C2-C9 heterocycloalkyl.In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is -C1-C6 alkyl-C2-C9 heterocycloalkyl, optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted -C1-C6 alkyl-C2-C9 heterocycloalkyl.

[0189] In some embodiments, the present disclosure provides that R

[0190] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0191] [ka] and p is 1. In some embodiments, the present invention provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0192] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0193] [ka] and p is 1 and q is 2. In some embodiments, the present invention provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0194] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0195] [ka]

[0023] In some embodiments, the present invention provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0196] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0197] In some embodiments, the present disclosure provides that R

[0198] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (II'), wherein R2 is

[0199] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (II'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0200] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (II'), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0201] [ka] and p is 1 and q is 2. In some embodiments, the present disclosure provides a compound of formula (II'), or a pharma- ceutically acceptable salt solvate thereof, wherein R 14 Provided herein is a compound of formula (II'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14 Provided herein is a compound of formula (II'), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -C(=O)H. 14 -C(=O)OR 15 In some embodiments, the present disclosure provides a compound of formula (II'), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen; or a pharma- ceutically acceptable salt or solvate thereof.

[0202] In some embodiments, provided herein are compounds of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0.

[0203] In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, provided herein are compounds of Formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, where n is 3. In some embodiments, the present specification provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 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. In some embodiments, the present specification provides a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 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. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 or 2, and each R3 is independently selected from halogen and C1-C6 alkyl.In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is halogen. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is C1-C6 alkyl.

[0204] In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is hydrogen. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is -CH3. In some embodiments, provided herein are compounds of formula (II') or (II), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 heteroalkyl.

[0205] In some embodiments, R 12 In some embodiments, R is a compound of formula (II') or (II), or a pharma- ceutically acceptable salt or solvate thereof. 12 In some embodiments, R is a halogen. 12is C1-C6 alkyl. 12 is -CH3, or a pharma- ceutically acceptable salt or solvate thereof.

[0206] In some embodiments, provided herein is a compound of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof:

[0207] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is -C(=O)OR6, or

[0208] [ka] and R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7)2, -S(=O)2R8, and -S(=O)2N(R7)2; R6 is hydrogen, C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl, or -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl; each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; R 13is C1-C6 alkyl, p is 0, 1, or 2; and q is 0, 1, or 2.

[0209] In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2CH2-.

[0210] In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C2-C9 heteroaryl. In some embodiments, provided herein is a compound of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein is a compound of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridinyl. In some embodiments, provided herein is a compound of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is oxazolyl. In some embodiments, provided herein are compounds of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein L2 is thiazolyl.In some embodiments, provided herein are compounds of formula (IIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein L2 is pyrazolyl.In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is thienyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrrolyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is imidazolyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyridinyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -C(H)(phenyl)-.

[0211] In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -C(=O)OR6 and R6 is C1-C6 alkyl optionally substituted with one or two Y. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH3. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2CH2CH3. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R2 is -CO2H. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salt solvates thereof, where R2 is -C(=O)OR6 and R6 is -C1-C6 alkyl-C2-C9 heterocycloalkyl optionally substituted with C1-C6 alkyl. In some embodiments, the present specification provides a compound of formula (IIa), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is -C(=O)OR6 and R6 is unsubstituted -C1-C6 alkyl-C2-C9 heterocycloalkyl.

[0212] In some embodiments, the present disclosure provides that R

[0213] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IIa), wherein R2 is

[0214] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (IIa), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0215] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (IIa), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0216] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (IIa), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0217] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IIa), wherein R2 is

[0218] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IIa), wherein R2 is

[0219] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0220] In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -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 pharma- ceutically acceptable salts or solvates thereof, where R3 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -C(=O)R8, and -S(=O)2R8. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is selected from C1-C6 alkyl and C1-C6 heteroalkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is selected from C1-C6 haloalkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is C1-C6 heteroalkyl. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is -C(=O)R8. In some embodiments, provided herein are compounds of formula (IIa), or pharma- ceutically acceptable salts or solvates thereof, where R3 is -S(=O)2R8.

[0221] In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof:

[0222] [ka] During the ceremony,

[0223] [ka] is a phenyl or a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is C1-C6 alkyl or C1-C6 heteroalkyl; L2 is a single bond, C1-C6 alkyl, or C1-C6 heteroalkyl; R1 is a C3-C9 alkyl, a C3-C6 alkenyl, a C3-C6 alkynyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C3-C9 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is

[0224] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; R 11 is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0225] In some embodiments, X is C(R 11 In some embodiments, there are compounds of formula (III) or a pharma- ceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments, there are compounds of formula (III) or a pharma- ceutically acceptable salt or solvate thereof, wherein X is N.

[0226] In some embodiments,

[0227] [ka] is phenyl; or a pharma- ceutically acceptable salt or solvate thereof.

[0228] In some embodiments,

[0229] [ka] is a C2-C9 heteroaryl ring, or a pharma- ceutically acceptable salt or solvate thereof.

[0230] [ka] is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0231] [ka] is a C2-C9 heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0232] [ka] but,

[0233] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0234] [ka] but

[0235] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0236] [ka] but

[0237] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0238] [ka] but

[0239] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0240] In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 heteroalkyl.

[0241] In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C9 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7)2.In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is unsubstituted C2-C9 heteroaryl. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, wherein C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0242] In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is a single bond. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 heteroalkyl.

[0243] In some embodiments, the present disclosure provides that R

[0244] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (III),

[0245] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0246] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0247] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0248] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (III),

[0249] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (III),

[0250] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0251] In some embodiments, the present disclosure provides that R

[0252] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (III),

[0253] [ka] and p is 1. In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0254] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R2 is

[0255] [ka] and p is 1 and q is 2. In some embodiments, the present disclosure provides a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein R 14 Provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14

[0023] In some embodiments, the present disclosure provides a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 14 -C(=O)OR 15 In some embodiments, the present disclosure provides a compound of formula (III), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0256] In some embodiments, provided herein are compounds of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0.

[0257] In some embodiments, provided herein are compounds of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, provided herein are compounds of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, provided herein are compounds of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, where n is 3. In some embodiments, the present specification provides a compound of formula (III), or a pharma- ceutically acceptable salt solvate thereof, wherein n is 1 or 2 and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, 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. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7), In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2, and each R6 is independently selected from halogen and C1-C6 alkyl.In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is halogen. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is C1-C6 alkyl.

[0258] In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R4 is hydrogen. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R4 is -CH3. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 heteroalkyl.

[0259] In some embodiments, R 12 In some embodiments, R is a compound of formula (III), or a pharma- ceutically acceptable salt or solvate thereof. 12 In some embodiments, R is a halogen. 12 is C1-C6 alkyl.12 is -CH3, or a pharma- ceutically acceptable salt or solvate thereof.

