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 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No.63 / 562,050, filed March 6, 2024, and U.S. Provisional Patent Application No. 63 / 684,966, filed August 20, 2024, which are incorporated herein by reference in their entireties.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;each R2aand each R3is independently selected from halogen, -OH, -CN, oxo, C1. 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3.6cycloalkyl, -CH2- Cs-ecycloalkyl, C2.9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2- C6.ioaryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -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, C1-6alkoxy, 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); each R5is independently selected from halogen, -CN, C1-6alkyl, -CF3, C2-6haloalkyl, C2-6alkenyl, C2.ealkynyl, C3.6cycloalkyl, -CH2-C3.6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2-C6.ioaryl, Ci.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-CI.9heteroaryl are optionally substituted with one, two, or three groups selected from C1-6alkyl, C1-6haloalkyl, -OR10, 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. gheteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2.ealkynyl, 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 Ci. 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 Ci.gheteroaryl, 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 C1-9hhteroaryl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p 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 m is 1 . In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0006] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from halogen, - OH, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0007] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2is independently selected from halogen and -OH.

[0008] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2, or 3. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is i .

[0009] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected frompharmaceutically acceptable salt or solvate thereof,F. 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. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereiis selected from morpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl.

[0010] 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. 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.

[0011] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen, - OH, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. 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 -OH.

[0012] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0013] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinselected from,, and. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinselected from. In some embodiments, is a compound ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof, whereinselected from

[0014] In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl substituted with one or two R5. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyridinyl substituted with one or two R5.

[0015] 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, -CF3, and C3-6cycloalkyl. In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen and cyclopropyl.

[0016] In some embodiments, is a compound of Formula (I), or a pharmaceuticallysome embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt orF solvate thereof, wherein R1is

[0017] In another aspect, described herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:Formula (II); wherein:X, Y, and Z are independently selected from N and C(R4), wherein at least two of X, Y, and Z are N;R1is a 5 - or 6-membered heteroaryl ring optionally substituted with one, two, or three R5;each R2ais independently selected from halogen, -OH, -SR10, -N(R10)(R11), -CN, Ci. 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3.6cycloalkyl, and C2. 9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, Ci. 6alkoxy, C3.6cycloalkyl, and C2.9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); or two R2aare combined to form a C3.6cycloalkyl; each R3ais independently selected from halogen, -OH, -SR10, -N(R10)(R11), -CN, Ci. 6alkyl, Ci-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C1-6alkoxy, C3.6cycloalkyl, and C2. 9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, Ci. 6alkoxy, C3.6cycloalkyl, and C2.9heterocycloalkyl are optionally substituted withone, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11);R4is selected from hydrogen, halogen, -OH, -N(R10)(R11), -CN, C1-6alkyl, and Ci. 6haloalkyl; each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2- ealkenyl, C2-e lkynyl, Cs-ecycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C1-9heteroaryl, -CH2-Ci-9heteroaryl, -OR10, -SR10, - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-ealkynyl, Cs-ecycloalkyl, -CH2-C3-6cycloalkyl, C2-9heterocycloalkyl, -CH2-C2- gheterocycloalkyl, Ci.gheteroaryl, and -CH2-Ci-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, Ci. 6haloalkyl, -OR10, and -C(O)OR10;R6is selected from hydrogen and C1-6alkyl; each R10is independently selected from hydrogen, C1-6alkyl, Ci_6haloalkyl, C2. 6alkenyl, C2-6alkynyl, C3.6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci. gheteroaryl, wherein C1-6alkyl, C2-ealkenyl, C2-ealkynyl, Cs-ecycloalkyl, C2- gheterocycloalkyl, C6- 10aryl, and Ci.gheteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, Ci. 6haloalkyl, C1-6alkoxy, C3.6cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and Ci. gheteroaryl; 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-ealkenyl, C2-ealkynyl, Cs-ecycloalkyl, 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, Cs-ecycloalkyl, C2- 9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0018] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ila):Formula (Ila).

[0019] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lib):Formula (lib).

[0020] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lie):Formula (lie).

[0021] In some embodiments, is a compound of Formula (II), (Ila), (lib), or (lie), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.

[0022] In some embodiments, is a compound of Formula (II), (Ila), (lib), or (lie), or a pharmaceutically acceptable salt or solvate thereof, wherein R4is halogen.

[0023] In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lid):

[0024] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R3isIn some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or(IId), or a pharmaceutically acceptable salt or solvate thereof, wherein each R3ais independently selected from halogen, -OH, -CN, Ci.6alkyl, C1-6haloalkyl, and C1-6alkoxy.

[0025] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0026] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is

[0027] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -N(R6)C1-6alkyl-OH.

[0028] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

[0029] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, wherein R2isH\ . In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R2isH

[0030] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R2is

[0031] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independentlyselected from halogen, -OH, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independently selected from halogen and -OH.

[0032] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2, or 3. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein two R2aare combined to form a C3.6cycloalkyl.

[0033] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

[0034] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or aF pharmaceutically acceptable salt or solvate thereof, wherein

[0035] In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a 5-membered heteroaryl ring optionally substituted with one, two, or three R5.

[0036] In some embodiments, is a compound of Formula (II), (Ila), (lib ), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a pyrazolyl ring optionally substituted with one, two, or three R5. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a pyrazolyl ring substituted with one, two, or three R5. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or(IId), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are substituted with one or two R5. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-6alkyl, Ci.6haloalkyl, and C3.6cycloalkyl. In some embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen and cyclopropyl. In some embodiments, is acompound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1issome embodiments, is a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is

[0037] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I), (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0038] In another aspect, described herein is a method of treating cancer in a mammal, comprising administering to the mammal a compound of Formula (I), (II), (Ila), (lib), (lie), or (lid), 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), (II), (Ila), (lib), (lie), or (lid), 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), (II), (Ila), (lib), (lie), or (lid), 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.

[0039] 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

[0040] 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) (DermanBA, et al 2015, Transl. Lung Cancer Res; 4, 524-532) (Marur S, et all 2008, Mayo Clinic Proceedings; Vol 83, 489-501) (AbnetCC, etal 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).

[0041] 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

[0042] The compounds described herein, including pharmaceutically acceptable salts and solvates thereof, are leucine zipper-bearing kinase (LZK) inhibitors.

[0043] In some embodiments, the present disclosure provides 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;each R2aand each R3is independently selected from halogen, -OH, -CN, oxo, Ci.6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3.6cycloalkyl, -CH2- Cs-ecycloalkyl, C2.9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2- C6.ioaryl, C1-9heteroaryl, -CH2-C1-9heteroaryl, -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. ealkynyl, C1-6alkoxy, Cs-ecycloalkyl, -CH2-C3-6cycloalkyl, C2.9heterocycloalkyl, - CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, Ci.gheteroaryl, and -CH2-CI. 9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); each R5is independently selected from halogen, -CN, C1-6alkyl, -CF3, C2-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C3.6cycloalkyl, -CH2-C3.6cycloalkyl, C2. 9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2-C6.ioaryl, Ci.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-CI. gheteroaryl are optionally substituted with one, two, or three groups selected from C1-6alkyl, C1-6haloalkyl, -OR10, and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, Ci_6haloalkyl, C2. 6alkenyl, C2.6alkynyl, C3.6cycloalkyl, C2.9heterocycloalkyl, C6- 10aryl, and Ci. gheteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2.ealkynyl, Cs-ecycloalkyl, C2. 9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, Ci. ehaloalkyl, C1-6alkoxy, Cs-ecycloalkyl, C2.9heterocycloalkyl, C6- 10aryl, and Ci. 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, Cs-ecycloalkyl, 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, Cs-ecycloalkyl, C2. 9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0044] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, m is 0. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, m is 1 . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, m is 2 .

[0045] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, and C1-6alkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen and -OH. In some embodients, each R2ais -OH. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R2ais fluoro.

[0046] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 1, 2, or 3. 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 acompound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 4. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, n is 0.

[0047] In some embodiments, for a compound of Formula (I), or a pharmaceuticallycompound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2isembodiments, 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,. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, R2is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2isIn some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2isjnsome 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 orsolvate thereof, R2isF. In some embodiments, for a compound of Formula (I),or a pharmaceutically acceptable salt or solvate thereof, R2isF. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt orsolvate thereof, R2isF. 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 apharmaceutically acceptable salt or solvate thereof, R2is0H. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2is0H. In some embodiments, for a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, R2is OH . in some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R2issome embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0048] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,9heterocycloalkyl is a monocyclic ring. In some embodiments, for a compound of Formula(I), or a pharmaceutically acceptable 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 I acceptable salt or solvate thereof,is piperidinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,pyrrolidinyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is azetidinyl. In some embodiments, for acompound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is piperazinyl.

[0049] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,is Cj. heterocycloalkyl, wherein the C2. pheterocycloalkyl 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,IS C2-9heterocycloalkyl, wherein the C^heterocycloalkyl comprises a bridged ring. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein the C2.9heterocycloalkyl 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. l]heptanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, and2-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 ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,-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.

[0050] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is independently selected from halogen, -OH, oxo, C1.6alkyl, Ci-cJialoalkyl, and C1.6alkoxy. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is independently selected from halogen, -OH, C1-6alkyl, and CiJbaloalkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, eachR3is independently selected from halogen. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is -OH. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R3is independently selected from C1-6alkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, eachR3is independently selected from Ci.ghaloalkyl.

[0051] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 0, 1, or 2. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 1 . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 2. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 3 . In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 4.

[0052] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, p is 0.

[0053] In some embodiments, for a compound of Formula (I), or a pharmaceuticallyand. 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,selected from. In 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 ofFormula (I), or a pharmaceutically acceptable salt or solvate thereof,. In some embodiments, for a compound of Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof,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,some embodiments, for a compound ofFormula (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,some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0054] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, Rlispyrazinyl optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl substituted with one, two, or three R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl substituted with one or two R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl substituted with one R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl substituted with one, two, or three R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl substituted with one or two R5. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl substituted with one R5.

[0055] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen, C1-6alkyl, - CF3, and Cs-gcycloalkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen and C^cycloalkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen and cyclopropyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R is independently selected from C^cycloalkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is cyclopropyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from C1-6alkyl. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is -CH3. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, each R5is -CF3.

[0056] In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1isembodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof,In some embodiments, fora compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of FormulaF(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, Rlis. In some embodiments, for a compound of Formula (I),F 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, R!is. 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, 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 orF solvate thereof, R1is. In some embodiments, for a compound of Formula (I), orF a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt orF solvate thereof, R1is. In some embodiments, for a compound of Formula (I),F or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt orCl solvate thereof, R1is. In some embodiments, for a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, R1is

[0057] In some embodiments, the present disclosure provides a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof :Formula (II); wherein;X, Y, and Z are ind ependently selected from N and C(R4), wherein at least two of X, Y, and Z are N;R1is a 5 - or 6-membered heteroaryl ring optionally substituted with one, two, or three R5;each R2ais independently selected from halogen, -OH, -SR10, -N(R10)R11), -CN, C1. ealkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C1-6alkoxy, C3.6cycloalkyl, and C2. gheterocycloalkyl, wherein C1.6alkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, C1- 6alkoxy, C3.6cycloalkyl, and C2.9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); or two R2aare combined to form a C3-6cycloalkyl; each R3ais independently selected from halogen, -OH, -SR10, -N(Ri0)(R11), -CN, C1- 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2.ealkynyl, C1-6alkoxy, C3.6cycloalkyl, and C2. 9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2.6alkenyl, C2.6alkynyl, Ci. 6alkoxy, C3-6cycloalkyl, and C2-9heterocycloalkyl 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, halogen, -OH, -N(R10)(R11), -CN, C1-6alkyl, and Ci. ehaloalkyl; 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, C1-9heteroaryl, -CH2-Cj.9heteroaryl, -OR10, -SR10, -S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkeny[, C2-6alkynyl, Cj-gcycloalkyl, -CH2-C3.gcycloalkyl, C2-9heterocycloalkyl, -CH2-C2. gheterocycloalkyl, Ci.gheteroaryl, and -CH2-Cj.9heteroaryl are optionally substituted with one, two, or three groups selected from halogen. Chalky 1, Ci„ ghaloalkyl, -OR10, and -C(O)OR10;R6is selected from hydrogen and Ci.galkyl; each Ri0is independently selected from hydrogen, C1-6alkyl, C^g haloalkyl, C2. 6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and Ci„ yheteroaryl, wherein Ci.galkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. gheterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, hydroxy, C1-6alkyl, C1- ghaloalkyl, 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 Ci.gheteroaryl, 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. gheterocycloalkyl, C6-10aryl, and Ci.gheteroaryl; m is 0, 1 , or 2, n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4.

