Lzk inhibitors

Abstract

Described herein are LZK inhibitors and methods of utilizing these compounds in the treatment of cancer. Also described herein are pharmaceutical compositions containing such compounds.

Description

LZK INHIBITORS CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Application No.63 / 487,817, filed on March 1, 2023, and U.S. Provisional Application No.63 / 552,601, filed on February 12, 2024, each of which is herein incorporated by reference in its entirety. BACKGROUND

[0002] Squamous cell carcinomas are known to develop in a broad range of anatomically distinct tumors including the head and neck, and esophagus. Collectively squamous cell tumors account for over two million incident cases per annum worldwide, with high morbidity and mortality rates due to a lack of precision therapeutic treatment options.

[0003] Currently, the standard of care for most squamous cell cancer patients, including head and neck and esophageal patients, remains limited. This is primarily due to a lack of actionable driver mutations that can be directly targeted with precision therapeutics. In addition to radiation and surgical interventions, the most common treatments include systemic therapies such as chemotherapeutics and / or checkpoint inhibitors (Johnson, DE, et al 2021, Nat Rev Dis Primers; 6(1): 92). The lack of efficacious and targeted treatment options for these patients has led researchers to seek to identify novel tumor drivers within incident patients which can be directly targeted with new therapeutic approaches. SUMMARY OF THE INVENTION

[0004] In one aspect, described herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5;R2is -N(R4)C1-6alkyl, -N(R4)C1-6alkyl-OH, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or -CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R4is selected from hydrogen and C1-6alkyl; each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, - S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, - CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -C(O)OR10; each R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0005] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C2-9heterocycloalkyl optionally substituted with one, two, or three R6.

[0006] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6.

[0007] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0008] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from halogen and Ci-ehaloalkyl.

[0009] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from

[0010] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -N(R4)Ci-6alkyl-OH.

[0011] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

[0012] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is, , , ,

[0013] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is, , , or

[0014] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptablesalt or solvate thereof, wherein R2isH

[0015] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinwherein the C2-9heterocycloalkyl is a monocyclic ring.

[0016] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinis selected from morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl.

[0017] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinwherein the C2-9heterocycloalkyl comprises a bridged ring or a spirocyclic ring.

[0018] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinis selected from 3,6-diazabicyclo[3.1.1]heptanyl, 6-oxa-3- azabicyclo[3.1.1]heptanyl, and 2-oxa-7-azaspiro[3.5]nonanyl.

[0019] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0020] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen and unsubstituted C1-6alkyl.

[0021] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

[0022] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0023] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0024] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinselected from, ,.

[0025] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are optionally substituted with one, two, or three R5.

[0026] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are optionally substituted with one R5.

[0027] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-6alkyl, C1- 6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0028] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are substituted with one R5and R5is cyclopropyl.

[0029] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable

[0030] In another aspect, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein: R7is C1-6alkyl, -N(R8)C1-6alkyl, -CH3-6cycloalkyl, -CH2-C3-6cycloalkyl, or, wherein-membered monocyclic heterocycloalkyl ring, and wherein C1-6alkyl,2-C2-9heterocycloalkyl, C3-6cycloalkyl, -CH2-C3-6care optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl; and R8is selected from hydrogen and C1-6alkyl.

[0031] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl.

[0032] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl.

[0033] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7is selected from.

[0034] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7is -N(R8)C1-6alkyl optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl.

[0035] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7is -N(R8)C1-6alkyl substituted with one -OH.

[0036] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R8is hydrogen.

[0037] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7is, , , ,

[0038] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7is, , , , or.

[0039] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptablesalt or solvate thereof, wherein R2is .

[0040] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0041] In another aspect, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a cancer with LZK alterations. In some embodiments, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from head and neck squamous cell carcinoma and esophageal squamous cell carcinoma.

[0042] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION OF THE INVENTION

[0043] One common genetic alteration that is frequently observed in squamous cell tumors is that of gene copy number alterations. The most common conserved progenitor of gene copy number alterations is the distal amplification of chromosome 3 (3q26-3q29) (Derman BA, et al 2015, Transl. Lung Cancer Res; 4, 524-532) (Marur S, et all 2008, Mayo Clinic Proceedings; Vol 83, 489-501) (Abnet CC, et al 2018, Gastroenterology; 154, 360-373). This chromosome region contains many genes, including MAP3K13 which codes for the serine / threonine kinase Leucine Zipper Kinase (LZK). Notably, this genetic alteration is observed in greater than 20% of head and neck squamous cell patients, and greater than 20% of esophageal squamous cell patients (TCGA).

[0044] Emerging evidence has implicated MAP3K13 amplification, and the resulting overexpression of LZK, as a critical element for the survival of head and neck squamous cell tumor cell lines. Both genetic knockdown at the RNA level, and catalytic inhibition of the LZK protein result in anti-proliferative effects and tumor cell killing (Edwards ZC, et all 2017, Cancer Res; Sep 15;77(18):4961-4972). The development of small molecule inhibitors targeting LZK activity represents a promising new avenue for a precision therapeutic treatment for patient harboring this mutation.Compounds

[0045] The compounds described herein, including pharmaceutically acceptable salts and solvates thereof, are leucine zipper-bearing kinase (LZK) inhibitors.

[0046] In some embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof.Formula (I);wherein;R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; R2is -N(R4)C1-6alkyl, -N(R4)C1-6alkyl-OH, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C3-6cycloalkyl, or -CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R4is selected from hydrogen and C1-6alkyl; each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, - N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, - S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, - CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -C(O)OR10; each R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

[0047] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5.

[0048] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[0049] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -C(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, - CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10;each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0050] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -C(O)OR10, -C(O)R13, -OC(O)R13, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0051] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1- 6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0052] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9hetero cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -C(O)OR10.

[0053] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0054] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0055] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one or two R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with halogen. In some embodients, R1is a 6-membered heteroaryl ring optionally substituted with one or two R5; and each R5is independently selected from fluoro, -CH3, -CHF2, -CF3, cyclopropyl, and azetidinyl, optionally substituted with one or two fluoro.

[0056] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one R5; and R5is independently selected from C1-6haloalkyl and C3-6cycloalkyl. In some embodiments, R1is a 6-membered heteroaryl ring optionally substituted with R5; and each R5is independently selected from -CHF2, -CF3, and cyclopropyl. In some embodiments, R1is a 6-membered heteroaryl ring optionally substituted with one R5; and R5is cyclopropyl.

[0057] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5

[0058] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10;each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1- 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[0059] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0060] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9hetero cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one,two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -C(O)OR10.

[0061] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0062] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one, two, or three R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0063] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one or two R5; and each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with halogen. In some embodients, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one or two R5; and each R5is independently selected from fluoro, -CH3, -CHF2, -CF3, cyclopropyl, and azetidinyl, optionally substituted with one or two fluoro.

[0064] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one R5; and R5is independently selected from C1-6haloalkyl and C3-6cycloalkyl. In some embodiments, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one R5. In some embodiments, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one R5; and R5is selected from -CHF2, - CF3, and cyclopropyl. In some embodiments, R1is pyrazinyl or pyridinyl, wherein the pyrazinyl or pyridinyl are optionally substituted with one R5; and R5is cyclopropyl. In some embodiments, R1ispyrazinyl optionally substititued with one R5, and R5is cyclopropyl or -CF3. In some embodiments, R1is pyridinyl, optionally substituted with one R5, and R5is -CF3 or -CHF2.

[0065] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable. In some embodiments, for a compound of Formula (I), or a pharmaceuticallysome embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1isIn some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1isIn some embodiments, for a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof, R1issome embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is.

[0066] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R10)(R11), C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or -CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6.

[0067] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R4)C1-6alkyl-OH, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl,C3-6cycloalkyl, or -CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; R4is selected from hydrogen and C1-6alkyl; each R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[0068] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -C(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, - CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0069] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, , - OR10, -C(O)OR10, -C(O)R13, -OC(O)R13, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1- 6alkoxy; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0070] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl-CH2-C2-9hetero cycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, wherein C1- 6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1- 6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0071] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, and-CH2-C2-9hetero cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, - N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0072] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3- 6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0073] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or - CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and - CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0074] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl or C3-6cycloalkyl, wherein C2-9heterocycloalkyl and C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0075] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl or C3-6cycloalkyl, wherein C2-9heterocycloalkyl and C3-6cycloalkyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0076] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3- 6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0077] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3- 6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0078] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is C2-9heterocycloalkyl optionally substituted with one, two, or three R6; and each R6is independently selected from halogen and C1-6haloalkyl.

[0079] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6.

[0080] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; andeach R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R13is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[0081] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - CH2-C3-6cycloalkyl, C2-9heterocycloalkyl-CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6 haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0082] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0083] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0084] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl,pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3- 6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

[0085] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; and each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl.

[0086] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6; and each R6is independently selected from halogen and C1-6haloalkyl.

[0087] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl. In some embodiments, R2is selected from 3- azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, and piperidinyl.

[0088] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from, , , ,. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is selected from, , and . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is .

[0089] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R4)C1-6alkyl-OH and R4is selected from hydrogen and C1-6alkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R4)C1-6alkyl-OH and R4is hydrogen. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R4)C1-6alkyl-OH and R4is C1-6alkyl.

[0090] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,,. In some embodiments, for a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, R2is , ,, , . In some embodiments, for a compound of Formula(I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvatethereof, R2is . In some embodiments, for a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvatethereof, R2is . In some embodiments, for a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof, R2is .

[0091] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein the C2-9heterocycloalkyl is a monocyclic ring. In some embodiments, for a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof,is selected from morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is morpholinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,piperidinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is pyrrolidinyl. In some embodiments, for a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,is azetidinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is piperazinyl.