[0260] In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof:

[0261] [ka] During the ceremony, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl; R1 is a C1-C9 alkyl, a C3-C6 cycloalkyl, a C2-C9 heterocycloalkyl, or a C2-C9 heteroaryl, where the C1-C9 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, or C2-C9 heteroaryl is optionally substituted by 1, 2, or 3 R5; R2 is

[0262] [ka] and each R5 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; R 13 is C1-C6 alkyl, R14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; p is 0, 1, or 2; and q is 0, 1, or 2.

[0263] In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond.

[0264] In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C1-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C3-C9 alkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C1-C9 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C9 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C3-C6 cycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is unsubstituted C3-C6 cycloalkyl.In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, where R1 is C2-C9 heterocycloalkyl, optionally substituted with 1, 2, or 3 R5.In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is C2-C9 heterocycloalkyl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or pharma- ceutically acceptable salts or solvates thereof, in which R1 is unsubstituted C2-C9 heterocycloalkyl. In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5. In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, in which R1 is C2-C9 heteroaryl optionally substituted with 1, 2, or 3 R5, each R5 being independently selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R1 is unsubstituted C2-C9 heteroaryl.In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein C2-C9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0265] In some embodiments, provided herein are compounds of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (III), or a pharma- ceutically acceptable salt or solvate thereof, where L2 is -CH2CH2CH2-.

[0266] In some embodiments, the present disclosure provides that R

[0267] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (IIIa),

[0268] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0269] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0270] [ka] and p is 1 and q is 2. In some embodiments, the present disclosure provides a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0271] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (IIIa),

[0272] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (IIIa),

[0273] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0274] In some embodiments, the present disclosure provides that R

[0275] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present invention provides a compound of formula (IIIa),

[0276] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0277] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0278] [ka] and p is 1 and q is 2. In some embodiments, provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 14 Provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14 Provided herein is a compound of formula (IIIa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -C(=O)H. 14 -C(=O)OR 15 In some embodiments, the present disclosure provides a compound of formula (IIIa), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0279] In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof:

[0280] [ka] During the ceremony,

[0281] [ka] is a C2-C9 heteroaryl ring; X is C(R 11 ) or N, L1 is a single bond or C1-C6 alkyl; L2 is C1-C6 alkyl, C2-C9 heteroaryl, or -C(H)(phenyl)-; R2 is

[0282] [ka] and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7); R4 is hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl; each R5 is independently selected from halogen, oxo, C1-C6 alkyl, C1-C6 haloalkyl, 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; each R7 is independently selected from hydrogen, C1-C6 alkyl, C3-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 heteroalkyl; each R8 is independently selected from C1-C6 alkyl, C3-C6 alkenyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, and C2-C9 heterocycloalkyl; R 11is hydrogen or C1-C6 alkyl optionally substituted by 1, 2 or 3 R5; R 12 is hydrogen, halogen, or C1-C6 alkyl; R 13 is C1-C6 alkyl, R 14 is -OH, -C(=O)H, or -C(=O)OR 15 and R 15 is hydrogen or C1-C6 alkyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; and q is 0, 1, or 2.

[0283] In some embodiments, X is C(R 11 In some embodiments, there are compounds of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof, wherein X is C(H). In some embodiments, there are compounds of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof, wherein X is N.

[0284] In some embodiments,

[0285] [ka] is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0286] [ka] is a C2-C9 heteroaryl ring selected from pyrazolyl, pyrrolyl, and imidazolyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0287] [ka] is pyrazolyl.

[0288] [ka] is pyrrolyl.

[0289] [ka] is imidazolyl.

[0290] [ka] but

[0291] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0292] [ka] but

[0293] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0294] [ka] but

[0295] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments,

[0296] [ka] but

[0297] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0298] In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L1 is a single bond. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L1 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2-. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L1 is -CH2CH2CH2-.

[0299] In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2-. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2-. In some embodiments, provided herein are compounds of formula (III), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -CH2CH2CH2-. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is C2-C9 heteroaryl. In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is a C2-C9 heteroaryl ring selected from oxazolyl, thiazolyl, pyrazolyl, thienyl, pyrrolyl, imidazolyl, and pyridinyl. In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, in which L2 is oxazolyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is thiazolyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrazolyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is thienyl.In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyrrolyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is imidazolyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is pyridinyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where L2 is -C(H)(phenyl)-.

[0300] In some embodiments, the present disclosure provides that R

[0301] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IV),

[0302] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0303] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0304] [ka] and p is 1 and q is 2. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0305] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IV),

[0306] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IV),

[0307] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0308] In some embodiments, the present disclosure provides that R

[0309] [ka] or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the present disclosure provides a compound of formula (IV),

[0310] [ka] and p is 1. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0311] [ka] and p is 1 and q is 0. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R2 is

[0312] [ka] and p is 1 and q is 2. In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 14 Provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -OH. 14

[0023] In some embodiments, the present disclosure provides a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is -C(=O)H. 14 -C(=O)OR 15 In some embodiments, the present disclosure provides a compound of formula (IV), wherein R 14 -C(=O)OR 15 and R 15 is hydrogen, or a pharma- ceutically acceptable salt or solvate thereof.

[0313] In some embodiments, provided herein are compounds of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 0.

[0314] In some embodiments, provided herein are compounds of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, where n is 1. In some embodiments, provided herein are compounds of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, where n is 2. In some embodiments, provided herein are compounds of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, where n is 3. In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7)2. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, -OR7, -N(R7), -CN, -C(=O)R8, -C(=O)OR7, -C(=O)N(R7), -NR7C(=O)R8, -NR7S(=O)2R8, -S(=O)2R8, and -S(=O)2N(R7), In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, wherein n is 1 or 2, and each R3 is independently selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein n is 1 or 2, and each R6 is independently selected from halogen and C1-C6 alkyl.In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR7, and -N(R7). In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is selected from halogen and C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is halogen. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where n is 1 and R3 is C1-C6 alkyl.

[0315] In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where R4 is hydrogen. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 alkyl. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where R4 is -CH3. In some embodiments, provided herein are compounds of formula (IV), or pharma- ceutically acceptable salts or solvates thereof, where R4 is C1-C6 heteroalkyl.

[0316] In some embodiments, R 12 In some embodiments, compounds of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof are provided, wherein R 12 In some embodiments, compounds of formula (IV) or a pharma- ceutically acceptable salt or solvate thereof are provided, wherein R is halogen. 12

[0023] Provided herein is a compound of formula (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein R is C1-C6 alkyl. 12is -CH3, or a pharma- ceutically acceptable salt or solvate thereof.

