Heterocyclic compounds as PI3K [alpha] inhibitors

Abstract

The present application provides heterocyclic compounds of formula (I) that modulate the activity of PI3Ka, which are useful in the treatment of various diseases, including cancer. # imgabs0 #

Description

Technical Field

[0001] The present disclosure provides heterocyclic compounds that modulate the activity of PI3Kα and can be used to treat various diseases related to PI3Kα, including cancer, and pharmaceutical compositions thereof. Background Art

[0002] In the past few decades, signal transduction events have been studied to demonstrate their crucial role in regulating almost all biological responses. Abnormal activation of signal transduction pathways that regulate cell survival and proliferation is commonly observed in many human cancers. The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway has been documented as one of the highly mutated pathways in human cancers (Vogelstein et al., Science, 2013, 339(6127), 1546-1558). The PI3K signal transduction pathway regulates cell survival and proliferation. Enhancement of the activity of this pathway is associated with tumor progression and resistance to cancer therapies (Fusco et al., Front Oncol., 2021, 11, 644737).

[0003] PI3K belongs to a family of lipid kinases that catalyze the phosphorylation of lipids contained within or associated with the cell membrane. The PI3K family has 15 kinases that have different substrates, expression patterns, and regulatory modes. Class I PI3Ks (p110α, p110β, p110δ, and p110γ) are typically activated by tyrosine receptor kinases or G protein-coupled receptors to produce PIP3, which activates downstream effectors of Akt, mTOR, or Rho GTPases (Fruman et al., Nat. Rev. Drug Discov., 2014, 13(2), 140-156)

[0004] Genetic mutations in the gene encoding PI3Kα are hotspot point mutations within the helical and kinase domains, such as E542K, E545K, and H1047R. These mutations have been observed to occur in many cancer types, such as lung cancer, gastric cancer, endometrial cancer, ovarian cancer, bladder cancer, breast cancer, colon cancer, brain cancer, prostate cancer, and skin cancer. Since these gain-of-function mutations in PI3Kα are associated with tumor progression, targeting this pathway can provide valuable therapeutic opportunities (Courtney et al., J. Clin. Oncol., 2010, 28(6), 1075-1083). Although multiple PI3K inhibitors have been developed (e.g., taselisib, alpelisib, buparlisib, etc.), these molecules inhibit multiple PI3K isoforms. These "pan-PI3K" inhibitors have encountered significant obstacles in clinical development due to their inability to achieve the required level of target inhibition in tumors while avoiding toxicity to cancer patients (Fruman et al., Nat. Rev. Drug Discov., 2014, 13(2), 140-156). The toxicity of PI3K inhibitors depends on their isoform selectivity profiles. Inhibition of PI3Kα is associated with hyperglycemia and rash, while inhibition of PI3Kδ or PI3Kγ is associated with diarrhea, myelosuppression, and elevated transaminases (Hanker et al., Cancer Discov., 2019, 9(4), 482-491). Thus, a selective inhibitor of PI3Kα can increase the therapeutic window, achieve sufficient target inhibition of tumors, and avoid dose-limiting toxicity in cancer patients. However, given the central role of PI3Kα in regulating glucose homeostasis and other key physiological processes, current PI3Kα selective inhibitors (which are equally potent against wild-type and mutant PI3Kα) often cause hyperglycemia and / or hyperinsulinemia (Busaidy et al., J. Clin. Oncol., 2012, 30, 2919-2928). In summary, developing inhibitors with enhanced selectivity for mutant PI3Kα relative to wild-type PI3Kα will be able to overcome the problems of compensatory insulin production and hyperglycemia. SUMMARY OF THE INVENTION

[0005] The present disclosure provides, among other things, compounds of formula I:

[0006]

[0007] or a pharmaceutically acceptable salt thereof, wherein the members are defined herein.

[0008] The present disclosure further provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0009] The present disclosure further provides a method for inhibiting PI3Kα activity, which comprises contacting PI3Kα with a compound described herein or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure further provides a method for treating a PI3Kα-related disease or disorder in a patient by administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0011] The present disclosure further provides a compound described herein or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0012] The present disclosure further provides the use of a compound described herein or a pharmaceutically acceptable salt thereof for the preparation of a medicament for use in any of the methods described herein. Detailed Description

[0013] The present disclosure provides a compound of formula I:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] X 1 is CR 5 , O, N or NR 6 ;

[0017] X 2 is CR 7 or N;

[0018] X 3 is CR 8 or N;

[0019] Y is C or N;

[0020] Z is C or N;

[0021] n is 0, 1, 2, 3, 4, 5 or 6;

[0022] m is 0, 1, 2, 3, 4, 5 or 6;

[0023] Ring A is C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0024] Ring B is C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, or 5-10 membered heteroaryl;

[0025] Ring C is a 5-membered heteroaryl having 2 to 3 heteroatoms selected from O and N as ring members;

[0026] L 1 and L 3 each independently selected from C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroaryl, -C 3-7 cycloalkylene-C 1-4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4 alkyl-, -(5- to 6-membered heteroaryl)-C 1-4 alkyl-, -O-, -S-, -N(R L )-, -C(O)-, -C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L )-, -S(O)2-, -N(R L )S(O)2-, -S(O)2N(R L )- and -N(R L )S(O)2N(R L )-, where L 1 and L 3 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroaryl, C 3-7 cycloalkylene-C 1-4 alkyl, (4- to 7-membered heterocycloalkylene)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0027] L 2 and L 4 each independently selected from a bond, C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroaryl, -C 3-7 cycloalkylene-C 1-4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4alkyl-, -(5-6-membered heteroarylene)-C 1-4 alkyl-, -O-, -S-, -N(R L )-, -C(O)-, -C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L )-, -S(O)2-, -N(R L )S(O)2-, -S(O)2N(R L )- and -N(R L )S(O)2N(R L )-, where L 2 and L 4 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4-7-membered heterocycloalkylene, 5-6-membered heteroarylene, C 3-7 cycloalkylene-C 1-4 alkyl, (4-7-membered heterocycloalkylene)-C 1-4 alkyl and (5-6-membered heteroarylene)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0028] Each R L is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0029] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10-membered heterocycloalkyl, 5-10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10-membered heterocycloalkyl)-C 1-4 alkyl, (5-10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1 -, -SR a1 -, -NR c1 Rd1 、 -C(O)R a1 、 -C(O)OR a1 、 -C(O)NR c1 R d1 、 -C(O)NR c1 (OR a1 )、 -OC(O)R a1 、 -OC(O)NR c1 R d1 、 -OC(O)OR a1 、 -OS(O)2R b1 、 -OS(O)2NR c1 R d1 、 -NR c1 C(O)R a1 、 -NR c1 C(O)OR a1 、 -NR c1 C(O)NR c1 R d1 、 -NR c1 S(O)2R b1 、 -NR c1 S(O)2NR c1 R d1 、 -NR c1 OR a1 、 -NR c1 S(O)R b1 、 -NR c1 S(O)NR c1 R d1 、 -S(O)R b1 、 -S(O)2R b1 、 -S(O)NR c1 R d1 、 -S(O)2NR c1 R d1 、 -C(=NR e1 )R a1 、 -C(=NR e1 )NR c1 R d1 、 -NR c1 C(=NR e1 )R a1 、 -NR c1 C(=NR e1 )NR c1 R d1 、 -NR c1 S(O)(=NR e1 )R b1 、 -NR c1 S(O)(=NR e1 )NRc1 R d1 、-OS(O)(=NR e1 )R b1 、-S(O)(=NR e1 )R b1 、-S(O)(=NR e1 )NR c1 R d1 、-C(O)NR c1 S(O)2R b1 、-C(O)NR c1 S(O)2NR c1 R d1 、-S(O)2NR c1 C(O)R b1 、-NR c1 S(O)NR c1 C(O)R b1 and-P(O)R f1 R g1 , where R 1 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 1A Substituent substitution;

[0030] Each R a1 , R b1 , R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4Alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein R a1 , R b1 , R c1 and R d1 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0031] Alternatively, any R c1 and R d1 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0032] Each R e1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0033] Each R f1 and R g1 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl;

[0034] each R 1A independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 alkyl, (5 - 10 - membered heteroaryl) - C 1-4 alkyl, - CN, - OR a1A , - SR a1A , - NR c1A R d1A , - C(O)R a1A , - C(O)OR a1A , - C(O)NR c1A R d1A , - C(O)NR c1A (OR a1A ), - OC(O)R a1A , - OC(O)NR c1A R d1A , - OC(O)OR a1A , - OS(O)2R b1A , - OS(O)2NR c1A R d1A , - NR c1A C(O)R a1A , - NR c1A C(O)OR a1A , - NR c1A , - NR c1A R d1A , - NR c1A S(O)2Rb1A ,-NR c1A S(O)2NR c1A R d1A ,-NR c1A OR a1A ,-NR c1A S(O)R b1A ,-NR c1A S(O)NR c1A R d1A ,-S(O)R b1A ,-S(O)2R b1A ,-S(O)NR c1A R d1A ,-S(O)2NR c1A R d1A ,-C(=NR e1A )R a1A ,-C(=NR e1A )NR c1A R d1A ,-NR c1A C(=NR e1A )R a1A ,-NR c1A C(=NR e1A )NR c1A R d1A ,-NR c1A S(O)(=NR e1A )R b1A ,-NR c1A S(O)(=NR e1A )NR c1A R d1A ,-OS(O)(=NR e1A )R b1A ,-S(O)(=NR e1A )R b1A ,-S(O)(=NR e1A )NR c1A R d1A ,-C(O)NR c1A S(O)2R b1A ,-C(O)NR c1A S(O)2NR c1A R d1A ,-S(O)2NR c1A C(O)R b1A ,-NR c1A S(O)NR c1A C(O)R b1A and -P(O)R f1A R g1A ,wherein R 1A of the said C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered heterocycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 The alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0035] Each R a1A , R b1A , R c1A and R d1A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 membered heteroaryl) - C 1-4 alkyl, wherein the C a1A , R b1A , R c1A and R d1A of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 membered heteroaryl) - C 1-4 alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0036] Alternatively, any R attached to the same N atom c1A and R d1A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0037] Each R e1A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0038] Each R f1A and R g1A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0039] Each R 2 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 10-membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a2 , -SR a2 , -NR c2 R d2 , -C(O)R a2 , -C(O)OR a2 , -C(O)NR c2 R d2 , -C(O)NR c2 (OR a2 ), -OC(O)R a2 , -OC(O)NR c2 R d2 , -OC(O)OR a2 , -OS(O)2R b2 , -OS(O)2NR c2 R d2 , -NR c2 C(O)R a2 , -NR c2 C(O)OR a2 , -NR c2 C(O)NR c2 R d2 , -NR c2 S(O)2R b2 , -NR c2 S(O)2NR c2 R d2 , -NR c2 OR a2 , -NR c2 S(O)R b2 , -NR c2 S(O)NR c2 R d2 , -S(O)R b2 , -S(O)2R b2 , -S(O)NR c2 R d2 , -S(O)2NR c2 R d2 , -C(=NR e2 )R a2 , -C(=NR e2 )NR c2 R d2 , -NRc2 C(=NR e2 )R a2 、-NR c2 C(=NR e2 )NR c2 R d2 、-NR c2 S(O)(=NR e2 )R b2 、-NR c2 S(O)(=NR e2 )NR c2 R d2 、-OS(O)(=NR e2 )R b2 、-S(O)(=NR e2 )R b2 、-S(O)(=NR e2 )NR c2 R d2 、-C(O)NR c2 S(O)2R b2 、-C(O)NR c2 S(O)2NR c2 R d2 、-S(O)2NR c2 C(O)R b2 、-NR c2 S(O)NR c2 C(O)R b2 and-P(O)R f2 R g2 , where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 2A Substituent substitution;

[0040] Each R a2 , R b2 , R c2 and R d2 Independently selected from H, C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 Alkyl, wherein R a2 , R b2 , R c2 and R d2 of said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0041] Alternatively, any R c2 and R d2 attached to the same N atom together with the N atom to which they are attached form a 4 - 10 membered hetero cycloalkyl, wherein the 4 - 10 membered hetero cycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0042] Each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C6-10 Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl;

[0043] Each R f2 and R g2 is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl;

[0044] Each R 2A is independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a2A 、-SR a2A 、-NR c2A R d2A 、-C(O)R a2A 、-C(O)OR a2A 、-C(O)NR c2A R d2A 、-C(O)NR c2A (OR a2A )、-OC(O)R a2A 、-OC(O)NR c2A R d2A 、-OC(O)ORa2A 、 -OS(O)₂R b2A 、 -OS(O)₂NR c2A R d2A 、 -NR c2A C(O)R a2A 、 -NR c2A C(O)OR a2A 、 -NR c2A C(O)NR c2A R d2A 、 -NR c2A S(O)₂R b2A 、 -NR c2A S(O)₂NR c2A R d2A 、 -NR c2A OR a2A 、 -NR c2A S(O)R b2A 、 -NR c2A S(O)NR c2A R d2A 、 -S(O)R b2A 、 -S(O)₂R b2A 、 -S(O)NR c2A R d2A 、 -S(O)₂NR c2A R d2A 、 -C(=NR e2A )R a2A 、 -C(=NR e2A )NR c2A R d2A 、 -NR c2A C(=NR e2A )R a2A 、 -NR c2A C(=NR e2A )NR c2A R d2A 、 -NR c2A S(O)(=NR e2A )R b2A 、 -NR c2A S(O)(=NR e2A )NR c2A R d2A 、 -OS(O)(=NR e2A )R b2A 、 -S(O)(=NR e2A )R b2A 、 -S(O)(=NR e2A )NR c2A R d2A 、 -C(O)NR c2A S(O)₂R b2A, -C(O)NR c2A S(O)2NR c2A R d2A , -S(O)2NR c2A C(O)R b2A , -NR c2A S(O)NR c2A C(O)R b2A and -P(O)R f2A R g2A , wherein R 2A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0045] Each R a2A , R b2A , R c2A and R d2A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl, wherein R a2A , R b2A , R c2A and R d2A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C6-10 An aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0046] Alternatively, any R c2A and R d2A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0047] Each R e2A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0048] Each R f2A and R g2A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0049] R 3 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -C(O)R a3 , -C(O)OR a3 , -C(O)NR c3 R d3 , -S(O)2R b3 , -S(O)2NR c3 R d3 , -S(O)(=NR e3 )R b3 and -S(O)(=NR e3 )NR c3 R d3 , wherein R 3 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0050] Or, R 3 and L 3 together with the atom to which they are attached form a 5-10 membered heterocycloalkyl, wherein the 5-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0051] each R a3 、R b3 、R c3 and R d3Independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein R a3 , R b3 , R c3 and R d3 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0052] Alternatively, any R c3 and R d3 attached to the same N atom together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl, wherein the 4-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0053] Each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0054] R 4 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4Alkyl, (4-7 membered heteroalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Alkyl, wherein R 4 said C of 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heteroalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0055] R 5 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heteroalkyl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-14 membered heteroalkyl)-C 1-4 alkyl, (5-14 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a5 、-SR a5 、-NR c5 R d5 、-NO2、-C(O)R a5 、-C(O)OR a5 、-C(O)NR c5 R d5 、-C(O)NR c5 (OR a5 )、-OC(O)R a5 、-OC(O)NR c5 R d5 、-OC(O)OR a5 、-OS(O)2R b5 、-OS(O)2NR c5 R d5 、-NR c5 C(O)R a5 、-NRc5 C(O)OR a5 、 -NR c5 C(O)NR c5 R d5 、 -NR c5 S(O)2R b5 、 -NR c5 S(O)2NR c5 R d5 、 -NR c5 OR a5 、 -NR c5 S(O)R b5 、 -NR c5 S(O)NR c5 R d5 、 -S(O)R b5 、 -S(O)2R b5 、 -S(O)NR c5 R d5 、 -S(O)2NR c5 R d5 、 -C(=NR e5 )R a5 、 -C(=NR e5 )NR c5 R d5 、 -NR c5 C(=NR e5 )R a5 、 -NR c5 C(=NR e5 )NR c5 R d5 、 -NR c5 S(O)(=NR e5 )R b5 、 -NR c5 S(O)(=NR e5 )NR c5 R d5 、 -OS(O)(=NR e5 )R b5 、 -S(O)(=NR e5 )R b5 、 -S(O)(=NR e5 )NR c5 R d5 、 -C(O)NR c5 S(O)2R b5 、 -C(O)NR c5 S(O)2NR c5 R d5 、 -S(O)2NR c5 C(O)R b5 、 -NR c5S(O)NR c5 C(O)R b5 and -P(O)R f5 R g5 , wherein R 5 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered heterocycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 14 - membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents;

[0056] Each R a5 , R b5 , R c5 and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered heterocycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 14 - membered heteroaryl)-C 1-4 alkyl, wherein R a5 , R b5 , R c5 and R d5 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered heterocycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered heterocycloalkyl)-C1-4 alkyl and (5-14 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents;

[0057] Alternatively, any R c5 and R d5 attached to the same N atom together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl, wherein the 4-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents;

[0058] Each R e5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0059] Each R f5 and R g5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0060] Each R 5A is independently selected from oxo, halo, C 1-6 alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero - cycloalkyl, 5 - 10 - membered hetero - aryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero - cycloalkyl)-C 1-4 Alkyl, (5 - 10 - membered hetero - aryl)-C 1-4 Alkyl, - CN, - OR a5A , - SR a5A , - NR c5A R d5A , - NO2, - C(O)R a5A , - C(O)OR a5A , - C(O)NR c5A R d5A , - C(O)NR c5A (OR a5A )、- OC(O)R a5A , - OC(O)NR c5A R d5A , - OC(O)OR a5A , - OS(O)2R b5A , - OS(O)2NR c5A R d5A , - NR c5A C(O)R a5A , - NR c5A C(O)OR a5A , - NR c5A C(O)NR c5A R d5A , - NR c5A S(O)2R b5A , - NR c5A S(O)2NR c5A R d5A , - NR c5A OR a5A , - NR c5A S(O)R b5A , - NR c5A S(O)NR c5A R d5A , - S(O)R b5A , - S(O)2R b5A , - S(O)NR c5A R d5A , - S(O)2NR c5A R d5A , - C(=NRe5A )R a5A 、-C(=NR e5A )NR c5A R d5A 、-NR c5A C(=NR e5A )R a5A 、-NR c5A C(=NR e5A )NR c5A R d5A 、-NR c5A S(O)(=NR e5A )R b5A 、-NR c5A S(O)(=NR e5A )NR c5A R d5A 、-OS(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )NR c5A R d5A 、-C(O)NR c5A S(O)2R b5A 、-C(O)NR c5A S(O)2NR c5A R d5A 、-S(O)2NR c5A C(O)R b5A 、-NR c5A S(O)NR c5A C(O)R b5A and-P(O)R f5A R g5A , where R 5A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R G Substituent substitution;

[0061] Each R a5A 、R b5A 、R c5A and R d5A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where the C a5A 、R b5A 、R c5A and R d5A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0062] Alternatively, any R c5A and R d5A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0063] Each R e5A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl;

[0064] Each R f5A and R g5A is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl;

[0065] R 6 is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 (4-14 membered heterocycloalkyl)-C 1-4 (5-14 membered heteroaryl)-C 1-4 Alkyl, -C(O)R a6 , -C(O)OR a6 , -C(O)NR c6 R d6 , -C(O)NR c6 (OR a6 ), -S(O)R b6 , -S(O)2R b6 , -S(O)NR c6 R d6、-S(O)2NR c6 R d6 、-C(=NR e6 )R a6 、-C(=NR e6 )NR c6 R d6 、-S(O)(=NR e6 )R b6 、-S(O)(=NR e6 )NR c6 R d6 、-C(O)NR c6 S(O)2R b6 、-C(O)NR c6 S(O)2NR c6 R d6 and -S(O)2NR c6 C(O)R b6 , where R 6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-14 membered heterocycloalkyl)-C 1-4 Alkyl and (5-14 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 6A Substituent substitution;

[0066] Each R a6 , R b6 , R c6 and R d6 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4Alkyl, wherein R a6 , R b6 , R c6 and R d6 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents;

[0067] Alternatively, any R c6 and R d6 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents;