[0092] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein the C2-9heterocycloalkyl comprises a bridged ring or a spirocyclic ring. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein the C2- gheterocycloalkyl comprises a bridged ring. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein theC2-9heterocycloalkyl comprises a spirocyclic ring. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is selected from 3,6- diazabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 2-oxa-7-azaspiro[3.5]nonanyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,-diazabicyclo[3.1.1]heptanyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is 6-oxa-3- azabicyclo[3.1.1]heptanyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,-oxa-7-azaspiro[3.5]nonanyl.

[0093] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2- C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1- 6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is independently selected from halogen, C1-6alkyl, and C1-6haloalkyl.

[0094] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 0. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 1. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 2. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 3. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 4.

[0095] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptablesome embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvatethereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0096] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof.Formula (II); wherein:R7i s-ecycloalkyl, -CH2-C3--membered monocyclic heterocycloalkyl ring, and wherein Ci-ealkyl, -N(R8)Ci-6alkyl, -CH2-C2-I gheterocycloalkyl, Cs-ecycloalkyl, -CFh-Cs-ecycloalkyl, and o are optionallysubstituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl; and R8is selected from hydrogen and C1-6alkyl.

[0097] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, whereinis a 5-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1- 6haloalkyl.

[0098] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,-membered monocyclic heterocycloalkyl ring optionally substituted with one or two groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one group selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,, whereinunsubstituted 6-membered monocyclic heterocycloalkyl ring.

[0099] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is selected from, , . In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is .

[0100] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is selected from hydrogen and C1-6alkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is hydrogen. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one or two groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is hydrogen. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyloptionally substituted with one group selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is hydrogen. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl substituted with one group selected from - OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is hydrogen. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1- 6alkyl substituted with -OH, and R8is hydrogen. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is C1-6alkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one or two groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is C1-6alkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl optionally substituted with one group selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is C1-6alkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl substituted with one group selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl, and R8is C1-6alkyl. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is -N(R8)C1-6alkyl substituted with -OH, and R8is C1-6alkyl.

[0101] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof,,. In some embodiments, for a compound of Formula(II), or a pharmaceutically acceptable salt or solvate thereof, R7is , ,. In some embodiments, for a compound of Formula(II), or a pharmaceutically acceptable salt or solvate thereof, R7is . In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is . In some embodiments, for a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, R7is H . in some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7is. In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, R7isinsome embodiments, for a compound ofFormula (II), or a pharmaceutically acceptable salt or solvate thereof, R7isin some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvatethereof, R7is \ . In some embodiments, for a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof, R7is \

[0102] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure:

[0103] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure:

[0104] In another aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0105] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0106] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley - VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal fluids than non-ionic species and so are useful in solid dosage forms.Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible, and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0107] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compound described herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1 -hydroxy -2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane-l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene- 1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ( / ?); and undecylenic acid.

[0108] In some embodiments, a compound described herein is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0109] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt."

[0110] In some embodiments, the compound described herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound described herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described hereinform salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0111] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of isolating or purifying the compound with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0112] The methods and formulations described herein include the use of A-oxides (if appropriate), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0113] In some embodiments, sites on the organic groups (e.g., alkyl groups, aromatic rings) of compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic groups will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0114] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0115] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example,2H,3H,13C,14C,15N,18O,170,35S,18F,36C1. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distributionassays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo halflife or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.

[0116] In some embodiments, the compounds described herein possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. The compounds presented herein include all diastereomeric, enantiomeric, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0117] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0118] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0119] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acidmolecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0120] In additional or further embodiments, the compounds are rapidly metabolized in plasma.

[0121] In additional or further embodiments, the compounds are rapidly metabolized by the intestines.

[0122] In additional or further embodiments, the compounds are rapidly metabolized by the liver.Synthesis of Compounds

[0123] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0124] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0125] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0126] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry:Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471- 60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871- 1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley- Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0127] In some embodiments, compounds are prepared as described in the Examples. Certain Terminology

[0128] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0129] As used herein, C1-Cxor C1-xincludes C1-C2, C1-C3... C1-Cx. By way of example only, a group designated as "C1-C4" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4alkyl" or "C1-4alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0130] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a C1- C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms,6 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0131] An “alkylene” group refers to a divalent alkyl group. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is aCi-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., Ci- C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises two carbon atoms (e.g., C2 alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, - CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0132] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0133] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR.2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0134] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -OCCH3, -OCCH2CH3, and -CH2OCH.

[0135] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0136] The term “alkylamine” refers to the -N(alkyl)xHy group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0137] The term “aromatic” refers to a planar ring having a delocalized n-electron system containing 4n+2 71 electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0138] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycle includes cycloalkyl and aryl.

[0139] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0140] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic group, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fully saturated. In some embodiments, cycloalkyls are partially unsaturated. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicyclo[1.1.1]pentyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like

[0141] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0142] The term “haloalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl.

[0143] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0144] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl.

[0145] The term “heteroalkylene” refers to a divalent heteroalkyl group.

[0146] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2- onyl, isoindolin-l-onyl, isoindoline- 1, 3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4- dihydroquinolin-2(lH)-onyl, isoindoline-1, 3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H- benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C- linked) or TV-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non- aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0147] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrativeexamples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, benzotriazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

[0148] A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyls are spirocyclic or bridged compounds. In some embodiments, heterocycloalkyls are fully saturated. In some embodiments, heterocycloalkyls are partially unsaturated. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0- 2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0149] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0150] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0151] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s). In some other embodiments, optional substituents are individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), - N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -CH2CO2H, -CH2CO2alkyl, -CH2C(=O)NH2, - CH2C(=O)NH(alkyl), -CH2C(=O)N(alkyl)2, -CH2S(=O)2NH2, -CH2S(=O)2NH(alkyl), - CH2S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, - S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1- C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, - S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1- C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1- C4alkyl. In some embodiments, optional substituents are independently selected from D, halogen, - CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, substituted groups are substituted with one of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=O).

[0152] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0153] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methodsdescribed herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0154] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0155] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0156] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0157] The terms “kit” and “article of manufacture” are used as synonyms.

[0158] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0159] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.Pharmaceutical compositions

[0160] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventionalmanner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0161] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.

[0162] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0163] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0164] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0165] Pharmaceutical compositions for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0166] Pharmaceutical compositions may also be formulated as a depot preparation. Such long- acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0167] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0168] Pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0169] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0170] Pharmaceutical compositions suitable for topical administration include liquid or semiliquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w / w, for instance from 1% to 2% by weight of the formulation.

[0171] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0172] In some embodiments, a compound disclosed herein is formulated to provide a controlled release of the compound. Controlled release refers to the release of the compound described herein from a dosage form in which it is incorporated according to a desired profile over an extended period of time. Controlled release profiles include, for example, sustained release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to a predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations.

[0173] Approaches to deliver the intact therapeutic compound to the particular regions of the gastrointestinal tract (e.g., such as the colon), include:(i) Coating with polymers: The intact molecule can be delivered to the colon without absorbing at the upper part of the intestine by coating of the drug molecule with the suitable polymers, which degrade only in the colon.(ii) Coating with pH-sensitive polymers: The majority of enteric and colon targeted delivery systems are based on the coating of tablets or pellets, which are filled into conventional hard gelatin capsules. Most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® LI 00 and S 100 are copolymers of methacrylic acid and methyl methacrylate. Additional pH-dependent coating polymers include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP) and cellulose acetate trimelliate.(iii) Coating with biodegradable polymers;(iv) Embedding in matrices;(v) Embedding in biodegradable matrices and hydrogels;(vi) Embedding in pH-sensitive matrices;(vii) Timed release systems;(viii) Redox-sensitive polymers;(ix) Bioadhesive systems;(x) Coating with microparticles;(xi) Osmotic controlled drug delivery.

[0174] Another approach towards colon-targeted drug delivery or controlled-release systems includes embedding the drug in polymer matrices to trap it and release it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure the drug release in the colon.

[0175] Additional pharmaceutical approaches to targeted delivery of therapeutics to particular regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Sci. 2003 Jan-Apr; 6(l):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007; 24(2): 147-202. Kumar P, Mishra B. Colon targeted drug delivery systems-an overview. Curr Drug Deliv. 2008 Jul; 5(3): 186-98. Van den Mooter G. Colon drug delivery. Expert Opin Drug Deliv. 2006 Jan; 3(1): 111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug; 16(4): 731-741.

[0176] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Methods of Dosing and Treatment Regimens

[0177] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of an LZK inhibitor. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt or solvate thereof, in therapeutically effective amounts to said mammal.

[0178] In some embodiments, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a cancer with LZK alterations. In some embodiments, the cancer is a squamous cell carcinoma. In some embodiments, the cancer is head and neck squamous cell carcinoma. In some embodiments, the cancer is esophageal squamous cell carcinoma.