[0317] In some embodiments, provided herein is a compound selected from the following, or an acceptable salt or solvate thereof:

[0318] [ka]

[0319] [ka]

[0320] [ka]

[0321] [ka]

[0322] [ka]

[0323] In some embodiments, provided herein is a compound selected from the following, or an acceptable salt or solvate thereof:

[0324] [ka]

[0325] In some embodiments, provided herein is a compound selected from the following, or an acceptable salt or solvate thereof:

[0326] [ka]

[0327] In some embodiments, the IC of the compounds provided herein 50 is about 50 nM or less in the JAK / TYK2 assay. In some embodiments, the IC 50 is about 100 nM or less in the JAK / TYK2 assay. In some embodiments, the IC 50is about 10 nM or less, about 20 nM or less, about 25 nM or less, about 50 nM or less, about 100 nM or less, about 250 nM or less, or about 500 nM or less in the JAK / TYK2 assay. In another embodiment, the compounds provided herein selectively inhibit JAK1 over JAK2, JAK3, and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK2 over JAK1, JAK3, and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK3 over JAK1, JAK2, and TYK2. In another embodiment, the compounds provided herein selectively inhibit TYK2 over JAK1, JAK2, and JAK3. In another embodiment, the compounds provided herein selectively inhibit JAK1 and JAK2 over JAK3 and TYK2. In another embodiment, the compounds provided herein selectively inhibit JAK1 and JAK3 over 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 JAK2, JAK3, and TYK2 relative to JAK1.

[0328] Any combination of the groups described above in terms of the various variations is contemplated herein. Throughout the specification, groups and substituents thereof may be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0329] 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 pharma- ceutically acceptable salt. In some embodiments, any of the compounds described above are suitable for the methods or compositions described herein.

[0330] Further forms of the compounds disclosed herein Isomers 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 described herein include cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as all of their corresponding mixtures. In some circumstances, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some circumstances, the compounds described herein have one or more chiral centers, with each center being in the R or S configuration. The compounds described herein include diastereomeric, enantiomeric, and epimeric forms, as well as all of their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic separation of a racemic mixture. In some embodiments, the compounds described herein are prepared as individual stereoisomers of the compound by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are subsequently recovered along with the resolving agent by any practical means that does not result in racemization.

[0331] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering the isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except 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 normally found in nature. Examples of isotopes that may be incorporated into the compounds described herein include: 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, and 36 Each of the isotopes includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharma- ceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, are within the scope of the present invention. Certain isotopically labeled compounds, e.g. 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred because they are easy to prepare and detect. In addition, deuterium, i.e. 2Substitution with heavy isotopes, such as H, offers certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharma- ceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are prepared by any suitable method.

[0332] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0333] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0334] In some embodiments, the compounds described herein contain acidic or basic groups and can be reacted with any of a number of inorganic or organic bases, inorganic or organic acids to produce pharma- ceutically acceptable salts. In some embodiments, these salts are prepared during the final isolation and purification of the compounds described herein, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the resulting salt.

[0335] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, there are methods of treating diseases by administering the solvates. Further described herein are methods of treating diseases by administering the solvates as pharmaceutical compositions.

[0336] Solvates include stoichiometric or non-stoichiometric amounts of a solvent, and in some embodiments are formed during the crystallization process using a pharma- ceutically acceptable solvent, such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including but not limited to dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0337] Compound synthesis In some embodiments, synthesis of the compounds described herein is accomplished using means described in the chemical literature, using methods described herein, or a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0338] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources, including, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), AcrosOrganics, and the like.

[0339] In further embodiments, the compounds described herein, and other related compounds having various substituents, are synthesized using techniques and materials described herein as well as art recognized techniques and materials, 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 Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992), Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for disclosure). General methods for the preparation of compounds as disclosed herein may be derived from reactions which may be modified using appropriate reagents and conditions to introduce the various moieties found in the formulae as provided herein. As a guide, the following synthetic methods may be used.

[0340] Use of Protecting Groups In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, to prevent these groups from participating in the reaction in an undesired manner if desired in the final product. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. Each protecting group is preferably removable by a different means. Protecting groups that are cleaved under generally different reaction conditions fulfill the requirement of differential removal.

[0341] The protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, t-butyldimethylsilyl, etc. are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of Cbz groups, which are hydrogenolytically removable, and amino groups protected with Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties may be blocked by acid labile groups such as t-butyl carbamate, or by base labile groups such as, but not limited to, methyl, ethyl, acetyl, etc., in the presence of amines blocked by carbamates, which are acid and base stable but hydrolytically removable.

[0342] Carboxylic acid and hydroxy reactive sites may further be blocked with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids may be blocked with base-labile groups such as Fmoc. Carboxylic acid reactive sites may be protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-labile silyl carbamates.

[0343] Allyl blocking groups are useful in the presence of acid and base protecting groups because the acid blocking groups are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-blocked carboxylic acids can be reacted with Pd 0 -catalyzed deprotection. Another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, the functional group is blocked and cannot react. Once released from the resin, the functional group becomes available for reaction.

[0344] In general, blocking / protecting groups may be selected from:

[0345] [ka]

[0346] Details of other protecting groups, as well as applicable techniques for the creation and removal of protecting groups, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for their disclosure.

[0347] Treatment and prevention methods In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, there is a method of treating an inflammatory disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, there is a method of treating an autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is rheumatoid arthritis.In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is multiple sclerosis. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is psoriasis. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is lupus. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is a bowel disease. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, wherein the disease, disorder, or condition is Crohn's disease.In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is ulcerative colitis. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is ankylosing spondylitis. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is vitiligo. In some embodiments, there is a method of treating an inflammatory or autoimmune disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV), or a pharma- ceutically acceptable salt or solvate thereof, and the disease, disorder, or condition is atopic dermatitis.

[0348] Pharmaceutical Compositions and Methods of Administration The JAK inhibitors described herein are administered to a subject in a biologically compatible form suitable for local administration to treat or prevent a disease, disorder, or condition. Administration of the JAK inhibitors as described herein may be in a pharmacological form that includes a therapeutically effective amount of the JAK inhibitor alone or in combination with a pharma- ceutically acceptable carrier.

[0349] In some embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharma- ceutically suitable or acceptable carrier (also referred to herein as a pharma- ceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, e.g., as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0350] Thus, provided herein are pharmaceutical compositions comprising at least one compound as described herein, or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (subject) of the composition.

[0351] In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (I'), (I), (Ia'), (Ia), (Ib), (II'), (II), (IIa), (III), (IIIa), or (IV) or a pharma- ceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (I) or a pharma- ceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (Ia) or a pharma- ceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (Ib) or a pharma- ceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (II) or a pharma- ceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition comprising a pharma- ceutically acceptable carrier and a compound of Formula (IIa) or a pharma- ceutically acceptable salt or solvate.

[0352] Another embodiment is 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. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt or solvate. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ib) or a pharmaceutically acceptable salt or solvate. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (II) or a pharmaceutically acceptable salt or solvate. In some embodiments, there is a pharmaceutical composition consisting essentially of a pharma- ceutically acceptable carrier and a compound of Formula (IIa), or a pharma- ceutically acceptable salt or solvate.

[0353] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, e.g., contaminating intermediates or by-products produced during one or more of the steps of a synthetic method.