[0068] Each R e6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0069] Each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A 、-SR a6A 、-NR c6A R d6A 、-NO2、-C(O)R a6A 、-C(O)OR a6A 、-C(O)NR c6A R d6A 、-C(O)NR c6A (OR a6A )、-OC(O)R a6A 、-OC(O)NR c6A R d6A 、-OC(O)OR a6A 、-OS(O)2R b6A 、-OS(O)2NR c6A R d6A 、-NR c6A C(O)R a6A 、-NR c6A C(O)OR a6A 、-NR c6A C(O)NR c6A R d6A 、-NR c6A S(O)2R b6A 、-NR c6A S(O)2NR c6A R d6A 、-NR c6A OR a6A 、-NR c6A S(O)R b6A 、-NR c6A S(O)NR c6A R d6A 、-S(O)R b6A 、-S(O)2R b6A 、-S(O)NR c6A R d6A 、-S(O)2NR c6A R d6A 、-C(=NR e6A )R a6A 、-C(=NR e6A )NR c6A Rd6A , -NR c6A C(=NR e6A )R a6A , -NR c6A C(=NR e6A )NR c6A R d6A , -NR c6A S(O)(=NR e6A )R b6A , -NR c6A S(O)(=NR e6A )NR c6A R d6A , -OS(O)(=NR e6A )R b6A , -S(O)(=NR e6A )R b6A , -S(O)(=NR e6A )NR c6A R d6A , -C(O)NR c6A S(O)2R b6A , -C(O)NR c6A S(O)2NR c6A R d6A , -S(O)2NR c6A C(O)R b6A , -NR c6A S(O)NR c6A C(O)R b6A and -P(O)R f6A R g6A , wherein R 6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0070] Each R a6A , R b6A , R c6A and R d6AIndependently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where R a6A , R b6A , R c6A and R d6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0071] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0072] Each R e6A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0073] Each R f6A and R g6A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0074] R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heteroalkyl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-14 membered heteroalkyl)-C 1-4 alkyl, (5-14 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7 , -SR a7 , -NR c7 R d7 , -NO2, -C(O)R a7 , -C(O)OR a7 , -C(O)NR c7 R d7 , -C(O)NR c7 (OR a7 ), -OC(O)R a7 , -OC(O)NR c7 R d7, -OC(O)OR a7 , -OS(O)2R b7 , -OS(O)2NR c7 R d7 , -NR c7 C(O)R a7 , -NR c7 C(O)OR a7 , -NR c7 C(O)NR c7 R d7 , -NR c7 S(O)2R b7 , -NR c7 S(O)2NR c7 R d7 , -NR c7 OR a7 , -NR c7 S(O)R b7 , -NR c7 S(O)NR c7 R d7 , -S(O)R b7 , -S(O)2R b7 , -S(O)NR c7 R d7 , -S(O)2NR c7 R d7 , -C(=NR e7 )R a7 , -C(=NR e7 )NR c7 R d7 , -NR c7 C(=NR e7 )R a7 , -NR c7 C(=NR e7 )NR c7 R d7 , -NR c7 S(O)(=NR e7 )R b7 , -NR c7 S(O)(=NR e7 )NR c7 R d7 , -OS(O)(=NR e7 )R b7 , -S(O)(=NR e7 )R b7 , -S(O)(=NR e7 )NR c7 R d7 , -C(O)NR c7 S(O)2Rb7 、-C(O)NR c7 S(O)2NR c7 R d7 、-S(O)2NR c7 C(O)R b7 、-NR c7 S(O)NR c7 C(O)R b7 and-P(O)R f7 R g7 , where R 7 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-14 membered heterocycloalkyl)-C 1-4 Alkyl and (5-14 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 7A Substituent substitution;

[0075] Or, R 5 and R 7 Together with the atoms to which they are attached, they form C 5-14 Cycloalkyl or 5-14 membered heterocycloalkyl, wherein the C 5-14 Cycloalkyl and 5-14 membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A Substituent substitution;

[0076] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 5-14 membered heterocycloalkyl group, wherein the 5-14 membered heterocycloalkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 7A Substituent substitution;

[0077] Each R a7 , R b7 , R c7 and R d7 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl, wherein R a7 , R b7 , R c7 and R d7 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0078] Alternatively, any R c7 and R d7 attached to the same N atom together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl, wherein the 4- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0079] Each R e7 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4alkyl;

[0080] each R f7 and R g7 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0081] each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7A , -SR a7A , -NR c7A R d7A , -NO2, -C(O)R a7A , -C(O)OR a7A , -C(O)NR c7A R d7A , -C(O)NR c7A (OR a7A ), -OC(O)R a7A , -OC(O)NR c7A R d7A , -OC(O)OR a7A , -OS(O)2R b7A , -OS(O)2NR c7A R d7A , -NR c7AC(O)R a7A 、 -NR c7A C(O)OR a7A 、 -NR c7A C(O)NR c7A R d7A 、 -NR c7A S(O)2R b7A 、 -NR c7A S(O)2NR c7A R d7A 、 -NR c7A OR a7A 、 -NR c7A S(O)R b7A 、 -NR c7A S(O)NR c7A R d7A 、 -S(O)R b7A 、 -S(O)2R b7A 、 -S(O)NR c7A R d7A 、 -S(O)2NR c7A R d7A 、 -C(=NR e7A )R a7A 、 -C(=NR e7A )NR c7A R d7A 、 -NR c7A C(=NR e7A )R a7A 、 -NR c7A C(=NR e7A )NR c7A R d7A 、 -NR c7A S(O)(=NR e7A )R b7A 、 -NR c7A S(O)(=NR e7A )NR c7A R d7A 、 -OS(O)(=NR e7A )R b7A 、 -S(O)(=NR e7A )R b7A 、 -S(O)(=NR e7A )NR c7A R d7A 、 -C(O)NR c7A S(O)2R b7A 、 -C(O)NR c7A S(O)2NR c7A R d7A 、 -S(O)2NR c7A C(O)Rb7A 、 -NR c7A S(O)NR c7A C(O)R b7A and -P(O)R f7A R g7A wherein R 7A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents;

[0082] Each R a7A , R b7A , R c7A and R d7A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl, wherein R a7A , R b7A , R c7A and R d7A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents;

[0083] alternatively, any two Rs attached to the same N atom c7A and R d7A together with the N atom to which they are attached form a 4-10 membered heteroalkyl, where the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents;

[0084] each R e7A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0085] each R f7A and R g7A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0086] each R 7BIndependently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7B , -SR a7B , -NR c7B R d7B , -NO2, -C(O)R a7B , -C(O)OR a7B , -C(O)NR c7B R d7B , -C(O)NR c7B (OR a7B ), -OC(O)R a7B , -OC(O)NR c7B R d7B , -OC(O)OR a7B , -OS(O)2R b7B , -OS(O)2NR c7B R d7B , -NR c7B C(O)R a7B , -NR c7B C(O)OR a7B , -NR c7B C(O)NR c7B R d7B , -NR c7B S(O)2R b7B , -NR c7B S(O)2NR c7B R d7B , -NR c7B OR a7B , -NR c7B S(O)R b7B , -NR c7B S(O)NR c7B R d7B , -S(O)R b7B , -S(O)2R b7B , -S(O)NR c7B R d7B , -S(O)2NRc7B R d7B 、 -C(=NR e7B )R a7B 、 -C(=NR e7B )NR c7B R d7B 、 -NR c7B C(=NR e7B )R a7B 、 -NR c7B C(=NR e7B )NR c7B R d7B 、 -NR c7B S(O)(=NR e7B )R b7B 、 -NR c7B S(O)(=NR e7B )NR c7B R d7B 、 -OS(O)(=NR e7B )R b7B 、 -S(O)(=NR e7B )R b7B 、 -S(O)(=NR e7B )NR c7B R d7B 、 -C(O)NR c7B S(O)2R b7B 、 -C(O)NR c7B S(O)2NR c7B R d7B 、 -S(O)2NR c7B C(O)R b7B 、 -NR c7B S(O)NR c7B C(O)R b7B and -P(O)R f7B R g7B ,wherein R 7B 's said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected RG Substituted by a substituent;

[0087] Each R a7B 、R b7B 、R c7B and R d7B is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where R a7B 、R b7B 、R c7B and R d7B of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0088] Alternatively, any R c7B and R d7B attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0089] Each R e7B is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0090] each R f7B and R g7B is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0091] R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a8 , -SR a8 , -NR c8 R d8 , -NO2, -C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 Rd8 ,-C(O)NR c8 (OR a8 ),-OC(O)R a8 ,-OC(O)NR c8 R d8 ,-OC(O)OR a8 ,-OS(O)2R b8 ,-OS(O)2NR c8 R d8 ,-NR c8 C(O)R a8 ,-NR c8 C(O)OR a8 ,-NR c8 C(O)NR c8 R d8 ,-NR c8 S(O)2R b8 ,-NR c8 S(O)2NR c8 R d8 ,-NR c8 OR a8 ,-NR c8 S(O)R b8 ,-NR c8 S(O)NR c8 R d8 ,-S(O)R b8 ,-S(O)2R b8 ,-S(O)NR c8 R d8 ,-S(O)2NR c8 R d8 ,-C(=NR e8 )R a8 ,-C(=NR e8 )NR c8 R d8 ,-NR c8 C(=NR e8 )R a8 ,-NR c8 C(=NR e8 )NR c8 R d8 ,-NR c8 S(O)(=NR e8 )R b8 ,-NR c8 S(O)(=NR e8 )NR c8 R d8 ,-OS(O)(=NR e8 )R b8 ,-S(O)(=NRe8 )R b8 ,-S(O)(=NR e8 )NR c8 R d8 ,-C(O)NR c8 S(O)2R b8 ,-C(O)NR c8 S(O)2NR c8 R d8 ,-S(O)2NR c8 C(O)R b8 ,-NR c8 S(O)NR c8 C(O)R b8 and -P(O)R f8 R g8 , where R 8 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0092] Each R a8 , R b8 , R c8 and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl, where R a8 , R b8 , Rc8 and R d8 said C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl is each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0093] Alternatively, any R c8 and R d8 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0094] each R e8 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0095] each R f8 and R g8 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 (4 - 10 membered hetero cycloalkyl)-C 1-4 Alkyl and (5 - 10 membered heteroaryl)-C 1-4 Alkyl;

[0096] Each R 8A Independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 (4 - 10 membered hetero cycloalkyl)-C 1-4 (5 - 10 membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a8A 、-SR a8A 、-NR c8A R d8A 、-NO2、-C(O)R a8A 、-C(O)OR a8A 、-C(O)NR c8A R d8A 、-C(O)NR c8A (OR a8A )、-OC(O)R a8A 、-OC(O)NR c8A R d8A 、-OC(O)OR a8A 、-OS(O)2R b8A 、-OS(O)2NR c8A R d8A 、-NR c8A C(O)R a8A 、-NR c8A C(O)OR a8A 、-NR c8A C(O)NR c8A R d8A 、-NR c8A S(O)2R b8A 、-NR c8A S(O)2NR c8A R d8A, -NR c8A OR a8A , -NR c8A S(O)R b8A , -NR c8A S(O)NR c8A R d8A , -S(O)R b8A , -S(O)2R b8A , -S(O)NR c8A R d8A , -S(O)2NR c8A R d8A , -C(=NR e8A )R a8A , -C(=NR e8A )NR c8A R d8A , -NR c8A C(=NR e8A )R a8A , -NR c8A C(=NR e8A )NR c8A R d8A , -NR c8A S(O)(=NR e8A )R b8A , -NR c8A S(O)(=NR e8A )NR c8A R d8A , -OS(O)(=NR e8A )R b8A , -S(O)(=NR e8A )R b8A , -S(O)(=NR e8A )NR c8A R d8A , -C(O)NR c8A S(O)2R b8A , -C(O)NR c8A S(O)2NR c8A R d8A , -S(O)2NR c8A C(O)R b8A , -NR c8A S(O)NR c8A C(O)R b8A and -P(O)R f8A R g8A , wherein R 8A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 Alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G Substituents;

[0097] Each R a8A , R b8A , R c8A And R d8A Is independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 Alkyl, wherein R a8A , R b8A , R c8A And R d8A Of the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered hetero cycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 membered heteroaryl) - C 1-4 Alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G Substituents;

[0098] Or, any R c8A And R d8Aform, together with the N atom to which they are attached, a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0099] each R e8A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0100] each R f8A and R g8A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; and

[0101] each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7Cycloalkyl, 4- to 7-membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, sulfanyl, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

[0102] In some embodiments:

[0103] X 1 is CR 5 , O, N or NR 6 ;

[0104] X 2 is CR 7 or N;

[0105] X 3 is CR 8 or N;

[0106] Y is C or N;

[0107] Z is C or N;

[0108] n is 0, 1, 2, 3, 4, 5 or 6;

[0109] m is 0, 1, 2, 3, 4, 5 or 6;

[0110] Ring A is C 3-14 cycloalkyl, C 6-10an aryl group, a 4- to 14-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group;

[0111] Ring B is a C 3-14 cycloalkyl group, a C 6-10 aryl group, a 4- to 14-membered heterocycloalkyl group, or a 5- to 10-membered heteroaryl group;

[0112] Ring C is a 5-membered heteroaryl group having 2 to 3 heteroatoms selected from O and N as ring members;

[0113] L 1 and L 3 each independently selected from C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, a 4- to 7-membered heterocycloalkylene, a 5- to 6-membered heteroarylene, -C 3-7 cycloalkylene-C1 -4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4 alkyl-, -(5- to 6-membered heteroarylene)-C 1-4 alkyl-, -O-, -S-, -N(R L )-, -C(O)-, -C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L )-, -S(O)2-, -N(R L )S(O)2-, -S(O)2N(R L )- and -N(R L )S(O)2N(R L )-, where L 1 and L 3 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, a 4- to 7-membered heterocycloalkylene, a 5- to 6-membered heteroarylene, C 3-7 cycloalkylene-C 1-4 alkyl, (4- to 7-membered heterocycloalkylene)-C 1-4 alkyl and (5- to 6-membered heteroarylene)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;

[0114] L 2 and L 4 each independently selected from a bond, C 1-6 alkylene, C1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -C 3-7 cycloalkylene-C 1-4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4 alkyl-, -(5- to 6-membered heteroarylene)-C 1-4 alkyl-, -O-, -S-, -N(R L )-, -C(O)-, -C(O)N(R L )-, -N(R L )C(O)-, -N(R L )C(O)N(R L )-, -N(R L )C(O)O-, -OC(O)N(R L )-, -S(O)2-, -N(R L )S(O)2-, -S(O)2N(R L )- and -N(R L )S(O)2N(R L )-, where L 2 and L 4 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroarylene, C 3-7 cycloalkylene-C 1-4 alkyl, (4- to 7-membered heterocycloalkylene)-C 1-4 alkyl and (5- to 6-membered heteroarylene)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0115] Each R L is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0116] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4alkyl, (4- to 10-membered heteroalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1 , -SR a1 , -NR c1 R d1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR c1 R d1 , -C(O)NR c1 (OR a1 ), -OC(O)R a1 , -OC(O)NR c1 R d1 , -OC(O)OR a1 , -OS(O)2R b1 , -OS(O)2NR c1 R d1 , -NR c1 C(O)R a1 , -NR c1 C(O)OR a1 , -NR c1 C(O)NR c1 R d1 , -NR c1 S(O)2R b1 , -NR c1 S(O)2NR c1 R d1 , -NR c1 OR a1 , -NR c1 S(O)R b1 , -NR c1 S(O)NR c1 R d1 , -S(O)R b1 , -S(O)2R b1 , -S(O)NR c1 R d1 , -S(O)2NR c1 R d1 , -C(=NR e1 )R a1 , -C(=NR e1 )NR c1 R d1 , -NR c1 C(=NR e1 )R a1 , -NR c1 C(=NR e1 )NR c1R d1 、-NR c1 S(O)(=NR e1 )R b1 、-NR c1 S(O)(=NR e1 )NR c1 R d1 、-OS(O)(=NR e1 )R b1 、-S(O)(=NR e1 )R b1 、-S(O)(=NR e1 )NR c1 R d1 、-C(O)NR c1 S(O)2R b1 、-C(O)NR c1 S(O)2NR c1 R d1 、-S(O)2NR c1 C(O)R b1 、-NR c1 S(O)NR c1 C(O)R b1 and-P(O)R f1 R g1 , where R 1 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 1A Substituent substitution;

[0117] Each R a1 , R b1 , R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein R a1 , R b1 , R c1 and R d1 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0118] Alternatively, any R c1 and R d1 attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0119] Each R e1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0120] Each R f1 and R g1 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0121] Each R 1A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1A 、-SR a1A 、-NR c1A R d1A 、-C(O)R a1A 、-C(O)OR a1A 、-C(O)NR c1A R d1A 、-C(O)NR c1A (OR a1A )、-OC(O)R a1A 、-OC(O)NR c1A R d1A 、-OC(O)OR a1A 、-OS(O)2R b1A 、-OS(O)2NR c1A R d1A 、-NR c1A C(O)Ra1A , -NR c1A C(O)OR a1A , -NR c1A C(O)NR c1A R d1A , -NR c1A S(O)2R b1A , -NR c1A S(O)2NR c1A R d1A , -NR c1A OR a1A , -NR c1A S(O)R b1A , -NR c1A S(O)NR c1A R d1A , -S(O)R b1A , -S(O)2R b1A , -S(O)NR c1A R d1A , -S(O)2NR c1A R d1A , -C(=NR e1A )R a1A , -C(=NR e1A )NR c1A R d1A , -NR c1A C(=NR e1A )R a1A , -NR c1A C(=NR e1A )NR c1A R d1A , -NR c1A S(O)(=NR e1A )R b1A , -NR c1A S(O)(=NR e1A )NR c1A R d1A , -OS(O)(=NR e1A )R b1A , -S(O)(=NR e1A )R b1A , -S(O)(=NR e1A )NR c1A R d1A , -C(O)NR c1A S(O)2R b1A , -C(O)NR c1A S(O)2NR c1A R d1A , -S(O)2NR c1A C(O)R b1A, -NR c1A S(O)NR c1A C(O)R b1A and -P(O)R f1A R g1A , where R 1A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0122] Each R a1A , R b1A , R c1A and R d1A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 [[ID=6I]]aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl, where R a1A , R b1A , R c1A and R d1A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0123] alternatively, any R c1A and R d1A attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heteroalkyl, where the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0124] each R e1A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0125] each R f1A and R g1A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0126] each R 2 is independently selected from oxo, halo, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a2 , -SR a2 , -NR c2 R d2 , -C(O)R a2 , -C(O)OR a2 , -C(O)NR c2 R d2 , -C(O)NR c2 (OR a2 ), -OC(O)R a2 , -OC(O)NR c2 R d2 , -OC(O)OR a2 , -OS(O)2R b2 , -OS(O)2NR c2 R d2 , -NR c2 C(O)R a2 , -NR c2 C(O)OR a2 , -NR c2 C(O)NR c2 R d2 , -NR c2 S(O)2R b2 , -NR c2 S(O)2NR c2 R d2 , -NR c2 OR a2 , -NR c2 S(O)R b2 , -NR c2 S(O)NR c2 R d2 , -S(O)R b2 , -S(O)2R b2 , -S(O)NR c2 R d2 , -S(O)2NR c2 Rd2 , -C(=NR e2 )R a2 , -C(=NR e2 )NR c2 R d2 , -NR c2 C(=NR e2 )R a2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 S(O)(=NR e2 )R b2 , -NR c2 S(O)(=NR e2 )NR c2 R d2 , -OS(O)(=NR e2 )R b2 , -S(O)(=NR e2 )R b2 , -S(O)(=NR e2 )NR c2 R d2 , -C(O)NR c2 S(O)2R b2 , -C(O)NR c2 S(O)2NR c2 R d2 , -S(O)2NR c2 C(O)R b2 , -NR c2 S(O)NR c2 C(O)R b2 and -P(O)R f2 R g2 , wherein R 2 of the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0127] Each R a2 、R b2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C a2 、R b2 、R c2 and R d2 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0128] Alternatively, any R c2 and R d2 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heterocycloalkyl, wherein the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0129] Each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 - membered heteroaryl) - C 1-4 Alkyl;