[0179] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0180] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.EXAMPLES

[0181] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0182] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: acac acetyl acetoneACN or MeCN acetonitrile AcOH acetic acidAc acetylBINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthaleneBn benzyl BOC or Boc tert-butyl carbamate i-Bu / .w-butyl t-Bu tert-butylCy cyclohexylCDI 1,1-carbonyldiimidazole CPME cyclopentyl methyl ether DAST (diethylamino)sulfur trifluoride DBA or dba dibenzylideneacetone DCE dichloroethane (ClCH2CH2Cl) DCM dichloromethane (CH2Cl2) DHP 3,4-dihydropyran DIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DMPU N,N DMSO dimethylsulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride EEDQ 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq equivalent(s) Et ethyl Et2O diethyl ether EtOH ethanol EtOAc ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HMPA hexamethylphosphoramide HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography IBX 2-iodoxybenzoic acid KOAc potassium acetate KHMDS potassium bis(trimethylsilyl)amide NaHMDS sodium bis(trimethylsilyl)amide LiHMDS lithium bis(trimethylsilyl)amideLAH lithium aluminum anhydride LC-MS liquid chromatography mass spectrometry 2-MeTHF 2-methyltetrahydrofuran Me methyl MeOH methanol MOM methoxymethyl ether MS mass spectroscopy Ms mesyl MTBE methyl tert-butyl ether NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMI 1-methylimidazole NMM N-methyl-morpholine NMP N-methyl-pyrrolidin-2-one NMR nuclear magnetic resonance OTf trifluoromethanesulfonate PCC pyridinium chlorochromate PE petroleum ether PG protecting group Ph phenyl PPTS pyridium p-toluenesulfonate iPr / i-Pr iso-propyl RP-HPLC reverse-phase high-pressure liquid chromatography rt room temperature SEM 2-(trimethylsilyl)ethoxymethyl TBS tert-butyldimethylsilyl TBAF tetra-n-butylammonium fluoride TBAI tetra-n-butylammonium iodide TCFH chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatographyTMEDA N,N,N N TMS trimethylsilyl TsOH / p-TsOH p-toluenesulfonic acid Procedure A 2,6-Dichloro-4-(3,3-difluoroazetidin-1-yl)pyridine (Intermediate 1-a)

[0183] To a stirred mixture of 2,4,6-trichloropyridine (1 g, 5.48 mmol, 1 equiv) and 3,3- difluoroazetidine hydrochloride (0.78 g, 6.03 mmol, 1.1 equiv) in DMA (15 mL) was added Cs2CO3 (4.46 g, 13.705 mmol, 2.5 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The resulting mixture was cooled to room temperature and diluted with water (100 mL). The resulting mixture was extracted with EtOAc (150 x mL). The organic layer was washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 2,6-dichloro-4-(3,3-difluoroazetidin-1- yl)pyridine (Intermediate 1-a) (0.6 g, 46%) as an off-white solid. LC-MS: (ESI, m / z): [M+H]+= 239.

[0184] Intermediates 2-a and 3-a were synthesized following Procedure A.Alternate conditions used:12.0 equiv. Cs2CO3, 12 h reaction time, order of addition (((3R)-3- methylmorpholine was added dropwise to the stirred mixture of 2,4,6-trichloropyridine and Cs2CO3in DMAC)), purification with C18 silica.Procedure B 3-(6-Chloro-4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane (Intermediate 1-b)

[0185] To a stirred mixture of 2,6-dichloro-4-(3,3-difluoroazetidin-1-yl)pyridine (Intermediate 1-a) (300 mg, 1.26 mmol, 1 equiv) and 3-azabicyclo[3.1.0]hexane hydrochloride (345 mg, 2.89 mmol, 2.3 equiv) in NMP (6 mL) were added DIEA (487 mg, 3.77 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 150 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature and diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-(6-chloro-4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-3- azabicyclo[3.1.0]hexane (Intermediate 1-b) (70 mg, 20%) as an off-white solid. LC-MS: (ESI, m / z): [M+H]+= 286.1.

[0186] Intermediates 2-b, 4-b, and 5-b were synthesized following Procedure B.Alternate conditions used:1DBU instead of DIEA, 160 °C, purification with C18 silica.2DBU instead of DIEA, 130 °C, 3 h reaction time, purification with C18 silicaProcedure C (3R)-4-(2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloropyridin-4-yl)-3-methylmorpholine (Intermediate 3-c)

[0187] To a stirred mixture of (3R)-4-(2,6-dichloropyridin-4-yl)-3-methylmorpholine (Intermediate 3-a) (300 mg, 1.21 mmol, 1 equiv), Cs2CO3(1187 mg, 3.64 mmol, 3 equiv) and 3- azabicyclo[3.1.0]hexane hydrochloride (174 mg, 1.46 mmol, 1.2 equiv) in THF (4 mL) was added X-Phos (60 mg, 0.13 mmol, 0.10 equiv) and 3rd Generation XPhos precatalyst (60 mg, 0.07 mmol, 0.06 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 100 °C. The resulting mixture was cooled to room temperature and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30 x 150 mm, 5m; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: isocratic 10% B to 30% B in 10 min; Wave Length: 254nm / 220nm nm) to afford (3R)-4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloropyridin-4-yl)-3-methylmorpholine (Intermediate 3-c) (70 mg, 20%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 294.2. Procedure D 3-[6-Chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexane (Intermediate 6-d)

[0188] A solution of 3-(6-chloro-4-iodopyridin-2-yl)-3-azabicyclo[3.1.0]hexane (300 mg, 0.94 mmol, 1 equiv) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was treated with 2-(3,6-dihydro-2H- pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (157 mg, 0.75 mmol, 0.8 equiv) for 2 min at room temperature under nitrogen atmosphere followed by the addition of K3PO4 (497 mg, 2.34 mmol, 2.5 equiv) in portions at room temperature. To the above mixture wasadded Pd(dppf)Cl2(69 mg, 0.09 mmol, 0.1 equiv) in portions over 1 min at room temperature. The resulting mixture was stirred for additional 2h at 90 °C. The reaction was cooled to room temperature and quenched with water. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-[6-chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2- yl]-3-azabicyclo[3.1.0]hexane (Intermediate 6-d) (89 mg, 34%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 277.0. Procedure E 6-(3-Azabicyclo[3.1.0]hexan-3-yl)-1'-(cyclopropylmethyl)-1',2',3',6'-tetrahydro-[4,4'- bipyridin]-2-amine (Intermediate 18-e)

[0189] To a stirred mixture of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-4-chloropyridin-2-amine (1 g, 4.77 mmol, 1 equiv) and 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine (2.51 g, 9.538 mmol, 2 equiv) in dioxane (20 mL) and H2O (4 mL) were added K3PO4(2.53 g, 11.92 mmol, 2.5 equiv), S-phos (294 mg, 0.72 mmol, 0.15 equiv) and Pd(OAc)2(268 mg, 1.19 mmol, 0.25 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C and then cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 6- (3-azabicyclo[3.1.0]hexan-3-yl)-1'-(cyclopropylmethyl)-1',2',3',6'-tetrahydro-[4,4'-bipyridin]-2- amine (Intermediate 18-e) (800 mg, 54%) as a yellow oil. Procedure F tert-Butyl 4-{[6-amino-1'-(cyclopropylmethyl)-3',6'-dihydro-2'H-[4,4'-bipyridin]-2- yl]methyl}piperidine-1-carboxylate (Intermediate 20-f)

[0190] To a stirred solution of Zn (0.68 g, 10.43 mmol, 1.7 equiv) in anhydrous DMA (10 mL) was added TMSCl (0.13 g, 1.23 mmol, 0.2 equiv) and dibromoethane (0.23 g, 1.23 mmol, 0.2 equiv) at room temperature and the resulting mixture was stirred for 30 min at 40 °C. tert-Butyl 4- (iodomethyl)piperidine-1-carboxylate (2.99 g, 9.2 mmol, 1.5 equiv) was added to the reaction and the resulting mixture was stirred for 30 min at 40 °C. Pd(dppf)Cl2 (0.45 g, 0.61 mmol, 0.1 equiv), CuI (0.12 g, 0.61 mmol, 0.1 equiv) and 4,6-dichloropyridin-2-amine (1 g, 6.1 mmol, 1.0 equiv) was added to the mixture and the resulting mixture was stirred for 3 h at 80°C. The reaction was cooled to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford tert-butyl 4-[(6-amino-4-chloropyridin-2- yl)methyl]piperidine-1-carboxylate (1.1 g, 55%) as a brown oil. LC-MS: (ESI, m / z): [M+H]+= 326.1.

[0191] To a stirred solution of tert-butyl 4-[(6-amino-4-chloropyridin-2-yl)methyl]piperidine-1- carboxylate (1.1 g, 3.38 mmol, 1 equiv) in anhydrous dioxane (8 mL) and H2O (2 mL) was added 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (1.07 g, 4.05 mmol, 1.2 equiv), Cs2CO3(2.75 g, 8.44 mmol, 2.5 equiv) and butyl[(3R,5S,7s)- adamantan-1-yl][(1s,3R,5S,7s)-adamantan-1-yl]phosphane{2'-amino-[1,1'-biphenyl]-2- yl}palladiumylium methanesulfonate (0.25 g, 0.34 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 100 °C. The mixture was cooled to room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford tert-butyl 4-{[6-amino-1'-(cyclopropylmethyl)-3',6'-dihydro-2'H- [4,4'-bipyridin]-2-yl]methyl}piperidine-1-carboxylate (Intermediate 20-f) (680 mg, 47%) as a brown solid. LC-MS: (ESI, m / z): [M+H]+= 427.3.

[0192] Intermediate 21-f and 65-f were synthesized following Procedure F.Procedure G 6-chloro-4-(3,3-difluoroazetidin-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (Intermediate 13-g)

[0193] To a stirred solution of 2,6-dichloro-4-(3,3-difluoroazetidin-1-yl)pyridine (Intermediate 1-a) (500 mg, 2.09 mmol, 1 equiv) and 5-(trifluoromethyl)pyridin-2-amine (305 mg, 1.88 mmol, 0.90 equiv) in THF (10 mL) were added Cs2CO3 (2 g, 6.14 mmol, 2.93 equiv), XPhos Pd G3 (125 mg, 0.15 mmol, 0.07 equiv) and XPhos (125 mg, 0.26 mmol, 0.13 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 °C. The mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford 6-chloro-4-(3,3-difluoroazetidin-1-yl)-N-[5- (trifluoromethyl)pyridin-2-yl]pyridin-2-amine (Intermediate 13-g) (360 mg, 47%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 364.9.

[0194] Intermediate 16-g was synthesized following Procedure G.Alternate conditions used:10.2 equiv. XantPhos Pd G3, 0.2 equiv. Xantphos Procedure H tert-butyl 4-(2,6-dichloropyridin-4-yl)piperazine-1-carboxylate (Intermediate 29-h)

[0195] To a stirred solution of 2,4,6-trichloropyridine (2 g, 10.963 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (2.45 g, 13.156 mmol, 1.2 equiv) in DMSO (20 mL) were added DIEA (2.13 g, 16.444 mmol, 1.5 equiv). The resulting mixture was stirred for 1 h at 80 °C. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (9:1) to afford tert-butyl 4-(2,6-dichloropyridin-4- yl)piperazine-1-carboxylate (1.5 g, 41.18%) as a white solid. LC-MS (ES, m / z): [M+H]+= 331.09.