[0354] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0355] Typical pharmaceutical compositions are used in the form of pharmaceutical preparations, such as solid, semi-solid, or liquid forms, which contain one or more of the disclosed compounds as active ingredients mixed with organic or inorganic carriers or excipients suitable for in vitro, enteral, or parenteral use. In some embodiments, the active ingredient is usually formulated with a non-toxic, pharma- ceutically acceptable carrier for, for example, tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and other forms suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect depending on the disease process or condition.

[0356] 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. "Biologically compatible form suitable for topical administration" refers to a form of the JAK inhibitor to be administered in which any toxic effects outweigh the therapeutic benefits of the inhibitor. Administration of the JAK inhibitor as described herein may be in a pharmacological form that includes a therapeutically effective amount of the JAK inhibitor alone or in combination with a pharma- ceutical acceptable carrier.

[0357] Topical administration of JAK inhibitors can be provided in the form of aerosol, semi-solid pharmaceutical composition, powder, or solution.The term "semi-solid composition" refers to ointments, creams, salves, jellies, or other pharmaceutical compositions with substantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are provided in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970), and Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition, published by Mack Publishing Company (1975).

[0358] Dermal or skin patches are another method of transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can provide an absorption enhancer, such as DMSO, to increase absorption of the compound. Patches may include those that control the rate of drug delivery to the skin. Patches may provide various administration systems, including reservoir systems or monolithic systems, respectively. Reservoir designs may have, for example, four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of the drug molecules, a reservoir of drug molecules, and a water-resistant backing. Such designs deliver a certain amount of drug over a specific period of time, and the delivery rate must be below the saturation limit of various skin types. For example, monolithic designs generally have only three layers: an adhesive layer, a polymer matrix that contains the compound, and a water-tight backing. This design provides a saturating amount of drug to the skin. Delivery is thereby controlled by the skin. When the amount of drug falls below the saturation amount in the patch, the delivery rate decreases.

[0359] In one embodiment, the topical composition may be in the form of a hydrogel, for example based on polyacrylic acid or polyacrylamide, in the form of an ointment containing polyethylene glycol (PEG) as a carrier, for example the standard ointment DAB8 (50% PEG300, 50% PEG1500), or in the form of an emulsion, in particular a microemulsion based on water-in-oil or oil-in-water, optionally with the addition of liposomes. Suitable penetration enhancers (entraining agents) include sulfoxide derivatives such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO), and transcutol (diethylene glycol monoethyl ether) or cyclodextrins, as well as pyrrolidones, such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and their fatty acid esters, urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3-diphenylurea, and terpenes, such as D-limonene, menthone, a-terpinol, carbol, limonene oxide, or 1,8-cineole.

[0360] Ointments, pastes, creams, and gels may further contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays may further 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 metals can be converted into an aerosol or spray by any of the known means routinely used to make aerosol formulations. Typically, such methods include pressurizing a container of the solution with, or providing a means for pressurization, a carrier gas, usually inert, and passing the pressurized gas through a small orifice. In addition, sprays may contain conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

[0361] The carrier may further include other pharma- ceutically acceptable excipients to modify or maintain the pH, osmolarity, viscosity, clarity, color, sterility, stability, dissolution rate, or odor of the formulation. The anti-skin aging composition may further include antioxidants, sunscreens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[0362] In some embodiments for preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical carrier, such as conventional tablet ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture of the disclosed compound or a non-toxic pharma- ceutically acceptable salt thereof. When such a preformulation composition is referred to as homogenous, it is meant that the active ingredient is evenly dispersed throughout the composition such that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0363] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions may be formulated with one or more pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or one or more of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicided microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) saccharides, such as carboxymethylcellulose, hypromellose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia. The composition may be mixed with any of the following: a binder, (3) a diluent such as glycerin, (4) a disintegrant such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) a solution retardant such as paraffin, (6) an absorption promoter such as a quaternary ammonium compound, (7) a wetting agent such as docusate sodium, cetyl alcohol, and glycerol monostearate, (8) an absorbent such as kaolin and bentonite clay, (9) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (10) a coloring agent. In the case of capsules, tablets, and pills, the composition may include a buffer in some embodiments. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0364] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersants. In some embodiments, molded tablets are made by molding a mixture of the subject composition moistened 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 scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0365] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders.Liquid dosage forms for oral administration include pharma-ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the subject compositions, in some embodiments, liquid dosage forms contain inert diluents such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrin, and mixtures thereof.

[0366] In some embodiments, suspensions contain a subject composition as well as a suspending agent such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, and mixtures thereof.

[0367] In some embodiments, powders and sprays contain the subject composition as well as excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, sprays further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0368] Alternatively, the compositions and compounds disclosed herein are administered by aerosol. This administration is accomplished by preparing an aerosol aqueous solution, liposomal preparation, or solid particles containing the compound. In some embodiments, a non-aqueous (e.g., fluorocarbon propellant) suspension is used. In some embodiments, a sonic nebulizer is used, which causes the compound contained in the subject composition to break down. This is because it minimizes the shearing of the drug. Typically, an aerosol aqueous solution is made by formulating an aqueous solution or suspension of the subject composition together with conventional pharma- ceutically acceptable carriers and stabilizers. Carriers and stabilizers vary according to the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronics, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, amino acids such as oleic acid, lecithin, glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0369] Pharmaceutical compositions suitable for parenteral administration may comprise the subject composition in combination with one or more pharma- ceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders to be reconstituted immediately before use into sterile injectable solutions or dispersions, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, suspending agents, or thickening agents.

[0370] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. Proper fluidity is maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0371] The dosage of a composition comprising at least one compound described herein will vary depending on the condition of the patient (eg, human), ie, the stage of the disease, general health, age, and other factors.

[0372] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented). The appropriate dosage, as well as the appropriate duration and frequency of administration, will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dosage and treatment regimen provides the composition in an amount sufficient to provide therapeutic and / or prophylactic benefits (e.g., improved clinical outcomes such as more frequent complete or partial remissions, longer disease-free and / or overall survival, or reduced severity of symptoms). Optimal dosages are generally determined using experimental models and / or clinical trials. In some embodiments, optimal dosages depend on the patient's body type, weight, or blood volume.

[0373] Oral administration is generally performed at about 1.0 mg to about 1000 mg per day, 1 to 4 times a day.

[0374] The dose may be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0375] It is particularly convenient to formulate compositions in dosage unit forms for ease of administration and uniformity of dosage. Dosage unit forms as used herein refer to physically discrete units suitable as unitary dosages for the mammalian subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for dosage unit forms are dictated by and directly dependent on (a) the inherent characteristics of the JAK inhibitor and the particular therapeutic effect to be achieved, and (b) the inherent limitations in the art of compounding such active compounds for the treatment of individual sensitivities. A specific dosage may be easily calculated by those skilled in the art according to, for example, the approximate body weight or body surface area of ​​the patient, or the volume of the body space to be occupied. The dosage is also calculated depending on the particular route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by those skilled in the art. Such calculations may be performed by those skilled in the art without undue experimentation, taking into account the activity of the JAK inhibitors disclosed herein in the assay preparation of target cells. The exact dosage is determined in conjunction with standard dose-response testing. It will be understood that the amount of composition actually administered will be determined by the medical practitioner taking into account the relevant circumstances, including the disease being treated, the choice of composition to be administered, the individual age, weight, and response of the patient, the severity of the patient's symptoms, and the chosen route of administration.