[0058] In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X and Y are N, and Z is C(R4). In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X and Z are N, and Y is C(R4). In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, Y and Z are N, and X is C(R4). In some embodiments, for a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, X, Y, and Z are N.

[0059] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ila):Formula (Ila).

[0060] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lib):Formula (lib).

[0061] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lie):Formula (He).

[0062] In some embodiments, for a compound of Formula (II), (Ila), (lib), or (lie), or a pharmaceutically acceptable salt or solvate thereof, R4is hydrogen. In some embodiments, fora compound of Formula (II), (Ila), (lib), or (lie), or a pharmaceutically acceptable salt or solvate thereof, R4is hydrogen.

[0063] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lid):

[0064] In some embodiments, for a compound of (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R3is. In some embodiments, for a compound of (II), (Ila), (lib), (lie), or (lid), or a pharmaceuticallyacceptable salt or solvate thereof, R3isIn some embodiments, for a compound of (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from halogen, -OH, -CN, Chalky 1, C1-6haloalkyl, and C1-6alkoxy . In some embodiments, for a compound of (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from halogen, C1-6alkyl, and C1-6haloalkyL In some embodiments, for a compound of (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from halogen. In some embodiments, for a compound of (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from C1-6alkyl. In some embodiments, for a compound of (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from CiJhaloalkyl. In some embodiments, for a compound of (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from -OH. In some embodiments, for a compound of (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R3ais independently selected from C1-6alkoxy.

[0065] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 0, 1, or 2. In some embodiments, for a compound of Formula (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 1 . In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 2. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 3 . In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 4.

[0066] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, p is 0.

[0067] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R3isjn SOme embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptablesalt or solvate thereof, R3is . In some embodiments, for a compound of Formula(II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R3is

[0068] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R6)Ci-6alkyl-OH. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is -N(R6)C1-6alkyl-OH and R6is hydrogen. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), ora pharmaceutically acceptable salt or solvate thereof, R2is -N(R6)Ci-6alkyl-OH and R6is Ci-6alkyl. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), ora pharmaceutically acceptable salt or solvate thereof, R2is -N(R6)Ci-6alkyl-OH and R6is - CH3. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isH,Hsome embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isH. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isH. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isHIn some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptablesalt or solvate thereof, R2isIn some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2isIn some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, R2is \ . In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2is \

[0069] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R is

[0070] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, m is 0. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, m is 1. In some embodiments, for a compound of Formula (II), (Ila), (lib),(lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, m is 2 .

[0071] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, C1-6alkyl, Ci.6haloalkyl, and C1-6alkoxy. In some embodiments, for a compound of Formula (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, C1-6alkyl, and C1-6haloalkyl. In some embodiments, for a compound of Formula (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen, -OH, and C1-6alkyl. In some embodiments, for a compound of Formula (II), (Ila), (Hb), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen and -OH. In some emb odients, eachR2ais -OH. In some embodiments, for a compound of Formula (II), (Ila), (Hb), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, each R2ais independently selected from halogen. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R2ais fluoro.

[0072] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 1, 2, or 3. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 1 . In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 2. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 3 . In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 4. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, n is 0.

[0073] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or aFormula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, R2is selected fromcompound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt orsolvate thereof, R2is OH . in some embodiments, for a compound of Formula (II),(Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2isF. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), orF(lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2isin some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isF. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isF. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or apharmaceutically acceptable salt or solvate thereof, R2isF. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptablesalt or solvate thereof, R2is0H. In some embodiments, for a compound of Formula(II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is0H. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, R2isOH. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2issome embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is

[0074] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, two R2aare combined to form a C3-6cycloalkyl. In some embodiments, fora compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R2is.

[0075] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a 5-membered heteroaryl ring optionally substituted with one, two. or three R5. In some embodiments, for a compound ofFormula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a pyrazolyl ring optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a pyrazolyl ring substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a pyrazolyl ring optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a pyrazolyl ring optionally substituted with one or two R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a pyrazolyl ring optionally substituted with one R5.

[0076] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, Rlis pyrazinyl substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl substituted with one or two R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyrazinyl substituted with one R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl optionally substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl substituted with one, two, or three R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), ora pharmaceutically acceptable salt or solvate thereof, Rlis pyridinyl substituted with one or two R5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), ora pharmaceutically acceptable salt or solvate thereof, R1is pyridinyl substituted with oneR5. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen, C1-6alkyl, Cj. ehaloalky 1, and Cs-ecycloalkyl. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen and Cs-ecycloalkyl. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen and cyclopropyl. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from halogen. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is cyclopropyl. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from C1.6alkyl. In some embodiments, for a compound of Formula (II), (Ila), (lib),(lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, each R5is independently selected from C1-6haloalkyl.

[0077] In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptablesalt or solvate thereof, R1is. In some embodiments, for a compound of Formula(II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or(lid), or a pharmaceutically acceptable salt or solvate thereof, R1is. in some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or aF pharmaceutically acceptable salt or solvate thereof, R1is. In some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or a pharmaceutically acceptable salt or solvate thereof, R1is. in some embodiments, for a compound of Formula (II), (Ila), (lib), (lie), or (lid), or aF pharmaceutically acceptable salt or solvate thereof, R1is

[0078] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure:

[0079] 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.

[0080] “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 isrelatively 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.

[0081] 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 nonionic 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.

[0082] 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-dichloroaceticacid; 2 -hydroxy ethanesulfonic 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-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoicacid; 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.

[0083] 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.

[0084] 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."

[0085] 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 herein form 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] Compounds described herein include isotopically -lab eled 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,17O,35S,18F,36C1. In one aspect, isotopically -lab eled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. 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 half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein is replaced with deuterium.

[0091] 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.

[0092] 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 thecompounds 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.

[0093] 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.

[0094] 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 glucuronyltransf erases catalyze the transfer of an activated glucuronic -acid molecule 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.

[0095] In additional or further embodiments, the compounds are rapidly metabolized in plasma.

[0096] In additional or further embodiments, the compounds are rapidly metabolized by the intestines.

[0097] In additional or further embodiments, the compounds are rapidly metabolized by the liver.Synthesis of Compounds

[0098] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0099] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0100] 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.

[0101] 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, "Modern 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.

[0102] In some embodiments, compounds are prepared as described in the Examples.Certain Terminology

[0103] 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.

[0104] As used herein, Ci-Cxor Ci-Xincludes C1-C2, C1-C3 . . . Ci-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, "Ci-C4alkyl" or "Ci-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, Ao-propyl, w-butyl, Ao-butyl, ec-butyl, and Z-butyl.

[0105] 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 Ci-CiOalkyl. 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 Ci-Cealkyl. 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.

[0106] 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 Ci-Cealkylene. In other embodiments, an alkylene is a Ci-C4alkylene. In certain embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-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 carbonatoms e.g., C2alkylene). In other embodiments, an alkylene comprises two to four carbon atoms (e.g., C2-C4alkylene). 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.

[0107] “Deuteroalkyl” refers to an alkyl group where 1 or more hydrogen atoms of an alkyl are replaced with deuterium.

[0108] 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)=CR2, 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 (z.e., vinyl), propenyl (z.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.

[0109] The term “alkynyl” refers to a type of alkyl group in which at least one carboncarbon 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, - C=CCH3-C=CCH2CH3, -CH2C=CH.

[0110] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0111] The term “alkylamine” refers to the -N(alkyl)xHygroup, 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.

[0112] The term “aromatic” refers to a planar ring having a delocalized rr-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 (z.e., rings which share adjacent pairs of carbon or nitrogen atoms) groups.

[0113] 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 atom which 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.

[0114] 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 Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0115] 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, norbomyl and bicyclofl . l .l]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), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0116] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0117] 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 Ci-Cefluoroalkyl.

[0118] 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 Ci-C6fluoroalkyl. In some embodiments, a fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2 -fluoroethyl, and the like.

[0119] 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 Ci- C6heteroalkyl.

[0120] The term “heteroalkylene” refers to a divalent heteroalkyl group.

[0121] The term "heterocycle" or “heterocyclic” refers to hetero aromatic 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) orimidazol-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.

[0122] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples 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 0 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 Ci-Cgheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[0123] 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-Ci0heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4- Cioheterocycloalkyl. 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.

[0124] 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 largersubstructure. 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.

[0125] 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.

[0126] 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(Ci-C4alkyl), -C(=O)NH2, - C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), - S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci- C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-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 (=0).

[0127] 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.

[0128] 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 methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] The terms “kit” and “article of manufacture” are used as synonyms.

[0133] 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.

[0134] 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, inhibitingthe 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

[0135] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner 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 & Wilkins 1999), herein incorporated by reference for such disclosure.

[0136] 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 feedingtube, rectal suppository andrectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intra vitreal, 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.

[0137] 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.

[0138] 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 machine the 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.

[0139] 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 presentedin 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.

[0140] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (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, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0141] Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulations maybe administered by implantation (for example subcutaneously or intramuscularly) orby 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid 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.

[0146] 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, dichlorotetrafluoroethane, 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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( 1 ):33 -66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific drugdelivery 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.

[0151] 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

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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 severityand 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

[0156] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[0157] 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 acetylacetoneACN or MeCN acetonitrile AcOH acetic acidAc acetylBINAP 2,2'-bis(diphenylphosphino)-l,r-binaphthaleneBn benzylBOC or Boc tert-butyl carbamate i-Bu / .w-butyl t-Bu tert-butylCy cyclohexylCDI 1,1 -carbonyldiimidazoleCPME cyclopentyl methyl etherDAST (diethylamino)sulfur trifluorideDBA or dba dibenzylideneacetoneDCE dichloroethane (CICH2CH2CI)DCM dichloromethane (CH2Q2)DHP 3,4-dihydropyranDIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-(7V,7V-dimethylamino)pyridineDME 1 ,2-dimeth oxy ethaneDMF .V-dimethylformamideDMA AA-dimethylacetamideDMPU AyV'-dimethylpropyleneureaDMSO dimethylsulfoxideDppf or dppf 1 , 1 ’-bis(diphenylphosphino)ferroceneEDC or EDCI A-(3-dimethylaminopropyl)-A’-ethylcarbodiimide hydrochlorideEEDQ 2-ethoxy-l -ethoxy carbonyl-1 ,2-dihydroquinoline eq equivalent(s)Et ethylEt2O diethyl etherEtOH ethanolEtOAc ethyl acetateHATU l-[bis(dimethylamino)methylene]-lA-l,2,3-triazolo[4,5-Z>]pyridinium3-oxid hexafluorophosphateHMPA hexamethylphosphoramideHOBt 1 -hydroxybenzotriazoleHPLC high performance liquid chromatographyIBX 2-iodoxybenzoic acidKO Ac potassium acetateKHMDS potassium bis(trimethylsilyl)amideNaHMDS sodium bis(trimethylsilyl)amideLiHMDS lithium bis(trimethylsilyl)amideLAH lithium aluminum anhydrideLC-MS liquid chromatography mass spectrometry2-MeTHF 2-methyltetrahydrofuranMe methylMeOH methanolMOM methoxymethyl etherMSmass spectroscopyMs mesylMTBE methyl / c / 7-butyl etherNBS A-bromosuccinimideNCS A-chlorosuccinimideNIS A-iodosuccinimideNMI 1 -methylimidazoleNMM A-methyl-morpholineNMP A-methyl-pyrrolidin-2-oneNMR nuclear magnetic resonanceOTf trifluoromethanesulfonatePCC pyridinium chlorochromatePE petroleum etherPG protecting groupPh phenylPPTS pyridium / ?-toluenesulf onate iPr / i-Pr / .w-propylRP-HPLC reverse-phase high-pressure liquid chromatography rt room temperatureSEM 2-(trimethylsilyl)ethoxymethylTBS tert-butyldimethylsilylTBAF tetra-w-butylammonium fluorideTBAI tetra-w-butylammonium iodideTCFH chloro-A,A,7V’,7V’ -tetramethylformamidinium hexafluorophosphateTEA triethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatographyTMEDA N, N, N1, A'-tetram ethylethylenediamineTMS trimethylsilylTsOH / / ?-TsOH / ?-toluenesulfonic acidExample 1: Synthesis of 3-(2-chloro-6-(l-(cyclopropylmethyl)piperidin-4-yl)pyrimidin-4-yl)-3-azabicyclo [3.1.0] hexane (Intermediate la)Intermediate 1a

[0158] A solution of 2,4,6-trichloropyrimidine (3 g, 16.36 mmol, 1 equiv), 3- azabicyclo[3.1.0]hexane (1.36 g, 16.36 mmol, 1 equiv) and K2CO3 (5.66 g, 40.9 mmol, 2.5 equiv) in DMA (50 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (5 x 150 mL). The combined organic layers were washed with water (5 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 PE / EA (12 : 1 ) to afford 3 -(2,6-dichloropyrimidin-4-yl)- 3-azabicyclo[3.1.0]hexane (1.5 g, 40%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 230.