[0130] Each R f2 and R g2 independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 Alkyl and (5 - 10 - membered heteroaryl) - C 1-4 Alkyl;

[0131] Each R 2A independently selected from oxo, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl) - C 1-4 Alkyl, (5 - 10 - membered heteroaryl) - C 1-4 Alkyl, - CN, - OR a2A , - SR a2A , - NR c2A R d2A , - C(O)R a2A , - C(O)OR a2A , - C(O)NR c2A R d2A , - C(O)NRc2A (OR a2A )、 -OC(O)R a2A 、 -OC(O)NR c2A R d2A 、 -OC(O)OR a2A 、 -OS(O)2R b2A 、 -OS(O)2NR c2A R d2A 、 -NR c2A C(O)R a2A 、 -NR c2A C(O)OR a2A 、 -NR c2A C(O)NR c2A R d2A 、 -NR c2A S(O)2R b2A 、 -NR c2A S(O)2NR c2A R d2A 、 -NR c2A OR a2A 、 -NR c2A S(O)R b2A 、 -NR c2A S(O)NR c2A R d2A 、 -S(O)R b2A 、 -S(O)2R b2A 、 -S(O)NR c2A R d2A 、 -S(O)2NR c2A R d2A 、 -C(=NR e2A )R a2A 、 -C(=NR e2A )NR c2A R d2A 、 -NR c2A C(=NR e2A )R a2A 、 -NR c2A C(=NR e2A )NR c2A R d2A 、 -NR c2A S(O)(=NR e2A )R b2A 、 -NR c2A S(O)(=NR e2A )NR c2A R d2A 、 -OS(O)(=NR e2A )R b2A 、 -S(O)(=NR e2A )R b2A,-S(O)(=NR e2A )NR c2A R d2A ,-C(O)NR c2A S(O)2R b2A ,-C(O)NR c2A S(O)2NR c2A R d2A ,-S(O)2NR c2A C(O)R b2A ,-NR c2A S(O)NR c2A C(O)R b2A and -P(O)R f2A R g2A , where R 2A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0132] Each R a2A , R b2A , R c2A and R d2A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl, where R a2A , R b2A , R c2A and R d2A of said C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0133] alternatively, any R c2A and R d2A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0134] each R e2A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0135] each R f2A and R g2A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 10-membered heteroaryl)-C 1-4 Alkyl;

[0136] R 3 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 6-membered heteroaryl)-C 1-4 Alkyl, -C(O)R a3 , -C(O)OR a3 , -C(O)NR c3 R d3 , -S(O)2R b3 , -S(O)2NR c3 R d3 , -S(O)(=NR e3 )R b3 And -S(O)(=NR e3 )NR c3 R d3 , where R 3 Of the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G Substituents;

[0137] Alternatively, R 3 And L 3 Together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl, where the 5- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected RG Substituted by a substituent;

[0138] Each R a3 、R b3 、R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl, wherein the C a3 、R b3 、R c3 and R d3 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl is each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0139] Alternatively, any R c3 and R d3 attached to the same N atom together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0140] Each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0141] R 4 is selected from H, C 1-6 alkyl, C 1-6Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyl, wherein R 4 The said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyl is each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G Substituents;

[0142] R 5 Is selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 14-membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a5 、-SR a5 、-NR c5 R d5 、-NO2、-C(O)R a5 、-C(O)OR a5 、-C(O)NR c5 R d5 、-C(O)NR c5 (OR a5 )、-OC(O)R a5 、-OC(O)NR c5 R d5 、-OC(O)OR a5, -OS(O)2R b5 , -OS(O)2NR c5 R d5 , -NR c5 C(O)R a5 , -NR c5 C(O)OR a5 , -NR c5 C(O)NR c5 R d5 , -NR c5 S(O)2R b5 , -NR c5 S(O)2NR c5 R d5 , -NR c5 OR a5 , -NR c5 S(O)R b5 , -NR c5 S(O)NR c5 R d5 , -S(O)R b5 , -S(O)2R b5 , -S(O)NR c5 R d5 , -S(O)2NR c5 R d5 , -C(=NR e5 )R a5 , -C(=NR e5 )NR c5 R d5 , -NR c5 C(=NR e5 )R a5 , -NR c5 C(=NR e5 )NR c5 R d5 , -NR c5 S(O)(=NR e5 )R b5 , -NR c5 S(O)(=NR e5 )NR c5 R d5 , -OS(O)(=NR e5 )R b5 , -S(O)(=NR e5 )R b5 , -S(O)(=NR e5 )NR c5 R d5 , -C(O)NR c5 S(O)2R b5 , -C(O)NRc5 S(O)2NR c5 R d5 、-S(O)2NR c5 C(O)R b5 、-NR c5 S(O)NR c5 C(O)R b5 and-P(O)R f5 R g5 , where R 5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-14 membered heterocycloalkyl)-C 1-4 Alkyl and (5-14 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 5A Substituent substitution;

[0143] Each R a5 , R b5 , R c5 and R d5 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-14 membered heterocycloalkyl)-C 1-4 Alkyl and (5-14 membered heteroaryl)-C 1-4 Alkyl, where R a5 , R b5 , R c5 and R d5 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-14 Cycloalkyl, C 6-10Aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 14-membered heteroaryl)-C 1-4 Alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A Substituents;

[0144] Alternatively, any R c5 And R d5 Attached to the same N atom together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl, wherein the 4- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A Substituents;

[0145] Each R e5 Independently selected from H, OH, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 10-membered heteroaryl)-C 1-4 Alkyl;

[0146] Each R f5 And R g5 Independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0147] each R 5A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a5A , -SR a5A , -NR c5A R d5A , -NO2, -C(O)R a5A , -C(O)OR a5A , -C(O)NR c5A R d5A , -C(O)NR c5A (OR a5A ), -OC(O)R a5A , -OC(O)NR c5A R d5A , -OC(O)OR a5A , -OS(O)2R b5A , -OS(O)2NR c5A R d5A , -NR c5A C(O)R a5A , -NR c5A C(O)OR a5A , -NR c5A C(O)NR c5A R d5A , -NR c5A S(O)2R b5A , -NR c5A , -NR c5A R d5A , -NR c5A OR a5A , -NR c5A S(O)R b5A , -NR c5A , -NR c5A R d5A , -S(O)Rb5A 、-S(O)2R b5A 、-S(O)NR c5A R d5A 、-S(O)2NR c5A R d5A 、-C(=NR e5A )R a5A 、-C(=NR e5A )NR c5A R d5A 、-NR c5A C(=NR e5A )R a5A 、-NR c5A C(=NR e5A )NR c5A R d5A 、-NR c5A S(O)(=NR e5A )R b5A 、-NR c5A S(O)(=NR e5A )NR c5A R d5A 、-OS(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )NR c5A R d5A 、-C(O)NR c5A S(O)2R b5A 、-C(O)NR c5A S(O)2NR c5A R d5A 、-S(O)2NR c5A C(O)R b5A 、-NR c5A S(O)NR c5A C(O)R b5A and-P(O)R f5A R g5A , where R 5A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0148] Each R a5A 、R b5A 、R c5A and R d5A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C a5A 、R b5A 、R c5A and R d5A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0149] Alternatively, any R c5A and R d5A attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heteroalkyl, wherein the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0150] Each R e5AIndependently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0151] Each R f5A and R g5A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0152] R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-14 membered heterocycloalkyl)-C 1-4 alkyl and (5-14 membered heteroaryl)-C 1-4 alkyl, where the C 6 of R 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered hetero cycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered hetero cycloalkyl)-C 1-4 alkyl and (5 - 14 - membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents;

[0153] each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered hetero cycloalkyl)-C 1-4 alkyl, (5 - 10 - membered heteroaryl)-C 1-4 alkyl, - CN, - OR a6A , - SR a6A , - NR c6A R d6A , - NO2, - C(O)R a6A , - C(O)OR a6A , - C(O)NR c6A R d6A , - C(O)NR c6A (OR a6A ), - OC(O)R a6A , - OC(O)NR c6A R d6A , - OC(O)OR a6A , - OS(O)2R b6A , - OS(O)2NR c6A R d6A , - NR c6A C(O)R a6A , - NR c6A C(O)OR a6A , - NR c6A , - NR c6A Rd6A , -NR c6A S(O)2R b6A , -NR c6A S(O)2NR c6A R d6A , -NR c6A OR a6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A , -S(O)2NR c6A R d6A , -C(=NR e6A )R a6A , -C(=NR e6A )NR c6A R d6A , -NR c6A C(=NR e6A )R a6A , -NR c6A C(=NR e6A )NR c6A R d6A , -NR c6A S(O)(=NR e6A )R b6A , -NR c6A S(O)(=NR e6A )NR c6A R d6A , -OS(O)(=NR e6A )R b6A , -S(O)(=NR e6A )R b6A , -S(O)(=NR e6A )NR c6A R d6A , -C(O)NR c6A S(O)2R b6A , -C(O)NR c6A S(O)2NR c6A R d6A , -S(O)2NR c6A C(O)R b6A , -NR c6A S(O)NR c6A C(O)R b6A and -P(O)R f6A R g6A, wherein R 6A the C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0154] each R a6A , R b6A , R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein R a6A , R b6A , R c6A and R d6A the C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected RG Substituted by a substituent;

[0155] Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0156] Each R e6A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0157] Each R f6A and R g6A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0158] R 7 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 14-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7 , -SR a7 , -NR c7 R d7 , -NO2, -C(O)R a7 , -C(O)OR a7 , -C(O)NR c7 R d7 , -C(O)NR c7 (OR a7 ), -OC(O)R a7 , -OC(O)NR c7 R d7 , -OC(O)OR a7 , -OS(O)2R b7 , -OS(O)2NR c7 R d7 , -NR c7 C(O)R a7 , -NR c7 C(O)OR a7 , -NR c7 C(O)NR c7 R d7 , -NR c7 S(O)2R b7 , -NR c7 S(O)2NR c7 R d7 , -NR c7 OR a7 , -NR c7 S(O)R b7 , -NR c7 S(O)NR c7 R d7 , -S(O)R b7 , -S(O)2R b7 , -S(O)NR c7 R d7 , -S(O)2NR c7 R d7 , -C(=NR e7 )R a7 , -C(=NR e7 )NR c7 Rd7 , -NR c7 C(=NR e7 )R a7 , -NR c7 C(=NR e7 )NR c7 R d7 , -NR c7 S(O)(=NR e7 )R b7 , -NR c7 S(O)(=NR e7 )NR c7 R d7 , -OS(O)(=NR e7 )R b7 , -S(O)(=NR e7 )R b7 , -S(O)(=NR e7 )NR c7 R d7 , -C(O)NR c7 S(O)2R b7 , -C(O)NR c7 S(O)2NR c7 R d7 , -S(O)2NR c7 C(O)R b7 , -NR c7 S(O)NR c7 C(O)R b7 and -P(O)R f7 R g7 , wherein R 7 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered hetero cycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 (4 - 14 - membered hetero cycloalkyl)-C 1-4 alkyl and (5 - 14 - membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0159] Or, R 5 and R 7 together with the atom to which they are attached form a C 5-10Cycloalkyl or 5- to 10-membered heteroalkyl, wherein the C 5-10 cycloalkyl and 5- to 10-membered heteroalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0160] Alternatively, R 6 and R 7 together with the atom to which they are attached form a 5- to 10-membered heteroalkyl, wherein the 5- to 10-membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0161] Each R a7 , R b7 , R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heteroalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heteroalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl, wherein the C a7 , R b7 , R c7 and R d7 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, C 3-14 aryl, 4- to 14-membered heteroalkyl, 5- to 14-membered heteroaryl, C 6-10 cycloalkyl-C 3-14 alkyl, C 1-4 aryl-C 6-10 alkyl, (4- to 14-membered heteroalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1-4 substituents; 7A

[0162] Alternatively, any Rattached to the same N atom and R c7 and R d7Together with the N atom to which they are attached, form a 4- to 14-membered heterocycloalkyl group, wherein the 4- to 14-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0163] Each R e7 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0164] Each R f7 and R g7 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0165] Each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a7A , -SR a7A , -NR c7A R d7A , -NO2, -C(O)R a7A , -C(O)OR a7A , -C(O)NR c7A R d7A , -C(O)NR c7A (OR a7A ), -OC(O)R a7A , -OC(O)NR c7A R d7A , -OC(O)OR a7A , -OS(O)2R b7A , -OS(O)2NR c7A R d7A , -NR c7A C(O)R a7A , -NR c7A C(O)OR a7A , -NR c7A C(O)NR c7A R d7A , -NR c7A S(O)2R b7A , -NR c7A S(O)2NR c7A R d7A , -NR c7A OR a7A , -NR c7A S(O)R b7A , -NR c7A S(O)NR c7A R d7A , -S(O)R b7A , -S(O)2R b7A , -S(O)NR c7A R d7A , -S(O)2NR c7A R d7A , -C(=NR e7A )R a7A , -C(=NR e7A )NR c7A R d7A , -NR c7A C(=NR e7A )R a7A , -NR c7A C(=NRe7A )NR c7A R d7A 、-NR c7A S(O)(=NR e7A )R b7A 、-NR c7A S(O)(=NR e7A )NR c7A R d7A 、-OS(O)(=NR e7A )R b7A 、-S(O)(=NR e7A )R b7A 、-S(O)(=NR e7A )NR c7A R d7A 、-C(O)NR c7A S(O)2R b7A 、-C(O)NR c7A S(O)2NR c7A R d7A 、-S(O)2NR c7A C(O)R b7A 、-NR c7A S(O)NR c7A C(O)R b7A and-P(O)R f7A R g7A , where R 7A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 7B Substituent substitution;

[0166] Each R a7A , R b7A , R c7A and R d7A Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where R a7A , R b7A , R c7A and R d7A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents;

[0167] Alternatively, any R c7A and R d7A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents;

[0168] Each R e7A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0169] each R f7A and R g7A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0170] each R 7B is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7B , -SR a7B , -NR c7B R d7B , -NO2, -C(O)R a7B , -C(O)OR a7B , -C(O)NR c7B R d7B , -C(O)NR c7B (OR a7B ), -OC(O)R a7B , -OC(O)NR c7B R d7B , -OC(O)OR a7B , -OS(O)2R b7B , -OS(O)2NR c7B Rd7B ,-NR c7B C(O)R a7B ,-NR c7B C(O)OR a7B ,-NR c7B C(O)NR c7B R d7B ,-NR c7B S(O)2R b7B ,-NR c7B S(O)2NR c7B R d7B ,-NR c7B OR a7B ,-NR c7B S(O)R b7B ,-NR c7B S(O)NR c7B R d7B ,-S(O)R b7B ,-S(O)2R b7B ,-S(O)NR c7B R d7B ,-S(O)2NR c7B R d7B ,-C(=NR e7B )R a7B ,-C(=NR e7B )NR c7B R d7B ,-NR c7B C(=NR e7B )R a7B ,-NR c7B C(=NR e7B )NR c7B R d7B ,-NR c7B S(O)(=NR e7B )R b7B ,-NR c7B S(O)(=NR e7B )NR c7B R d7B ,-OS(O)(=NR e7B )R b7B ,-S(O)(=NR e7B )R b7B ,-S(O)(=NR e7B )NR c7B R d7B ,-C(O)NR c7B S(O)2R b7B ,-C(O)NR c7B S(O)2NR c7B R d7B, -S(O)2NR c7B C(O)R b7B , -NR c7B S(O)NR c7B C(O)R b7B and -P(O)R f7B R g7B , where R 7B of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0171] Each R a7B , R b7B , R c7B and R d7B is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 10 - membered heteroaryl) - C 1-4 alkyl, where R a7B , R b7B , R c7B and R d7B of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 each alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0172] alternatively, any R c7B and R d7B attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heteroalkyl, where the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0173] each R e7B is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0174] each R f7B and R g7B is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0175] R 8 selected from H, a halogen group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a8 , -SR a8 , -NR c8 R d8 , -NO2, -C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 R d8 , -C(O)NR c8 (OR a8 )、-OC(O)R a8 , -OC(O)NR c8 R d8 , -OC(O)OR a8 , -OS(O)2R b8 , -OS(O)2NR c8 R d8 [[ID=6l]], -NR c8 C(O)R a8 , -NR c8 C(O)OR a8 , -NR c8 C(O)NR c8 R d8 , -NR c8 S(O)2R b8 , -NR c8 S(O)2NR c8 R d8 , -NR c8 OR a8 , -NR c8 S(O)R b8 , -NR c8 S(O)NR c8 R d8 , -S(O)R b8 , -S(O)2R b8 , -S(O)NR c8 Rd8 、 -S(O)2NR c8 R d8 、 -C(=NR e8 )R a8 、 -C(=NR e8 )NR c8 R d8 、 -NR c8 C(=NR e8 )R a8 、 -NR c8 C(=NR e8 )NR c8 R d8 、 -NR c8 S(O)(=NR e8 )R b8 、 -NR c8 S(O)(=NR e8 )NR c8 R d8 、 -OS(O)(=NR e8 )R b8 、 -S(O)(=NR e8 )R b8 、 -S(O)(=NR e8 )NR c8 R d8 、 -C(O)NR c8 S(O)2R b8 、 -C(O)NR c8 S(O)2NR c8 R d8 、 -S(O)2NR c8 C(O)R b8 、 -NR c8 S(O)NR c8 C(O)R b8 and -P(O)R f8 R g8 wherein R 8 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0176] Each R a8 , R b8 , R c8 and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where the C a8 , R b8 , R c8 and R d8 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0177] Alternatively, any R c8 and R d8 attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, where the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents;

[0178] Each R e8 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl)-C 1-4 Alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Alkyl;

[0179] Each R f8 and R g8 independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl)-C 1-4 Alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Alkyl;

[0180] Each R 8A independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 - membered hetero cycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 - membered hetero cycloalkyl)-C 1-4 Alkyl, (5 - 10 - membered heteroaryl)-C 1-4 Alkyl, - CN, - OR a8A , - SR a8A , - NR c8A R d8A , - NO2, - C(O)R a8A , - C(O)ORa8A 、 -C(O)NR c8A R d8A 、 -C(O)NR c8A (OR a8A )、 -OC(O)R a8A 、 -OC(O)NR c8A R d8A 、 -OC(O)OR a8A 、 -OS(O)2R b8A 、 -OS(O)2NR c8A R d8A 、 -NR c8A C(O)R a8A 、 -NR c8A C(O)OR a8A 、 -NR c8A C(O)NR c8A R d8A 、 -NR c8A S(O)2R b8A 、 -NR c8A S(O)2NR c8A R d8A 、 -NR c8A OR a8A 、 -NR c8A S(O)R b8A 、 -NR c8A S(O)NR c8A R d8A 、 -S(O)R b8A 、 -S(O)2R b8A 、 -S(O)NR c8A R d8A 、 -S(O)2NR c8A R d8A 、 -C(=NR e8A )R a8A 、 -C(=NR e8A )NR c8A R d8A 、 -NR c8A C(=NR e8A )R a8A 、 -NR c8A C(=NR e8A )NR c8A R d8A 、 -NR c8A S(O)(=NR e8A )R b8A 、 -NR c8A S(O)(=NR e8A )NR c8A R d8A 、 -OS(O)(=NRe8A )R b8A 、 -S(O)(=NR e8A )R b8A 、 -S(O)(=NR e8A )NR c8A R d8A 、 -C(O)NR c8A S(O)2R b8A 、 -C(O)NR c8A S(O)2NR c8A R d8A 、 -S(O)2NR c8A C(O)R b8A 、 -NR c8A S(O)NR c8A C(O)R b8A and -P(O)R f8A R g8A , wherein R 8A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0181] Each R a8A , R b8A , R c8A and R d8A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 alkyl, wherein Ra8A , R b8A , R c8A and R d8A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0182] Alternatively, any R c8A and R d8A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0183] Each R e8A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl;

[0184] Each R f8A and R g8A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 10-membered heteroaryl)-C 1-4 Alkyl; and

[0185] Each R G Is independently selected from H, OH, CN, halogen, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Halogenated alkyl, cyano-C 1-4 Alkyl, HO-C 1-4 Alkyl, C 1-4 Alkoxy-C 1-4 Alkyl, C 3-7 Cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, amino, C 1-3 Alkylamino, di(C 1-3 Alkyl)amino, thio, C 1-3 Alkylthio, C 1-3 Alkylsulfinyl, C 1-3 Alkylsulfonyl, carbamoyl, C 1-3 Alkylcarbamoyl, di(C 1-3 Alkyl)carbamoyl, carboxy, C 1-3 Alkylcarbonyl, C 1-3 Alkoxycarbonyl, C 1-3 Alkylcarbonyloxy, C 1-3 Alkylcarbonylamino, C 1-3 Alkoxycarbonylamino, aminocarbonyloxy, C 1-3 Alkylaminocarbonyloxy, di(C 1-3 Alkyl)aminocarbonyloxy, C 1-3 Alkylsulfonylamino, aminosulfonyl, C 1-3 Alkylaminosulfonyl, di(C 1-3 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 Alkylaminosulfonylamino, di(C 1-3 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 Alkylaminocarbonylamino and di(C 1-3 Alkyl)aminocarbonylamino.