[0196] The below intermediates were synthesized following Procedure H.Procedure J 4-(6-chloro-4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)morpholine (Intermediate 66-j)

[0197] A solution of 2,6-dichloro-4-(3,3-difluoroazetidin-1-yl)pyridine (1 g, 4.183 mmol, 1 equiv) in morpholine (15 mL) was stirred overnight h at 90 °C . The mixture was allowed to cool down to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 4-[6-chloro-4-(3,3-difluoroazetidin-1- yl)pyridin-2-yl]morpholine (0.8 g, 66.01%) as a yellow solid. LC-MS (ES, m / z): [M+H]+= 349.

[0198] The below intermediates were synthesized following Procedure J.Alternate conditions used:180 °C reaction temperature. Procedure K tert-butyl 4-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-6-chloropyridin-4-yl)piperazine-1- carboxylate (Intermediate 3

[0199] To a stirred solution of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperazine-1-carboxylate (530 mg, 1.595 mmol, 1 equiv) and 2-oxa-5-azabicyclo[2.2.1]heptane (189.77 mg, 1.914 mmol, 1.20 equiv) in 1,4-dioxane (8 mL) were added 3rd Generation RuPhos precatalyst (133.43 mg, 0.160 mmol, 0.1 equiv) and Cs2CO3 (1039.55 mg, 3.190 mmol, 2 equiv). The resulting mixture was stirred for 2 h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water (50 mL) at room temperature. The resulting mixture wasextracted with EA (3 x 100mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford tert-butyl 4-(2-chloro-6-{2-oxa-5-azabicyclo[2.2.1]heptan-5-yl}pyridin-4-yl)piperazine-1- carboxylate (120 mg, 19.05%) as a brown solid. LC-MS (ES, m / z): [M+H]+= 394.18.

[0200] The below intermediate was synthesized following Procedure K.Procedure L (S)-2-((6-chloro-4-morpholinopyridin-2-yl)amino)propan-1-ol (Intermediate 43-l)

[0201] A mixture of 4-(2,6-dichloropyridin-4-yl)morpholine (1.2 g, 5.148 mmol, 1 equiv), Cs2CO3 (3.35 g, 10.296 mmol, 2 equiv), (2S)-2-aminopropan-1-ol (0.46 g, 6.178 mmol, 1.2 equiv), Xphos Pd G3 (0.44 g, 0.515 mmol, 0.1 equiv), and Xphos (0.25 g, 0.515 mmol, 0.1 equiv) in DMF (30 mL) was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction was quenched with water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3x60 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford (2S)-2-{[6-chloro-4-(morpholin-4-yl)pyridin-2-yl]amino}propan-1-ol (440 mg, 31.4%) as a yellow solid. LC-MS (ES, m / z): [M+H]+ = 272.

[0202] The below intermediates were synthesized following Procedure L.Alternate conditions used:4 h reaction time and 100 °C reaction temperature.26 h reaction time.3BrettPhos Pd G3 used instead of XPhos Pd G3, BrettPhos used instead of XPhos, dioxane used instead of DMF, 1 h reaction time, and 90 °C reaction temperature.4XantPhos Pd G4 used instead of XPhos Pd G3, XantPhos used instead of XPhos, dioxane instead of DMF, and 90 °C reaction temperature.5BrettPhos Pd G3 used instead of XPhos Pd G3, BrettPhos used instead of XPhos, dioxane used instead of DMF, and 100 °C reaction temperature.6Dioxane used instead of DMF and 3 h reaction time.Procedure M tert-butyl 4-(2-chloro-6-((1-hydroxy-2-methylpropan-2-yl)amino)pyridin-4-yl)piperazine-1- carboxylate (Intermediate 95-m)

[0203] A solution of 2,6-dichloro-4-iodopyridine (1.0 g, 3.7 mmol, 1 equiv) in 2-amino-2- methyl-1-propanol (10.0 mL, 0.022 mmol) was stirred for 16 h at 120 °C. The reaction was quenched by the addition of Water / Ice (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:4) to afford 2-[(6-chloro-4-iodopyridin-2-yl)amino]-2-methylpropan-1-ol (600.0 mg, 50.3%) as a light yellow oil. LC-MS (ES, m / z): [M+H]+= 327.

[0204] To a stirred mixture of 2-[(6-chloro-4-iodopyridin-2-yl)amino]-2-methylpropan-1-ol (500.0 mg, 1.5 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (342.2 mg, 1.8 mmol, 1.2 equiv) in dioxane (12.0 mL) were added X-phos (146.0 mg, 0.3 mmol, 0.2 equiv) and XPhos Pd G3 (13.0 mg, 0.02 mmol, 0.1 equiv) in portions at room temperature. The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The reaction was quenched by the addition of Water / Ice (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:4) to afford tert-butyl 4-{2- chloro-6-[(1-hydroxy-2-methylpropan-2-yl)amino]pyridin-4-yl}piperazine-1-carboxylate (300.0 mg, 50.9%) as a white solid. LC-MS (ES, m / z): [M+H]+= 385. Procedure N tert-butyl 6'-chloro-1''-(cyclopropylmethyl)-1'',2'',3,3'',6,6''-hexahydro-[4,2':4',4''- terpyridine]-1(2H)-carboxylate (Intermediate 64-n)

[0205] To a stirred solution of 2,6-dichloro-4-iodopyridine (50 mg, 0.183 mmol, 1 equiv) and 1- (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (52.9 mg, 0.201 mmol, 1.1 equiv) and K3PO4 (96.9 mg, 0.458 mmol, 2.5 equiv) in 1,4-dioxane (1 mL) and H2O (0.2 mL) was added Pd(dppf)C12 (13.4 mg, 0.018 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 15 mL), dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford 2',6'-dichloro-l-(cyclopropylmethyl)-3,6-dihydro-2H- 4,4'-bipyridine (42 mg, 81.24%) as a colorless oil. LC-MS: (ES, m / z): [M+H]+= 283.10.

[0206] To a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-l -carboxylate (400 mg, 1.294 mmol, 1.00 equiv) and 2',6'-dichloro-l- (cyclopropylmethyl)-3,6-dihydro-2H-4,4'-bipyridine (549.5 mg, 1.941 mmol, 1.5 equiv) and K3PO4 (686.5 mg, 3.235 mmol, 2.5 equiv) in 1,4-dioxane (6 mL) and H2O (1.2 mL) was added Pd(dppf)C12 (94.7 mg, 0.129 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of Water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford tert-butyl 6- chloro-4-[l-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]- 1 '-carboxylate (349 mg, 62.74%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 430.25.Procedure P 3-(6-chloro-4-(l-(cyclopropylmethyl)piperidin-4-yl)pyridin-2-yl)-3-azabicyclo[3.1.0]hexane (Intermediate 23-p)

[0207] A mixture of 2,6-dichloro-4-iodopyridine (5 g, 18.256 mmol, 1 equiv), 1- (cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (5.77 g, 21.907 mmol, 1.2 equiv), Pd(dppf)C12 (1.34 g, 1.826 mmol, 0.1 equiv) and K^CCh (3.78 g, 27.384 mmol, 1.5 equiv) in Dioxane (50 mL) and H2O (5 mL) was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (2 x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 2',6'-dichloro-l-(cyclopropylmethyl)-3,6-dihydro-2H-4,4'-bipyridine (4.5 g, 87.04%) as a black oil. LC-MS (ES, m / z): [M+H]+ = 293.

[0208] A mixture of 2',6'-dichloro-l-(cyclopropylmethyl)-3,6-dihydro-2H-4,4'-bipyridine (4.5 g, 15.890 mmol, 1 equiv), 3-azabicyclo[3.1.0]hexane (1.59 g, 19.068 mmol, 1.2 equiv) and CS2CO3 (10.35 g, 31.780 mmol, 2 equiv) in DMAc (50 mL) was stirred overnight at 120 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with water (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9: 1) to afford 2'-{3- azabicyclo[3.1.0]hexan-3-yl}-6'-chloro-l-(cyclopropylmethyl)-3,6-dihydro-2H-4,4'-bipyridine (4.0 g, 76.31%) as a yellow oil. LC-MS (ES, m / z): [M+H]+ = 330.

[0209] A mixture of 2'-{3-azabicyclo[3.1.0]hexan-3-yl}-6'-chloro-l-(cyclopropylmethyl)-3,6- dihydro-2H-4,4'-bipyridine (4.0 g, 12.126 mmol, 1 equiv) and PtCL (1.38 g, 6.063 mmol, 0.5 equiv) in MeOH (60 mL) was stirred overnight at 40 °C under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7: 1) to afford 3-{6-chloro-4-[l- (cyclopropylmethyl)piperidin-4-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hexane (3.5 g, 86.97%) as an orange oil. LC-MS (ES, m / z): [M+H]+ = 332.Procedure Q tert-butyl 4-(6-chloro-4-(3,3-difluoroazetidin-l-yl)pyridin-2-yl)piperidine-l-carboxylate (Compound 68-q)

[0210] To a stirred solution of 2,6-dichloro-4-(3,3-difluoroazetidin-l-yl)pyridine (1 g, 4.183 mmol, 1 equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1 -carboxylate (1.29 g, 4.183 mmol, 1 equiv) in dioxane (10 mL, 41.830 mmol) and H2O (2 mL, 8.366 mmol) were added Pd(dppf)C12CH2C12 (0.34 g, 0.418 mmol, 0.1 equiv) and dioxane (10 mL, 41.830 mmol). The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford tertbutyl 6-chloro-4-(3, 3 -difluoroazetidin-l-yl)-3',6'-dihydro-2'H-[2,4'-bipyridine]-l '-carboxylate (0.7 g, 43.37%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 386.