[0376] The toxicity and therapeutic efficacy of such JAK inhibitors are e.g. 50 (a dose lethal to 50% of the population) and ED 50The dose that is therapeutically effective in 50% of the population can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD 50 / ED 50 The therapeutic index can be expressed as a ratio of 0.01 to 0.02. JAK inhibitors that exhibit a large therapeutic index are preferred. JAK inhibitors that exhibit toxic side effects may be used, but care must be taken to design a delivery system that targets such inhibitors to the site of affected tissue in order to reduce side effects by minimizing potential damage to uninfected cells.

[0377] Data from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. Such doses of JAK inhibitors can be used to achieve ED with little or no toxicity. 50 The dose may vary within this range depending on the dosage form and 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. The IC 50 Dosages may be formulated in animal models to achieve a circulating plasma concentration range (the concentration of the JAK inhibitor that achieves half-maximal inhibition of symptoms) that includes. Such information can be used to more accurately determine useful doses in humans. Plasma concentrations can be measured, for example, by high performance liquid chromatography. EXAMPLES

[0378] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein.All references cited in these examples and throughout this specification are incorporated herein by reference for all legal purposes provided thereby.The starting materials and reagents used in the synthesis of 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.

[0379] Standard abbreviations and acronyms are used herein as defined in J. Org. Chem. 2007 72(1):23A-24A. Other abbreviations and acronyms used herein are as follows:

[0380] [Table 1]

[0381] [ka]

[0382] Basic steps To a solution of 2 (1.0 eq) in DMF was added Cs2CO3 (2.5 eq). The mixture was stirred at room temperature under N2 for 5 min. Then 1 (1.5 eq) was added to the reaction mixture. The resulting mixture was heated at 50-90 °C to give 3.

[0383] 3 (1.0 eq) and 4 (HCl salt, 1.4 eq) were combined in dry EtOH and the mixture was heated in a sealed tube at 120 °C for 20-48 h to give 5.

[0384] Example A: Synthesis of Intermediate 1

[0385] [ka]

[0386] The alcohol was dissolved in DCM and pyridine (5 eq). To this solution was added MsCl (1.5 eq) or TsCl (1.5 eq) at 0° C. The reaction mixture was stirred at room temperature for 2 h to give 1.

[0387] Example B: Synthesis of intermediates 4-a, 4-b, 4-c, 4-d, and 4-e

[0388] [ka]

[0389] Synthesis of 4-a To a solution of 4-nitropyrazole (1.13 g, 1.0 eq) in dry DMF (15 mL) was added Cs2CO3 (8.13 g, 2.5 eq). The mixture was stirred at room temperature under N2 for 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 hexane. The inorganics were removed by filtration. The filtrate was washed three times with 30 mL water and brine. The crude was purified on ISCO silica gel to give 6 (1.65 g, 83% yield) as a white solid.

[0390] To a solution of intermediate 6 (1.65 g) in ethyl acetate (40 mL) was added Pd / C (10% Pd on carbon, 165 mg). The mixture was hydrogenated at 30 psi for 2 h. The catalyst was removed by filtration. To the acetate solution was added 2N HCl in ether (10 mL) and stirred at room temperature for 5 min. The solvent was removed in vacuo to give 4-a as the HCl salt.

[0391] 4-c, 4-d, and 4-e were prepared in a similar manner as described for 4-a.

[0392] Synthesis of intermediate 4-b NaH (60% in mineral oil, 0.48 g, 1.0 eq) was suspended in dry THF (15 mL) under N2 at 0° C. A solution of 3-aminopyrazole (1.0 g, 1.0 eq) in dry 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 h and then at room temperature overnight. The precipitate was filtered off 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). Treatment of 7 with 2N HCl in ether gave 4-b as the HCl salt.

[0393] 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)

[0394] [ka]

[0395] 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 N2 for 5 min. 3-(Bromomethyl)pentane (162 mg, 1.5 eq) was added to the reaction mixture. The resulting mixture was heated at 50 °C overnight. The reaction mixture was diluted with 30 mL ethyl acetate and 10 mL hexane and washed with 20 mL water three times 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.

[0396] 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) were combined in dry EtOH (4 mL). The resulting mixture was heated in a sealed tube at 120° C. for 28 h. The solvent was removed in vacuo and 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-((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] + .

[0397] 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)

[0398] [ka]

[0399] 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 1N HCl 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, 78% yield). MS: 343.1 [M+H] + .

[0400] Compounds 10-33 were prepared by procedures similar to those described in Examples 1 or 2.

[0401] [Table 2-1]

[0402] [Table 2-2]

[0403] [Table 2-3]

[0404] [Table 2-4]

[0405] 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)

[0406] [ka]

[0407] To a solution of 1-(hydroxymethyl)adamantine (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 and then at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3. The organic phase was washed with 1N HCl and brine, dried over Na2SO4, and concentrated to give adamantine methanesulfonate (34) (216 mg, 98% yield), which was used without further purification.

[0408] Adamantine methanesulfonate (34) (200 mg, 1.5 eq), 2 (84 mg, 1.0 eq), and Cs2CO3 (670 mg, 2.5 eq) were combined in dry DMF (12 mL). The mixture was heated at 90 °C under N2 for 15 h. Workup and purification on silica gel gave adamantine 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (35) (163 mg, 66% yield).

[0409] Adamantine 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (35) (150 mg, 1.0 eq) and 4-a (155 mg, 1.5 eq) were combined in dry EtOH (8 mL). The resulting mixture was heated in a sealed tube at 120° C. for 20 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-((7-(((1s,3s)-adamantan-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] + .

[0410] Compounds 35-52 were prepared by procedures similar to those described in Examples 3 or 2.

[0411] [Table 3-1]

[0412] [Table 3-2]

[0413] [Table 3-3]

[0414] Example 4: Synthesis of 7-(cyclohexylmethyl)-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (54)

[0415] [ka]

[0416] 2 (60 mg, 1.0 eq), (bromomethyl)cyclohexane (104 mg, 1.5 eq), and Cs2CO3 (318 mg, 2.5 eq) were combined in dry DMF (10 mL). The mixture was heated at 50 °C under N2 for 15 h. Workup and purification on silica gel gave 2-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (90 mg, 92% yield).

[0417] 2-Chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (90 mg, 1.0 eq) and 4 (72 mg, 1.5 eq) were combined in dry EtOH (5 mL). The resulting mixture was heated in a sealed tube at 120° C. for 20 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 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] + .