[0159] A solution of 3-(2,6-dichloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane (500 mg, 2.17 mmol, 1 equiv), l-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine (572 mg, 2.17 mmol, 1 equiv), Pd(dppf)C12 (177 mg, 0.22 mmol, 0.1 equiv) and K2CO3(601 mg, 4.35 mmol, 2 equiv) in dioxane (3 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with water (70 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 CH2CI2 / MeOH (12:1) to afford 3-{2-chloro-6-[l-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4-yl]pyrimidin-4-yl}-3- azabicyclo[3.1.0]hexane (200 mg, 28%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 331.

[0160] A solution of 3-{2-chloro-6-[l-(cyclopropylmethyl)-3,6-dihydro-2H-pyridin-4- yl]pyrimidin-4-yl}-3-azabicyclo[3.1.0]hexane (200 mg, 0.60 mmol, 1 equiv) and PtC>2 (41 mg, 0.18 mmol, 0.3 equiv) in MeOH (15 mL) was stirred for 6 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed withMeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (12:1) to afford 3-(2-chloro-6-(l- (cyclopropylmethyl)piperidin-4-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexane (Intermediate la) (145 mg, 72%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 333.

[0161] Intermediate 1 a was used in the synthesis of Compound 1 described in in Example 8.Example 2: Synthesis of tert-butyl 4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5,6- dichloropyrimidin-4-yl)piperazine-l-carboxylate (Intermediate 50a)Intermediate 50a

[0162] A solution of perchloropyrimidine (1.5 g, 6.89 mmol, 1 equiv), tert-butyl piperazine-1 -carboxylate (1.03 g, 5.51 mmol, 0.8 equiv) and DIEA (1.78 g, 13.77 mmol, 2 equiv) in DMSO (20 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (4 x 200 mL). The combined organic layers were washed with brine (4 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 (12 : 1 ) to afford tert-butyl 4-(2,5 ,6-trichloropyrimidin-4-yl) piperazine-1 -carboxylate (1.3 g, 51%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 369.

[0163] A solution of tert-butyl 4-(2,5,6-trichloropyrimidin-4-yl) piperazine-1 -carb oxy late (1 g, 2.72 mmol, 1 equiv), 3-azabicyclo[3.1.0]hexane (181 mg, 2.18 mmol, 0.8 equiv) and K2CO3 (752 mg, 5.44 mmol, 2 equiv) in DMA (20 mL) was stirred for 3 h at room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with brine (5 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 PE / EA (10:1) to afford tert-butyl 4-(2-(3- azabicyclo[3.1.0]hexan-3 -yl)-5,6-dichloropyrimidin-4-yl)piperazine-l -carboxylate(Intermediate 50a) (300 mg, 27%) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+= 414.

[0164] Intermediate 50a was used in the synthesis of Compound 50 described in Example 14.Example 3: Synthesis of tert-butyl 4-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-l,3,5- triazin-2-yl)piperazine-l-carboxylate (Intermediate 51a)iBocIntermediate 51a

[0165] A solution of 2,4,6-trichloro-l,3,5-triazine (2 g, 10.85 mmol, 1 equiv), 3- azabicyclo[3.1.0]hexane (992 mg, 11.93 mmol, 1.1 equiv) andK2COs (7.07 g, 21.69 mmol, 2 equiv) in DMA (50 mL) was stirred for 1 h at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (4 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 (12:1) to afford 3-(4,6-dichloro-l,3,5-triazin-2-yl)-3-azabicyclo[3. L0]hexane (1.8 g, 72%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 231.

[0166] A solution of 3-(4,6-dichloro-l,3,5-triazin-2-yl)-3-azabicyclo[3.1.0]hexane (200 mg, 0.87 mmol, 1 equiv), tert-butyl piperazine-l-carboxylate (129 mg, 0.69 mmol, 0.8 equiv) and DIEA (224 mg, 1.73 mmol, 2 equiv) in DMSO (8 mL) was stirred for 1 h at 80 °C under nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 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 (12:1) to afford tert-butyl 4-(4-(3- azabicyclo[3.1.0]hexan-3 -yl)-6-chloro-l, 3, 5-tri azin-2 -yl)piperazine-l -carboxylate (Intermediate 51a) (180 mg, 55%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 381.

[0167] Intermediate 51a was used in the synthesis of Compound 51 described in Example 13.Example 4: Synthesis of tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-l-yl)pyrimidin- 4-yl)piperazine-l-carboxylate (Intermediate 54a)

[0168] A solution of 2,4,6-trichloropyrimidine (2 g, 10.90 mmol, 1 equiv), 3,3- difluoropyrrolidine (0.93 g, 8.72 mmol, 0.8 equiv) and DIEA (2.82 g, 21.81 mmol, 2 equiv) in DMSO (40 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with water (5 x 30 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 (12:1) to afford 2,4-dichloro-6-(3,3-difluoropyrrolidin-l-yl) pyrimidine (2.2 g, 79%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 254.

[0169] A solution of 2,4-dichloro-6-(3,3-difluoropyrrolidin-l-yl)pyrimidine (2 g, 7.87 mmol, 1 equiv), tert-butyl piperazine- 1-carboxylate (1.47 g, 7.87 mmol, 1 equiv) and DIEA (2.03 g, 15.74 mmol, 2 equiv) in DMSO (20 mL) was stirred for 1 h at 90°C. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with water (5 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 (9: 1) to afford tert-butyl 4-(2-chloro-6-(3,3- difluoropyrrolidin-l-yl)pyrimidin-4-yl)piperazine-l -carboxylate (Intermediate 54a) (800 mg, 25%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 404.

[0170] Intermediate 54a was used in the synthesis of Compound 54 described in Example 15.

[0171] The below intermediates were synthesized following the procedure in Example 4. Intermediate 52a was used in the synthesis of Compound 52 and Intermediate 53 a was used in the synthesis of Compound 53 described in Example 15.Example 5: Synthesis of 5-methyl-4-(trifluoromethyl)pyridin-2-amine (Intermediate72a)H2O / 90 °C / oveminghtIntermediate 72a

[0172] To a stirred mixture of 5-bromo-4-(trifluoromethyl)pyridin-2 -amine (1.0 g, 4.1 mmol, 1.0 equiv) and K2CO3 (2.3 g, 16.6 mmol, 4.0 equiv) in dioxane (12.0 mL) and H2O (3.0 mL) were added trimethyl-l,3,5,2,4,6-trioxatriborinane (1 .6 g, 12.4 mmol, 3.0 equiv) and Pd(dppf)Cl2(304 mg, 0.4 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water / ice (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 120 mL). The combined organic layers were washed with brine (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:l) to afford 5-methyl-4-(trifluoromethyl)pyridin-2- amine (Intermediate 72a) (470 mg, 64%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 177.

[0173] Intermediate 72a was used in the synthesis of Compound 72 described in Example 10.Example 6: Synthesis of 5-cyclopropyl-4-(trifluoromethyl)pyridin-2-amine (Intermediate 73a)Intermediate 73a

[0174] To a stirred mixture of 5-bromo-4-(trifluoromethyl)pyridin-2 -amine (1.0 g, 4.1 mmol, 1.0 equiv), K3PO4(2.6 g, 12.4 mmol, 3.0 equiv) and cyclopropylboronic acid (535 mg, 6.2 mmol, 1.5 equiv) in toluene (20.0 mL) / H2O (4.0 mL) were added Pd(OAc)2(93 mg, 0.4 mmol, 0.1 equiv) and PCy3(233 mg, 0.8 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water / ice (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 150 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 (4:1) to afford 5 - cyclopropyl-4-(trifluoromethyl)pyridin-2 -amine (Intermediate 73a) (700 mg, 83%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 203.

[0175] Intermediate 73 a was used in the synthesis of Compound 73 described in Example 10.Example 7: Synthesis of tert-butyl 4-(2-chloro-6-((3R,4S)-3-fluoro-4-hydroxypiperidin- l-yl)pyridin-4-yl)piperazine-l-carboxylate (Intermediate 83a)

[0176] A solution of tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-l-carboxylate (1 g, 4.561 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (20 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in (3R,4S)-3-fluoropiperidin-4-ol hydrochloride (500 mg,70%) as a light brown solid. The crude product was used in the next step directly without further purification. LC-MS: (ES, m / z): [M+H]+ = 120.

[0177] A mixture of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperazine-l-carboxylate (1 g, 3.010 mmol, 1 equiv), (3R,4S)-3-fhroropiperidin-4-ol hydrochloride (0.47 g, 3.010 mmol, 1 equiv), CS2CO3 (3.92 g, 12.040 mmol, 4 equiv), XPhos Pd G3 (0.25 g, 0.301 mmol, 0.1 equiv) and XPhos (0.29 g, 0.602 mmol, 0.2 equiv) in dioxane (10 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were 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- ((3R,4S)-3-fluoro-4-hydroxypiperidin-l-yl)pyridin-4-yl)piperazine-l -carboxylate (Intermediate 83a) (400 mg, 32%) as a brown solid. LC-MS (ES, m / z): [M+H]+= 415.

[0178] Intermediate 83 a was used in the synthesis of Compound 83 described in Example 9.

[0179] The below intermediates were synthesized following the procedure in Example 7. Intermediate 79a was used in the synthesis of Compound 79 described in Example 9.Intermediate 81a was used in the synthesis of Compound 81 described in Example 9.Example 8: Synthesis of 4-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-6-(l-(cyclopropylmethyl)piperidin-4-yl)pyrimidin-2-amine (Compound 1)Intermediate 1 a Compound 1

[0180] A solution of 3-(2-chloro-6-(l-(cyclopropylmethyl)piperidin-4-yl)pyrimidin-4-yl)- 3-azabicyclo[3.1.0]hexane (Intermediate la) (140 mg, 0.421 mmol, 1 equiv), tert-butyl 3- amino-5-cyclopropylpyrazole-l-carboxylate (66 mg, 0.30 mmol, 0.7 equiv), Cs2CO3(274 mg, 0.84 mmol, 2 equiv), XPhos Pd G3 (36 mg, 0.04 mmol, 0.1 equiv) and XPhos (40.10 mg, 0.08 mmol, 0.2 equiv) in dioxane (10 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with water (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 PE / EA (10:1) to afford tert-butyl 3-[(4-{3- azabicyclo[3.1.0]hexan-3-yl}-6-[l-(cyclopropylmethyl)piperidin-4-yl]pyrimidin-2-yl)amino]- 5-cyclopropylpyrazole-l-carboxylate (100mg, 46%) as a lightyellow oil. LC-MS: (ES, m / z): [M+H]+ = 520.