[0211] A solution of tert-butyl 6-chloro-4-(3,3-difluoroazetidin-l-yl)-3',6'-dihydro-2'H-[2,4'- bipyridine]-l'-carboxylate (0.65 g, 1.685 mmol, 1 equiv) and PtCh (0.19 g, 0.843 mmol, 0.5 equiv) in MeOH (20 mL) was stirred for 3 h at 40 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford tert-butyl 4-[6-chloro-4-(3,3-difluoroazetidin-l-yl)pyridin-2-yl]piperidine- 1-carboxylate (0.41 g, 62.75%) as a white oil. LC-MS (ES, m / z): [M+H]+= 388.

[0212] The below intermediates were synthesized following Procedure Q.Example 1: N-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-5- cyclopropylpyrazin-2-amine (Compound 1)

[0213] To a stirred mixture stirred mixture of 3-(6-chloro-4-(3,3-difluoroazetidin-1-yl)pyridin-2- yl)-3-azabicyclo[3.1.0]hexane (Intermediate 1-b) (70 mg, 0.25 mmol, 1 equiv) and 5- cyclopropylpyrazin-2-amine (33 mg, 0.25 mmol, 1 equiv) in 1,4-dioxane (1 mL) were added Cs2CO3 (160 mg, 0.5 mmol, 2 equiv), dppf (11 mg, 0.02 mmol, 0.08 equiv) and Pd(dppf)Cl2 (7 mg, 0.010 mmol, 0.04 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100 °C under nitrogen atmosphere. The resulting mixture was cooled to room temperature and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: CAN(1% 2mM NH3- MEOH); Flow rate: 60 mL / min mL / min; Gradient: 47% B to 65% B in 10 min; Wave Length: 254nm / 220nm) to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3,3-difluoroazetidin-1- yl)pyridin-2-yl)-5-cyclopropylpyrazin-2-amine (Compound 1) (47 mg, 49%) as an off-white solid. LC-MS: (ESI, m / z): [M+H]+= 385.2.1H-NMR (400 MHz, Chloroform-d 1H), 6.84 (s, 1H), 5.57 (s, 1H), 4.95 (s, 1H), 4.23 (t, J = 11.8 Hz, 4H), 3.68 (d, J = 9.8 Hz, 2H), 3.42 (d, J = 9.7 Hz, 2H), 2.03 – 1.96 (m, 1H), 1.69 – 1.61 (m, 2H), 1.00 – 0.93 (m, 4H), 0.72 (q, J = 7.0 Hz, 1H), 0.27 (q, J = 4.2 Hz, 1H).

[0214] Compound 2 and Compound 3 were synthesized following the procedure from Example 1 from Intermediate 2-b and 3-c, respectively.Alternate conditions used:10.08 equiv. XPhos Pd G3, 0.15 equiv. XPhos Example 2: N-(6-(6,6-Difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-(3,3-difluoroazetidin-1- yl)pyridin-2-yl)-5-(trifluoromethyl)pyrazin-2-amine formate (Compound 4)

[0215] A solution of 3-[6-chloro-4-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]-6,6-difluoro-3- azabicyclo[3.1.0]hexane (Intermediate 4-b) (50 mg, 0.16 mmol, 1 equiv), 5- (trifluoromethyl)pyrazin-2-amine (38 mg, 0.23 mmol, 1.48 equiv), Cs2CO3 (152 mg, 0.47 mmol, 3.01 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (15 mg, 0.016 mmol, 0.10 equiv) in dioxane (2 mL) was stirred for 12 h at 100 °C under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-4-(3,3-difluoroazetidin-1-yl)pyridin-2- yl)-5-(trifluoromethyl)pyrazin-2-amine formate (Compound 4) (2 mg, 2%) as a white solid. LC- MS: (ES, m / z): [M+H]+= 449.2.1H-NMR:(400 MHz, DMSO-d6 8.63 (s, 1H), 6.04 (d, J = 1.6 Hz, 1H), 5.23 (s, 1H), 4.32 (t, J = 12.3 Hz, 4H), 3.82 – 3.66 (m, 4H), 2.72 – 2.64 (m, 2H).19F-NMR:(376 MHz, DMSO-d6J = 4.5 Hz), -98.92 (d, J = 3.1 Hz), -128.24, -128.66 (d, J = 3.1 Hz), -154.57, -154.99 (d, J = 4.2 Hz). Example 3: N-(6-(3-Azabicyclo[3.2.0]heptan-3-yl)-4-(1-methylazetidin-3-yl)pyridin-2-yl)-5- methylpyrazin-2-amine (Compound 5)

[0216] To a stirred solution of tert-butyl 3-(2-{3-azabicyclo[3.2.0]heptan-3-yl}-6-chloropyridin- 4-yl)azetidine-1-carboxylate (Intermediate 5-b) (583 mg, 1.60 mmol, 1 equiv) in anhydrous THF (8 mL) was added 5-methylpyrazin-2-amine (210 mg, 1.92 mmol, 1.2 equiv), XPhos Pd G3 (136 mg, 0.160 mmol, 0.1 equiv), Cs2CO3 (1.57 g, 4.81 mmol, 3 equiv) and XPhos (76 mg, 0.160 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The mixture was stirred for overnight at 100 °C under nitrogen atmosphere. The mixture was cooled to room temperature and quenched by the addition of water (1 mL). The resulting mixture was filtered and the filter cake was purified by reverse-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% TFA), 5% to 90% gradient in 10 min; detector, UV 254 / 220 nm to afford tert-butyl 3-(2-{3-azabicyclo[3.2.0]heptan-3-yl}-6-[(5-methylpyrazin-2-yl)amino]pyridin-4- yl)azetidine-1-carboxylate (865 mg) as a yellow oil. LC-MS: (ESI, m / z): [M+H]+= 437.3.

[0217] To a stirred solution of tert-butyl 3-(2-{3-azabicyclo[3.2.0]heptan-3-yl}-6-[(5- methylpyrazin-2-yl)amino]pyridin-4-yl)azetidine-1-carboxylate (80 mg, 0.18 mmol, 1 equiv) in anhydrous THF (1 mL) was added LiAlH4 (0.2 mL, 0.4 mmol, 2.18 equiv, 2M in THF) at 0 °C under nitrogen atmosphere. The mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of water (0.5 mL) at room temperature. The resulting mixture was filtered and the filter cake was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: 20 mM NaOH+10% ACN; Flow rate: 60 mL / min; Gradient: isocratic 2% B t10% B in 10 min; Wave Length: 254nm / 220nm) to afford N-(6-(3-azabicyclo[3.2.0]heptan- 3-yl)-4-(1-methylazetidin-3-yl)pyridin-2-yl)-5-methylpyrazin-2-amine (Compound 5) (19 mg, 30% yield) as a light yellow solid. LC-MS: (ESI, m / z): [M+H]+= 351.2.1H NMR:(400 MHz, DMSO-d6 J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.38 (s, 1H), 6.02 (s, 1H), 4.14 – 4.01 (m, 2H), 3.86 – 3.68 (m, 3H), 3.60 (d, J = 10.9 Hz, 2H), 3.29 – 3.12 (m, 2H), 2.99 (s, 2H), 2.63 (s, 3H), 2.34 (s, 3H), 2.25 – 2.11 (m, 2H), 1.70 – 1.58 (m, 2H).Example 4: N-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-(tetrahydro-2H-pyran-4-yl)pyridin-2-yl)- 5-cyclopropylpyrazin-2-amine (Compound 6)

[0218] A solution of 3-[6-chloro-4-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl]-3- azabicyclo[3.1.0]hexane (Intermediate 6-d) (70 mg, 0.25 mmol, 1 equiv) in THF (1 mL) was treated with 5-cyclopropylpyrazin-2-amine (41 mg, 0.30 mmol, 1.2 equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of Cs2CO3 (247 mg, 0.76 mmol, 3 equiv) in portions at room temperature. To the mixture was added XPhos Pd G3 (14 mg, 0.017 mmol, 0.07 equiv) and XPhos (14 mg, 0.029 mmol, 0.12 equiv) in portions over 2 min at room temperature. The reaction mixture was heated for 2.5 h at 100 °C. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3,6-dihydro-2H-pyran-4- yl)pyridin-2-yl)-5-cyclopropylpyrazin-2-amine (90 mg, 95%) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+= 376.2.

[0219] To a solution of N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(3,6-dihydro-2H-pyran-4- yl)pyridin-2-yl)-5-cyclopropylpyrazin-2-amine (72 mg, 0.19 mmol, 1 equiv) in 4 mL MeOH was added Pd / C (10%, 69 mg) in a pressure tank. The mixture was hydrogenated at 50 °C under (40atm) of hydrogen pressure overnight. The mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 49% B to 67% B in 10 min;Wave Length: 254 nm / 220 nm) to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(tetrahydro-2H- pyran-4-yl)pyridin-2-yl)-5-cyclopropylpyrazin-2-amine (Compound 6) (3.5 mg, 5%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 378.0.1H NMR (400 MHz, DMSO-d6 9.25 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 1.5 Hz, 1H), 6.44 (s, 1H), 5.81 (d, J = 1.1 Hz, 1H), 3.97 – 3.88 (m, 2H), 3.63 (d, J = 10.0 Hz, 2H), 3.46 – 3.32 (m, 4H), 2.60 (tq, J = 10.7, 6.0, 4.8 Hz, 1H), 2.12 – 2.01 (m, 1H), 1.72 – 1.55 (m, 6H), 0.91 (tdd, J = 8.7, 5.1, 2.5 Hz, 2H), 0.85 (dt, J = 5.0, 2.7 Hz, 2H), 0.72 (td, J = 7.8, 4.4 Hz, 1H), 0.20 (q, J = 4.1 Hz, 1H). Example 5: N-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2-yl)-5- cyclopropylpyrazin-2-amine (Compound 7)