[0418] Compounds 55-58 were prepared by procedures similar to those described in Example 4.

[0419] [Table 4]

[0420] 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)

[0421] [ka]

[0422] To a solution of 2-chloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (53) (100 mg, 1.0 eq) in dry 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 an ISCO to give 2,5-dichloro-7-(cyclohexylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (59) (82 mg, 73% yield).

[0423] 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) were combined in dry EtOH (3 mL). 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] + .

[0424] 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)

[0425] [ka]

[0426] To a suspension of NaH (60%, 170 mg, 1.0 eq) in dry THF (10 mL) was added dropwise 2-ethylpropane-1,3-diol (500 mg, 1.0 eq) in dry THF (10 mL). The mixture was stirred at room temperature for 1 h. To the reaction was added tert-butylchlorodimethylsilane (640 mg, 1.0 eq). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuum 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).

[0427] 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 1N HCl and brine. The crude was purified on a silica gel column to give 2-(((tert-butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (546 mg, 64% yield).

[0428] 2-(((tert-Butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (200 mg, 1.5 eq), 2 (55 mg, 1.0 eq), and Cs2CO3 (300 mg, 2.5 eq) were combined in dry DMF (8 mL). The mixture was heated at 80 °C under N2 for 15 h. Work-up 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).

[0429] 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 (1N 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 NH4Cl 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).

[0430] 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) were combined in dry EtOH (3 mL). The resulting mixture was heated in a microwave reactor at 140° C. for 2 h. The solvent was removed in vacuo and 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-((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] + .

[0431] 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)

[0432] [ka]

[0433] 2-(((tert-butyldimethylsilyl)oxy)methyl)butyl 4-methylbenzenesulfonate (62) (500 mg, 1.0 eq), KCN (175 mg, 2.0 eq), and (Bu)N+ CN - (20 mg) were combined in dry CH3CN (30 mL). The resulting mixture was heated in a sealed tube at 90 °C for 24 h. CH3CN was removed in vacuo and the residue was directly purified on a silica gel column to give 3-(((tert-butyldimethylsilyl)oxy)methyl)pentanenitrile (66) (210 mg, 69% yield).

[0434] 3-(((tert-Butyldimethylsilyl)oxy)methyl)pentanenitrile (66) (210 mg) in THF (10 mL) was treated with 1 N TABF (10 eq) at room temperature for 3 h. The crude mixture was purified on a silica gel column to give 3-(hydroxymethyl)pentanenitrile (67) (74 mg, 70% yield).

[0435] To a solution of 3-(hydroxymethyl)pentanenitrile (67) (70 mg, 1.0 eq) in DCM (5 mL) was added DIEA (2.5 eq). The mixture was cooled in an ice-water bath. MsCl (1.5 eq) was added dropwise. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with 1N HCl. The crude mixture was purified on a silica gel column to give 2-(cyanomethyl)butyl methanesulfonate (68) (109 mg, 92% yield).

[0436] 2-(Cyanomethyl)butyl methanesulfonate (68) (108 mg, 1.2 eq), 2 (98 mg, 1.0 eq), and Cs2CO3 (390 mg, 2.5 eq) were combined in dry DMF (8 mL). The mixture was heated at 80 °C under N2 for 15 h. Workup and purification on silica gel gave 3-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pentanenitrile (69) (87 mg, 74% yield).

[0437] 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) were combined in dry EtOH (5 mL). 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 ethyl acetate (30 mL) and washed with saturated NaHCO3. The crude mixture was purified 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).

[0438] 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)

[0439] [ka]

[0440] To a stirred solution of 4-nitro-1H-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). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then 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 (3×1 L) and brine (1 L). The organic solution was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was washed with 3% EtOAc / hexane (500 mL) to give a solid. The solid was dried under vacuum to give 3-(4-nitro-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one 73 (80 g, 70%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 9.13(s,1H),8.38(s,1H),5.66(t,J=9.7Hz,1H),4.59-4.54(m,1H),4.46-4.38(m,1H),3.05-2.59(m,2H).

[0441] To a stirred solution of 3-(4-nitro-1H-pyrazol-1-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% humidity) 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 CHCl (2×100 mL) and concentrated under reduced pressure. To a solution of the above amine in CHCl (1.23 L) was added HCl (492 mL, 2.0 N in EtO) 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 give 3-(4-amino-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one hydrochloride 74 (82 g) as a light brown solid. 1H NMR(400MHz,DMSO-d6) δ 7.14(s,1H),7.01(s,1H),5.27(t,J=9.5Hz,1H),4.50-4.45(m,1H),4.37-4.12(m,1H),3.91(brs,2H),2.68-2.58(m,2H).

[0442] To a stirred solution of (S)-4-benzyloxazolidin-2-one 75 (300 g, 1.69 mol) in CHCl (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 3-methylbutanoyl chloride (224.4 g, 1.86 mol) in CHCl (900 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (2 L) and extracted with CHCl (2×1 L). The combined organic extracts were washed with saturated sodium bicarbonate solution (1.0 L), water (1.0 L), 2.0 N aqueous HCl (1 L), and brine (1 L). The organic solution was dried over anhydrous NaSO, 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 give a solid, which was filtered and dried under vacuum to give (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 76 (402 g, 1.54 mol, 91%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6) δ 7.37-7.16(m,5H),4.74-4.57(m,1H),4.32(t,J=8.7Hz,1H),4.17(dd,J=8.7,2.9Hz,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).

[0443] To a stirred solution of LiHMDS (1.724 mL, 1.14 mol) in THF (2.1 L) under inert atmosphere, (S)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one 76 (300 g, 1.14 mol) in THF (900 mL) was added portionwise over 20 min at −78 °C and the mixture was stirred for 1.5 h. Ethyl iodide (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 about −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 × 1 L). The combined organic extracts were diluted with 1.0 M The mixture was washed with aqueous HCl (500 mL) and saturated sodium bicarbonate solution (500 mL). The organic solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 2% EtOAc / hexane) 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(500MHz,DMSO-d6) δ 7.34-7.18(m,5H),4.72-4.68(m,1H),4.30(t,J=8.4Hz,1H),4.15(dd,J=8.7,2.7Hz,1H),3.54-3.50(m,1H) ,3.05(dd,J=13.4,3.4Hz,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).

[0444] 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 inert atmosphere was added 30% aqueous HO (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 NaSO (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 Na2SO4, filtered and concentrated under reduced pressure to give (S)-2-ethyl-3-methylbutanoic acid 78 (44 g, crude) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) 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).

[0445] To a stirred solution of (S)-2-ethyl-3-methylbutanoic acid 78 (44 g, 0.33 mol) in THF (1.5 L) under inert atmosphere, lithium aluminum hydride (1.01 L, 1.01 mol, 1.0 M in THF) was added at 0 °C. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with 2.0 N aqueous HCl to pH ∼1 and extracted with CHCl (2 × 1 L). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (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 (500MHz, CDCl3) 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).