[0181] A solution of tert-butyl 3-[(4-{3-azabicyclo[3.1.0]hexan-3-yl}-6-[l- (cyclopropylmethyl)piperidin-4-yl]pyrimidin-2-yl)amino]-5-cyclopropylpyrazole-l- carboxylate (90 mg, 0.173 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (10 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 25*250 mm, 10m; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 100 mL / min; Gradient: 35% B to 35% B in 65 min; Wavelength: 254nm / 220nm; RTl(min): 28) to afford 4-(3-azabicyclo[3.1.0]hexan-3- yl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-6-(l-(cyclopropylmethyl)piperidin-4-yl)pyrimidin-2- amine (Compound 1) (25.8 mg, 35%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 420. 'H-NMR (400 MHz, DMSO-d6) 5 12.29 (s, 1H), 10.73 (s, 1H), 5.99 (s, 2H), 4.16 - 3.50 (m, 6H), 3.18-2.91 (m,4H), 2.89-2.77 (m, 1H), 2.36-1.99 (m, 4H), 1.97-1.86 (m, 1H), 1.83- 1.76(m, 2H), 1.30-1.08(s, 1H), 0.96-0.88 (m, 2H), 0.85-0.78 (m, 1H), 0.74 - 0.62 (m, 4H), 0.41 (d, J = 4.8 Hz, 2H), 0.18 (d, J = 4.4 Hz, 1H).Example 9: Synthesis of l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l- yl)pyridin-2-yl)azetidin-3-ol (Compound 2)

[0182] To a stirred solution of tert-butyl 4-(2,6-dichloropyridin-4-yl) piperazine-1- carb oxy late (500 mg, 1.50 mmol, 1 equiv) and azetidin-3-ol hydrochloride (165 mg, 1.50 mmol, 1 equiv) in dioxane (30 mL) were added XPhos Pd G3 (127 mg, 0.150 mmol, 0.1 equiv) and XPhos (72 mg, 0.150 mmol, 0.1 equiv) and CS2CO3 (981 mg, 3.010 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 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 MeOH in DCM (5%-7%) to afford tert-butyl 4-[2-chloro-6-(3-hydroxyazetidin-l-yl) pyridin-4-yl] piperazine-1 -carboxylate (250 mg, 45%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 369.

[0183] To a stirred solution of tert-butyl 4-[2-chloro-6-(3-hydroxyazetidin-l-yl)pyridin-4- yl]piperazine-l -carboxylate (200 mg, 0.542 mmol, 1 equiv) and 5-cyclopropylpyrazin-2- amine (88 mg, 0.650 mmol, 1.2 equiv) in dioxane (10 mL) were added XPhos Pd G3 (46 mg, 0.0540 mmol, 0.1 equiv), XPhos (26 mg, 0.0540 mmol, 0.1 equiv)and CS2CO3 (353 mg, 1.08 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM (5%-7%) to afford tert-butyl 4-{2-[(5- cyclopropylpyrazin-2-yl) amino]-6-(3-hydroxyazetidin-l-yl) pyridin-4-yl} piperazine-1- carboxylate (100 mg, 39%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 468.

[0184] To a stirred solution of tert-butyl 4-{2-[(5-cyclopropylpyrazin-2-yl)amino]-6-(3- hydroxyazetidin-l-yl)pyridin-4-yl}piperazine-l -carboxylate (100 mg, 0.214 mmol, 1 equiv) in DCM (5 mL) was added TFA (1 mL) dropwise at room temperature .The resulting mixture was stirred for 1 h at room temperature. The mixture was neutralized to pH 7 with NH3• H2O. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8 ExRS 30* 150 mm, 5 pm; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05%NH3H20), Mobile PhaseB: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 29.3% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 10.73) to afford l-(6-((5- cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)azetidin-3-ol (Compound 2) (25.8 mg, 33%) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+ = 370. 'H-NMR (400 MHz, DMSO-d6): 5 9.12-9.08 (m, 2H), 8.11 (s, 1H), 6.36 (s, 1H), 5.55 (d, J = 6.0 Hz, 1H), 5.32 (s, 1H), 4.52 (s, 1H), 4.08 (t, J= 7.6 Hz, 2H), 3.61 (q, J= 4.8 Hz, 2H), 3.15-3.06 (m, 4H), 2.81-2.74 (m, 4H), 2.38 (s, 1H), 2.10-1.99 (m, 1H), 0.94-0.77 (m, 4H).

[0185] The below compounds were synthesized following the procedure in Example 9.Alternate conditions used:xStep 3 : HCl / dioxane instead of TFA / DCM2Step 1 : BrettPhos PdG3, BrettPhos, CS2CO3, dioxane, 100°C, overnightExample 10: Synthesis of l-(6-((5-cyclopropylpyridin-2-yl)amino)-4-(piperazin-l- yl)pyridin-2-yl)pyrrolidin-3-ol (Compound 6)Compound 6

[0186] To a stirred solution of tert-butyl 4-[2-chloro-6-(3-hydroxypyrrolidin-l-yl)pyridin- 4-yl]piperazine-l-carboxylate (120 mg, 0.313 mmol, 1 equiv) in dioxane (6 mL) were added CS2CO3 (204 mg, 0.626 mmol, 2 equiv), 5 -cyclopropylpyridin-2-amine (63 mg, 0.470 mmol, 1.5 equiv), XPhos Pd G3 (27 mg, 0.031 mmol, 0.1 equiv) and X-phos (22 mg, 0.047 mmol, 0.15 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (4:1) to afford tert-butyl 4-{2-[(5-cyclopropylpyridin-2-yl)amino]-6-(3-hydroxypyrrolidin-l- yl)pyridin-4-yl}piperazine-l -carboxylate (120 mg, 80%) as a brown solid. LC-MS: (ES, m / z): [M+H]+ = 481.

[0187] A solution of tert-butyl 4-{2-[(5-cyclopropylpyridin-2-yl)amino]-6-(3- hydroxypyrrolidin-l-yl)pyridin-4-yl}piperazine-l-carboxylate (120 mg, 0.250 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.1%NH3.H2O), Mobile Phase B: MEOH; Flow rate: 60 mL / min; Gradient: 47% B to 67 % B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 6.98) to afford l-(6-((5-cyclopropylpyridin-2- yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)pyrrolidin-3-ol (Compound 6) (20.2 mg, 20%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 381. 'H-NMR (400 MHz, DMSO-t / 6): 8 8.70 (s, 1H), 8.05 (d, .7=8.8 Hz, 1H), 7.98 (d, = 2.4 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 6.19- 6.15 (m, 1H), 5.32-5.26 (m, 1H), 4.87 (d, J= 3.6 Hz, 1H), 4.39-4.31 (m, 1H), 3.48 (dd, J =10.8, 4.8 Hz, 1H), 3.45-3.38 (m, 2H), 3.30-3.23 (m, 2H), 3.14-3.04 (m, 4H), 2.82-2.72 (m, 4H), 2.05-1.94 (m, 1H), 1.90-1.78 (m, 2H), 0.91-0.82 (m, 2H), 0.65-0.59 (m, 2H).

[0188] The below compounds were synthesized following the procedure in Example 10.Alternate conditions used:'Step 2: TFA / DCM instead of HCl / dioxaneExample 11: Synthesis of l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l- yl)pyridin-2-yl)-4,4-difluoropyrrolidin-3-ol (Compound 15), (S)-l-(6-((5- cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)-4,4-difluoropyrrolidin-3-ol (Compound 88), and (R)-l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l- yl)pyridin-2-yl)-4,4-difluoropyrrolidin-3-ol (Compound 89)

[0189] A solution of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperazine-l -carboxylate (500 mg, 1.51 mmol, 1 equiv), 4,4-difluoropyrrolidin-3-ol (148 mg, 1.20 mmol, 0.8 equiv), CS2CO3 (981 mg, 3.01 mmol, 2 equiv), XPhos (72 mg, 0.15 mmol, 0.1 equiv) and XPhos Pd G3 (255 mg, 0.30 mmol, 0.2 equiv) in dioxane (10 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (1 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (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 (6:1) to afford tert-butyl 4-[2-chloro- 6-(3, 3 -difluoro-4-hydroxypyrrolidin-l-yl)pyridin-4-yl]piperazine-l -carboxylate (321 mg, 51%) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+= 419.

[0190] A solution of tert-butyl 4-[2-chloro-6-(3,3-difluoro-4-hydroxypyrrolidin-l-yl) pyridin-4-yl]piperazine-l-carboxylate(90 mg, 0.22 mmol, 1 equiv), 5-cyclopropylpyrazin-2- amine (29 mg, 0.22 mmol, 1 equiv), CS2CO3 (140 mg, 0.43 mmol, 2 equiv), XPhos (20.5 mg, 0.04 mmol, 0.2 equiv) and XPhos Pd G3 (18 mg, 0.02 mmol, 0.1 equiv) in dioxane (2 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50mL). The combined organic layers were washed with water (2 x 20 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, Cl 8 silica gel; mobile phase, MeCN in water (0.1% NH3.H2O), 30% to 60% gradient in 20 min; detector, UV 254 nm to afford tert-butyl 4-{2-[(5-cyclopropylpyrazin-2-yl)amino]- 6-(3, 3 -difluoro-4-hydroxypyrrolidin-l-yl)pyridin-4-yl (piperazine- 1 -carboxylate (60 mg, 54%) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+= 518.

[0191] A solution of tert-butyl 4-{2-[(5-cyclopropylpyrazin-2-yl)amino]-6-(3,3-difluoro-4- hydroxypyrrolidin-l-yl)pyridin-4-yl}piperazine-l -carboxylate (60 mg, 0.12 mmol, 1 equiv) in TFA (1 mL) and DCM (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8 ExRS 30* 150 mm, 5 pm; Mobile Phase A: Water (10mmol / LNH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 19% B to 38% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 11.87) to afford l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4- (piperazin-l-yl)pyridin-2-yl)-4,4-difluoropyrrolidin-3-ol (Compound 15) (22.9 mg, 45%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 418. 'H-NMR (400 MHz, DMSO-d6) 5 9.20- 9.11 (m, 2H), 8.13 (d, J = 1.6 Hz, 1H), 6.26 (s, 1H), 6.04 (d, J = 5.2 Hz, 1H), 5.43 (s, 1H), 4.34 (s, 1H), 3.88-3.69 (m, 3H), 3.38 (d, J= 11 .6 Hz, 1H), 3.31-3.28 (m, 1H), 3.14 (d, J= 6.4 Hz, 4H), 2.82-2.75 (m, 4H), 2.05 (td, J = 8.4, 4.4 Hz, 1H), 0.95-0.79 (m, 4H).