[0220] To a stirred solution of N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-chloropyridin-2-yl)-5- cyclopropylpyrazin-2-amine (50 mg, 0.15 mmol, 1 equiv) in anhydrous THF (1 mL) was added morpholine (20 mg, 0.23 mmol, 1.5 equiv), Cs2CO3 (149 mg, 0.46 mmol, 3.0 equiv), 3rd Generation XPhos precatalyst (10 mg, 0.012 mmol, 0.08 equiv) and dicyclohexyl[2',4',6'- tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (10 mg, 0.02 mmol, 0.14 equiv) at room temperature under N2 and the resulting mixture was stirred overnight at 100 °C. The mixture was cooled to room temperature and filtered. The filter cake was washed with THF (3 x 3 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m, Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 42% B to 60% B in 10 min; Wave Length: 254nm / 220nm) to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-morpholinopyridin-2-yl)-5-cyclopropylpyrazin-2-amine (Compound 7) (22 mg, 38%) as an off-white solid. LC-MS: (ESI, m / z): [M+H]+= 379.2.1H NMR (400 MHz, DMSO-d6J= 1.6 Hz, 1H), 9.12 (s, 1H), 8.16 (d, J= 1.5 Hz, 1H), 6.20 (d, J= 1.8 Hz, 1H), 5.43 (d, J= 1.8 Hz, 1H), 3.74 (t, J= 4.8 Hz, 4H), 3.66 (d, J= 9.9 Hz, 2H), 3.39–3.36 (m, 2H), 3.18 (t, J= 4.8 Hz, 4H), 2.13–2.07 (m, 1H), 1.69 (dt, J= 7.4, 3.3 Hz, 2H), 0.99–0.92 (m, 2H), 0.90-0.84 (m, 2H), 0.74 (td, J= 7.8, 4.4 Hz, 1H), 0.22 (q, J= 4.1 Hz, 1H).

[0221] Compounds 8-12 were synthesized from the corresponding morpholine or piperazine derivative following the procedure of Example 5.Alternate conditions used:'Work up: After overnight stirring, the mixture was extracted with EtOAc, and the combined organic layers were washed with water and dried over anhydrous ISfeSCU. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC.2Work up: After overnight stirring, the mixture was quenched by the addition of water and extracted with CH2Q2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and purified by Prep- HPLC.3Tert-butyl piperazine- 1 -carboxylate was used. Work up: After overnight stirring, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure andpurified by Prep-HPLC. The mixture underwent a subsequent Boc deprotection with TFA in DCM to afford the final product.4Tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used. Work up: After overnight stirring, the mixture was extracted with EtOAc, and the combined organic layers were washed with water and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and purified by Prep-HPLC. The mixture underwent a subsequent Boc deprotection with TFA in DCM to afford the final product. Example 6: N-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin- 2-yl)-5-cyclopropylpyrazin-2-amine (Compound 13)

[0222] To a stirred mixture of N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-chloropyridin-2-yl)-5- cyclopropylpyrazin-2-amine (30 mg, 0.09 mmol, 1 equiv) and 2-oxa-7-azaspiro[3.5] nonane (14 mg, 0.11 mmol, 1.2 equiv) in dioxane (1 mL) were added Cs2CO3 (90 mg, 0.28 mmol, 3 equiv) and Pd-PEPPSI-IHeptCl 3-chloropyridine (9 mg, 0.01 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C and then cooled to room temperature. The mixture was filtered and the filter cake was washed with CH2Cl2 (3 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 47% B to 64% B in 9 min; Wave Length: 254nm / 220nm) to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(2-oxa-7-azaspiro[3.5]nonan-7- yl)pyridin-2-yl)-5-cyclopropylpyrazin-2-amine (Compound 13) (5 mg, 13%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 419.4.1H NMR (400 MHz, DMSO-d6 J = 1.5 Hz, 1H), 9.01 (s, 1H), 8.11 (d, J = 1.5 Hz, 1H), 6.15 (d, J = 1.8 Hz, 1H), 5.37 (d, J = 1.8 Hz, 1H), 4.33 (s, 4H), 3.61 (d, J = 9.9 Hz, 2H), 3.35 – 3.27 (m, 2H), 3.20 – 3.13 (m, 4H), 2.10 – 1.99 (m, 1H), 1.87 – 1.77 (m, 4H), 1.64 (dt, J = 7.3, 3.0 Hz, 2H), 0.89 (dt, J = 8.2, 2.8 Hz, 2H), 0.86 – 0.79 (m, 2H), 0.70 (td, J = 7.8, 4.4 Hz, 1H), 0.18 (q, J = 4.1 Hz, 1H). Example 7: 4-(3,3-Difluoroazetidin-1-yl)-6-morpholino-N-(5-(trifluoromethyl)pyridin-2- yl)pyridin-2-amine (Compound 14)

[0223] A solution of 6-chloro-4-(3,3-difluoroazetidin-1-yl)-N-[5-(trifluoromethyl)pyridin-2- yl]pyridin-2-amine (Intermediate 13-g) (50 mg, 0.14 mmol, 1 equiv), morpholine (24 mg, 0.28 mmol, 2.01 equiv), Cs2CO3(134 mg, 0.41 mmol, 3.00 equiv), and Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) (12 mg, 0.014 mmol, 0.10 equiv) in dioxane (1 mL) was stirred for 8 h at 90 °C under nitrogen atmosphere and then cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30 x 150 mm, 5 m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 49% B to 66% B in 10 min; Wave Length: 254nm / 220nm nm) to afford 4-(3,3-difluoroazetidin-1- yl)-6-morpholino-N-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2-amine (Compound 14) (16 mg, 28%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 416.2.1H-NMR: (400 MHz, DMSO-d6 (s, 1H), 8.50 (s, 1H), 7.93 (t, J = 2.1 Hz, 2H), 6.23 (d, J = 1.6 Hz, 1H), 5.54 (d, J = 1.7 Hz, 1H), 4.33 (d, J = 12.2 Hz, 3H), 4.28 (s, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.40 (t, J = 4.8 Hz, 4H).19F-NMR: (376 MHz, DMSO-d6

[0224] Compound 15 was synthesized following the procedure described in Example 7.Example 8: 5-Cyclopropyl-N-(4-(1-(cyclopropylmethyl)piperidin-4-yl)-6-morpholinopyridin- 2-yl)pyrazin-2-amine (Compound 16)Pd-PEPPSI-IHeptCl 3- chloropyridine,Cs2CO3, dioxane, 90oC, overnightPd / C, H2MeOH, 50oC, 16 h

[0225] To a stirred solution of 6-chloro-1'-(cyclopropylmethyl)-N-(5-cyclopropylpyrazin-2-yl)- 1',2',3',6'-tetrahydro-[4,4'-bipyridin]-2-amine (Intermediate 16-g) (70 mg, 0.18 mmol, 1 equiv) and morpholine (24 mg, 0.28 mmol, 1.53 equiv) in dioxane (2 mL) were added Cs2CO3(178 mg, 0.55 mmol, 2.98 equiv) and {1,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H- imidazol-2-yl}dichloro(3-chloro-1lambda4-pyridin-1-yl)palladium (18 mg, 0.018 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The mixture was cooled room temperature and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 1'-(cyclopropylmethyl)-N-(5-cyclopropylpyrazin-2-yl)-6- morpholino-1',2',3',6'-tetrahydro-[4,4'-bipyridin]-2-amine (50 mg, 63%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 433.2.

[0226] To a solution of 1'-(cyclopropylmethyl)-N-(5-cyclopropylpyrazin-2-yl)-6-morpholino- 1',2',3',6'-tetrahydro-[4,4'-bipyridin]-2-amine (50 mg, 0.12 mmol, 1 equiv) in MeOH (3 mL) was added Pd / C (50 mg, 10%wt) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen pressure for 16 h, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30 x 150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: 20mm NaOH+10%ACN; Flow rate: 60 mL / min mL / min; Gradient: 37% B to 55% B in 10 min; Wave Length: 254nm / 220nm) to afford 5- cyclopropyl-N-(4-(1-(cyclopropylmethyl)piperidin-4-yl)-6-morpholinopyridin-2-yl)pyrazin-2- amine (Compound 16) (12 mg, 23%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 435.3.1H-NMR: (400 MHz, DMSO-d6J = 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 6.62 (s, 1H), 6.13 (s, 1H), 3.66 – 3.59 (m, 4H), 3.33 (t, J = 4.9 Hz, 4H), 2.98 (dt, J = 11.7, 3.4 Hz, 2H), 2.26 (s, 1H), 2.11 (d, J = 6.5 Hz, 2H), 1.99 (d, J = 4.9 Hz, 1H), 1.89 (td, J = 11.5, 2.9 Hz, 2H), 1.68 – 1.49 (m, 4H), 0.84 (ddt, J = 8.1, 5.6, 3.0 Hz, 2H), 0.76 (qt, J = 4.5, 1.8 Hz, 3H), 0.43 – 0.32 (m, 2H), -0.00 (dt, J = 4.9, 2.8 Hz, 2H).

[0227] Compound 17 was synthesized following the procedure described in Example 8.Alternate conditions used:1Purification by silica gel in Step 1 Example 9: N-(6-(3-Azabicyclo[3.1.0]hexan-3-yl)-4-(1-(cyclopropylmethyl)piperidin-4- yl)pyridin-2-yl)-5-(difluoromethyl)pyrazin-2-amine (Compound 18)

[0228] To a stirred mixture of 2-chloro-5-(difluoromethyl)pyrazine (80 mg, 0.49 mmol, 1 equiv) and 6-(3-azabicyclo[3.1.0]hexan-3-yl)-1'-(cyclopropylmethyl)-1',2',3',6'-tetrahydro-[4,4'- bipyridin]-2-amine (Intermediate 18-e) (181 mg, 0.58 mmol, 1.2 equiv) in THF (1 ml ) were added Cs2CO3 (475 mg, 1.46 mmol, 3 equiv), XPhos Pd G3 (15 mg, 0.018 mmol, 0.04 equiv) and Xphos (15 mg, 0.03 mmol, 0.06 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C. The mixture was filtered and the filter cake was washed with DCM (3 x 3 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford 6-(3-azabicyclo[3.1.0]hexan-3-yl)-1'-(cyclopropylmethyl)-N-(5-(difluoromethyl)pyrazin-2-yl)-1',2',3',6'-tetrahydro-[4,4'- bipyridin]-2-amine (100 mg, 47%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+=439.35.