[0446] To a stirred solution of (S)-2-ethyl-3-methylbutan-1-ol 79 (38 g, 0.32 mol) in CHCl (400 mL) under inert atmosphere, diisopropylethylamine (126.77 g, 0.98 mol) and methanesulfonyl chloride (56 g, 0.50 mol) were added at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 1.0 N HCl solution (2 × 300 mL) and extracted with CHCl (2 × 1 L). The combined organic extracts were washed with saturated sodium bicarbonate solution (1 L), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give (S)-2-ethyl-3-methylbutyl methanesulfonate 80 (63 g, crude) as a pale yellow syrup.

[0447] To a stirred solution of (S)-2-ethyl-3-methylbutyl methanesulfonate 80 (63 g, 0.32 mol) in DMF (1.3 L) under inert atmosphere, cesium carbonate (263 g, 0.81 mol) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (49.68 g, 0.32 mol) were added at room temperature. The reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2×500 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (eluent: 10% EtOAc / hexanes) to give (S)-2-chloro-7-(2-ethyl-3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidine 81 (52 g, 64%) as a colorless oil. 1 H NMR(400MHz,CDCl3) δ 8.77(s,1H),7.19(d,J=3.7Hz,1H),6.56(d,J=3.5Hz,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=7.5Hz,3H).

[0448] 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) under inert atmosphere, 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) were added at room temperature. 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 the volatiles were evaporated under reduced pressure. The residue was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: 60% EtOH / hexane) to give 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 an off-white solid. 1 H NMR(400MHz,DMSO-d6) δ 9.24(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),4.16-3.9 9(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) + .

[0449] Chiral HPLC of 40 g of 82 gave 15 g of 82a and 15 g of 82b. 82a: 1H NMR(400MHz,DMSO-d6) δ 9.24(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),4.16-3.9 9(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 (150 x 4.6 mm, 3.5 μm); RT 16.49 min; mobile phase: n-heptane; EtOAc; MTBE (60:35:5); flow rate: 0.7 mL / min). 82b: 1 H NMR(400MHz,DMSO-d6) δ 9.24(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),4.16-3.9 9(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 (150 x 4.6 mm, 3.5 μm); RT 19.03 min; Mobile phase: n-heptane; EtOAc; MTBE (60:35:5); Flow rate: 0.7 mL / min).

[0450] Compounds 83-147 were prepared by procedures similar to those described in the above examples.

[0451]

Table 5-1

[0452]

Table 5-2

[0453]

Table 5-3

[0454]

Table 5-4

[0455]

Table 5-5

[0456]

Table 5-6

[0457]

Table 5-7

[0458]

Table 5-8

[0459]

Table 5-9

[0460]

Table 5-10

[0461]

Table 5-11

[0462] [Table 5-12]

[0463] Example 9: JAK / TYK2 Assay 10 mM test compound stocks or 1 mM control compound stocks (tofocitinib, ruxolitinib, or staurosporine) in DMSO were diluted to 0.4 mM in DMSO. 3-fold serial dilutions were then performed in DMSO to generate 10 different concentrations of compound. The assay was performed in a 384-well white plate. 0.5 μL of 40x compound DMSO solutions at different concentrations were mixed with 10 μL of 2x enzyme prepared in reaction buffer (20 mM HEPES, 10 mM MgCl2, 0.01% Tween, 1 mM DTT, pH 7.5). 10 μL of 2x substrate mix prepared in reaction buffer was then added to start the reaction. All the solution was allowed to drop to the bottom of the plate by briefly swirling. The final concentrations of test compounds in the reaction mixtures were 10000, 3333, 1111, 370, 123, 41.2, 13.7, 4.57, 1.52, and 0.51 nM. The concentration of control compounds was 10 times lower. The enzyme reaction was carried out at 25°C for 1-2 hours. The reaction was stopped by adding 10 μL of KinaseGlo reagent to generate a luminescent signal, which was measured using Envision. The luminescent signal was inversely correlated with kinase activity. Reaction mixtures that did not contain enzyme were negative controls. Compound-free reaction mixtures were positive controls. The final concentrations of enzyme and substrate, as well as incubation times, are summarized in the table below.

[0464] [Table 6]

[0465] I C 50 The values ​​are shown in the table below.

[0466] [Table 7-1]

[0467] [Table 7-2]

[0468] Example 10: JAK1 / JAK3: Assay of IL-2-stimulated STAT5 phosphorylation on PBMC

[0469] Human PBMC: (Precision Biomedicine) Thaw according to instructions. Thaw frozen PBMCs in a 37°C water bath. Transfer cell suspension to 9 mL pre-warmed complete medium (RPMI + 10% FBS + L-Glu + Pen / Strep). Centrifuge at 400xg for 5 minutes and wash cells with 10 mL complete medium. Resuspend pellet to a cell count of 3 x 106 cells / mL.

[0470] Compound and cytokine treatment Cells are seeded into 96-deep wells at 80 μL / well based on the experimental plate layout. Add 10 μL of various concentrations of compounds (10x concentrated) to all wells except for the control (unstimulated), which are mixed with a 200 μL multichannel pipette. Add 10 μL of complete RPMI medium with the same %DMSO as the control. See the attachment for compound dilutions and dilution ranges. Incubate at 37°C for 1 hour in a 5% CO2 incubator. Add 10 μL of (10x concentrated) IL-2 (final concentration 50 ng / mL) to each well except for the unstimulated and unstained controls, and further incubate at 37°C for 20 minutes in a water bath.

[0471] fixed Add 900 μL of pre-warmed 1X Fix / Lyse solution (supplied) and mix using a 1000 μL multichannel pipette as appropriate. Incubate in a water bath for an additional 10 minutes at 37°C. Centrifuge at 800xg for 5 minutes, remove 900 μL of supernatant, and add 1000 μL of freshly prepared wash buffer or 1xPBS. Centrifuge at 800xg for 5 minutes, remove 900 μL of supernatant, and resuspend pellet in remaining buffer.

[0472] Permeabilization Break up the pellet by tapping gently, add 1000 μL of ice-cold BD Phosflow Perm Buffer III, and incubate on ice for an additional 30 min. Centrifuge at 800 x g for 5 min. Wash two more times with 1000 μL of BD stain buffer, removing all but 100 μL of the supernatant after the final wash.

[0473] Antibody treatment Break up the pellet by tapping and add 100 μL staining buffer and 5 μL pSTAT5_Alex488(pY701) to all appropriate wells and mix using a 200 μL multichannel pipette as appropriate. Incubate the plate overnight at 40°C. Add 900 μL BD staining buffer and centrifuge at 800xg for 5 minutes. Wash once more with 1000 μL buffer. Finally, resuspend the pellet in 300 μL BD staining buffer. Transfer the cells to a 96-well v-bottom plate and acquire the cells in a Beckman Coulter Cytoflex. Acquire the cells in a flow cytometer and keep the threshold at 250. Acquire at least 8,000-10,000 cells.