[0192] l-(6-((5-Cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)-4,4- difluoropyrrolidin-3-ol (Compound 15) (300 mg) was purified by CHIRAL -Prep-HPLC with the following conditions (Column: CHIRAL ART Cellulose-SB, 3*25 cm, 5 pm; Mobile Phase A: Hex: MtBE=l : 1(0.5% 2MNH3-MEOH), Mobile Phase B: EtOH-HPLC; Flow rate: 40 mL / min; Gradient: isocratic 10; Wavelength: 240 / 260 nm; RTl(min): 19.4; RT2(min): 27.2; Sample Solvent: EtOH: MeOH=l : 2 -HPLC; Injection Volume: 0.8 mL; Number if Runs: 9) to afford (S)-l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2- yl)-4,4-difluoropyrrolidin-3-ol (Compound 88) (94.8 mg) as a light yellow solid and (R)-l- (6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)-4,4- difluoropyrrolidin-3-ol (Compound 89) (79.1 mg) as a light yellow solid. LC-MS: (ES, m / z): [M+H]+= 418. The single enantiomers were isolated, but the absolute stereochemistry was arbitrarily assigned.Example 12: Synthesis of l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l- yl)pyridin-2-yl)piperidin-3-ol (Compound 18)Compound 18

[0193] A solution of tert-butyl 4-(2,6-dichloropyridin-4-yl)piperazine-l-carboxylate (1 g, 3.01 mmol, 1 equiv), piperidin-3-ol (456.68 mg, 4.52 mmol, 1.5 equiv), CS2CO3 (1.96 g, 6.02 mmol, 2 equiv), XPhos Pd G3 (255 mg, 0.30 mmol, 0.1 equiv) and XPhos (287 mg, 0.60 mmol, 0.2 equiv) in dioxane (15 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 200 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 (1 :l)to afford tert -butyl 4-[2-chloro- 6-(3-hydroxypiperidin-l-yl)pyridin-4-yl]piperazine-l-carboxylate (200 mg, 17%) as a light yellow solid. LC-MS (ES, m / z): [M+H]+= 397.

[0194] A solution of tert-butyl 4-[2-chloro-6-(3-hydroxypiperidin-l-yl)pyridin-4- yl]piperazine-l -carboxylate (120 mg, 0.30 mmol, 1 equiv) in TFA (1 mL) and DCM (10 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with DCM (2 x 60 mL). The combined organic layers were washed with water (2 x 20 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% NH3.H2O), 40% to 80% gradient in 30 min; detector, UV 254 nm. This resulted in 1 -[6-chloro-4-(piperazin-l-yl)pyridin-2- yl]piperidin-3-ol (80 mg, 89%) as a yellow solid. LC-MS (ES, m / z): [M+H]+= 297.

[0195] A solution of l-[6-chloro-4-(piperazin-l-yl)pyridin-2-yl]piperidin-3-ol (70 mg, 0.24 mmol, 1 equiv), 5-cyclopropylpyrazin-2-amine (32 mg, 0.24 mmol, 1 equiv), XPhos Pd G3 (20 mg, 0.02 mmol, 0.1 equiv), XPhos (22.5 mg, 0.05 mmol, 0.2 equiv) andCs2CO3 (154 mg,0.47 mmol, 2 equiv) in dioxane (3 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtO Ac (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 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: 24% B to 39 % B in lO min; Wavelength: 254nm / 220nm nm; RTl(min): 12.3) to afford l-(6-((5-cyclopropylpyrazin-2-yl)amino)-4-(piperazin-l-yl)pyridin-2-yl)piperidin-3-ol (Compound 18) (21.8 mg, 23%) as a light yellow solid. 'H-NMR (400 MHz, DMSO-d6) 5 9.05 (s, 1H), 8.98 (d, J= 1.6 Hz, 1H), 8.12 (d, J= 1.6 Hz, 1H), 6.33 (d, J = L6 Hz, 1H), 5.71 (d,J= 1.6 Hz, 1H), 4.77 (d, .7=4.8 Hz, 1H), 4.07 (dd, J= 12.8, 4.0Hz, 1H), 3.94 (d, J= 12.4 Hz, 1H), 3.46 (d, J= 11.0 Hz, 1H), 3.12 (dd, J= 6.4, 3.6 Hz, 4H), 2.78 (dd, J = 6.0, 3.6 Hz, 5H), 2.62 (dd, J = 12.4, 9.2 Hz, 1H), 2.10-2.02 (m, 1H), 1.94-1.86 (m, 1H), 1.74-1.66 (m, 1H), 1.50-1.26 (m, 2H), 0.94-0.78 (m, 4H). LC-MS: (ES, m / z): [M+H]+= 396.

[0196] The below compound was synthesized following the procedure in Example 12.Example 13: Synthesis of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-5-chloro-N-(5-cyclopropyl- lH-pyrazol-3-yl)-6-(piperazin-l-yl)pyrimidin-4-amine (Compound 50)

[0197] A solution of tert-butyl 4-(2-(3-azabicyclo[3.1.0]hexan-3-yl)-5,6-dichloropyrimidin- 4-yl)piperazine-l-carboxylate (Intermediate 50a) (150 mg, 0.36 mmol, 1 equiv), tert-butyl 3-amino-5-cyclopropylpyrazole-l-carboxylate (80.83 mg, 0.36mmol, 1 equiv), Cs2CO3(236 mg, 0.72 mmol, 2 equiv), XPhos (35 mg, 0.07 mmol, 0.2 equiv) and XPhos Pd G3 (3 1 mg, 0.04 mmol, 0.1 equiv) in dioxane (6 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 4- (2-{3-azabicyclo[3.1.0] hexan-3-yl}-6-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-5-chloropyrimidin-4-yl)piperazine-l-carboxylate (130 mg, 60%) as a yellow oil. LC-MS (ES, m / z): [M+H]+= 601.

[0198] A solution of tert-butyl 4-(2-{3-azabicyclo[3.1.0] hexan-3-yl}-6-{[l -(tertbutoxy carbonyl)-5-cyclopropylpyrazol-3 -yl]amino}-5-chloropyrimidin-4-yl)piperazine-l- carboxylate (100 mg, 0.17 mmol, 1 equiv) in HC1 (10 mL) was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (1 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart Cl 8 ExRS 30*150 mm, 5 pm; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 57.3% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 7.65) to afford 2-(3-azabicyclo[3.1.0]hexan- 3 -yl)-5 -chloro-N-(5 -cyclopropyl- 1 H-pyrazol-3 -y l)-6-(piperazin- 1 -y l)py rimidin-4-amine(Compound 50) (19 mg, 28%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 501. 'H-NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.84 (s, 1H), 6.08 (s, 1H), 4.02 (d, J= 10.8 Hz, 2H), 3.52 (d, J = 10.8 Hz, 2H), 3.30 (d, J = 4.4 Hz, 2H), 2.83-2.77 (m, 4H), 2.50-2.46(m, 2H), 1.89-1.79 (m, 1H), 1.63-1.57 (m, 2H), 0.89 (d, J = 8.0 Hz, 2H), 0.67-0.57 (m, 3H), 0.14- 0.05(m, 1H).

[0199] The below compound was synthesized following the procedure in Example 13.Alternate conditions used:xStep 2: TFA / DCM instead of HCl / dioxaneExample 14: Synthesis of 4-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(5-cyclopropyl-lH- pyrazol-3-yl)-6-(piperazin-l-yl)-l,3,5-triazin-2-amine (Compound 51)

[0200] A solution of tert-butyl 4-(4-(3 -azabi cyclo[3.1 ,0]hexan-3-yl)-6-chloro-l,3,5-triazin-2-yl)piperazine-l-carboxylate (Intermediate 51a) (150 mg, 0.39 mmol, 1 equiv), tert-butyl3-amino-5-cyclopropylpyrazole-l-carboxylate (87.93 mg, 0.39mmol, 1 equiv), Cs2CO3(257 mg, 0.788 mmol, 2 equiv), XPhos (38 mg, 0.08 mmol, 0.2 equiv) and XPhos Pd G3 (33 mg, 0.04 mmol, 0.1 equiv) in dioxane (10 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers werewashed with water (2 x 30 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 tert-butyl 4-(4-{3- azabicyclo[3.1.0]hexan-3 -yl}-6-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-l,3,5-triazin-2-yl)piperazine-l-carboxylate (100 mg, 45%) as a light yellow oil. LC-MS: (ES, m / z): [M+H]+= 568.

[0201] A solution of tert-butyl 4-(4-{3-azabicyclo[3.1.0]hexan-3-yl}-6-{[l-(tert- butoxycarbonyl)-5-cyclopropylpyrazol-3 -yl]amino}-l, 3, 5-tri azin-2 -yl)piperazine-l - carboxylate (100 mg, 0.18 mmol, 1 equiv) in HC1 (gas) in 1,4-dioxane (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 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: 24% B to 39 % B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 12.3): 10.68; Number of Runs: 0) to afford 4-(3- azabicyclo[3.1.0]hexan-3-yl)-N-(5-cyclopropyl-lH-pyrazol-3-yl)-6-(piperazin-l-yl)-l,3,5- triazin-2 -amine (Compound 51) (29.2 mg, 45%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 368. 1H-NMR (400 MHz, DMSO-d6) 5 11.77 (s, 1H), 88.95 (s, 1H), 6.11 (s, 1H), 3.82-3.73 (m, 2H), 3.65-3.56 (m, 4H), 3.45-3.36 (m, 2H), 3.31 (m, 1H), 2.72-2.65 (m, 4H), 1.88-1.81 (m, 1H), 1.64-1.53 (m, 2H), 0.92-0.85 (m, 2H), 0.77-0.66 (m, 1H), 0.67-0.61 (m, 2H), 0.12-0.04 (m, 1H).

[0202] The below compounds were synthesized following the procedure in Example 14.Alternate conditions used:xStep 2: TFA / DCM instead of HCl / dioxaneExample 15: Synthesis of N-(5-cyclopropyl-lH-pyrazol-3-yl)-4-(3,3-difluoropyrrolidin- l-yl)-6-(piperazin-l-yl)pyrimidin-2-amine (Compound 54)

[0203] A solution of tert-butyl 4-(2-chloro-6-(3,3-difluoropyrrolidin-l-yl)pyrimidin-4- yl)piperazine-l -carboxylate (Intermediate 54a) (150 mg, 0.37 mmol, 1 equiv), tert-butyl 3- amino-5-cyclopropylpyrazole-l -carboxylate (83 mg, 0.37 mmol, 1 equiv), Cs2CO3(242 mg, 0.7 mmol, 2 equiv), XPhos (35 mg, 0.07 mmol, 0.2 equiv) and XPhos Pd G3 (31 mg, 0.04mmol, 0.1 equiv) in dioxane (4 mL) was stirred for 1 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 20 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-cyclopropyl-lH- pyrazol-3-yl)amino]-6-(3 ,3 -difluoropyrrolidin-l-yl)pyrimidin-4-yl}piperazine-l -carboxylate (150 mg, 82%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 591.

[0204] A solution of tert-butyl 4-(2-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin-l-yl)pyrimidin-4-yl)piperazine-l -carboxylate (80 mg, 0.14 mmol, 1 equiv) in TFA (1 mL) and DCM (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 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: 9% B to27% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 11.18) to afford N-(5- cyclopropyl-lH-pyrazol-3-yl)-4-(3,3-difluoropyrrolidin-l-yl)-6-(piperazin-l-yl)pyrimidin-2- amine (Compound 54) (12.4 mg, 23%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 391.'H-NMR (400 MHz, DMSO-d6) 611.55 (s, 1H), 8.6O (s, lH), 6.01 (s, lH), 5.18 (s, 1H), 3.81 (t, J= 13.2 Hz, 2H), 3.61 (t, J=12 Hz, 2H), 3.42 (t, J= 5.2 Hz, 4H), 2.71 (t, J= 5.2 Hz, 4H), 2.53 (s, 1H), 2.50-2.42 (m, 1H), 1.82 (tt, J= 8.4, 5.2 Hz, 1H), 0.90-0.82 (m, 2H), 0.65-0.57 (m, 2H).

[0205] The below compounds were synthesized following the procedure in Example 15.Example 16: Synthesis of N-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-6-(piperazin-l- yl)pyrimidin-2-yl)-5-cyclopropylisoxazol-3-amine (Compound 56)Compound 56

[0206] A solution of tert-butyl 4-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-chloropyrimidin-4- yl)piperazine-l -carboxylate (100 mg, 0.26 mmol, 1 equiv), 5 -cyclopropyl- l,2-oxazol-3- amine (36 mg, 0.29 mmol, 1.1 equiv), CS2CO3 (172 mg, 0.53 mmol, 2 equiv), P(Z-Bu)s Palladacycle Gen. 3 (15 mg, 0.03 mmol, 0.1 equiv) and P(Z-Bu)3.HBF4 (7.6 mg, 0.03 mmol, 0.1 equiv) in dioxane (5 mL) was stirred overnight at 90°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 10 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 tert-butyl 4-(6-{3- azabicyclo[3.1.0]hexan-3 -yl}-2-[(5-cyclopropyl-l,2-oxazol-3-yl)amino]pyrimidin-4- yl)piperazine-l -carboxylate (80 mg, 65%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 468.