[0186] In some embodiments, X 1 is N or NR 6 .

[0187] In some embodiments, X 1 is N.

[0188] In some embodiments, X 1 is NR 6 .

[0189] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 14-membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 , -C(O)OR a6 , -C(O)NR c6 R d6 , -S(O)R b6 and -S(O)2R b6 , wherein each of the C 6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, C 3-14 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 6-10 cycloalkyl-C 3-14 alkyl, C 1-4 aryl-C 6-10 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl is optionally substituted with 1, 2, 3, or 4 independently selected R 1-4 substituents. 6A

[0190] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 ​Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 14 membered heterocycloalkyl) - C 1-4 Alkyl, (5 - 14 membered heteroaryl) - C 1-4 Alkyl, -C(O)R a6 And -S(O)2R b6 , wherein R 6 The said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 14 membered heterocycloalkyl) - C 1-4 Alkyl and (5 - 14 membered heteroaryl) - C 1-4 Alkyl each is optionally substituted by 1, 2, 3 or 4 independently selected R 6A Substituents.

[0191] In some embodiments, R 6 Is selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 14 membered heterocycloalkyl) - C 1-4 Alkyl and (5 - 14 membered heteroaryl) - C 1-4 Alkyl, wherein R 6 The said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C3-14 Cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0192] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 and -S(O)2R b6 wherein the C 6 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0193] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10Cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein R 6 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents.

[0194] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 and -S(O)2R b6 wherein R 6 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 6ASubstituted by a substituent.

[0195] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein the C 6 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 6A substituents.

[0196] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C(O)R a6 and -S(O)2R b6 wherein the C 6 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R 6A substituents.

[0197] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, wherein the C 6 of R 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Haloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0198] In some embodiments, R 6 is selected from H, C 1-6 alkyl, -C(O)R a6 and -S(O)2R b6 , where the C 6 alkyl of R 1-6 is optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0199] In some embodiments, each R a6 , R b6 , R c6 and R d6 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

[0200] In some embodiments, each R a6 , R b6 , R c6 and R d6 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0201] In some embodiments, each R a6 , R b6 , R c6 and R d6 is independently selected from H and C 1-6 alkyl.

[0202] In some embodiments, each R a6 , R b6 , R c6 and R d6 is independently selected from H and C 1-3 alkyl.

[0203] In some embodiments, each R a6 and R b6 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

[0204] In some embodiments, each R a6 and R b6 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0205] In some embodiments, each R a6 and R b6 is independently selected from H and C 1-6 alkyl.

[0206] In some embodiments, each R a6 and R b6 is independently selected from H and C 1-3 alkyl.

[0207] In some embodiments, R 6 is selected from H and C 1-6 alkyl, wherein the C 6 alkyl of R 1-6 is optionally substituted with 1, 2, 3, or 4 independently selected R 6A substituents.

[0208] In some embodiments, R 6 is selected from H, methyl, ethyl, methylcarbonyl, and methylsulfonyl, wherein the methyl and ethyl of R 6 are optionally substituted with 1 or 2 independently selected R 6A substituents.

[0209] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl, (5-6-membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 and -S(O)2R b6 , wherein the C 6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heteroalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents; and

[0210] Each R a6 and R b6 is independently selected from H and C 1-6 alkyl.

[0211] In some embodiments, R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C(O)R a6 and -S(O)2R b6 , where the C 6 alkyl, C 1-6 alkenyl, C 2-6 alkynyl and C 2-6 haloalkyl of R 1-6 are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents; and

[0212] Each R a6 and R b6 is independently selected from H and C 1-6 alkyl.

[0213] In some embodiments, R 6 is selected from H, C 1-6 alkyl, -C(O)R a6 and -S(O)2R b6 , where the C 6 alkyl of R 1-6 is optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents; and

[0214] Each R a6 and R b6 is independently selected from H and C 1-6 alkyl.

[0215] In some embodiments, R 6 is selected from H, C 1-6 alkyl, -C(O)R a6 and -S(O)2R b6 , where the C 6 alkyl of R 1-6 is optionally substituted with 1, 2, 3 or 4 independently selected R6A Substituted by a substituent; and

[0216] Each R a6 and R b6 is independently selected from H and C 1-3 alkyl.

[0217] In some embodiments, R 6 is selected from H, methyl, ethyl, methylcarbonyl, and methylsulfonyl, wherein the methyl and ethyl of R 6 are optionally substituted by 1 or 2 independently selected R6A substituents.

[0218] In some embodiments, R 6 is selected from H, methyl, and ethyl, wherein the methyl and ethyl of R 6 are optionally substituted by 1 or 2 independently selected R 6A substituents.

[0219] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl, (5-6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A 、-SR a6A 、-NR c6A R d6A 、-NO2、-C(O)R a6A 、-C(O)OR a6A 、-C(O)NR c6A R d6A 、-OC(O)R a6A 、-OC(O)NR c6A R d6A 、-OC(O)OR a6A 、-NR c6A C(O)R a6A 、-NR c6A C(O)OR a6A 、-NR c6A C(O)NR c6A R d6A 、-NR c6A S(O)2R b6A 、-NRc6A S(O)R b6A 、-NR c6A S(O)NR c6A R d6A 、-S(O)R b6A 、-S(O)2R b6A 、-S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , where R 6A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R G Substituent substitution.

[0220] In some embodiments, each R a6A , R b6A , R c6A and R d6A Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl.

[0221] In some embodiments, each R a6A , R b6A , R c6A and R d6A Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;

[0222] Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0223] In some embodiments, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0224] In some embodiments, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;

[0225] In some embodiments, each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

[0226] Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;

[0227] In some embodiments, each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4alkyl, (4-7-membered heteroalkyl)-C 1-4 alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl;

[0228] alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4-10-membered heteroalkyl, where the 4-10-membered heteroalkyl is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents.

[0229] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heteroalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heteroalkyl)-C 1-4 alkyl, (5-6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A , -SR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -NR c6A C(O)NR c6A R d6A , -NR c6A S(O)2R b6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NRc6A R d6A and -S(O)2NR c6A R d6A wherein R 6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 7 - membered heterocycloalkyl, 5 - 6 - membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 6 - membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R G substituents; and

[0230] each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4 - 7 - membered heterocycloalkyl, 5 - 6 - membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 6 - membered heteroaryl)-C 1-4 alkyl;

[0231] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4 - 10 - membered heterocycloalkyl, wherein the 4 - 10 - membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G substituents.

[0232] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 1-6 haloalkyl, 4 - 7 - membered heterocycloalkyl, -CN, -OR a6A 、-NR c6A R d6A 、-NO2、-C(O)R a6A 、-C(O)OR a6A, -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein R 6A of said C 1-6 alkyl, C 1-6 haloalkyl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0233] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 1-6 haloalkyl, -CN, -OR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein R 6A of said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0234] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 1-6 haloalkyl, 4- to 7-membered heterocycloalkyl, -CN, -OR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein the C 6A alkyl, C 1-6 haloalkyl, and 4- to 7-membered heterocycloalkyl of R 1-6 are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; and

[0235] each R a6A , R b6A , R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

[0236] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0237] In some embodiments, each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 1-6haloalkyl, -CN, -OR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein R 6A of said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; and

[0238] each R a6A , R b6A , R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0239] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4 - 10 membered heterocycloalkyl, wherein the 4 - 10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents.

[0240] In some embodiments, each R 6A is independently selected from CN, 4 - 7 membered heterocycloalkyl and -C(O)NR c6A R d6A .

[0241] In some embodiments, each R 6A is independently selected from -C(O)NR c6A R d6A .

[0242] In some embodiments, each R 6A is independently selected from CN, 4- to 7-membered heterocycloalkyl, and -C(O)NR c6A R d6A ; and

[0243] each R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

[0244] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0245] In some embodiments, each R 6A is independently selected from -C(O)NR c6A R d6A ; and

[0246] each R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

[0247] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents.

[0248] In some embodiments, each R 6A is independently selected from CN, azetidinyl, aminocarbonyl, methylaminocarbonyl, and morpholinocarbonyl.

[0249] In some embodiments, each R 6A is independently selected from methylaminocarbonyl and morpholinocarbonyl.

[0250] In some embodiments, X 2 is CR 7 .

[0251] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-14 membered heterocycloalkyl)-C 1-4 alkyl, (5-14 membered heteroaryl)-C 1-4 alkyl and -C(O)NR c7 R d7 , where the C 7 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, C 3-14 aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 6-10 cycloalkyl-C 3-14 alkyl, C 1-4 aryl-C 6-10 alkyl, (4-14 membered heterocycloalkyl)-C 1-4 alkyl and (5-14 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 1-4 substituents. 7A

[0252] In some embodiments, each R a7 , R b7 , R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl. a7

[0253] In some embodiments, each R b7 , R c7 , R d7 and R d7 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0254] In some embodiments, each R a7 , R b7, R c7 and R d7 are independently selected from H and C 1-6 alkyl groups.

[0255] In some embodiments, each R<> c7 and R d7 are independently selected from H, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups, and C 1-6 haloalkyl groups.

[0256] In some embodiments, each R c7 and R d7 are independently selected from H, C 1-6 alkyl groups, and C 1-6 haloalkyl groups.

[0257] In some embodiments, each R c7 and R d7 are independently selected from H and C 1-6 alkyl groups.

[0258] In some embodiments, each R c7 and R d7 are independently selected from H and C 1-3 alkyl groups.

[0259] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl groups, C 2-6 alkenyl groups, C 2-6 alkynyl groups, C 1-6 haloalkyl groups, C 3-14 cycloalkyl groups, C 6-10 aryl groups, 4- to 14-membered heterocycloalkyl groups, 5- to 14-membered heteroaryl groups, C 3-14 cycloalkyl-C 1-4 alkyl groups, C 6-10 aryl-C 1-4 alkyl groups, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl groups, (5- to 14-membered heteroaryl)-C 1-4 alkyl groups, and -C(O)NR c7 R d7 , where the C 7 alkyl groups, C 1-6 alkenyl groups, C 2-6 alkynyl groups, C 2-6 haloalkyl groups, C 1-6 cycloalkyl groups, C 3-14 aryl groups, 4- to 14-membered heterocycloalkyl groups, 5- to 14-membered heteroaryl groups, C 6-10 cycloalkyl-C 3-14 alkyl groups, and C 1-4Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 14-membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and

[0260] each R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0261] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl, and (5- to 14-membered heteroaryl)-C 1-4 alkyl, where the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl, and (5- to 14-membered heteroaryl)-C 1-4 alkyls are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0262] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Halogenoalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered hetero cycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered hetero cycloalkyl)-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl and -C(O)NR c7 R d7 wherein the C of R 7 Alkyl, C 1-6 Alkenyl, C 2-6 Alkynyl, C 2-6 Halogenoalkyl, C 1-6 Cycloalkyl, C 3-10 Aryl, 4-10 membered hetero cycloalkyl, 5-10 membered heteroaryl, C 6-10 Cycloalkyl-C 3-10 Alkyl, C 1-4 Aryl-C 6-10 Alkyl, (4-10 membered hetero cycloalkyl)-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl is each optionally substituted by 1, 2, 3 or 4 independently selected R 7A substituents.

[0263] In some embodiments, R 7 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenoalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered hetero cycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered hetero cycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl and -C(O)NR c7 R d7 wherein the C of R 7 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 halogenoalkyl, C 1-6 cycloalkyl, C 3-10 aryl, C 6-10Aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and

[0264] each R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0265] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and (5- to 10-membered heteroaryl)-C 1-4 alkyl, where the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0266] In some embodiments, R 7 is selected from H, halo, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 10 membered heterocycloalkyl, 5 - 6 membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 membered heterocycloalkyl) - C 1-4 alkyl, (5 - 6 membered heteroaryl) - C 1-4 alkyl and -C(O)NR c7 R d7 wherein the C 7 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 10 membered heterocycloalkyl, 5 - 6 membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 membered heterocycloalkyl) - C 1-4 alkyl and (5 - 6 membered heteroaryl) - C 1-4 alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents.

[0267] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 10 membered heterocycloalkyl, 5 - 6 membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 membered heterocycloalkyl) - C 1-4 alkyl, (5 - 6 membered heteroaryl) - C 1-4 alkyl and -C(O)NR c7 R d7 wherein the C 7 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 10 membered heterocycloalkyl, 5 - 6 membered heteroaryl, C 3-7 cycloalkyl - C 1-4Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heteroalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents; and

[0268] Each R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl

[0269] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents.

[0270] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-10 membered heteroalkyl, 5-6 membered heteroaryl and -C(O)NR c7 R d7, wherein R 7 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0271] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-10 membered heterocycloalkyl, 5-6 membered heteroaryl, and -C(O)NR c7 R d7 , wherein R 7 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and

[0272] each R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0273] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl, wherein R 7 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0274] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, 5-6 membered heteroaryl, and -C(O)NR c7 R d7 , wherein the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0275] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, 5-6 membered heteroaryl, and -C(O)NR c7 R d7 , wherein the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and

[0276] each R c7 and R d7 is independently selected from H and C 1-6 alkyl.

[0277] In some embodiments, R 7 is selected from H, halo, C 1-6 alkyl, phenyl, and 5-6 membered heteroaryl, wherein the C 7 of R 1-6 alkyl, phenyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

[0278] In some embodiments, each R 7 is H, chloro, bromo, methyl, ethyl, vinyl, ethynyl, propynyl, dimethylpropynyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, phenyl, pyrazolyl, pyridyl, triazolyl, pyrimidinyl, and ethylaminocarbonyl, wherein R 7The methyl, ethyl, vinyl, ethynyl, propynyl, dimethylpropynyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, phenyl, pyrazolyl, pyridyl, triazolyl and pyrimidinyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents.

[0279] In some embodiments, each R 7 is H, chloro, bromo, methyl, phenyl, pyrazolyl and pyridyl, wherein the methyl, phenyl, pyrazolyl and pyridyl of R 7 are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents.

[0280] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 haloalkyl, C 1-6 cycloalkyl, C 3-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 6-10 cycloalkyl-C 3-10 alkyl, C 1-4 aryl-C 6-10 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents.

[0281] In some embodiments, each R a7A , R a7B , R a7C and R a7D is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

[0282] In some embodiments, each R a7A , R a7B , R a7C and R a7D is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0283] In some embodiments, each R a7A , R a7B , R a7C and R a7D is independently selected from H and C 1-6 alkyl.

[0284] In some embodiments, each R a7A , R a7C and R a7D is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

[0285] In some embodiments, each R a7A , R a7C and R a7D is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0286] In some embodiments, each R a7A , R a7C and R a7D is independently selected from H and C 1-6 alkyl.

[0287] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4 - 10 membered heteroalkyl)-C 1-4 alkyl, (5 - 10 membered heteroaryl)-C 1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , where R 7A the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heteroalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4 - 10 membered heteroalkyl)-C 1-4 alkyl and (5 - 10 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents; and

[0288] each R a7A , R c7A and R d7A is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0289] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heteroalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4 - 10 membered heteroalkyl)-C 1-4 alkyl, (5 - 10 membered heteroaryl)-C 1-4 alkyl, where R 7A the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 Alkyl and (5 - 10 membered heteroaryl)-C 1-4 Alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B Substituents.

[0290] In some embodiments, each R 7A Is independently selected from oxo, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 Alkyl, (5 - 10 membered heteroaryl)-C 1-4 Alkyl, CN, OR a7A , -NR c7A R d7A And C(O)NR c7A R d7A Wherein the C 7A Of R 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 Cycloalkyl - C 1-4 Alkyl, C 6-10 Aryl - C 1-4 Alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 Alkyl and (5 - 10 membered heteroaryl)-C 1-4 Alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R 7B Substituents.

[0291] In some embodiments, each R 7Aindependently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , where R 7A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents; and

[0292] each R a7A , R c7A and R d7A is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0293] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C6-10 Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl.

[0294] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents.

[0295] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein R 7A the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R 7B substituents; and

[0296] each R a7A , R c7A and R d7A is independently selected from H and C 1-6 alkyl.

[0297] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl.

[0298] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A Rd7A , wherein R 7A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents.

[0299] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents; and

[0300] each R a7A , R c7A and R d7A is independently selected from H and C 1-6 alkyl.

[0301] In some embodiments, each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.

[0302] In some embodiments, each R 7A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C3-7 Cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein R 7A the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B substituents.

[0303] In some embodiments, each R 7A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein R 7A the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B substituents; and

[0304] each R a7A , R c7A and R d7A is independently selected from H and C 1-6 alkyl.

[0305] In some embodiments, each R 7A is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl and 4- to 7-membered heterocycloalkyl.

[0306] In some embodiments, each R 7A is independently selected from C 1-6 alkyl, C1-6 haloalkyl, C 3-7 cycloalkyl, 4- to 7-membered heteroalkyl, 5- or 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, 4- to 7-membered heteroalkyl and 5- or 6-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 independently selected R 3-7 substituents. 7B In some embodiments, each R

[0307] is independently selected from C 7A alkyl, C 1-6 haloalkyl, C 1-6 cycloalkyl, 4- to 7-membered heteroalkyl, 5- or 6-membered heteroaryl, CN, OR 3-7 , -NR a7A R c7A and C(O)NR d7A R c7A wherein the C d7A alkyl, C 7A haloalkyl, C 1-6 cycloalkyl, 4- to 7-membered heteroalkyl and 5- or 6-membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 independently selected R 1-6 substituents; and

[0308] each R a7A , R c7A and R d7A is independently selected from H and C 1-6 alkyl. 7A In some embodiments, each R 1-6 is independently selected from C

[0309] alkyl, C 1-6 haloalkyl and 4- to 7-membered heteroalkyl. 7A In some embodiments, each R 1-6 is independently selected from C

[0310] alkyl, C 3-7 cycloalkyl, 4- to 7-membered heteroalkyl, 5- or 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A wherein R 7A alkyl, C 1-6 haloalkyl, C7A said C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents.

[0311] In some embodiments, each R 7A is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A alkyl, C 1-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl of R 3-7 are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents; and

[0312] each R a7A , R c7A and R d7A is independently selected from H and C 1-3 alkyl.

[0313] In some embodiments, each R 7A is independently selected from C 1-6 alkyl and 4- to 7-membered heterocycloalkyl.

[0314] In some embodiments, each R 7A is independently selected from C 1-6 alkyl.

[0315] In some embodiments, each R 7A is independently selected from 4- to 7-membered heterocycloalkyl.

[0316] In some embodiments, each R 7A is independently selected from methyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, imidazolyl, pyrazolyl, pyridinyl, cyano, hydroxy, amino, and aminocarbonyl, wherein the methyl, isopropyl, cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, imidazolyl, pyrazolyl, and pyridinyl of R 7A are each optionally substituted with 1, 2, 3, or 4 independently selected R 7B substituents.

[0317] In some embodiments, each R7B Independently selected from C 1-6 alkyl, OR a7B , NR c7B R d7B , C(O)R a7B and -C(O)NR c7B R d7B , where the C 1-6 alkyl is optionally substituted by R G .

[0318] In some embodiments, each R 7B is independently selected from C 1-6 alkyl, OR a7B , NR c7B R d7B , C(O)R a7B and -C(O)NR c7B R d7B , where the C 1-6 alkyl is optionally substituted by OH.