[0229] To a solution of 6-(3-azabicyclo[3.1.0]hexan-3-yl)-1'-(cyclopropylmethyl)-N-(5- (difluoromethyl)pyrazin-2-yl)-1',2',3',6'-tetrahydro-[4,4'-bipyridin]-2-amine (100 mg, 0.23 mmol, 1 equiv) in 5 mL MeOH was added Pd / C (10%, 100 mg) under nitrogen atmosphere. The mixture was hydrogenated at 50 °C overnight under hydrogen atmosphere using a hydrogen balloon. The mixture was then filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 5% B to 25% B in 10 min; Wave Length: 254nm / 220nm) to afford N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(1-(cyclopropylmethyl)piperidin-4-yl)pyridin-2-yl)- 5-(difluoromethyl)pyrazin-2-amine (Compound 18) (14 mg, 14%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 441.2.1H NMR (400 MHz, DMSO-d6J= 1.4 Hz, 1H), 8.47 (s, 1H), 6.96 (s, 1H), 6.57 (s, 1H), 5.93 (s, 1H), 3.65 (d, J= 10.0 Hz, 2H), 3.43 – 3.35 (m, 2H), 3.08 (d, J= 11.0 Hz, 2H), 2.39 – 2.29 (m, 1H), 2.21 (d, J = 6.5 Hz, 2H), 2.01 (t, J = 11.0 Hz, 2H), 1.76 – 1.57 (m, 6H), 0.85 (t, J = 6.9 Hz, 1H), 0.74 (td, J = 7.8, 4.4 Hz, 1H), 0.52 – 0.42 (m, 2H), 0.21 (q, J = 4.3 Hz, 1H), 0.08 (d, J = 5.0 Hz, 2H).

[0230] Compounds 19-21 were synthesized following the procedure described in Example 9.Alternate conditions used:12 h reaction time in Step 1.2After Step 2, the mixture underwent a subsequent Boc deprotection with TFA in DCM to afford the final product. Example 10: N-(6-(azetidin-3-yl)-4-(1-(cyclopropylmethyl)piperidin-4-yl)pyridin-2-yl)-5- cyclopropylpyrazin-2-amine (Compound 65)

[0231] To a solution of tert-butyl 3-[6-amino-1'-(cyclopropylmethyl)-3',6'-dihydro-2'H-[4,4'- bipyridin]-2-yl]azetidine-1-carboxylate (Intermediate 65-F, 355 mg, 0.923 mmol, 1 equiv) in MeOH (7 mL) was added Pd / C (180 mg, 10%wt) in a pressure tank. The mixture was hydrogenated at room temperature under 1 atm of hydrogen pressure for 6 h, filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobilephase, MeCN in Water (0.1% TFA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford tert-butyl 3-{6-amino-4-[l-(cyclopropylmethyl)piperidin-4-yl]pyridin-2-yl}azetidine-l- carboxylate (250 mg, 70.06%) as a yellow solid. LC-MS (ES, m / z): [M+H]+= 387.30.

[0232] To a stirred solution of tert-butyl 3-{6-amino-4-[l-(cyclopropylmethyl)piperidin-4- yl]pyri din-2 -yl} azetidine- 1 -carboxylate (150 mg, 0.388 mmol, 1 equiv) and 2-chloro-5- cyclopropylpyrazine (72 mg, 0.466 mmol, 1.20 equiv) in THF (3 mL) were added CS2CO3 (379 mg, 1.163 mmol, 3.00 equiv), XPhos Pd G3 (50 mg, 0.059 mmol, 0.15 equiv) and XPhos (50 mg, 0.105 mmol, 0.27 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 0% to 100% gradient in 10 min; detector, UV 254 nm to afford tert-butyl 3-{4-[l-(cyclopropylmethyl)piperidin-4-yl]-6-[(5- cyclopropylpyrazin-2-yl)amino]pyridin-2-yl} azetidine- 1 -carboxylate (130 mg, 66.38%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 505.35.Example 11 : 5-cyclopropyl-N-(4-(l-(cyclopropylmethyl)piperidin-4-yl)-6-(piperidin-4- yl)pyridin-2-yl)pyrazin-2-amine (Compound 64)

[0233] To a stirred solution of tert-butyl 6-chloro-4-[l-(cyclopropylmethyl)-3,6-dihydro-2H- pyridin-4-yl]-3',6'-dihydro-2'H-[2,4'-bipyridine]-l'-carboxylate (445 mg, 1.035 mmol, 1 equiv) and5-cyclopropylpyrazin-2-amine (167.9 mg, 1.242 mmol, 1.2 equiv) and CS2CO3 (1.01 g, 3.105 mmol, 3 equiv) in THF (8 mL) was added XPhos (89 mg, 0.187 mmol, 0.18 equiv) and XPhos Pd G3 (89 mg, 0.105 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford tert-butyl 4-[l-(cyclopropylmethyl)-3,6- dihydro-2H-pyridin-4-yl]-6-[(5-cyclopropylpyrazin-2-yl)amino]-3',6'-dihydro-2'H-[2,4'- bipyridine]-l'-carboxylate (187 mg, 34.18%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 529.25.

[0234] To a stirred solution of tert-butyl 4-[l-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4-yl]-6-[(5-cyclopropylpyrazin-2-yl)amino]-3',6'-dihydro-2'H-[2,4'-bipyridine]-l '-carboxylate (187 mg, 0.354 mmol, 1 equiv) in MeOH (10 mL) was added Pd / C (187 mg, 10%wt) at room temperature under air atmosphere. The resulting mixture was stirred for 48 h at 50°C under hydrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (2 x 2 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-{4-[l-(cyclopropylmethyl)piperidin-4-yl]-6-[(5- cyclopropylpyrazin-2-yl)amino]pyridin-2-yl}piperidine-l-carboxylate (150 mg, crude) as a yellow oil. The crude product was used in the next step directly without further purification. LC-MS: (ES, m / z): [M+H]+= 533.30.

[0235] To a stirred solution of tert-butyl 4-{4-[l-(cyclopropylmethyl)piperidin-4-yl]-6-[(5- cyclopropylpyrazin-2-yl)amino]pyridin-2-yl}piperidine-l-carboxylate (150 mg, 0.282 mmol, 1 equiv) in DCM (3 mL) was added TFA (1 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for Ih at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHCCL (aq.) (15 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 15 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (187 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5pm, n; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: MeOH— HPLC; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 23% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.25) to afford 5-cyclopropyl-N-{4- [l-(cyclopropylmethyl)piperidin-4-yl]-6-(piperidin-4-yl)pyridin-2-yl}pyrazin-2-amine (22.8 mg,18.72%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+ =433.251H-NMR (400 MHz, DMSO-d69.90 (s, 1H), 9.24 (s, 1H), 8.23 (s, 1H), 7.09 (s, 1H), 6.69 (s, 1H), 3.67 (d, J = 12.1 Hz, 2H), 3.42 (d, J = 12.6 Hz, 2H), 3.27 – 2.85 (m, 6H), 2.80 (s, 1H), 2.51 (s, 1H), 2.12 (s, 1H), 2.10 – 1.73 (m, 8H), 1.11 (ddt, J = 12.7, 8.2, 4.1 Hz, 1H), 0.95 (dt, J = 8.1, 3.0 Hz, 2H), 0.87 (dq, J = 6.8, 4.2, 3.7 Hz, 2H), 0.73 – 0.54 (m, 2H), 0.40 (t, J = 5.0 Hz, 2H). Example 12: 6-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(5-chloropyridin-2-yl)-4-(1- (cyclopropylmethyl)piperidin-4-yl)pyridin-2-amine (Compound 22)

[0236] A solution of 6-{3-azabicyclo [3.1.0] hexan-3-yl}-N-(5-chloropyridin-2-yl)-1'- (cyclopropylmethyl)-3',6'-dihydro-2'H-[4,4'-bipyridin]-2-amine (0.1 g, 0.237 mmol, 1 equiv) and PtO2(0.03 g, 0.118 mmol, 0.5 equiv) in MeOH (5 mL) was stirred for 2 h at 40 °C under hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford crude product. The crude product (50 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3+0.1%NH3`H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 59% B to75% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 11.23) to afford 6-{3-azabicyclo[3.1.0]hexan-3-yl}-N-(5-chloropyridin-2-yl)-4-[1- (cyclopropylmethyl)piperidin-4-yl]pyridin-2-amine (15.9 mg, 15.67%) as a yellow solid. LC-MS (ES, m / z): [M+H]+=424.1H-NMR (400 MHz, DMSO-d6): 9.28 (s, 1H), 8.14 - 8.03 (m, 2H), 7.65 (dd, J = 9.2, 2.8 Hz, 1H), 6.38 (s, 1H), 5.73 (s, 1H), 3.56 (d, J = 10.0 Hz, 2H), 3.14 (d, J = 11.2, 2H), 2.97 (dt, J = 11.6, 3.2 Hz, 2H), 2.21 (tt, J = 11.6, 4.0 Hz, 1H), 2.11 (d, J = 6.4 Hz, 2H), 1.88 (dt, J = 11.2, 6.0 Hz, 2H), 1.67 - 1.46 (m, 6H), 0.82 - 0.71 (m, 1H), 0.65 (td, J = 7.6, 4.4 Hz, 1H), 0.45 - 0.32 (m, 2H), 0.13 (q, J = 4.0 Hz, 1H), 0.01 (s, 2H). Example 13: 6-((6-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(1-(cyclopropylmethyl)piperidin-4- yl)pyridin-2-yl)amino)nicotinonitrile (Compound 23)