[0207] A solution of tert-butyl 4-(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-[(5-cyclopropyl- l,2-oxazol-3-yl)amino]pyrimidin-4-yl)piperazine-l -carboxylate (80 mg, 0.17 mmol, 1 equiv )in DCM (5 mL) and TFA (1 mL) was stirred for 1 h at room temperature. The resultingmixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 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: 6% B to24% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 11.33) to afford N-(4-(3-azabicyclo[3.1.0]hexan-3-yl)-6- (piperazin-l-yl)pyrimidin-2-yl)-5-cyclopropylisoxazol-3-amine (Compound 56) (24.5 mg, 38%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 368. ' H-NMR (400 MHz, DMSO-d6) 5 9.02 (s, 1H), 6.53 (s, 1H), 5.01 (s, 1H), 3.50 (d, J = 9.2 Hz, 2H), 3.28-3.19 (m, 6H), 2.59 (t, J = 5.0 Hz, 4H), 2.02-1.92 (m,lH), 1.55-1.48 (m, 2H), 0.96-0.85 (m, 2H), 0.83-0.67 (m, 2H), 0.60 (td, J = 7.6, 4.4 Hz, 1H).

[0208] The below compound was synthesized following the procedure in Example 16.Example 17: Synthesis of N-(5-(difluoromethyl)-lH-pyrazol-3-yl)-4-(3,3- difluoropyrrolidin-l-yl)-6-(piperazin-l-yl)-l,3,5-triazin-2-amine formate (Compound

[0209] To a stirred solution of 5 -(difluoromethyl)- lH-pyrazol-3 -amine (1 g, 7.513 mmol, 1 equiv) in DCM (25 mL) were added TEA (1.52 g, 15.026 mmol, 2 equiv) and Boc2O (1.64 g,7.513 mmol, 1 equiv) dropwise at 0 °C. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:4) to afford tertbutyl 3-amino-5-(difhroromethyl)pyrazole-l-carboxylate (600 mg, 34%) as a white solid. LC- MS: (ES, m / z): [M+H]+= 234.

[0210] To a stirred solution of tert-butyl 3-amino-5-(difluoromethyl)pyrazole-l-carboxylate (100 mg, 0.429 mmol, 1 equiv) in dioxane (15 mL) were added Cs2CO3(279 mg, 0.858 mmol, 2 equiv), tert-butyl 4-[4-chloro-6-(3,3-difluoropyrrolidin-l-yl)-l,3,5-triazin-2- yl]piperazine-l -carboxylate (174 mg, 0.429 mmol, 1 equiv), Xphos Pd G3 (36 mg, 0.043 mmol, 0.1 equiv) and Xphos (30.66 mg, 0.064 mmol, 0.15 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were 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 (3 :2) to afford tert-butyl 4-(4-{[l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin- 1 -yl)-l , 3, 5-triazin-2-yl)piperazine-l -carboxylate (100 mg, 39%) as a yellow solid. LC-MS (ES, m / z): [M+H]+= 502.

[0211] A solution of tert-butyl 4-(4-{[l-(tert-butoxycarbonyl)-5-(difluoromethyl)pyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin- 1 -yl)-l , 3, 5-triazin-2-yl)piperazine-l -carboxylate (130 mg, 0.216 mmol, 1 equiv) in TFA (1 mL) and DCM (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 17% B to 32% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 4.81+6.19) to afford N-(5 -(difluoromethyl)- 1H- pyrazol-3-yl)-4-(3,3-difluoropyrrolidin-l-yl)-6-(piperazin-l-yl)-l,3,5-triazin-2-amine formate (Compound 60) (42.7 mg, 36%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 402.1H- NMR (400 MHz, DMSO-d6): 3 12.45 (s, 1H), 9.86 (s, 1H), 8.21-8.13 (m, 1H), 6.92 (t, J = 54.8 Hz, 1H), 6.43-6.11 (m, 1H), 4.02-3.62 (m, 10H), 3.04-2.96 (m, 4H).

[0212] The below compounds were synthesized following the procedure in Example 17.Example 18: Synthesis of 4-(3,3-difluoropyrrolidin-l-yl)-N-(l-(methylsulfonyl)-lH- pyrazol-4-yl)-6-(piperazin-l-yl)-l,3,5-triazin-2-amine (Compound 63)Compound 63

[0213] To a stirred solution of tert-butyl 4-(4,6-dichloro-l,3,5-triazin-2-yl)piperazine-l- carboxylate (2.5 g, 7.481 mmol, 1 equiv) in DCM (30 mL) was added K2CO3(2.07 g, 14.962 mmol, 2 equiv) and 3,3 -difluoropyrrolidine hydrochloride (0.97 g, 6.733 mmol, 0.9 equiv) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:3) to afford tertbutyl 4-[4-chloro-6-(3,3-difluoropyrrolidin-l-yl)- 1,3, 5 -triazin-2-yl]piperazine-l -carboxylate (2.1 g, 69%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 405.

[0214] A solution of tert-butyl 4-[4-chloro-6-(3,3-difluoropyrrolidin-l-yl)-l,3,5-triazin-2- yl]piperazine-l -carboxylate (200 mg, 0.494 mmol, 1 equiv) in DCM (10 mL) and TFA (2mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in 2-chloro-4-(3,3-difluoropyrrolidin-l-yl)-6-(piperazin-l-yl)- 1,3,5-triazine (130 mg, 86%) as a lightyellow solid. The crude product was used in the next step directly without further purification. LC-MS: (ES, m / z): [M+H]+= 305.

[0215] To a stirred solution of 2-chloro-4-(3,3-difluoropyrrolidin-l-yl)-6-(piperazin-l-yl)- 1,3,5-triazine (130 mg, 0.427 mmol, 1 equiv) in dioxane (10 mL, 109.709 mmol) were added CS2CO3 (278 mg, 0.854 mmol, 2 equiv), 1 -methanesulfonylpyrazol-4-amine (103 mg, 0.640 mmol, 1.5 equiv), Xphos Pd G3 (36 mg, 0.043 mmol, 0.1 equiv) and Xphos (31 mg, 0.064 mmol, 0.15 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL).The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2C12 / MeOH (9: 1) to afford a brown solid as a crude product. The crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 Column 30* 150 mm, 5m; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min;Gradient: 13% B to 31% B in 10 min; Wavelength: 254nm / 220nm nm; RTl(min): 12.7) to afford 4-(3,3-difhroropyrrolidin-l-yl)-N-(l-(methylsulfonyl)-lH-pyrazol-4-yl)-6-(piperazin- l-yl)-l,3,5-triazin-2-amine (Compound 63) (55 mg, 30%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 430. 'H-NMR (400MHz, DMSO-t / 6): 8 9.51-9.38 (m, 1H), 8.32-8.14 (m, 1H), 8.01 (s, 1H), 3.99-3.80 (m, 2H), 3.79-3.58 (m, 6H), 3.47 (s, 3H), 2.78-2.62 (m, 4H), 2.49-2.40 (m, 2H).Example 19: Synthesis of N-(5-cyclopropyl-lH-pyrazol-3-yl)-6-(3,3-difluoropyrrolidin- l-yl)-5-fluoro-2-(piperazin-l-yl)pyrimidin-4-amine (Compound 67)

[0216] A mixture of 2,4, 6-trichloro-5-fluoropyrimidine (1 ,0 g, 5.0 mmol, l.O equiv), DIEA (1.3 g, 9.9 mmol, 2.0 equiv) and 3,3-difluoropyrrolidine hydrochloride (784 mg, 5.5 mmol, 1.1 equiv) in NMP (15.0 mL) was stirred for 4 h at room temperature. The reaction was quenched by the addition of water / ice (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 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:l)to afford2,4-dichloro-6-(3,3-difhroropyrrolidin- l-yl)-5 -fluoropyrimidine (1.0 g, 74%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 272.

[0217] A mixture of 2,4-dichloro-6-(3,3-difluoropyrrolidin-l-yl)-5-fluoropyrimidine (1.0g, 3.7 mmol, 1.0 equiv), CS2CO3 (2.4 g, 7.4 mmol, 2.0 equiv) and tert-butyl piperazine-1- carboxylate (0.8 g, 4.0 mmol, 1.1 equiv) in ACN (20.0 mL) was stirred for 8 h at 80 °C. The reaction was quenched by the addition of water / ice (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (2 x 150 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 tert-butyl 4-[4-chloro-6-(3,3- difluoropyrrolidin-l-yl)-5-fluoropyrimidin-2-yl]piperazine-l-carboxylate (480 mg, 31%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 422.

[0218] To a stirred mixture of tert-butyl 4-[4-chloro-6-(3,3-difluoropyrrolidin-l-yl)-5- fluoropyrimidin-2-yl]piperazine-l-carboxylate (100 mg, 0.2 mmol, 1.0 equiv), Cs2CO3(232 mg, 0.7 mmol, 3.0 equiv) and tert-butyl 3-amino-5-cyclopropylpyrazole-l-carboxylate (63.5mg, 0.3 mmol, 1.2 equiv) in dioxane (8.0 mL) were added Brettphos Pd G3 (43 mg, 0.05 mmol, 0.2 equiv) and Brettphos (13 mg, 0.02 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °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 60 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 silica gel column chromatography, eluted with PE / EA (3 :1) to afford tert -butyl 4-(4-{[l- (tert-butoxycarbonyl)-5-cyclopropylpyrazol-3-yl]amino}-6-(3,3-difluoropyrrolidin-l-yl)-5- fluoropyrimidin-2-yl)piperazine-l-carboxylate (lOO mg, 69%) as a brown solid. LC-MS: (ES, m / z): [M+H]+ = 609.

[0219] A mixture of tert-butyl 4-(4-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin-l-yl)-5-fluoropyrimidin-2-yl)piperazine-l -carboxylate (100 mg, 0.2 mmol, 1.0 equiv) and TFA (1 .0 mL) in DCM (8.0 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 46% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 2.218+5.177) to afford N-(5-cyclopropyl- lH-pyrazol-3-yl)-6-(3,3-difluoropyrrolidin-l-yl)-5-fluoro-2-(piperazin-l-yl)pyrimidin-4- amine (Compound 67) (41 mg, 61%) as an off-white solid. LC-MS: (ES, m / z): [M+H]+= 409. >HNMR (400 MHz, DMSO-d6) 5 11.90 (s, 1H), 8.88 (s, 1H), 6.08 (s, 1H), 3.92 (t, J = 13.2 Hz, 2H), 3.77 (t, J= 7.6 Hz, 2H), 3.67 (t, J= 4.8 Hz, 4H), 2.98 (t, J= 4.8 Hz, 4H), 2.49- 2.39 (m, 2H), 1.91 -1.81 (m, 1H), 0.90 (d, J = 8.4 Hz, 2H), 0.69-0.61 (m, 2H).Example 20: Synthesis of N-(5-cyclopropyl-lH-pyrazol-3-yl)-4-(3,3-difluoropyrrolidin- l-yl)-5-fluoro-6-(piperazin-l-yl)pyrimidin-2-amine (Compound 69)

[0220] To a stirred mixture of 2,4,6-trichloro-5-fluoropyrimidine (750.0 mg, 3.7 mmol, 1 .0 equiv), Cs2CO3(2.43 g, 7.448 mmol, 2 equiv) and tert -butyl piperazine- 1 -carboxylate (763 mg, 4.1 mmol, 1.1 equiv) in dioxane (20.0 mL) were added X-phos (355 mg, 0.7 mmol, 0.2 equiv) and XPhos Pd G3 (315 mg, 0.4 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 °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 (9:1) to afford tert- butyl 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)piperazine-l-carboxylate (560 mg, 43%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 351.