[0319] In some embodiments, each R a7B , R b7B , R c7B and R d7B is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

[0320] In some embodiments, each R a7B , R b7B , R c7B and R d7B is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

[0321] In some embodiments, each R a7B , R b7B , R c7B and R d7B is independently selected from H and C 1-6 alkyl.

[0322] In some embodiments, each R a7B , R b7B , R c7B and R d7B is independently selected from H and C 1-3 alkyl.

[0323] In some embodiments, each R a7B , R c7B and Rd7B independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0324] In some embodiments, each R a7B , R c7B and R d7B is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0325] In some embodiments, each R a7B , R c7B and R d7B is independently selected from H and C 1-6 alkyl.

[0326] In some embodiments, each R a7B , R c7B and R d7B is independently selected from H and C 1-3 alkyl.

[0327] In some embodiments, each R 7B is independently selected from methyl, hydroxymethyl, hydroxy, amino, methylcarbonyl, and methylaminocarbonyl.

[0328] In some embodiments, each R 7A is methyl.

[0329] In some embodiments, each R 7A is morpholinyl.

[0330] In some embodiments, R 7 is selected from H, chloro, bromo, methyl, hydroxymethyl, cyanomethyl, hydroxyethyl, cyanoethyl, pyridylethyl, cyanovinyl, pyridylvinyl, ethynyl, cyclopropyl ethynyl, (hydroxycyclopropyl) ethynyl, (hydroxymethylcyclopropyl) ethynyl, (aminocyclopropyl) ethynyl, (hydroxy)(dimethyl) propynyl, (amino)(dimethyl) propynyl, (methyloxetanyl) ethynyl, tetrahydropyranyl ethynyl, (methylcarbonylpiperidyl) ethynyl, (methylaminocarbonylpiperidyl) ethynyl, pyridyl ethynyl, (methylpyrazolyl) ethynyl, (methylimidazolyl) ethynyl, 5,6,7,8-tetrahydro-[1,2,4] triazolo [1,5-a] pyrazinyl, pyrimidinyl, isopropylpyrazolyl, tetrahydrofuranylpyrazolyl, methyltriazolyl, phenyl, aminocarbonylphenyl, ethylaminocarbonyl, methylpyrazolyl, pyridyl, and morpholinylmethyl.

[0331] In some embodiments, R 7Selected from H, chloro, bromo, methyl,

[0332] In some embodiments, R 7 is selected from H, chloro, bromo, methyl, phenyl, methylpyrazolyl, pyridyl, and morpholinomethyl.

[0333] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 7A substituents.

[0334] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 7A substituents.

[0335] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl.

[0336] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 7-membered heterocycloalkyl.

[0337] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl selected from thereof.

[0338] In some embodiments, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl selected from thereof.

[0339] In some embodiments, X 3 is CR 8 .

[0340] In some embodiments, R 8 is selected from H, halo, C 1-6 alkyl, C 2-6Alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0341] In some embodiments, X 3 is CH.

[0342] In some embodiments, Y is C.

[0343] In some embodiments, Y is N.

[0344] In some embodiments, Z is C.

[0345] In some embodiments, Z is N.

[0346] In some embodiments, Y is C and Z is C.

[0347] In some embodiments, Y is C and Z is N.

[0348] In some embodiments, R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 .

[0349] In some embodiments, each R a3 , R b3 , R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0350] In some embodiments, each R a3 , R b3 , R c3 and R d3 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0351] In some embodiments, each R a3 , R b3 , R c3 and R d3 is independently selected from H and C 1-6 alkyl.

[0352] In some embodiments, each R a3 , R b3 , R c3 and R d3 is independently selected from H and C1-3 Alkyl

[0353] In some embodiments, each R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0354] In some embodiments, each R c3 and R d3 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0355] In some embodiments, each R c3 and R d3 is independently selected from H and C 1-6 alkyl.

[0356] In some embodiments, each R c3 and R d3 is independently selected from H and C 1-3 alkyl.

[0357] In some embodiments, R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 ; and

[0358] each R c3 and R d3 is independently selected from H and C 1-6 alkyl.

[0359] In some embodiments, R 3 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0360] In some embodiments, R 3 is selected from H, C 1-6 alkyl, and -C(O)NR c3 R d3 .

[0361] In some embodiments, R 3 is selected from H, C 1-6 alkyl, and -C(O)NR c3 R d3 ; and

[0362] each R c3 and Rd3 Independently selected from H and C 1-3 alkyl group.

[0363] In some embodiments, R 3 is H or C 1-6 alkyl group.

[0364] In some embodiments, R 3 is H.

[0365] In some embodiments, R 3 is C 1-6 alkyl group.

[0366] In some embodiments, R 3 is -C(O)NR c3 R d3 .

[0367] In some embodiments, R 3 is -C(O)NR c3 R d3 ; and

[0368] each R c3 and R d3 is independently selected from H and C 1-3 alkyl group.

[0369] In some embodiments, R 3 is selected from H, methyl, and aminomethylcarbonyl.

[0370] In some embodiments, R 3 is H.

[0371] In some embodiments, R 3 is methyl.

[0372] In some embodiments, R 3 is aminomethylcarbonyl.

[0373] In some embodiments, R 4 is selected from H, C 1-6 alkyl group and C 1-6 haloalkyl group. In some embodiments, R 4 is selected from H and C 1-6 alkyl group.

[0374] In some embodiments, R 4 is selected from H and C 1-3 alkyl group.

[0375] In some embodiments, R 4 is H.

[0376] In some embodiments, R4 is C 1-6 alkyl

[0377] In some embodiments, R 4 is C 1-3 alkyl

[0378] In some embodiments, R 4 is methyl

[0379] In some embodiments:

[0380] R 3 is selected from H, C 1-6 alkyl, and -C(O)NR c3 R d3 ;

[0381] Each R c3 and R d3 is independently selected from H and C 1-3 alkyl; and R 4 is selected from H and C 1-6 alkyl

[0382] In some embodiments:

[0383] R 3 is selected from H, C 1-3 alkyl, and -C(O)NR c3 R d3 ;

[0384] Each R c3 and R d3 is independently selected from H and C 1-3 alkyl; and R 4 is selected from H and C 1-3 alkyl

[0385] In some embodiments, R 3 is H or C 1-6 alkyl; and R 4 is H. In some embodiments, L 1 is -N(R L )C(O)- or -N(R L )-

[0386] In some embodiments, L 1 is -N(R L )C(O)-

[0387] In some embodiments, L 1 is -N(R L )-

[0388] In some embodiments, L 1is -NHC(O)-.

[0389] In some embodiments, L 1 is -NH-.

[0390] In some embodiments, L 2 is a bond.

[0391] In some embodiments, L 3 is selected from C 1-6 alkylene, -O-, and -N(R L )-.

[0392] In some embodiments, L 3 is selected from methylene, -O-, and -NH-.

[0393] In some embodiments, L 3 is methylene.

[0394] In some embodiments, L 3 is -O-.

[0395] In some embodiments, L 3 is -NH-.

[0396] In some embodiments, L 4 is a bond or -O-.

[0397] In some embodiments, L 4 is a bond.

[0398] In some embodiments, L 4 is -O-.

[0399] In some embodiments, ring A is C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl.

[0400] In some embodiments, ring A is C 6-10 aryl, 4-10 membered heterocycloalkyl, or 5-10 membered heteroaryl.

[0401] In some embodiments, ring A is C 6-10 aryl.

[0402] In some embodiments, ring A is phenyl.

[0403] In some embodiments, ring A is 4-10 membered heterocycloalkyl.

[0404] In some embodiments, ring A is 8-10 membered heterocycloalkyl.

[0405] In some embodiments, Ring A is a 5-10 membered heteroaryl.

[0406] In some embodiments, Ring A is an 8-10 membered heteroaryl.

[0407] In some embodiments, Ring A is phenyl, 8-10 membered heterocycloalkyl, or 8-10 membered heteroaryl.

[0408] In some embodiments, Ring A is phenyl, benzo[b]thienyl, or indolinyl.

[0409] In some embodiments, n is 0, 1, 2, 3, or 4.

[0410] In some embodiments, n is 0, 1, 2, or 3.

[0411] In some embodiments, n is 0, 2, or 3.

[0412] In some embodiments, each R 1 Independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, and -OR a1 , where R 1 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Each haloalkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 1A Substituent substitution.

[0413] In some embodiments, each R 1 Independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -CN, and -OR a1 .

[0414] In some embodiments, each R a1 , R b1 , R c1 and R d1 Independently selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 1-6 Halogenated alkyl.

[0415] In some embodiments, each R a1 , R b1 , Rc1 and R d1 are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0416] In some embodiments, each R a1 , R b1 , R c1 , and R d1 are independently selected from H and C 1-6 alkyl.

[0417] In some embodiments, each R a1 , R b1 , R c1 , and R d1 is H.

[0418] In some embodiments, each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, and -OR a1 ; and

[0419] each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0420] In some embodiments, each R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OR a1 ; and

[0421] each R a1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0422] In some embodiments, each R 1 is independently selected from fluoro, chloro, trifluoromethyl, and hydroxy.

[0423] In some embodiments, each R 1 is independently selected from fluoro, trifluoromethyl, and hydroxy.

[0424] In some embodiments, ring A is selected from

[0425] In some embodiments, ring A is

[0426] In some embodiments, ring A is

[0427] In some embodiments, ring A is

[0428] In some embodiments, ring A is

[0429] In some embodiments, ring A is and

[0430] R 1 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, and OR a1 ; and

[0431] each R a1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

[0432] In some embodiments, ring A is and

[0433] R 1 is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.

[0434] In some embodiments, ring A is and

[0435] each R 1 is independently selected from fluorine, chlorine, trifluoromethyl.

[0436] In some embodiments, ring A is

[0437] In some embodiments, ring B is C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered hetero cycloalkyl, or 5-10 membered heteroaryl.

[0438] In some embodiments, ring B is C 3-7 cycloalkyl, phenyl, 4-7 membered hetero cycloalkyl, or 5-6 membered heteroaryl.

[0439] In some embodiments, ring B is C 6-10 aryl, or 5-10 membered heteroaryl.

[0440] In some embodiments, ring B is phenyl or 5-6 membered heteroaryl.

[0441] In some embodiments, ring B is phenyl or pyridyl.

[0442] In some embodiments, m is 0, 1, 2, or 3.

[0443] In some embodiments, m is 1 or 2.

[0444] In some embodiments, each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl, wherein the C 2 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, and C 2-6 haloalkyl of each R 1-6 is optionally substituted with 1, 2, 3, 4, 5, or 6 independently selected R 2A substituents.

[0445] In some embodiments, each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0446] In some embodiments, each R 2 is independently selected from halo.

[0447] In some embodiments, each R 2 is independently chloro or fluoro.

[0448] In some embodiments, ring B is

[0449] In some embodiments, ring B is

[0450] In some embodiments:

[0451] X 1 is CR 5 , N, or NR 6 ;

[0452] X 2 is CR 7 or N;

[0453] X 3 is CR 8 or N;

[0454] Y is C or N;

[0455] Z is C or N;

[0456] n is 0, 1, 2, 3 or 4;

[0457] m is 0, 1, 2, 3 or 4;

[0458] L 1 is -NHC(O)- or -NH-;

[0459] L 2 is a bond;

[0460] L 3 is selected from C 1-6 alkylene, -O- and -NH-;

[0461] L 4 is a bond or -O-;

[0462] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1 、-SR a1 、-NR c1 R d1 、-C(O)R a1 、-C(O)OR a1 、-C(O)NR c1 R d1 、-C(O)NR c1 (OR a1 )、-OC(O)R a1 、-OC(O)NR c1 R d1 、-OC(O)OR a1 、-OS(O)2R b1 、-OS(O)2NR c1 R d1 、-NR c1 C(O)R a1 、-NR c1 C(O)OR a1 、-NR c1 C(O)NRc1 R d1 、 -NR c1 S(O)2R b1 、 -NR c1 S(O)2NR c1 R d1 、 -NR c1 OR a1 、 -NR c1 S(O)R b1 、 -NR c1 S(O)NR c1 R d1 、 -S(O)R b1 、 -S(O)2R b1 、 -S(O)NR c1 R d1 、 -S(O)2NR c1 R d1 、 -C(=NR e1 )R a1 、 -C(=NR e1 )NR c1 R d1 、 -NR c1 C(=NR e1 )R a1 、 -NR c1 C(=NR e1 )NR c1 R d1 、 -NR c1 S(O)(=NR e1 )R b1 、 -NR c1 S(O)(=NR e1 )NR c1 R d1 、 -OS(O)(=NR e1 )R b1 、 -S(O)(=NR e1 )R b1 、 -S(O)(=NR e1 )NR c1 R d1 、 -C(O)NR c1 S(O)2R b1 、 -C(O)NR c1 S(O)2NR c1 R d1 、 -S(O)2NR c1 C(O)R b1 、 -NR c1 S(O)NR c1 C(O)R b1 and -P(O)R f1R g1 , wherein R 1 of the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0463] Each R a1 , R b1 , R c1 and R d1 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein R a1 , R b1 , R c1 and R d1 of the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0464] Alternatively, any R c1 and R d1Together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-10 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents;

[0465] Each R e1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0466] Each R f1 and R g1 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0467] Each R 1A is independently selected from H, OH, CN, halogen, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C1-3 (alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino;

[0468] Each R 2 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a2 , -SR a2 , -NR c2 R d2 , -C(O)R a2 , -C(O)OR a2 , -C(O)NR c2 R d2 , -C(O)NR c2 (OR a2 ), -OC(O)R a2 , -OC(O)NR c2 R d2 , -OC(O)OR a2 , -OS(O)2R b2 , -OS(O)2NR c2 R d2 , -NR c2 C(O)R a2 , -NR c2 C(O)OR a2 , -NR c2 , -NR c2 R d2 , -NR c2 S(O)2R b2 , -NR c2 , -NR c2 R d2 , -NR c2 OR a2 , -NR c2 , -NR b2, -NR c2 S(O)NR c2 R d2 , -S(O)R b2 , -S(O)₂R b2 , -S(O)NR c2 R d2 , -S(O)₂NR c2 R d2 , -C(=NR e2 )R a2 , -C(=NR e2 )NR c2 R d2 , -NR c2 C(=NR e2 )R a2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 S(O)(=NR e2 )R b2 , -NR c2 S(O)(=NR e2 )NR c2 R d2 , -OS(O)(=NR e2 )R b2 , -S(O)(=NR e2 )R b2 , -S(O)(=NR e2 )NR c2 R d2 , -C(O)NR c2 S(O)₂R b2 , -C(O)NR c2 S(O)₂NR c2 R d2 , -S(O)₂NR c2 C(O)R b2 , -NR c2 S(O)NR c2 C(O)R b2 and -P(O)R f2 R g2 , wherein R 2 of the 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heteroalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0469] Each R a2 , R b2 , R c2 and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, where the C a2 , R b2 , R c2 and R d2 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0470] Alternatively, any R c2 and R d2 attached to the same N atom together with the N atom to which they are attached form a 4-7 membered heteroalkyl, where the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents;

[0471] Each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C1-6 haloalkyl, C 1-6 haloalkoxy;

[0472] Each R f2 and R g2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy;

[0473] Each R 2A is independently selected from H, OH, CN, halogen, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino;

[0474] R 3 is selected from H, C1-6 alkyl, C 1-6 haloalkyl, -C(O)R a3 , -C(O)OR a3 , -C(O)NR c3 R d3 , -S(O)2R b3 , -S(O)2NR c3 R d3 , -S(O)(=NR e3 )R b3 and -S(O)(=NR e3 )NR c3 R d3 , wherein R 3 of said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0475] Alternatively, R 3 and L 3 together with the atom to which they are attached form a 5 - 10 membered heteroalkyl, wherein the 5 - 10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0476] Each R a3 , R b3 , R c3 and R d3 is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0477] Alternatively, any R c3 and R d3 attached to the same N atom together with the N atom to which they are attached form a 4 - 7 membered heteroalkyl, wherein the 4 - 7 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents;

[0478] Each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0479] R 4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0480] R8 Selected from H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; and

[0481] each R G is independently selected from H, OH, CN, halogen, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

[0482] In some embodiments:

[0483] X 1 is N or NR 6 ;

[0484] X2 is CR 7 ;

[0485] X 3 is CR 8 ;

[0486] Y is C or N;

[0487] Z is C or N;

[0488] n is 0, 1, 2, 3 or 4;

[0489] m is 0, 1, 2, 3 or 4;

[0490] Ring A is phenyl, 8 - 10 - membered heteroalkyl or 8 - 10 - membered heteroaryl;

[0491] Ring B is phenyl or 5 - 6 - membered heteroaryl;

[0492] Ring C is a 5 - membered heteroaryl having 2 to 3 nitrogen atoms as ring members;

[0493] L 1 is -N(R L )C(O)- or -N(R L )-;

[0494] L 2 is a bond;

[0495] L 3 is selected from C 1-6 alkylene, -O- and -N(R L )-;

[0496] L 4 is a bond or -O-;

[0497] Each R L is independently selected from H and C 1-6 alkyl;

[0498] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN and -OR a1 ;

[0499] Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0500] Each R 2Independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl;

[0501] R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl and -C(O)NR c3 R d3 ;

[0502] Each R c3 and R d3 is independently selected from H and C 1-6 alkyl

[0503] R 4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0504] R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 、-C(O)OR a6 、-C(O)NR c6 R d6 、-C(O)NR c6 (OR a6 )、-S(O)R b6 、-S(O)2R b6 、-S(O)NR c6 R d6 、-S(O)2NR c6 R d6 、-C(=NR e6 )R a6 、-C(=NR e6 )NR c6 R d6 、-S(O)(=NR e6 )R b6 、-S(O)(=NR e6 )NR c6R d6 、-C(O)NR c6 S(O)2R b6 、-C(O)NR c6 S(O)2NR c6 R d6 and -S(O)2NR c6 C(O)R b6 , where R 6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 6A Substituent substitution;

[0505] Each R a6 , R b6 , R c6 and R d6 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Alkyl, where R a6 , R b6 , R c6 and R d6 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C6-10 Aryl-C 1-4 Alkyl, (4-10 membered heteroalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents;

[0506] Alternatively, any R c6 and R d6 attached to the same N atom together with the N atom to which they are attached form a 4-10 membered heteroalkyl, wherein the 4-10 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents;

[0507] Each R e6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heteroalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heteroalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl;

[0508] Alternatively, R 6 and R 7 attached to the atom to which they are attached together form a 5-14 membered heteroalkyl, wherein the 5-14 membered heteroalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0509] Each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heteroalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heteroalkyl)-C 1-4Alkyl, (5-6-membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a6A , -SR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -NR c6A C(O)NR c6A R d6A , -NR c6A S(O)2R b6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein R 6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0510] Each R a6A , R b6A , R c6A and R d6A is independently selected from H, C 1-6 alkyl, C1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- or 6-membered heteroaryl)-C 1-4 alkyl, wherein R a6A , R b6A , R c6A and R d6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- or 6-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; or

[0511] alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0512] R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; and

[0513] each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7Cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, sulfanyl, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

[0514] In some embodiments:

[0515] X 1 is N or NR 6 ;

[0516] X 2 is CR 7 ;

[0517] X 3 is CR 8 ;

[0518] Y is C or N;

[0519] Z is C or N;

[0520] n is 0, 1, 2, 3, or 4;

[0521] m is 0, 1, 2, 3, or 4;

[0522] Ring A is phenyl, 8- to 10-membered heterocycloalkyl, or 8- to 10-membered heteroaryl;

[0523] Ring B is phenyl or 5- to 6-membered heteroaryl;

[0524] Ring C is a 5-membered heteroaryl having 2 to 3 nitrogen atoms as ring members;

[0525] L 1 is -N(R L )C(O)- or -N(R L )-;

[0526] L 2 is a bond;

[0527] L 3 is selected from C 1-6 alkylene, -O-, and -N(R L )-;

[0528] L 4 is a bond or -O-;

[0529] Each R L is independently selected from H and C 1-6 alkyl;

[0530] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, and -OR a1 ;

[0531] Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0532] Each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0533] R 3 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0534] R 4 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0535] R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl, wherein R 6 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents;