[0474] Preparation of reagents RPMI 1640 complete medium: RPMI 1640 medium + 10% FBS.

[0475] Cytokine dilutions: 1) IL-2 stock at 100 μg / mL. Prepare a dilution of 0.5 μg / mL by adding 5 μL of stock to 995 μL of cRPMI. Store this frozen until use.

[0476] Preparation of Lyse / Fix Buffer: Dilute 5X Lyse / Fix Buffer to 1X using MQ water and store at 37° C. until use.

[0477] BD Phosflow perm buffer III: Store on ice / refrigerator.

[0478] [Table 8]

[0479] Example 11: Costimulation assay on lysed whole blood; Assay of JAK2:GM-CSF stimulated STAT5 phosphorylation and JAK1 / TYK2 stimulated STAT1 phosphorylation

[0480] Human blood lysis using Abcam's RBC lysis buffer Dilute 1X RBC Lysis Buffer in distilled water. Add 2 mL of blood to 38 mL of 1X RBC Lysis Buffer. Incubate at room temperature for 15 minutes in the dark. Spin at 300g for 5 minutes and collect pellet. Resuspend if necessary in 5 mL of cRPMI.

[0481] Compound and cytokine treatment Aliquot 80 μL of lysed human blood and place into wells of a 96-deep-well plate. Add 10 μL of compounds of various concentrations (10x concentrated) to all wells, except for the controls (unstimulated and unstained), which are mixed with the aid of a 100 μL multichannel. Add 10 μL of RPMI medium to the controls. See attachment for compound dilutions and dilution ranges. Incubate for 1 hour at 37°C in a water bath or CO2 incubator. Add 10 μL of (10x concentrated) cytokine mixture (GM-CSF and IFNa) (final concentration of GM-CSF 10 ng / mL, final concentration of IFNa 100 ng / mL) to each well, except for the unstimulated and unstained controls, and incubate for 20 minutes at 37°C in a water bath.

[0482] RBC lysis and fixation Add 900 μL of pre-warmed 1X Fix / Lyse solution (supplied), mix using a 1000 μL multichannel as appropriate, and further incubate in a water bath for 10 minutes (including addition time) at 37°C. Centrifuge at 800xg for 5 minutes at 40°C, remove 900 μL of supernatant, add 900 μL of 1X PBS. Centrifuge at 800xg for 5 minutes at 40°C, remove 900 μL of supernatant. Wash once more with 900 μL PBS (optional) and resuspend pellet in 100 μL of PBS.

[0483] Permeabilization The pellet is broken up by gentle tapping and resuspended in 1000 μL of BD Phosflow Perm Buffer III and the plate is incubated on ice for 30 minutes. The plate is centrifuged at 800×g for 5 minutes at 40° C. Wash two more times with 1000 μL of BD Pharmingen Stain Buffer.

[0484] Antibody treatment Tap gently to break up the pellet. Resuspend the pellet in 100 μL staining buffer and add 5 μL pSTAT5_AF488 Ab and 5 μL pSTAT1_PE to all wells except the unstained control, mix using the 200 μL multichannel as appropriate, and incubate overnight at 40°C. Add 900 μL wash buffer and centrifuge at 1800 rpm for 3 minutes at 40°C. Wash once more with 1000 μL BD Pharmingen Stain Buffer. Finally, resuspend the pellet in 300 μL BD Pharmingen Stain 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 and keep the threshold at 250. The cell concentration should not exceed 100-500 cells / μL. Acquire at least 5,000-10,000 cells.

[0485] Preparation of reagents RPMI 1640 complete medium: RPMI 1640 medium + 10% FBS.

[0486] Cytokine dilutions: 1) 100 μg / mL GM-CSF stock. Prepare intermediate dilution 1 μg / mL by adding 2 μL of stock to 198 μL of cRPMI. Further dilute to 100 ng / mL by adding 100 μL of intermediate stock to 900 μL of cRPMI. 2) 200 μg / mL IFNa stock. Dilute IFNa stock 1:200 by adding 5 μL of stock to 1000 μL of 100 ng / mL GM-CSF working stock as above to obtain a working stock of 1000 ng / mL IFNa and 100 ng / mL GM-CSF (10x). Store frozen until use.

[0487] Preparation of Lyse / Fix Buffer: Dilute 5X Lyse / Fix Buffer to 1X using MQ water and store at 37° C. until use.

[0488] BD Phosflow perm buffer III: Store on ice / refrigerator.

[0489] [Table 9]

[0490] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications and variations are within the scope of the disclosure and the appended claims.

Claims

1. A compound of formula (I') or a pharma- ceutically acceptable salt or solvate thereof, 【Chemistry 1】 During the ceremony, 【Chemistry 2】 teeth, 【Chemistry 3】 and X is C(R １１ ) and L １ is C １ -C ６ is alkyl, L ２ is a single bond, or C １ -C ６ is alkyl, R １ is unsubstituted C ３ -C ９ is alkyl, R ２ は、-C(=O)OR ６ 、 【Chemistry 4】 and R ４ is hydrogen, R ６ is hydrogen, C optionally substituted by one or two Y １ -C ６ C optionally substituted by alkyl, 1 or 2 Y ３ -C ６ Cycloalkyl, C １ -C ６ C optionally substituted with alkyl ２ -C ９ Heterocycloalkyl, or C １ -C ６ -C optionally substituted with alkyl １ -C ６ Alkyl-C ２ -C ９ is heterocycloalkyl, Each Y is independently -CN, -OR ９ , -SR ９ , and -N(R １０ ) ２ is selected from Each R ９ are independently hydrogen and C １ -C ６ alkyl, Each R １０ are independently hydrogen and C １ -C ６ alkyl, R １１ is hydrogen, R １２ is hydrogen, R １３ is C １ -C ６ is alkyl, R １４ is -OH, -C(=O)H, or -C(=O)OR １５ and R １５ is hydrogen or C １ -C ６ is alkyl, n is 0, p is 0, 1, or 2; and q is 0, 1, or 2 The compound, or a pharma- ceutically acceptable salt or solvate thereof.

2. L ２ C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein R is an alkyl group.

3. R ２ -C(=O)OR ６ and R ６ Unsubstituted C １ -C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein R is an alkyl group.

4. R ２ but 【Chemistry 5】 and R 13 is C 1 -C 6 alkyl; p is 0, 1, or 2; and 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2.

5. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 6】

6. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 7】

7. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 8】

8. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 9】

9. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 10】

10. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 11】

11. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, which is: 【Chemistry 12】

12. 2. The compound of claim 1 selected from: or a pharma- ceutically acceptable salt or solvate thereof. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】

13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient.

14. 13. Use of a compound according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating an inflammatory or autoimmune disease in a patient in need thereof.

15. 15. The use according to claim 14, wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, bowel disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.

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