[0221] To a stirred mixture of tert-butyl 4-(2,6-dichloro-5-fluoropyrimidin-4-yl)piperazine- 1-carboxylate (200 mg, 0.6 mmol, 1.0 equiv), Cs2CO3(371 mg, 1.1 mmol, 2.0 equiv) and 3,3 -difluoropyrrolidine hydrochloride (98.1 mg, 0.7 mmol, 1.2 equiv) in dioxane (10 mL) were added X-phos (54 mg, 0.1 mmol, 0.2 equiv) and XPhos Pd G3 (48 mg, 0.06 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °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 80 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 silica gel column chromatography, eluted with PE / EA (5 : 1) to afford tert-butyl 4-[2-chloro-6-(3,3-difluoropyrrolidin-l-yl)-5-fluoropyrimidin-4-yl]piperazine-l -carboxylate (100 mg, 42%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 422.

[0222] To a stirred mixture of tert-butyl 4-[2-chloro-6-(3,3-difluoropyrrolidin-l-yl)-5- fluoropyrimidin-4-yl]piperazine-l-carboxylate (100 mg, 0.2 mmol, 1.0 equiv), Cs2CO3(232 mg, 0.7 mmol, 3.0 equiv) and tert-butyl 3-amino-5-cyclopropylpyrazole-l-carboxylate (63.5 mg, 0.3 mmol, 1.2 equiv) in dioxane (5.0 mL) were added Brettphos (26 mg, 0.05 mmol, 0.2 equiv) and BrettPhos Pd G3 (22 mg, 0.02 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °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 80 mL). The combined organic layers were washed with brine (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 (7:3) to afford tert-butyl 4-(2-{ [ 1 - (tert-butoxycarbonyl)-5-cyclopropylpyrazol-3-yl]amino}-6-(3,3-difluoropyrrolidin-l-yl)-5- fluoropyrimidin-4-yl)piperazine-l-carboxylate (80 mg, 56%) as a brown solid. LC-MS: (ES, m / z): [M+H]+= 609.

[0223] A mixture of tert-butyl 4-(2-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin-l-yl)-5-fluoropyrimidin-4-yl)piperazine-l -carboxylate (80 mg, 0.1 mmol, 1.0 equiv) and TFA (1.0 mL) in DCM(5.0 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (60.0 mg) was purified by Prep-HPLC with the following conditions (Column: YMC -Actus Triart Cl 8 ExRS 30*150 mm, 5 pm; Mobile Phase A: Water (0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 50% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 8.28)to afford N-(5-cyclopropyl-lH-pyrazol-3-yl)- 4-(3,3-difluoropyrrolidin-l-yl)-5-fluoro-6-(piperazin-l-yl)pyrimidin-2-amine (Compound 69) (31.7 mg, 59%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 409.JH NMR (400 MHz, DMSO-d6) 8 11.74 (s, 1H), 8.55 (s, 1H), 6.11 (s, 1H), 3.99-3.85 (m, 2H), 3.81-3.72 (m, 2H), 3.42 (t, J= 4.8 Hz, 4H), 2.75 (t, J= 4.8 Hz, 4H), 2.49-2.39 (m, 2H), 1.82 (tt, J= 8.8, 5.2 Hz, 1H), 0.87 (d, J= 8.0 Hz, 2H), 0.68-0.54 (m, 2H).Example 21: Synthesis of 5-cyclopropyl-N-(4-(3,3-difluoropiperidin-l-yl)-6-(3,3- difluoropyrrolidin-l-yl)pyridin-2-yl)pyrazin-2-amine (Compound 74)

[0224] A mixture of 2,6-dichloro-4-iodopyridine (10 g, 36.51 mmol, 1 equiv), 3,3- difluoropyrrolidine hydrochloride (5.24 g, 36.512 mmol, 1 equiv) and DIEA (9.44 g, 73.024 mmol, 2 equiv) in NMP (20 mL) was stirred for 4 h at 120 °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 (12:1) to afford 2-chloro-6-(3,3-difluoropyrrolidin-l- yl)-4-iodopyridine (10 g, 79%) as a light brown solid. LC-MS: (ES, m / z): [M+H]+= 345.

[0225] A mixture of 2-chloro-6-(3,3-difluoropyrrolidin-l-yl)-4-iodopyridine (0.4 g, 1.161 mmol, 1 equiv), 3,3 -difluoropiperidine (0.14 g, 1.161 mmol, 1 equiv), XPhos Pd G3 (0.10 g, 0.116 mmol, 0.1 equiv), XPhos (0.11 g, 0.232 mmol, 0.2 equiv) and CS2CO3 (0.76 g, 2.322 mmol, 2 equiv) in dioxane (10 mL) was stirred for 1 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with water (2 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 PE / EA (10:1) to afford 2-chloro-4-(3,3-difluoropiperidin-l- yl)-6-(3,3-difluoropyrrolidin-l-yl)pyridine(300 mg, 77%) as a brown oil. LC-MS: (ES, m / z): [M+H]+= 338.

[0226] A mixture of 2-chloro-4-(3,3-difluoropiperidin-l-yl)-6-(3,3-difluoropyrrolidin-l- yl)pyridine (250 mg, 0.740 mmol, 1 equiv), 5-cyclopropylpyrazin-2-amine (100 mg, 0.740 mmol, 1 equiv), XPhos Pd G3 (63 mg, 0.074 mmol, 0.1 equiv), XPhos (71 mg, 0.148 mmol, 0.2 equiv) and Cs2CO3 (724 mg, 2.220 mmol, 3 equiv) in dioxane (lOmL) was stirred for 3 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (50mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 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 PE / EA (7: 1) to afford crude product. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: YMC -Actus Triart Cl 8 ExRS 30*150 mm, 5 pm; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min ; Gradient: 48% B to 66% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 12.7) to afford 5-cyclopropyl-N-(4-(3,3-difluoropiperidin-l-yl)-6-(3,3-difluoropyrrolidin-l- yl)pyridin-2-yl)pyrazin-2-amine (Compound 74) (114.6 mg, 35%) as a white solid. LC-MS: (ES, m / z): [M+H]+ = 437.1H-NMR(400 MHz, DMSO-d6) 59.19 (s, 1H), 9.13 (s, 1H), 8.15 (s, 1H), 6.29 (s, 1H), 5.53 (s, 1H), 3.82 (t, J= 13.2 Hz, 2H), 3.63 (d, J = 10.0 Hz, 4H), 3.34 (s, 2H), 2.55 (d, J= 8.2 Hz, 2H), 2.17-2.00 (m, 3H), 1.75 (m, 2H), 1.00-0.88 (m, 2H), 0.84 (s, 2H).

[0227] The below compounds were synthesized following the procedure in Example 21.Example 22: Synthesis of 4-(2-((5-cyclopropylpyrazin-2-yl)amino)-6-(3,3- difluoropyrrolidin-l-yl)pyridin-4-yl)piperazin-2-one (Compound 78)

[0228] To a stirred solution of 2-chloro-6-(3,3-difluoropyrrolidin-l-yl)-4-iodopyridine (300 mg, 0.87 mmol, 1 equiv) in dioxane (15 mL) were added Cs2CO3(567.41 mg, 1.74 mmol, 2 equiv), tert-butyl 2-oxopiperazine-l-carboxylate (157 mg, 0.78 mmol, 0.9 equiv), Xphos Pd G3 (74 mg, 0.087 mmol, 0.1 equiv) and Xphos (83 mg, 0.17 mmol, 0.2 equiv) in portions at room temperature. The resulting mixture was stirred for 1 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were 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 (2:1) to afford tert-butyl 4-[2-chloro-6-(3,3- difluoropyrrolidin-l-yl)pyridin-4-yl]-2 -oxopiperazine- 1 -carboxylate (180 mg, 50%) as a yellow solid. LC-MS: (ES, m / z): [M+H]+= 417.

[0229] A solution of tert-butyl 4-[2-chloro-6-(3,3-difluoropyrrolidin-l-yl) pyridin-4-yl]-2- oxopiperazine-l-carboxylate(180 mg, 0.43 mmol, 1 equiv), 5-cyclopropylpyrazin-2-amine (88 mg, 0.65 mmol, 1.5 equiv), Cs2CO3(281 mg, 0.864 mmol, 2 equiv), XPhos Pd G3 (37 mg, 0.04 mmol, 0.1 equiv) and XPhos (41 mg, 0.07 mmol, 0.2 equiv) in dioxane (10 mL) was stirred for 2 h at 90 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 20 mL) and 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 (7:1) to afford tert-butyl 4-{2-[(5-cyclopropylpyrazin-2-yl)amino]-6-(3,3-difluoropyrrolidin-l-yl)pyridin-4-yl}-2-oxopiperazine-l- carboxylate (160 mg, 72%) as a brown solid. LC-MS: (ES, m / z): [M+H]+ = 516.

[0230] A solution of tert-butyl 4-{2-[(5-cyclopropylpyrazin-2-yl) amino]-6-(3,3- difluoropyrrolidin-l-yl) pyridin-4-yl}-2-oxopiperazine-l -carboxylate (160 mg, 0.31 mmol, 1 equiv) in DCM (1 mL) and TFA (5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (160 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 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: 9% B to27% B in 10 min;Wavelength: 254nm / 220nm; RTl(min): 11.18) to afford 4-(2-((5-cyclopropylpyrazin-2- yl)amino)-6-(3,3-difluoropyrrolidin-l-yl)pyridin-4-yl)piperazin-2-one (Compound 78) (37.2 mg, 28%) as an off-white solid. LC-MS: (ES, m / z): [M+H]+ = 416. 'H-NMR (400 MHz, DMSO-d6): δ 9.17 (s, 2H), 8.14 (s, 2H), 6.24 (s, 1H), 5.46 (s, 1H), 3.87-3.75 (m, 4H), 3.62 (t, J= 7.2 Hz, 2H), 3.45 (t, J= 5.2 Hz, 2H), 3.31-3.28 (m, 2H), 2.59-2.51 (m, 2H), 2. 11-2.02 (m, 1H), 0.94-0.81 (m, 4H).Example 23: Synthesis of 5-cyclopropyl-N-(6-(3,3-difluoropyrrolidin-l-yl)-4-(2-oxa-6- azaspiro [3.3]heptan-6-yl)pyridin-2-yl)pyrazin-2-amine (Compound 87)

[0231] To a stirred solution of (2S)-2-[(6-chloro-4-iodopyridin-2-yl) amino] propan- l-ol (200 mg, 0.640 mmol, 1 equiv) and 2-oxa-6-azaspiro [3.3] heptane (63 mg, 0.640 mmol, 1 equiv) in dioxane (5 mL) were added XPhos Pd G3 (54 mg, 0.0640 mmol, 0.1 equiv), XPhos (31 mg, 0.064 mmol, 0.1 equiv) and Cs2CO3(417 mg, 1.28 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (1 x 50mL). The combined organic layers were washed with brine (1 x 50 mL), dried overanhydrous 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 (2S)-2- [(6-chloro-4- {2-oxa-6-azaspiro [3.3] heptan-6-yl} pyridin-2-yl) amino] propan-l-ol (110 mg, 61%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 316.