[0536] Alternatively, R 6 and R 7 together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0537] Each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A 、-SR a6A 、-NR c6A R d6A 、-NO2、-C(O)R a6A 、-C(O)OR a6A 、-C(O)NR c6A Rd6A 、 -OC(O)R a6A 、 -OC(O)NR c6A R d6A 、 -OC(O)OR a6A 、 -NR c6A C(O)R a6A 、 -NR c6A C(O)OR a6A 、 -NR c6A C(O)NR c6A R d6A 、 -NR c6A S(O)2R b6A 、 -NR c6A S(O)R b6A 、 -NR c6A S(O)NR c6A R d6A 、 -S(O)R b6A 、 -S(O)2R b6A 、 -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A wherein R 6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 7 - membered heterocycloalkyl, 5 - 6 - membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 - membered heterocycloalkyl) - C 1-4 alkyl and (5 - 6 - membered heteroaryl) - C 1-4 alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R G substituents;

[0538] Each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4 - 7 - membered heterocycloalkyl, 5 - 6 - membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 - membered heterocycloalkyl) - C 1-4Alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl, wherein R a6A , R b6A , R c6A and R d6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R G substituents; or

[0539] alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4-10-membered heterocycloalkyl, wherein the 4-10-membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 independently selected R G substituents;

[0540] R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; and

[0541] each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4-7-membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl,1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyl-oxy, C 1-3 alkylaminocarbonyl-oxy, di(C 1-3 alkyl)aminocarbonyl-oxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

[0542] In some embodiments:

[0543] X 1 is N or NR 6 ;

[0544] X 2 is CR 7 ;

[0545] X 3 is CR 8 ;

[0546] Y is C or N;

[0547] Z is C or N;

[0548] n is 0, 1, 2, 3 or 4;

[0549] m is 0, 1, 2, 3 or 4;

[0550] Ring A is phenyl, 8-10 membered heteroalkyl or 8-10 membered heteroaryl;

[0551] Ring B is phenyl or 5-6 membered heteroaryl;

[0552] Ring C is a 5-membered heteroaryl having 2 to 3 nitrogen atoms as ring members;

[0553] L 1 is -N(R L )C(O)- or -N(R L )-;

[0554] L2 is a bond;

[0555] L 3 is selected from C 1-6 alkylene, -O-, and -N(R L )-;

[0556] L 4 is a bond or -O-;

[0557] Each R L is independently selected from H and C 1-6 alkyl;

[0558] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, and -OR a1 ;

[0559] Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0560] Each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0561] R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 ;

[0562] Each R c3 and R d3 are independently selected from H and C 1-6 alkyl;

[0563] R 4 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0564] R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 6-membered heteroaryl)-C 1-4 Alkyl, -C(O)R a6 And -S(O)2R b6 Wherein R 6 Of said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A Substituents;

[0565] Each R a6 And R b6 Are independently selected from H and C 1-6 Alkyl;

[0566] Or, R 6 And R 7 Together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A Substituents;

[0567] Each R 6A Is independently selected from oxo, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 6-membered heteroaryl)-C 1-4 Alkyl, -CN, -OR a6A 、-SR a6A 、-NR c6A Rd6A 、 -NO2, -C(O)R a6A 、 -C(O)OR a6A 、 -C(O)NR c6A R d6A 、 -OC(O)R a6A 、 -OC(O)NR c6A R d6A 、 -OC(O)OR a6A 、 -NR c6A C(O)R a6A 、 -NR c6A C(O)OR a6A 、 -NR c6A C(O)NR c6A R d6A 、 -NR c6A S(O)2R b6A 、 -NR c6A S(O)R b6A 、 -NR c6A S(O)NR c6A R d6A 、 -S(O)R b6A 、 -S(O)2R b6A 、 -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A wherein R 6A of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4 - 7 - membered heteroalkyl, 5 - 6 - membered heteroaryl, C 3-7 cycloalkyl - C 1-4 alkyl, phenyl - C 1-4 alkyl, (4 - 7 - membered heteroalkyl) - C 1-4 alkyl and (5 - 6 - membered heteroaryl) - C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0568] Each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyl, wherein R a6A , R b6A , R c6A and R d6A of said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 Alkyl and (5- to 6-membered heteroaryl)-C 1-4 Alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G Substituents; or

[0569] Or, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 independently selected R G Substituents;

[0570] R 7 is selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 Alkyl, (5- to 14-membered heteroaryl)-C 1-4 Alkyl and -C(O)NR c7 R d7 , wherein R 7 of said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Halogenated alkyl, C 3-14 Cycloalkyl, C 6-10 Aryl, 4-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-14 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-14 membered heterocycloalkyl)-C 1-4 Alkyl and (5-14 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents;

[0571] Each R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 halogenated alkyl;

[0572] Each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A wherein the C 7A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 halogenated alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4Alkyl and (5-10-membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3 or 4 independently selected R 7B substituents;

[0573] Each R a7A 、R c7A and R d7A is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl;

[0574] Each R 7B is independently selected from C 1-6 alkyl, OR a7B 、NR c7B R d7B 、C(O)R a7B and -C(O)NR c7B R d7B wherein C 1-6 alkyl is optionally substituted with OH;

[0575] Each R a7B 、R c7B and R d7B is independently selected from H and C 1-3 alkyl;

[0576] R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; and

[0577] Each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4-7-membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C1-3 (alkyl)carbamoyl, carboxyl, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, bis(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, bis(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, bis(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and bis(C 1-3 alkyl)aminocarbonylamino.

[0578] In some embodiments:

[0579] X 1 is N or NR 6 ;

[0580] X 2 is CR 7 ;

[0581] X 3 is CR 8 ;

[0582] Y is C or N;

[0583] Z is C or N;

[0584] n is 0, 1, 2, 3 or 4;

[0585] m is 0, 1, 2, 3 or 4;

[0586] Ring A is phenyl, 8 - 10 membered heterocycloalkyl or 8 - 10 membered heteroaryl;

[0587] Ring B is phenyl or 5 - 6 membered heteroaryl;

[0588] Ring C is a 5 - membered heteroaryl having 2 to 3 nitrogen atoms as ring members;

[0589] L 1 is -N(R L )C(O)- or -N(R L )-;

[0590] L 2 is a bond;

[0591] L 3 selected from C 1-6 alkylene, -O-, and -N(R L )-;

[0592] L 4 is a bond or -O-;

[0593] Each R L is independently selected from H and C 1-6 alkyl;

[0594] Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN, and -OR a1 ;

[0595] Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0596] Each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;

[0597] R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 ;

[0598] Each R c3 and R d3 are independently selected from H and C 1-6 alkyl;

[0599] R 4 is selected from H, C 1-6 alkyl, and C 1-6 haloalkyl;

[0600] R 6 is selected from H, C 1-6 alkyl, -C(O)R a6 and -S(O)2R b6 ;

[0601] Each R a6 and R b6Independently selected from H and C 1-3 alkyl;

[0602] Alternatively, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents;

[0603] Each R 6A is independently selected from CN, 4- to 7-membered heterocycloalkyl and -C(O)NR c6A R d6A ;

[0604] Each R c6A and R d6A are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl;

[0605] Alternatively, any R c6A and R d6A attached to the same N atom together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents;

[0606] R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl and -C(O)NR c7 R d7 , wherein the C 7 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, phenyl, 8- to 10-membered heterocycloalkyl and 5- to 6-membered heteroaryl of R 2-6 are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents;

[0607] Each R c7 and R d7 are independently selected from H and C 1-6 alkyl;

[0608] Each R 7A is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, ORa7A 、 -NR c7A R d7A and C(O)NR c7A R d7A wherein R 7A of said C 1-6 alkyl, C 3-7 cycloalkyl, 4 - 7 - membered heterocycloalkyl and 5 - 6 - membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B substituents;

[0609] Each R a7A 、R c7A and R d7A is independently selected from H and C 1-3 alkyl;

[0610] Each R 7B is independently selected from C 1-6 alkyl, OR a7B 、NR c7B R d7B 、C(O)R a7B and -C(O)NR c7B R d7B wherein C 1-6 alkyl is optionally substituted by OH;

[0611] Each R a7B 、R c7B and R d7B is independently selected from H and C 1-3 alkyl;

[0612] R 8 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; and

[0613] Each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano - C 1-4 alkyl, HO - C 1-4 alkyl, C 1-4 alkoxy - C 1-4 alkyl, C 3-7 cycloalkyl, 4 - 7 - membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3(alkyl)amino, sulfanyl, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

[0614] In some embodiments, the compound of formula I is a compound of formula II:

[0615]

[0616] or a pharmaceutically acceptable salt thereof.

[0617] In some embodiments, the compound of formula I is a compound of formula IIa:

[0618]

[0619] or a pharmaceutically acceptable salt thereof.

[0620] In some embodiments, the compound of formula I is a compound of formula III:

[0621]

[0622] or a pharmaceutically acceptable salt thereof.

[0623] In some embodiments, the compound of formula I is a compound of formula IIIa:

[0624]

[0625] or a pharmaceutically acceptable salt thereof.

[0626] In some embodiments, the compound of Formula I is a compound of Formula IV:

[0627]

[0628] or a pharmaceutically acceptable salt thereof.

[0629] In some embodiments, the compound of Formula I is a compound of Formula IVa:

[0630]

[0631] or a pharmaceutically acceptable salt thereof.

[0632] In some embodiments, the compounds provided herein are selected from:

[0633] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0634] N-(4-(2-Chloro-5-fluorophenoxy)-3-(methylamino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0635] N-(3-Amino-4-((5-chloropyridin-3-yl)oxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0636] N-(3-Amino-4-((2-chloro-5-fluorophenyl)amino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0637] N-(3-Amino-4-(2-chloro-5-fluorobenzyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0638] N-(3-Amino-4-((2-chloro-5-fluorophenoxy)methyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0639] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0640] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-ethyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0641] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0642] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-morpholino-2-oxoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0643] N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0644] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0645] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0646] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0647] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-methyl-1H-pyrazol-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0648] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(pyridin-3-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0649] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-phenyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0650] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)benzo[b]thiophene-3-carboxamide;

[0651] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide;

[0652] N-(3-Amino-5-(2-chloro-5-fluorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0653] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(morpholinomethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0654] N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0655] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(hydroxymethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0656] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0657] N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0658] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-isopropyl-1H-pyrazol-4-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0659] N-(3-Amino-7-(4-carbamoylphenyl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0660] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0661] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(pyrimidin-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0662] N-(3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0663] N-(3-amino-4-(2-chloro-5-fluorophenoxy)-7-(cyanomethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0664] N-(6-amino-7-(2-chloro-5-fluorophenoxy)-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0665] N-(3-amino-1-(2-amino-2-oxoethyl)-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0666] N-(3-amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-(2-cyanoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0667] N-(3-(2-aminoacetamido)-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0668] N-(2-amino-3-(2-chloro-5-fluorophenoxy)-8-oxo-6,7,8,9-tetrahydro-[1,4]diazepine 4-(6,7,1-hi]indazol-3-yl)-5-(trifluoromethyl)benzamide;

[0669] N-(3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(pyridin-2-ylethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0670] N-(3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0671] N-(3-amino-4-(2-chloro-5-fluorophenoxy)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0672] N-(3-Amino-7-(3-amino-3-methylbut-1-yn-1-yl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0673] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((tetrahydrofuran-3-yl)ethynyl)-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0674] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(cyclopropylethynyl)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0675] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-((1-hydroxycyclopropyl)ethynyl)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0676] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-((1-(hydroxymethyl)cyclopropyl)ethynyl)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0677] N-(3-Amino-7-((1-aminocyclopropyl)ethynyl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0678] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0679] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-ethynyl-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0680] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methyl-1H-pyrazol-3-yl)ethynyl)-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0681] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(3-hydroxyprop-1-yn-1-yl)-1-methyl-1H-indazole-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0682] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methyl-1H-imidazol-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0683] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0684] N-(7-((1-Acetylpiperidin-4-yl)ethynyl)-3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0685] N-(7-Chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-3-(methylamino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0686] N-(7-Chloro-4-(2-chloro-5-fluorophenoxy)-3-(dimethylamino)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0687] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0688] N-(3-Amino-1-(2-(azetidin-1-yl)ethyl)-7-chloro-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0689] (E)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethenyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0690] (Z)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethenyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0691] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0692] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-chloro-5-fluorobenzamide;

[0693] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-(trifluoromethyl)benzamide;

[0694] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)nicotinamide;

[0695] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)benzo[b]thiophene-3-carboxamide;

[0696] N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)indoline-1-carboxamide;

[0697] 3-Amino-4-(2-chloro-5-fluorophenoxy)-N-ethyl-5-(3-fluoro-5-(trifluoromethyl)benzamido)-1-methyl-1H-indazole-7-carboxamide;

[0698] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-hydroxyethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0699] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-hydroxyethyl)-7-(pyridin-2-ylethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0700] N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0701] N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-methyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0702] N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0703] N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-cyclopropyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0704] N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-cyclobutyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0705] N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0706] N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-7,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,5,1-ij]quinolin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0707] N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-8,9,10,11-tetrahydro-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0708] (E)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(2-(pyridin-2-yl)vinyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0709] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(2-(pyridin-2-yl)ethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0710] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(piperidin-2-yl ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0711] N-(7-((1-Acetylpiperidin-2-yl)ethynyl)-3-amino-4-(2-chloro-ftuorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0712] 2-((3-Amino-4-(2-chloro-5-fluorophenoxy)-5-(3-fluoro-5-(trifluoromethyl)benzamido)-1-methyl-1H-indazol-7-yl)ethynyl)-N-methylpiperidine-1-carboxamide

[0713] N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1-(methylsulfonyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; and

[0714] N-(1-Acetyl-3-amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide;

[0715] or a pharmaceutically acceptable salt thereof.

[0716] It should also be understood that, for the sake of clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0717] Throughout this specification, divalent linking substituents are described. Each divalent linking substituent is specifically intended to include the forward and backward forms of the linking substituent. For example, -NR(CR'R”) n - includes -NR(CR'R”) n - and -(CR'R”) n NR-. In cases where a linking group is explicitly required for the structure, the Markush variables listed for that group should be understood as the linking group.

[0718] The term “n-membered” (where n is an integer) generally describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl.

[0719] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and the substitution can occur at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, such as oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by valence.

[0720] As used herein, the phrase “each ‘variable’ is independently selected from” means substantially the same as “‘variable’ is selected from” at each occurrence.

[0721] Throughout the definition, the term "C n-m " and "C m-n " indicate a range that includes the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-3 、C 1-4 、C 1-6 and so on.

[0722] As used herein, the term "C n-m alkyl", used alone or in combination with other terms, refers to a saturated hydrocarbon group having n to m carbons that can be straight-chain or branched-chain. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl (Me), ethyl (Et), n-propyl (n-Pr), isopropyl (iPr), n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc. In some embodiments, the alkyl contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0723] As used herein, "C n-m alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Exemplary alkenyls include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, etc. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0724] As used herein, the term "C n-m alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and having n to m carbons. Exemplary alkynyls include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, etc. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0725] As used herein, the term "C n-m alkoxy", used alone or in combination with other terms, refers to a group of the formula -O-alkyl, where the alkyl has n to m carbons. Exemplary alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy), etc. In some embodiments, the alkyl has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0726] As used herein, the term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group, which can be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings). The term "C n-m"Aryl" means an aryl group having from n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, anthracenyl, phenanthryl, and the like. In some embodiments, the aryl group has 5 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0727] As used herein, "halo" means F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0728] As used herein, "C n-m "Haloalkoxy" means a group of the formula -O-haloalkyl having from n to m carbon atoms. Exemplary haloalkoxy groups include OCF3 and OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0729] As used herein, the term "C n-m "Haloalkyl", used alone or in combination with other terms, means an alkyl group having from one halogen atom to 2s + 1 halogen atoms, which may be the same or different, where "s" is the number of carbon atoms in the alkyl group, and where the alkyl group has from n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CH2F, CCl3, CHCl2, C2Cl5, and the like.

[0730] As used herein, "cycloalkyl" means a non-aromatic cyclic hydrocarbon, including cycloalkyl and alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2 fused rings) groups, spiro rings, and bridged rings (e.g., bridged bicycloalkyl). The ring-forming carbon atoms of the cycloalkyl group can optionally be substituted with oxo or sulfido (e.g., C(O) or C(S)). The definition of cycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond with the cycloalkyl), such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom (including the ring-forming atoms of the fused aromatic ring). The cycloalkyl group can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (i.e., C 3-10 ). In some embodiments, the cycloalkyl group is a C 3-10 monocyclic or bicyclic cycloalkyl group. In some embodiments, the cycloalkyl group is a C 3-7 monocyclic cycloalkyl group. In some embodiments, the cycloalkyl group is a C 4-7Monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 4-10 Spiro or bridged cycloalkyl (e.g., bridged bicycloalkyl). Exemplary cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarny, cubane, adamantane, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, spiro[3.3]heptyl, and the like. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0731] As used herein, "heteroaryl" refers to a monocyclic or polycyclic (e.g., having 2 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5- to 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5-, 7-, 8-, 9-, or 10-membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl is a 5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, S, and B. In some embodiments, the heteroaryl is a 5-membered monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from N, O, and S. In some embodiments, the heteroaryl contains 5 to 10, 5 to 7, 3 to 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl has 1 to 4 ring-forming heteroatoms, 1 to 3 ring-forming heteroatoms, 1 to 2 ring-forming heteroatoms, or 1 ring-forming heteroatom. When the heteroaryl contains more than one heteroatom ring member, the heteroatoms can be the same or different.Exemplary heteroaryl groups include, but are not limited to, thienyl (or thiophenyl), furyl (or furanyl), pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, and 1,2-dihydro-1,2-azaborine, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuryl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, thieno[3,2-b]pyridyl, imidazo[1,2-a]pyridyl, 1,5-naphthyridinyl, 1H-pyrazolo[4,3-b]pyridyl, triazolo[4,3-a]pyridyl, 1H-pyrrolo[3,2-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, pyrazolo[1,5-a]pyridyl, indazolyl, and the like.

[0732] As used herein, "heterocycloalkyl" refers to a monocyclic or polycyclic heterocycle having at least one non-aromatic ring (saturated or partially unsaturated ring), wherein one or more of the ring-forming carbon atoms of the heterocycloalkyl are replaced by heteroatoms selected from N, O, S, and B, and wherein the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may optionally be substituted by one or more oxo or thio groups (such as C(O), S(O), C(S), or S(O)2, etc.). When the ring-forming carbon atoms or heteroatoms of the heterocycloalkyl are optionally substituted by one or more oxo or thio groups, the O or S of the group is supplementary to the number of ring-forming atoms specified herein (for example, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl is a 6-membered heterocycloalkyl, wherein the ring-forming carbon atoms are replaced by an oxo group, and wherein the 6-membered heterocycloalkyl is further substituted by a methyl group). Heterocycloalkyl includes monocyclic and polycyclic (e.g., having 2 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3- to 10-, 4- to 10-, 5- to 10-, 4- to 7-, 5- to 7-, or 5- to 6-membered heterocycloalkyls. Heterocycloalkyl may also include spiro and bridged rings (e.g., a 5- to 10-membered bridged bicycloheterocycloalkyl ring in which one or more of the ring-forming carbon atoms are independently replaced by heteroatoms selected from N, O, S, and B). Heterocycloalkyl may be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds.

[0733] The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused (i.e., having a common bond) to a non-aromatic heterocycle, such as benzo- or thienyl derivatives of piperidine, morpholine, azepane, etc. Heterocycloalkyls containing fused aromatic rings can be attached through the ring-forming atoms (including the ring-forming atoms of the fused aromatic rings). In some embodiments, the heterocycloalkyl contains 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, 4 to 8 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl has 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. In some embodiments, the heterocycloalkyl is a monocyclic 4- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5- to 10-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, S, and B and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 5- to 10-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic 5- to 6-membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S and having one or more oxidized ring members.