[0237] A mixture of 2'-{3-azabicyclo[3.1.0]hexan-3-yl}-6'-chloro-1-(cyclopropylmethyl)-3,6- dihydro-2H-4,4'-bipyridine (50 mg, 0.152 mmol, 1 equiv), 6-aminopyridine-3-carbonitrile (18.06 mg, 0.152 mmol, 1 equiv), Xphos Pd G3 (12.83 mg, 0.015 mmol, 0.1 equiv), XPhos (7.23 mg, 0.015 mmol, 0.1 equiv) and Cs2CO3(98.77 mg, 0.304 mmol, 2 equiv) in dioxane (5 ml) was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with water (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (12:1) to afford crude product. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5m; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 53% B in 9 min; Wave Length: 254nm / 220nm; RT1(min): 12.12) to afford 6-[(6-{3-azabicyclo[3.1.0]hexan-3- yl}-4-[1-(cyclopropylmethyl)piperidin-4-yl]pyridin-2-yl)amino]pyridine-3-carbonitrile (24.2 mg, 37.94%) as a white solid. LC-MS (ES, m / z): [M+H]+=415.1H-NMR (400 MHz, DMSO-d6): 9.88 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 9.2 Hz, 1H), 8.0 (dd, J = 9.2, 2.4 Hz, 1H), 6.55 (s, 1H), 5.91 (s, 1H), 3.64 (d, J = 10.4 Hz, 2H), 3.40 (d, J = 11.2 Hz, 2H), 3.05 (d, J = 11.2 Hz, 2H), 2.31 (tt, J = 11.6, 4.0 Hz, 1H), 2.18 (d, J = 6.4 Hz, 2H), 1.96 (td, J = 11.6, 2.8 Hz, 2H), 1.77 - 1.53 (m, 6H), 0.90 - 0.69 (m, 2H), 0.46 (dt, J = 8.0, 3.2 Hz, 2H), 0.20 (q, J = 4.0 Hz, 1H), 0.13 - 0.00 (m, 2H).

[0238] The compounds below were synthesized following the procedure described in Example 13.-Ill-Alternate conditions used:46 h reaction time.290 °C reaction temperature.3BrettPhos Pd G3 used instead of XPhos Pd G3 and BrettPhos used instead of XPhos.Example 14: N-(5-(difluoromethyl)pyridin-2-yl)-6-morpholino-4-(piperazin-l-yl)pyridin-2- amine (Compound 29)

[0239] To a stirred solution of tert-butyl 4-[2-chloro-6-(morpholin-4-yl)pyridin-4-yl]piperazine- 1-carboxylate (300 mg, 0.784 mmol, 1 equiv) and 5-(difluoromethyl)pyridin-2-amine (135.51 mg, 0.941 mmol, 1.2 equiv) in 1,4-dioxane (5 mL) were added CS2CO3 (510.57 mg, 1.568 mmol, 2equiv),X-Phos (37.35 mg, 0.078 mmol, 0.1 equiv) and XPhos Pd G3 (37.35 mg, 0.078 mmol, 0.1 equiv). The resulting mixture was stirred overnight at 90 °C. The reaction was monitored by LCMS. The reaction was quenched with Water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4-(2-{[5-(difluoromethyl)pyridin-2-yl]amino}-6-(morpholin-4-yl)pyridin-4- yl)piperazine-1-carboxylate (250 mg, 65.04%) as a brown solid. LC-MS (ES, m / z): [M+H]+=490.35.

[0240] To tert-butyl 4-(2-{[5-(difluoromethyl)pyridin-2-yl]amino}-6-(morpholin-4-yl)pyridin-4- yl)piperazine-1-carboxylate (60 mg, 0.122 mmol, 1 equiv) in DCM (3 mL) was added TFA (3 mL, 40.389 mmol, 330.22 equiv). The resulting mixture was stirred for 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5m; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 2% B to 18% B in 10 min; Wave Length: 254nm / 220nm; RT1(min): 11.38) to afford N-[5-(difluoromethyl)pyridin-2-yl]-6-(morpholin-4-yl)-4-(piperazin-1- yl)pyridin-2-amine (19.3 mg, 40.41%) as a light yellow solid. LC-MS (ES, m / z): [M+H]+= 618.18.1H-NMR (400 MHz, DMSO-d6): J = 8.8 Hz, 1H), 7.25 – 6.95 (m, 2H), 6.43 (s, 1H), 6.05 (s, 1H), 3.82-3.75 (m, 8H), 3.50 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 4.8 Hz, 4H).19F-NMR (400 MHz, DMSO-d6

[0241] The compounds below were synthesized following the procedure described in Example 14.Alternate conditions used:'2 h reaction time and 100 °C temperature in Step 1.23 h reaction time and 80 °C temperature in Step 1.31 h reaction time, 120 °C temperature, and DMF in place of 1,4 dioxane in Step 1.4HCl / dioxane used instead of TFA / DCM for Boc deprotection in Step 2.51 h reaction time and 100 °C temperature in Step 1.63 h reaction time in Step 1.716 h reaction time, 120 °C temperature, and DMF in place of 1,4 dioxane in Step 1.83 h reaction time, 100 °C temperature, and DMF in place of 1,4 dioxane in Step 1.9110 °C temperature in Step 1.103 h reaction time and 100 °C temperature in Step 1.11120 °C temperature in Step 1.12BrettPhos Pd G3 used instead of XPhos Pd G3 and BrettPhos used instead of XPhos in Step 1.Example 15: LZK and DLK inhibition assay

[0242] The kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for the kinase assays. The liganded beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and to reduce nonspecific binding. Binding reactions were assembled by combining LZK and DLK kinases, liganded affinity beads, and test compounds in lx binding buffer (20% SeaBlock, 0.17x PBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 11 IX stocks in 100% DMSO. Kds were determined using an 11 -point 3 -fold compound dilution series with three DMSO control points. All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%. All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 mL. The assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (lx PBS, 0.05% Tween 20). The beads were then re-suspended in elution buffer (lx PBS, 0.05% Tween 20, 0.5 pM nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured by qPCR.

[0243] Representative data for exemplary compounds disclosed herein is presented in Table 1.Table 1where ‘++++’ means IC50M; where ‘+++’ means 0.1 M < IC50M; where ‘++’ means 1.0 M < IC50 M; where ‘+’ means >30 M; NT means not tested

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5; R2is -N(R4)C1-6alkyl, -N(R4)C1-6alkyl-OH, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, or -CH2-C3-6cycloalkyl, wherein C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three R6; each R3is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- 9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); R4is selected from hydrogen and C1-6alkyl; each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -OR10, -SR10, -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, - S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, - CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -C(O)OR10; each R6is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2- C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, - OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), - N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(R10)(R11), -N(R12)C(O)R13, -S(O)2R13, -S(O)2N(R10)(R11)-, -CH2C(O)N(R10)(R11), - CH2N(R12)C(O)R13, -CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2- 9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and n is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is C2-9heterocycloalkyl optionally substituted with one, two, or three R6.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[3.2.0]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl, wherein 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.2.0]heptanyl, 3- azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl are optionally substituted with one, two, or three R6.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein each R6is independently selected from halogen and C1-6haloalkyl.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from, , , ,7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -N(R4)C1-6alkyl-OH.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

9. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein10. The compound of any one of claims 7-9, or a pharmaceutically acceptable salt or solvate.

11. The compound of any one of claims 7-10, or a pharmaceutically acceptable salt or solvate thereof, wherein.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein:, wherein the C2-9heterocycloalkyl is a monocyclic ring.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein:is selected from morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl.

14. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein:, wherein the C2-9heterocycloalkyl comprises a bridged ring or a spirocyclic ring.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein:is selected from 3,6-diazabicyclo[3.1.1]heptanyl, 6-oxa-3- azabicyclo[3.1.1]heptanyl, and 2-oxa-7-azaspiro[3.5]nonanyl.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and -CH2-C3-6cycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl,and -CH2-C3-6cycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen and unsubstituted C1-6alkyl.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

20. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

21. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are optionally substituted with one, two, or three R5.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are optionally substituted with one R5.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein the pyrazinyl are pyridinyl are substituted with one R5and R5is cyclopropyl.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate.

27. A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein: R7i 3-6cycloalkyl, -CH2-C3--membered monocyclic heterocycloalkyl ring, and wherein C1-6alkyl, -N(R8)C1- 2-C2- 9heterocycloalkyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl,are optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1- 6haloalkyl; and R8is selected from hydrogen and C1-6alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from - OH, halogen, C1-6alkyl, and C1-6haloalkyl.

29. The compound of claim 27 or claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein, wherein-membered monocyclic heterocycloalkyl ring optionally substituted with one, two, or three groups selected from - OH, halogen, C1-6alkyl, and C1-6haloalkyl.

30. The compound of any one of claims 27-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is selected from, , and .

31. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is -N(R8)C1-6alkyl optionally substituted with one, two, or three groups selected from -OH, halogen, C1-6alkyl, and C1-6haloalkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R7is -N(R8)C1-6alkyl substituted with one -OH.

33. The compound of claim 31 or claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R8is hydrogen.

34. The compound of any one of claims 31-33, or a pharmaceutically acceptable salt or solvate35. The compound of any one of claims 31-34, or a pharmaceutically acceptable salt or solvate.

36. The compound of any one of claims 31-35, or a pharmaceutically acceptable salt or solvateor a pharmaceutically acceptable salt or solvate thereof.

40. A pharmaceutical composition comprising a compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

41. A method of treating cancer in a mammal, comprising administering to the mammal a compound of any one of claims 1-39, or a pharmaceutically acceptable salt or solvate thereof.

42. The method of claim 41, wherein the cancer is selected from head and neck squamous cell carcinoma and esophageal squamous cell carcinoma.

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