[0232] To a stirred solution of 6-[2-chloro-6-(3,3-difluoropyrrolidin-l-yl) pyridin-4-yl]-2- oxa-6-azaspiro [3.3] heptane (110 mg, 0.348 mmol, 1 equiv) and 5-cyclopropylpyrazin-2- amine (47 mg, 0.348 mmol, 1 equiv) in dioxane (10 mL) were added XPhos Pd G3 (30 mg, 0.0350 mmol, 0.1 equiv), XPhos (17 mg, 0.0350 mmol, 0.1 equiv) and CS2CO3 (227 mg, 0.696 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 30* 150 mm, 5 u m; Mobile Phase A: Water (lOmmol / L NH4HC03+0.05%NH3H20), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 43% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 9.47) to afford 5-cyclopropyl-N-(6-(3,3-difluoropyrrolidin-l-yl)-4-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyridin-2-yl)pyrazin-2-amine (Compound 87) (107.3 mg, 73%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 415.1H-NMR (400 MHz, DMSO-d6): 89.15 (d, J = 16.8Hz, 2H), 8.13 (s, 1H), 5.86 (s, 1H), 5.04 (s, 1H), 4.72 (s, 4H), 4.00 (s, 4H), 3.78 (t, J= 13.6Hz, 2H), 3.57 (d, J= 6.8Hz, 2H), 2.57-2.45 (m, 2H), 2.10-2.00 (m, 1H), 0.94-0.79 (m, 4H).Example 24: Synthesis of N-(5-cyclopropyl-lH-pyrazol-3-yl)-6-(3,3-difluoropyrrolidin- l-yl)-2-(piperazin-l-yl)pyrimidin-4-amine (Compound 90)Compound 90

[0233] A solution of tert-butyl 4-[4-chloro-6-(3,3-difluoropyrrolidin-l-yl)pyrimidin-2- yl]piperazine-l -carboxylate (150 mg, 0.37 mmol, 1 equiv), tert -butyl 3-amino-5- cyclopropylpyrazole-l-carboxylate (83 mg, 0.37 mmol, 1 equiv), CS2CO3 (242 mg, 0.74 mmol, 2 equiv), XPhos Pd G3 (31 mg, 0.04 mmol, 0.1 equiv) andXPhos (35 mg, 0.08 mmol, 0.2 equiv) in dioxane (8 mL) was stirred for 1 h at 100°C under nitrogen atmosphere. The reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 20 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 tert-butyl 4-(4-{[l -(tertbutoxy carbonyl)-5-cyclopropylpyrazol-3 -yl]amino}-6-(3,3-difluoropyrrolidin-l- yl)pyrimidin-2-yl)piperazine-l-carboxylate (110 mg, 50%) as a yellow oil. LC-MS: (ES, m / z): [M+H]+= 591.

[0234] A solution of tert-butyl 4-(4-{[l-(tert-butoxycarbonyl)-5-cyclopropylpyrazol-3- yl]amino}-6-(3, 3 -difluoropyrrolidin-l-yl)pyrimidin-2-yl)piperazine-l -carboxylate (80 mg, 0.14 mmol, 1 equiv) in DCM (5 mL) and TFA (1 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD Cl 8 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: 6% B to24% B in 10 min; Wavelength: 254nm / 220nm; RTl(min): 11.33) to afford N-(5- cyclopropyl-lH-pyrazol-3-yl)-6-(3,3-difluoropyrrolidin-l-yl)-2-(piperazin-l-yl)pyrimidin-4- amine (Compound 90) (32.4 mg, 60%) as a white solid. LC-MS: (ES, m / z): [M+H]+= 391. 'H-NMR (400 MHz, DMSO-d6) 5 11.80 (s, 1H), 8.77 (s, lH), 5.88 (s, lH), 5.65 (s, 1H), 3.76 (t, J= 13.2 Hz, 2H), 3.61-3.48 (m, 6H), 2.69 (t, J = 4.8 Hz, 4H), 2.55-2.51 (m, 1H), 2.45-2.41 (m, 1H), 1.83 (tt, J= 8.4, 5.0 Hz, 1H), 0.95-0.83 (m, 2H), 0.68-0.59 (m, 2H).Example A: LZK and DLK inhibition assay

[0235] 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 non-specific binding. Binding reactions were assembled by combining LZK andDLK 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 were 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.

[0236] Representative data for exemplary compounds disclosed herein is presented inTable 1.Table 1

Claims

CLAIMSWHAT 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;each R2aand each R3is independently selected from halogen, -OH, -CN, oxo, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3.ecycloalkyl, -CH2- C3..6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2.9heterocycloalkyl, C6- 10aryl, -CH2- C6- 10aryl, Ci.oheteroaryl, -CH2-Ci-9heteroaryl, -SR10, -N(R10)(R11), -C(O)OR10, - OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R! !), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, -S(O)R13, -OC(O)R13, -C(O)N(Ri0)(R11), -N(R12)C(O)R13, -S(O)2R13, - S(0)2N(R10)(R11)-, -CH2C(0)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, C1-6alkoxy, C3-6cycloalkyl, -CH2-C3.ecycloalkyl, 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); each R5is independently selected from halogen, -CN, C1-6alkyl, -CF3, C2-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3.6cycloalkyl, -CH2-C3.6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6- 10aryl, -CH2-C6- 10aryl, Ci.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 C1-6alkyl, C1-6haloalkyl, -OR10, and -C(O)OR10; each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2. galkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C1. 9heteroaryl, wherein Cj.galkyl, 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, Ci. ghaloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and Cj. 9heteroaryl; each R11is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R12is independently selected from hydrogen, C1-6alkyl, C a1n-6dalk C1-6haloalkyl; each R13is independently selected C1-6alkyl, C2.galkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2.6alkenyl, C2.galkynyl, 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, C1-6 haloalkyl , C1-6alkoyoxy, C3 -6gcycloalkyl, C2.9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4, and p is 0, 1, 2, 3, or 4.

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

3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2.

4. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

5. The compound of any one of claims 1 -4, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independently selected from halogen, -OH, oxo, C1-6alkyl, C1-6haloalky 1, and C1-6alkoxy.

6. The compound of any one of claims 1 -5, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independently selected from halogen and -OH.

7. The compound of any one of claims 1 -6, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2, or 3.

8. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 3.

9. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

10. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 .

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is selected from13. The compound of any one of claims 1 -12, or a pharmaceutically acceptable salt or solvate thereof, wherein:wherein the C2.9heterocycloalkyl is a monocyclic ring.

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

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein:wherein the C2-9heterocycloalkyl comprises a bridged ring or a spirocyclic ring.

16. The compound of claim 15, or a pharmaceutically acceptable salt or solvate thereof, wherein:Iis 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.

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, -OO, oxo, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein each R3is independently selected from halogen and -OH.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2.21 . The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

22. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, whereinselected from24. The compound of claim 23, or a pharmaceutically acceptable salt or solvate thereof,25. The compound of claim 24, or a pharmaceutically acceptable salt or solvate thereof,26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl or pyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl substituted with one or two R5.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyridinyl substituted with one or two R5.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-6alkyl, - CF3, and C3-6cycloalkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen and cyclopropyl.

31. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt orThe compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof,33. A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof :wherein:X, Y, and Z are independently selected from N and C(R4), wherein at least two of X, Y, and Z are N;R1is a 5 - or 6-membered heteroaryl ring optionally substituted with one, two, or three R5;each R2ais independently selected from halogen, -OH, -SR10, -N(R10)(R11), -CN, Ci. 6alkyl, C1-6haloalkyl, C2-6alkenyl, C2.ealkynyl, C1-6alkoxy, C3-6cycloalkyl, and C2. 9 heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyi, C2.ealkenyl, C2.6alkynyl, C1- 6alkoxy, C3.ecycloalkyl, and C2.9heterocycloalkyl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, C1-6haloalkyl, -OR10, and -N(R10)(R11); or two R2aare combined to form a C3<, cycloalkyl; each R3ais independently selected from halogen, -OH, -SR10, -N(R10)(R11), -CN, C1. ealkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3.ecycloalkyl, and C2. 9heterocycloalkyl, wherein C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2.ealkynyl, C1. ealkoxy , C3.ecycloalkyl, and C2.9heterocycloalkyl 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, halogen, -OH, -N(R10)(R11), -CN, C1-6alkyl, andC 1-6haloalky 1, each R5is independently selected from halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2. ealkenyl, C2.e,alkynyl, C3.ecycloalkyl, -CH2-C3.ecycloalkyl, C2.9heterocycloalkyl, - CH2-C2.9heterocycloalkyl, C1-9heteroaryl, -CH2- C1-9heteroaryl, -OR10, -SR10, - S(O)2R13, and -S(O)2N(R10)(R11)-, wherein C1-6alkyl, C1-6haloalkyl, C2-ealkenyl, C2.ealkynyl, C3-6cycloalkyl, -CH2-C3-6cycloalkyl, C2.9heterocycloalkyl, -CH2-C2. 9heterocycloalkyl, C1-9heteroaryl, and -CH2-C1-9heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6alkyl, Ci. ehaloalkyl, -OR10, and -C(O)OR10;R6is selected from hydrogen and C1-6alkyl;each R10is independently selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2.. 6alkenyl, C2-6alkynyl, C-3-6cloalkyl, 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, Ci. bhaloalkyl, C1-6alkoxy, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-10aryl, and C-.. 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, Cxgalkynyl, 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; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1 , 2, 3, or 4.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ila):Formula (Ila).

35. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (llb):Formula (llb).

36. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (llc):The compound of any one of claims 33-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is hydrogen.The compound of any one of claims 33-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R4is halogen.

39. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (lld):

40. The compound of any one of claims 33-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is41. The compound of any one of claims 33-39, or a pharmaceutically acceptable salt or42. The compound of any one of claims 33-41 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R3ais independently selected from halogen, -OH, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6alkoxy.

43. The compound of any one of claims 33-42, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2.

44. The compound of any one of claims 33-41 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.The compound of any one of claims 33-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is46. The compound of any one of claims 33-45, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is -N(R6)Ci-6alkyl-OH.

47. The compound of any one of claims 33-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R6is hydrogen.

48. The compound of any one of claims 33-46, or a pharmaceutically acceptable salt orsolvate thereof, wherein R2isH,H, H49. The compound of claim 48, or a pharmaceutically acceptable salt or solvate thereof, wherein50. The compound of any one of claims 33-45, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is51. The compound of claim 50, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independently selected from halogen, -OH, C1-6alkyl, C1„ 6haloalkyl, and C1-6alkoxy.

52. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2ais independently selected from halogen and -OH.

53. The compound of any one of claims 50-52, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1, 2, or 3.

54. The compound of any one of claims 50-53, or a pharmaceutically acceptable salt or solvate thereof, wherein two R2aare combined to form a C3-6cycloalkyl.

55. The compound of any one of claims 50-54, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.

56. The compound of any one of claims 33-45, or a pharmaceutically acceptable salt or solvate thereof, wherein R2is57. The compound of any one of claims 33-56, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a 5 -membered heteroaryl ring optionally substituted with one, two, or three R5.

58. The compound of any one of claims 33-57, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a pyrazolyl ring optionally substituted with one, two, or three R5.

59. The compound of any one of claims 33-58, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a pyrazolyl ring substituted with one R5.

60. The compound of any one of claims 33-56, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is a 6-membered heteroaryl ring optionally substituted with one, two, or three R5.

61. The compound of claim 60, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl orpyridinyl, wherein pyrazinyl and pyridinyl are optionally substituted with one, two, or three R5.

62. The compound of claim 61, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is pyrazinyl orpyridinyl, wherein pyrazinyl and pyridinyl are substituted with one or two R5.

63. The compound of any one of claims 33-62, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl.

64. The compound of any one of claims 33-63, or a pharmaceutically acceptable salt or solvate thereof, wherein each R5is independently selected from halogen and cyclopropyl.

65. The compound of any one of claims 33-56, or a pharmaceutically acceptable salt or solvate thereof, wherein R1isThe compound of any one of claims 33-56, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is67. A compound selected from:or a pharmaceutically acceptable salt or solvate thereof.

68. A compound selected from:pharmaceutically acceptable salt or solvate thereof.

69. A pharmaceutical composition comprising a compound of any one of claims 1 -68, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

70. A method of treating cancer in a mammal, comprising administering to the mammal a compound of any one of claims 1-68, or a pharmaceutically acceptable salt or solvate thereof.

71. The method of claim 70, wherein the cancer is a cancer with LZK alterations.

72. The method of claim 70 or claim 71, wherein the cancer is selected from head and neck squamous cell carcinoma and esophageal squamous cell carcinoma.

Images