[0734]

[0735] ​Exemplary heterocycloalkyls include pyrrolidin-2-one (or 2-oxopyrrolidinyl), 1,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, 1,2,3,4-tetrahydroisoquinoline, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, benzazapene, azabicyclo[3.1.0]hexyl, diazabicyclo[3.1.0]hexyl, oxabicyclo[2.1.1]hexyl, azabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[3.1.1]heptyl, diazabicyclo[3.1.1]heptyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxabicyclo[2.2.2]octyl, azabicyclo[2.2.2]octyl, azadamantyl, diazadamantyl, oxo-adamantyl, azaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, diazaspiro[3.3]heptyl, azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, oxo-azaspiro[3.3]heptyl, azaspiro[3.4]octyl, diazaspiro[3.4]octyl, oxo-azaspiro[3.4]octyl, azaspiro[2.5]octyl, diazaspiro[2.5]octyl, azaspiro[4.4]nonyl, diazaspiro[4.4]nonyl, oxo-azaspiro[4.4]nonyl, azaspiro[4.5]decyl, diazaspiro[4.5]decyl, diazaspiro[4.4]nonyl, oxo-diazaspiro[4.4]nonyl, oxo-dihydropyridazinyl, oxo-2,6-diazaspiro[3.4]octyl, oxo-hexahydropyrrolo[1,2-a]pyrazinyl, 3-oxopiperazinyl, oxo-pyrrolidinyl, oxo-pyridinyl, and the like.

[0736] As used herein, "C o-p cycloalkyl-C n-m alkyl-" refers to a group of the formula cycloalkyl-alkylene-, wherein the cycloalkyl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0737] As used herein, "C o-p aryl-C n-m alkyl-" refers to a group of the formula aryl-alkylene-, wherein the aryl has o to p carbon atoms and the alkylene linking group has n to m carbon atoms.

[0738] As used herein, "heteroaryl-C n-m alkyl-" refers to a group of the formula heteroaryl-alkylene-, wherein the alkylene linking group has n to m carbon atoms.

[0739] As used herein, "heteroalkyl-C n-m alkyl-" refers to a group of the formula heteroalkyl-alkylene-, wherein the alkylene linking group has from n to m carbon atoms.

[0740] As used herein, "alkyl linking group" or "alkylene linking group" is a divalent straight-chain or branched alkyl linking group ("alkylene"). For example, "C o-p cycloalkyl-C n-m alkyl-", "C o-p aryl-C n-m alkyl-", "phenyl-C n-m alkyl-", "heteroaryl-C n-m alkyl-", and "heteroalkyl-C n-m alkyl-" contain an alkyl linking group. Examples of "alkyl linking group" or "alkylene" include methylene, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, and the like.

[0741] As used herein, "haloalkyl linking group" or "haloalkylene linking group" is a divalent straight-chain or branched haloalkyl linking group ("haloalkylene"). Exemplary haloalkylenes include -CF2-, -C2F4-, -CHF-, -CCl2-, -CHCl-, -C2Cl4-, and the like.

[0742] As used herein, "cycloalkyl linking group" or "cycloalkylene linking group" is a divalent straight-chain or branched cycloalkyl linking group ("cycloalkylene"). Examples of "cycloalkyl linking group" or "cycloalkylene" include cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,3-diyl, cyclopentyl-1,3-diyl, cyclopentyl-1,4-diyl, cyclohexyl-1,2-diyl, cyclohexyl-1,3-diyl, cyclohexyl-1,4-diyl, and the like.

[0743] As used herein, "heteroalkyl linking group" or "heteroalkylene linking group" is a divalent straight-chain or branched heteroalkyl linking group ("heteroalkylene"). Examples of "heteroalkyl linking group" or "heteroalkylene" include azetidine-1,2-diyl, azetidine-1,3-diyl, pyrrolidine-1,2-diyl, pyrrolidine-1,3-diyl, pyrrolidine-2,3-diyl, piperidine-1,2-diyl, piperidine-1,3-diyl, piperidine-1,4-diyl, piperidine-2,3-diyl, piperidine-2,4-diyl, and the like.

[0744] As used herein, "heteroaryl linking group" or "heteroarylene linking group" is a divalent straight-chain or branched heteroaryl linking group ("heteroarylene"). Examples of "heteroaryl linking group" or "heteroarylene" include pyrazole-1,3-diyl, imidazole-1,2-diyl, pyridine-2,3-diyl, pyridine-2,4-diyl, pyridine-3,4-diyl, and the like.

[0745] In some instances, a definition or embodiment refers to a specific ring (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member, so long as the valence of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, while a pyridin-3-yl ring is attached at the 3-position.

[0746] As used herein, the term "oxo" refers to an oxygen atom as a divalent substituent (i.e., =O), which forms a carbonyl group (e.g., C=O or C(O)) when attached to carbon, or a nitroso, sulfinyl, or sulfonyl group when attached to a nitrogen or sulfur heteroatom.

[0747] As used herein, the term "independently selected from" means that each occurrence of a variable or substituent (e.g., each R G ) is independently selected from the applicable list at each occurrence.

[0748] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended. Compounds of the present disclosure containing an asymmetrically substituted carbon atom can be isolated in optically active or racemic form. Methods for how to prepare optically active forms from optically inactive starting materials are known in the art, e.g., by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers of alkenes, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are encompassed by the present invention. The cis and trans geometric isomers of the compounds of the present disclosure are described and can be isolated as a mixture of isomers or as individual isomer forms. In some embodiments, the compound has an (R)-configuration. In other embodiments, the compound has an (S)-configuration. The chemical formulas provided herein (e.g., Formula I, Formula II, etc.) include the stereoisomers of the compounds.

[0749] The resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using a chiral resolving acid, which is an optically active salt-forming organic acid. Suitable resolving agents for the fractional recrystallization method are, for example, optically active acids such as tartaric acid in its D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids (such as β-camphorsulfonic acid). Other resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of α-methylbenzylamine (e.g., the S and R forms, or diastereomerically pure forms), 2-phenylglycol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0750] The resolution of a racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl phenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0751] The compounds provided herein also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, 2-hydroxypyridine and 2-pyridone, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or can be sterically locked into one form by appropriate substitution.

[0752] All compounds and their pharmaceutically acceptable salts can exist with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated therefrom.

[0753] In some embodiments, the preparation of a compound can involve the addition of an acid or a base to affect, for example, the catalysis of a desired reaction or the formation of a salt form (such as an acid addition salt).

[0754] In some embodiments, the compounds or salts thereof provided herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compound provided herein. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound or salt thereof provided herein.

[0755] As used herein, the term "compound" means to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. Unless otherwise indicated, a compound identified herein by name or structure as a specific tautomeric form is intended to include other tautomeric forms.

[0756] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions, and / or dosage forms within the scope of sound medical judgment that are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0757] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both; typically, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0758] Synthesis

[0759] The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and according to various possible synthetic routes. Example synthetic methods for preparing the compounds of the present invention are provided in the following schemes.

[0760] The compounds of formula I (such as the compound of formula I-6) can be prepared, for example, according to the procedure shown in Scheme I. Intermediate I-3 is prepared by a process including reacting a compound of formula I-1 with I-2 promoted by a suitable reagent (such as NaH, LDA). Intermediate I-4 is prepared by a process including reacting intermediate I-3 under reducing conditions (such as Fe). Intermediate I-5 is prepared by a process including reacting intermediate I-4 with a suitable reagent (such as benzoyl chloride). Then the compound of formula I-6 can be prepared by a process including reacting intermediate I-5 under suitable conditions (such as N2H4 monohydrate).

[0761] Scheme I.

[0762]

[0763] The compounds of formula I (such as the compound of formula II-6) can be prepared, for example, according to the procedure shown in Scheme II. Intermediate II-1 is prepared by a process including reacting a compound of formula I-1 with a suitable reagent (such as NH4OH). Intermediate II-2 is prepared by a process including reacting intermediate II-1 under Sandmeyer reaction conditions. Intermediate II-3 is prepared by a process including reacting intermediate II-2 under reducing conditions (such as Fe). Intermediate II-4 is prepared by a process including reacting intermediate II-3 with a suitable reagent (such as benzoyl chloride). Intermediate II-5 is prepared by a process including reacting intermediate II-4 under suitable conditions (such as N2H4 monohydrate). Then the compound of formula II-6 is prepared by a process including reacting intermediate II-5 under appropriate conditions (such as a transition metal-catalyzed cross-coupling reaction).

[0764] Scheme II.

[0765]

[0766] The compounds of formula I (such as the compound of formula III-3) can be prepared, for example, according to the procedure shown in Scheme III. Intermediate III-1 is prepared by a process including reacting a compound of formula II-6 with a suitable protecting group (such as isobenzofuran-1,3-dione). Then intermediate III-2 is prepared by a process including reacting intermediate III-1 with a suitable reagent (such as an alkyl halide). Next, the compound of formula III-3 is prepared by a process including reacting formula III-2 under appropriate conditions (such as N2H4 monohydrate).

[0767] Scheme III.

[0768]

[0769] The compound of formula I (e.g., the compound of formula IV-2) can be prepared, for example, according to the procedure shown in Scheme IV. The intermediate IV-1 is prepared by a process including reacting the compound of formula III-1 with a suitable reagent (e.g., NBS). Then the compound of formula IV-2 is prepared by a process including reacting the intermediate IV-1 under appropriate conditions (e.g., a transition metal-catalyzed cross-coupling reaction).

[0770] Scheme IV.

[0771]

[0772] The compound of formula I (e.g., the compound of formula V-9) can be prepared, for example, according to the procedure shown in Scheme V. The intermediate V-3 is prepared by a process including reacting the compound of formula V-1 with V-2 promoted by a suitable reagent (e.g., NaH, LDA). Then the intermediate V-4 is prepared by a process including reacting the intermediate V-3 with a suitable reagent (e.g., tert-butyl carbazate). The intermediate V-5 is prepared by a process including reacting the intermediate V-4 under reducing conditions (e.g., Fe), followed by adding a suitable protecting group ("PG" in Scheme V). The intermediate V-6 is prepared by deprotecting the intermediate V-5 with a suitable reagent (e.g., TFA). The intermediate V-7 is prepared by a process including reacting the compound of V-6 with a suitable reagent (e.g., bis(1H-imidazol-1-yl)methanimine). The intermediate V-8 is prepared by deprotecting the intermediate V-7 with a suitable reagent. Next, the compound of formula V-9 is prepared by a process including reacting the intermediate V-8 with a suitable reagent (e.g., benzoyl chloride).

[0773] Scheme V.

[0774]

[0775] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be easily selected by a person skilled in the art of organic synthesis. The suitable solvent can substantially not react with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (e.g., a temperature within the range from the freezing temperature to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, a person skilled in the art can select a suitable solvent for a specific reaction step.

[0776] The preparation of the compounds of the present invention may include the protection and deprotection of various chemical groups. Those skilled in the art can readily determine the need for protection and deprotection and the selection of suitable protecting groups. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0777] The reaction can be monitored according to any suitable method known in the art. For example, it can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography to monitor product formation.

[0778] As used herein, the expressions "ambient temperature", "room temperature", and "r.t." are understood in the art and generally refer to the temperature, e.g., the reaction temperature, i.e., the temperature of the room in which the reaction is approximately carried out, e.g., a temperature of about 20 °C to about 30 °C.

[0779] Method of Use

[0780] The present disclosure provides uses of the compounds and compositions described herein. The compounds described herein can inhibit the activity of PI3Kα kinase. In some embodiments, the provided compounds and compositions are for use in medicine (e.g., as a therapy). In some embodiments, the provided compounds and compositions can be used to treat a disease, disorder, or condition in which the underlying pathology is mediated in whole or in part by PI3Kα. In some embodiments, the provided compounds and compositions can be used as, for example, analytical tools and / or control compounds in biological assays for research.

[0781] In some embodiments, the present disclosure provides a method of administering the provided compound or composition to a subject in need thereof. In some embodiments, the present disclosure provides a method of administering the provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition associated with PI3Kα. In some embodiments, the present disclosure provides a method of administering the provided compound or composition to a subject suffering from or susceptible to a disease, disorder, or condition in which the underlying pathology is mediated in whole or in part by PI3Kα. In some embodiments, the underlying pathology of the disease, disorder, or condition provided herein is mediated in whole or in part by mutant PI3Kα. In some embodiments, the disease, disorder, or condition provided herein is associated with mutant PI3Kα.

[0782] In some embodiments, the compounds provided herein can be used as PI3Kα inhibitors. In some embodiments, the present disclosure provides methods of inhibiting PI3Kα in a subject, which comprise administering the provided compounds or compositions. In some embodiments, the present disclosure provides methods of inhibiting PI3Kα in a biological sample, which comprise contacting the sample with the provided compounds or compositions. In some embodiments, the compounds provided herein selectively inhibit PI3Kα over one or more other PI3K isoforms (e.g., class I PI3K isoforms such as PI3Kβ, PI3Kδ, PI3Kγ, etc.). In some embodiments, the compounds provided herein selectively inhibit mutant PI3Kα over wild-type PI3Kα.

[0783] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition associated with PI3Kα in a subject in need thereof, which comprise administering to the subject a compound, salt, or composition of the present disclosure. In some embodiments, the disease, disorder, or condition is associated with a mutation in PI3Kα. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a subject in need thereof, wherein the underlying pathology is mediated, in whole or in part, by PI3Kα, which comprise administering to the subject the provided compounds or compositions.

[0784] In some embodiments, the present disclosure provides methods of treating a variety of PI3Kα-dependent diseases and conditions. In some embodiments, the disease or condition is cancer (e.g., breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer). In some embodiments, diseases or conditions associated with PI3Kα include, but are not limited to, CLOVES syndrome (congenital lipomatosis overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome), PIK3CA-related overgrowth syndrome (PROS), endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small cell lung cancer, esophagogastric cancer, schwannoma, head and neck squamous cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear cell carcinoma, renal clear cell carcinoma, germ cell carcinoma, thymic tumors, pheochromocytoma, mixed neuroepithelial tumors, thyroid cancer, leukemia, and encapsulated glioma. In some embodiments, the cancer is breast cancer.

[0785] In some embodiments, provided herein are methods of increasing the survival or progression-free survival of a patient, which comprise administering to the patient a compound provided herein. In some embodiments, the patient has cancer. In some embodiments, the patient has a disease or disorder described herein. As used herein, progression-free survival refers to the length of time during and after treatment of a solid tumor during which the patient lives with the disease without the disease worsening. Progression-free survival can refer to the length of time from the first administration of the compound until death or disease progression, whichever occurs first. Progression of the disease can be defined by, for example, RECIST v.1.1 (Response Evaluation Criteria in Solid Tumors) as evaluated by an independent central radiology review committee. In some embodiments, administration of the compound results in a progression-free survival of greater than about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, about 12 months, about 16 months, or about 24 months. In some embodiments, administration of the compound results in a progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months. In some embodiments, administration of the compound results in an increase in progression-free survival of at least about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 8 months, about 9 months, or about 12 months; and less than about 24 months, about 16 months, about 12 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, or about 2 months.

[0786] The present disclosure further provides a compound or a pharmaceutically acceptable salt thereof described herein for use in any of the methods described herein.

[0787] The present disclosure further provides the use of a compound or a pharmaceutically acceptable salt thereof described herein for the preparation of a medicament for use in any of the methods described herein.

[0788] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be a part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism, such as a mammal.

[0789] As used herein, the term "contact" refers to bringing the indicated moieties together in an in vitro or in vivo system. For example, contacting PI3Kα kinase with a compound described herein includes administering a compound described herein to an individual or patient (such as a human) having PI3Kα enzyme, and, for example, introducing a compound described herein into a sample of a cell preparation or purified preparation containing the PI3Kα protein kinase.

[0790] As used herein, the terms "individual" or "patient" are used interchangeably and refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0791] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or agent (such as an amount of any of the solid forms or salts thereof disclosed herein) that elicits a biological or medical response in a tissue, system, animal, individual or human being sought by a researcher, veterinarian, physician or other clinician. The appropriate "effective amount" in any individual case can be determined using techniques known to those of skill in the art.

[0792] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, substances, compositions and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0793] As used herein, the phrase "pharmaceutically acceptable carrier or excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. An excipient or carrier is generally safe, non-toxic, and without biological or other untoward effects, and includes excipients or carriers acceptable for veterinary and human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0794] As used herein, the term "treating" or "treatment" refers to inhibiting a disease; e.g., inhibiting a disease, disorder, or condition in an individual who is experiencing or manifesting the pathology or symptomatology of the disease, disorder, or condition (i.e., arresting further development of the pathology and / or symptomatology); or ameliorating a disease; e.g., ameliorating a disease, disorder, or condition in an individual who is experiencing or manifesting the pathology or symptomatology of the disease, disorder, or condition (i.e., reversing the pathology and / or symptomatology), such as reducing the severity of the disease.

[0795] In some embodiments, the compounds of the invention can be used to prevent or reduce the risk of developing any of the diseases mentioned herein; e.g., preventing or reducing the risk of developing a disease, disorder, or condition in an individual who may be predisposed to the disease, disorder, or condition but has not yet experienced or manifested the pathology or symptoms of the disease.

[0796] It should also be understood that, for clarity, certain features of the present disclosure that are described in the context of separate embodiments may also be provided in combination in a single embodiment (although the embodiments are intended to be combined as if written in multiple dependent forms). Conversely, for brevity, the various features of the present disclosure that are described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0797] Combination therapy

[0798] One or more additional therapeutic agents, such as, for example, chemotherapeutic agents or other anti-cancer agents, anti-inflammatory agents, steroids, immunosuppressive agents, anesthetics (e.g., for use in combination with surgical procedures), or other agents useful in treating diseases associated with PI3Kα, may be used in combination with the compounds and salts provided herein. The agent may be combined with the compound of the invention in a single dosage form, or the agent may be administered simultaneously or sequentially in separate dosage forms.

[0799] The compounds described herein may be used in combination with one or more other kinase inhibitors for the treatment of diseases affected by multiple signaling pathways, such as cancer. For example, the combination may include one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, Pim, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, CDK4 / 6, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR / FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR / Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK, and B-Raf. In addition, the solid forms of the inhibitors as described herein may be combined with inhibitors of kinases associated with the PIK3 / Akt / mTOR signaling pathway, such as PI3K, Akt (including Akt1, Akt2, and Akt3), and mTOR kinases.

[0800] For the treatment of cancer and other proliferative diseases, the compounds described herein can be used in combination with targeted therapies that include JAK kinase inhibitors (ruxolitinib, additional JAK1 / 2 and JAK1 selective inhibitors, baricitinib or itacitinib); Pim kinase inhibitors (such as LGH447 and SGI-1776); PI3 kinase inhibitors, including PI3K-δ selective inhibitors and broad-spectrum PI3K inhibitors (such as parsaclisib); PI3K-γ inhibitors, such as PI3K-γ selective inhibitors; MEK inhibitors; CSF1R inhibitors (such as PLX3397 and LY3022855); TAM receptor tyrosine kinase inhibitors (Tyro-3, Axl and Mer); angiogenesis inhibitors; interleukin receptor inhibitors; cyclin-dependent kinase inhibitors (such as palbociclib, ribociclib and abemaciclib); BRAF inhibitors; mTOR inhibitors; proteasome inhibitors (bortezomib, carfilzomib); HDAC inhibitors (panobinostat, vorinostat); DNA methyltransferase inhibitors; dexamethasone; bromodomain and additional terminal family member inhibitors (such as bromodomain inhibitors or BET inhibitors, such as OTX015, CPI-0610); LSD1 inhibitors (such as GSK2979552 and INCB59872); estrogen receptor modulators (such as fulvestrant); androgen receptor modulators (such as enzalutamide); BCL2 inhibitors (such as venetoclax); hypoxia-inducible factor-2α inhibitors (such as belzutifan); exportin-1 (XPO-1) inhibitors (such as selinexor); KRAS inhibitors (such as sotorasib); arginase inhibitors (such as INCB1158); indoleamine 2,3-dioxygenase inhibitors (such as epacadostat; NLG919 or BMS-986205); PARP inhibitors (such as olaparib or rucaparib) and BTK inhibitors (such as ibrutinib).

[0801] For treating cancer and other proliferative diseases, the compounds described herein can be used in combination with chemotherapeutic agents, agonists or antagonists of nuclear receptors, or other anti-proliferative agents. The compounds described herein can also be used in combination with medical therapies such as surgery or radiation therapy, e.g., gamma-radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes.

[0802] Examples of suitable chemotherapeutic agents include any of the following: abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amidoz, amsacrine, anastrozole, aphidicolin, arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide, bleomycin, bortezomib, bortezomib, brivanib, buparlisib, intravenous busulfan, oral busulfan, calusterone, camptosar, capecitabine, carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine, degarelix, denileukin, denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxeltaxel), doxorubicin, droloxafine, dromostanolone propionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mithramycin, mitomycin CC), Mitotane, Mitoxantrone, Nandrolone phenpropionate, Navelbene, Necitumumab, Nelarabine, Neratinib, Nilotinib, Nilutamide, Niraparib, Nofetumomab, Osere lin (Oxaliplatin), Paclitaxel, Pamidronate, Panitumumab, Panobinostat, Pazopanib, Pegaspargase, Pegfilgrastim, Pemetrexed disodium, Pentostatin, Pilaralisib, Pipobroman, Plicamycin, Ponatinib, Porfimer, Prednisone, Procarbazine, Quinacrine, Ranibizumab, Rasburicase, Regorafenib, Reloxafine, Revlimid, Rituximab, Rucaparib, Ruxolitinib, Sorafenib, Streptozocin, Sunitinib, Sunitinib maleatemaleate), tamoxifen, tegafur, temozolomide, teniposide, testolactone, tezacitabine, thalidomide, thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, triapine, trimido x, triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine, vincristine, vindesine, vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

[0803] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those of skill in the art. Additionally, their administration is described in standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0804] Exemplary anti-inflammatory agents include, but are not limited to, aspirin, choline salicylate, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.

[0805] Exemplary steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.

[0806] Exemplary immunosuppressive agents include, but are not limited to, azathioprine, chlorambucil, cyclophosphamide, cyclosporine, daclizumab, infliximab, methotrexate, and tacrolimus.

[0807] Exemplary anesthetics include, but are not limited to, local anesthetics (e.g., lidocaine, procain, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, mmobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).

[0808] In some embodiments, the additional therapeutic agent is administered concurrently with the compounds or salts provided herein. In some embodiments, the additional therapeutic agent is administered after the compounds or salts provided herein. In some embodiments, the additional therapeutic agent is administered before the compounds or salts provided herein. In some embodiments, the compounds or salts provided herein are administered during surgery. In some embodiments, the compounds or salts provided herein are administered in combination with an additional therapeutic agent during a surgical procedure.

[0809] As provided herein, the additional compounds, inhibitors, agents, etc. can be formulated with the compounds provided herein into a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0810] Pharmaceutical Formulations and Dosage Forms

[0811] When used as a drug, the compounds of the present invention can be administered in the form of a pharmaceutical composition, which refers to a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is needed and the area to be treated. Administration can be topical (including ophthalmic and mucosal administration, including intranasal, vaginal and rectal delivery), pulmonary administration (e.g., by inhalation or insufflation of powder or aerosol, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral administration. Methods for ocular delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, or introduction by a balloon catheter or an ophthalmic insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular or injection or infusion; or intracranial, such as intrathoracic or intraventricular administration. Parenteral administration can be in the form of a single bolus dose, or can be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0812] The present invention also includes pharmaceutical compositions containing one or more of the compounds of the present invention described above as active ingredients in combination with one or more pharmaceutically acceptable carriers. When making the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted by an excipient, or encapsulated in such a carrier in the form of, for example, a capsule, pouch, paper, or other container. When an excipient is used as a diluent, it can be a solid, semisolid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injections, and sterile packaged powders.

[0813] When preparing the formulation, the active compound can be ground to provide an appropriate particle size before mixing with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example, about 40 mesh.

[0814] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. However, it should be understood that the actual amount of compound administered is generally determined by a physician based on relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0815] In order to prepare solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition containing a homogeneous mixture of the compound of the invention. When these preformulated compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The solid preformulation is then subdivided into the above-mentioned types of unit dosage forms.

[0816] The tablets or pills of the present invention may be coated or otherwise mixed to provide a dosage form that provides a prolonged effect. For example, a tablet or pill may comprise an inner dose and an outer dose component, the latter being in the form of a film coating over the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to enter the duodenum intact or to be delayed in release.

[0817] Liquid forms in which the compounds and compositions of the present invention can be incorporated for oral administration or administration by injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils.

[0818] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to achieve local or systemic effect. An inert gas may be used to aerosolize the composition. The aerosolized solution may be inhaled directly from the aerosolizing device, or the aerosolizing device may be attached to a mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0819] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of the administration (such as prevention or therapy), the patient's condition, the mode of administration, and the like. In therapeutic applications, the composition can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending physician, which will depend on factors such as the severity of the disease, the patient's age, weight, and general condition, and the like.

[0820] The compositions administered to a patient can be in the form of the above-described pharmaceutical compositions. These compositions can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be packaged as such or lyophilized for use, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH value of the compound preparation will generally be between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It should be understood that the use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

[0821] The therapeutic dose of the compounds of the present invention can vary depending on, for example, the particular use for which the treatment is being carried out, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compounds of the present invention in the pharmaceutical composition can vary depending on many factors, which include the dose, chemical characteristics (e.g., hydrophobicity) and route of administration. The dose may depend on variables such as the type and degree of development of the disease or disorder, the overall health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipients and its route of administration. The effective dose can be extrapolated from the dose-response curve derived from in vitro or animal model test systems.

[0822] The compositions of the present disclosure can further comprise one or more additional medicaments, such as chemotherapeutic agents, steroids, anti-inflammatory compounds or immunosuppressants, examples of which are provided herein.

[0823] Labeled compounds and assay methods

[0824] Another aspect of the present invention relates to the fluorescent dyes, spin labels, heavy metals or radioactively labeled compounds of the present invention, which can be used not only in imaging, but also in in vitro and in vivo assays for localizing and quantifying PI3Kα enzyme in tissue samples (including human), and for identifying PI3Kα enzyme ligands by inhibitory binding of the labeled compounds. Thus, the present invention includes PI3Kα enzyme assays containing such labeled compounds.

[0825] The present invention further includes the isotopically labeled compounds of the present invention. "Isotopically labeled" or "radioactively labeled" compounds are compounds of the present invention in which one or more atoms are replaced or substituted by atoms having an atomic mass or mass number different from that normally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include, but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I. The radionuclide incorporated into the radiolabeled compounds of the present invention will depend on the specific application of the radiolabeled compound. For example, for in vitro FGFR enzyme labeling and competitive assays, compounds incorporated with 3 H, 14 C, 82 Br, 125 I, 131 I or 35 S are generally most useful. For radioimaging applications, 11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br are generally most useful.

[0826] One or more of the constituent atoms of the compounds presented herein can be replaced or substituted with isotopes of the natural or non-natural abundance of that atom. In some embodiments, one or more atoms are replaced or substituted with deuterium. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced with deuterium atoms (e.g., one or more hydrogen atoms in the C 1-6 alkyl of formula I can be optionally replaced with deuterium atoms, such as -CD3- replacing CH3). In some embodiments, the alkyl groups of the disclosed formulas (e.g., compounds of any of formulas I-IVa) can be fully deuterated.

[0827] In some embodiments, the compounds provided herein (e.g., compounds of any of formulas I-IVa) or pharmaceutically acceptable salts thereof contain at least one deuterium atom.

[0828] In some embodiments, the compounds provided herein (e.g., compounds of any of formulas I-IVa) or pharmaceutically acceptable salts thereof contain two or more deuterium atoms.

[0829] In some embodiments, the compounds provided herein (e.g., compounds of any of formulas I-IVa) or pharmaceutically acceptable salts thereof contain three or more deuterium atoms.

[0830] In some embodiments, for the compounds provided herein (e.g., compounds of any of Formulas I-IVa) or pharmaceutically acceptable salts thereof, all hydrogen atoms are replaced with deuterium atoms (i.e., the compound is “fully deuterated”).

[0831] It should be understood that a “radioactively labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S, and 82 Br.

[0832] Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, such as NMR spectroscopy, metabolic experiments, and / or assays.

[0833] Replacement with a heavier isotope such as deuterium can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and is thus preferred in some cases. (See, e.g., A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312). Specifically, replacement at one or more metabolic sites may confer one or more of these therapeutic advantages.

[0834] The radiolabeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. Generally, a newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to reduce the binding of the radiolabeled compound of the present invention to the PI3Kα enzyme. Thus, the ability of the test compound to compete with the radiolabeled compound for binding to the PI3Kα enzyme is directly related to its binding affinity.

[0835] Kit

[0836] The present invention also includes a pharmaceutical kit that can be used, for example, to treat or prevent PI3Kα-related diseases or disorders mentioned herein, which includes one or more containers containing a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the present invention. If desired, such a kit can further include one or more of various conventional pharmaceutical kit components, such as, for example, a container having one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. The kit can also include instructions, either as an insert or as a label, that indicate the quantity of the components to be administered, administration guidelines, and / or guidelines for mixing the components.

[0837] The present invention will be described in more detail below by way of specific examples. The following examples are for illustrative purposes only and are not intended to limit the present invention in any way. Those skilled in the art will readily identify a variety of non-critical parameters that can be changed or modified to produce substantially the same results. As described below, the compounds of the examples were found to be inhibitors of PI3Kα.

[0838] Examples

[0839] The experimental procedures for the compounds of the present invention are provided below. Some of the prepared compounds are purified by preparative LC-MS on a Waters mass-directed fractionation system. The basic equipment settings, protocols, and control software for the operation of these systems are described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The isolated compounds are generally subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity checks.

[0840] Some of the prepared compounds are also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with an MS detector as indicated in the examples.

[0841] The following abbreviations may be used in this text: AcOH (acetic acid); aq. (aqueous solution); br (broad peak); calc. (calculated); d (doublet); dd (doublet of doublets); DCM (dichloromethane); DIEA (N,N - diisopropylethylamine); DMF (N,N - dimethylformamide); Et (ethyl); EtOAc (ethyl acetate); g (gram); h (hour); HCl (hydrochloric acid); HPLC (high - performance liquid chromatography); Hz (hertz); J (coupling constant); LCMS (liquid chromatography - mass spectrometry); LDA (lithium diisopropylamide); m (multiplet); M (mole); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min. (minute); mL (milliliter); mmol (millimole); N (normal); NBS (N - bromosuccinimide); NCS (N - chlorosuccinimide); nM (nanomole); NMR (nuclear magnetic resonance spectroscopy); Ph (phenyl); pM (picomole); RP - HPLC (reverse - phase high - performance liquid chromatography); rt (room temperature), s (singlet); t (triplet or tert); tert (tert); tt (triplet of triplets); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram); μL (microliter); μM (micromole); wt% (weight percentage). Brine is a saturated aqueous solution of sodium chloride. Vacuum is under vacuum.

[0842] Example 1. N-(3 - Amino - 4-(2 - chloro - 5 - fluorophenoxy)-1H - indazol - 5 - yl)-3 - fluoro - 5-(trifluoromethyl)benzamide

[0843]

[0844] Step 1. 2-(2 - Chloro - 5 - fluorophenoxy)-6 - fluoro - 3 - nitrobenzonitrile

[0845]

[0846] Under a nitrogen atmosphere at 0 °C, NaH (60% in mineral oil, 43.4 mg, 1.09 mmol) was added to a solution of 2 - chloro - 5 - fluorophenol (159.2 mg, 1.09 mmol) in anhydrous tetrahydrofuran (3 mL). The resulting mixture was stirred at the same temperature for 30 min, then 2,6 - difluoro - 3 - nitrobenzonitrile (200 mg, 1.09 mmol) was added in one portion. The reaction mixture was then warmed to room temperature and stirred for 1 h, then quenched with water; the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane, to give the desired product as a pale yellow oil (270 mg, 80%).

[0847] Step 2. 3-Amino-2-(2-chloro-5-fluorophenoxy)-6-fluorobenzonitrile

[0848]

[0849] Iron (230 mg, 4.1 mmol) was added to a mixture of 2-(2-chloro-5-fluorophenoxy)-6-fluoro-3-nitrobenzonitrile (270 mg, 0.87 mmol) in MeOH (2 mL), THF (2 mL) and saturated NH4Cl (1 mL). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with 50% ethyl acetate in hexane to give the desired product as a colorless oil (170 mg, 70%).

[0850] Step 3. N-(2-(2-Chloro-5-fluorophenoxy)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0851]

[0852] 3-Fluoro-5-(trifluoromethyl)benzoyl chloride (157 mg, 0.7 mmol) was added to a mixture of 3-amino-2-(2-chloro-5-fluorophenoxy)-6-fluorobenzonitrile (170 mg, 0.61 mmol) in pyridine (1 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 30 min, then quenched with water. The mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with 50% ethyl acetate in hexane to give the desired product as a colorless oil (229 mg, 80%).

[0853] Step 4. N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0854] At room temperature, hydrazine monohydrate (0.2 mL) was added to a mixture of N-(2-(2-chloro-5-fluorophenoxy)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide (229 mg, 0.49 mmol) in n-BuOH (1 mL). The resulting mixture was stirred at 110 °C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. C 21 H 13 The LCMS calculated value (M+H)+ m / z for ClF5N4O2 = 483.1; found 483.1.

[0855] Example 2. N-(4-(2-Chloro-5-fluorophenoxy)-3-(methylamino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0856]

[0857] N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (Example 1; 20 mg, 0.04 mmol) was dissolved in MeOH (1 mL), then paraformaldehyde (6 mg, 0.2 mmol) and sodium methoxide (25% wt in MeOH, 0.12 mmol) were added. The resulting mixture was heated to 65 °C for 3.5 h and then removed from the heat source. NaBH4 (4 mg, 0.1 mmol) was added and heating was continued for 2 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. C 22 H 15 The LCMS calculated value (M+H)+ m / z for ClF5N4O2 = 497.1; found 497.1.

[0858] Example 3. N-(3-Amino-4-((5-chloropyridin-3-yl)oxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0859]

[0860] The title compound was prepared using a procedure similar to that described for Example 1, where 5-chloropyridin-3-ol was used instead of 2-chloro-5-fluorophenol in Step 1. The final product was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. C 20 H 13 The LCMS calculated value (M+H)+ m / z for ClF4N5O2 = 466.1; found 466.1.

[0861] Example 4. N-(3-Amino-4-((2-chloro-5-fluorophenyl)amino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0862]

[0863] The title compound was prepared using a procedure similar to that described for Example 1, where 2-chloro-5-fluoroaniline was used instead of 2-chloro-5-fluorophenol and LDA was used instead of NaH in Step 1. The final product was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. C 21 H 14 The LCMS calculated value (M+H)+ m / z for ClF5N5O = 482.1; found 482.1.

[0864] Example 5. N-(3-Amino-4-(2-chloro-5-fluorobenzyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0865]

[0866] Step 1. 2-Amino-6-fluoro-3-nitrobenzonitrile

[0867]

[0868] Under a nitrogen atmosphere, an ammonium hydroxide solution (30 mL) was added dropwise to a solution of 2,6-difluoro-3-nitrobenzonitrile (7.6 g, 41.3 mmol) in anhydrous tetrahydrofuran (30 mL) at 0 °C. The resulting mixture was stirred at the same temperature for 30 min, and then 30 mL of ice water was added. The crude product precipitated out, and the crude product was collected by filtration, then washed with water (2 x 30 mL) and dried at room temperature to obtain a yellow solid, which was used in the next step without further purification.

[0869] Step 2. 6-Fluoro-2-iodo-3-nitrobenzonitrile

[0870]

[0871] 2-Amino-6-fluoro-3-nitrobenzonitrile (3.0 g, 16.5 mmol) was suspended in 60 mL of water with stirring. The mixture was cooled in an ice bath, and 60 mL of concentrated sulfuric acid was slowly added. A solution of sodium nitrite (1.2 g, 17 mmol) in 60 mL of water was added dropwise over 0.5 h. The reaction mixture was stirred at 0 - 5 °C for an additional 0.25 h. The mixture was poured into a well-stirred solution of potassium iodide (3.0 g, 18 mmol) in 60 mL of water. The resulting solid was collected by filtration and then stirred in 200 mL of ethyl acetate. 200 mL of 20% sodium bisulfite solution was added slowly. The organic layer was separated, washed with saturated sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product as a brown solid, which was then purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane to obtain the desired product as a light brown solid (3.8 g, 80%).

[0872] Step 3. 3-Amino-6-fluoro-2-iodobenzonitrile

[0873]

[0874] Iron (3.1 g, 55 mmol) was added to a mixture of 6-fluoro-2-iodo-3-nitrobenzonitrile (3.8 g, 13 mmol) in MeOH (200 mL), THF (200 mL) and saturated NH4Cl (100 mL). The resulting mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (2 x 400 mL). The combined organic matter was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with 50% ethyl acetate in hexane to obtain the desired product as a colorless oil (2.7 g, 80%).

[0875] Step 4. N-(3-Cyano-4-fluoro-2-iodophenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0876]

[0877] Under a nitrogen atmosphere at 0 °C, 3-fluoro-5-(trifluoromethyl)benzoyl chloride (1.6 g, 7.0 mmol) was added to a mixture of 3-amino-6-fluoro-2-iodobenzonitrile (1.7 g, 6.1 mmol) in pyridine (10 mL). The resulting mixture was warmed to room temperature and stirred for 30 minutes, then quenched with water. The mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with 50% ethyl acetate in hexane, to give the desired product as a colorless oil (2.3 g, 85%). C 15 Calculated LCMS value (M+H) for C + H7F5IN2O: m / z = 453.0; found 453.0.

[0878] Step 5. N-(3-Amino-4-iodo-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0879]

[0880] Hydrazine monohydrate (1 mL) was added to a mixture of N-(3-cyano-4-fluoro-2-iodophenyl)-3-fluoro-5-(trifluoromethyl)benzamide (560 mg, 1.0 mmol) in n-BuOH (5 mL) at room temperature. The resulting mixture was stirred at 110 °C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product precipitated out and was collected by filtration, then washed with water (2 x 30 mL) and dried at room temperature to give a light brown solid, which was used in the next step without further purification. C 15 H 10 Calculated LCMS value (M+H) for C + H4F4IN4O: m / z = 465.0; found 465.0.

[0881] Step 6. N-(3-Amino-4-(2-chloro-5-fluorobenzyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0882] Under nitrogen, to a suspension of zinc powder (64 mg, 1.0 mmol) in tetrahydrofuran (1.5 mL) at 65 °C was added 1,2-dibromoethane (4 mg, 0.025 mmol) and trimethylchlorosilane (5 mg, 0.045 mmol). The mixture was stirred at 65 °C for 30 minutes. A solution of 2-chloro-6-fluorobenzyl bromide (0.2 g, 0.9 mmol) in THF (3 mL) was added dropwise and the mixture was stirred under heating at 65 °C for 3 h. The mixture was cooled to ambient temperature and N-(3-amino-4-iodo-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (240 mg, 0.45 mmol), Sphos (20 mg, 0.045 mmol) and Pd(OAc)2 (10 mg, 0.045 mmol) were added. The mixture was heated to 70 °C for 1 h and then quenched with saturated NH4Cl solution. The mixture was extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by preparative HPLC (column: Sunfire prep C18 column, 30 * 150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. C 22 H 15 LCMS calculated value (M + H) for ClF5N4O + m / z = 481.1; found 481.1.

[0883] Example 6. N-(3-Amino-4-((2-chloro-5-fluorophenoxy)methyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0884]

[0885] Step 1. N-(3-Cyano-4-fluoro-2-vinylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0886]

[0887] N-(3-Cyano-4-fluoro-2-iodophenyl)-3-fluoro-5-(trifluoromethyl)benzamide (Example 5, Step 4, 300 mg, 0.66 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (122 mg, 0.8 mmol), K3PO4 (169 mg, 0.8 mmol) and XPhos Pd G2 (39 mg, 0.05 mmol) in a mixture of 1,4-dioxane (3 mL) and water (0.3 mL) were stirred at 80 °C for 7 h under a nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate in hexane, to give the desired product as a white solid (174 mg, 75%).

[0888] Step 2. N-(3-Cyano-4-fluoro-2-formylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0889]

[0890] To a mixture of N-(3-cyano-4-fluoro-2-vinylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (174 mg, 0.5 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added OsO4 (4% wt aqueous solution, 63 μL, 0.01 mmol) and sodium periodate (430 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 2 h and then quenched by the addition of water. The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then purified by silica gel column chromatography, eluting with 50% ethyl acetate in hexane, to give the desired product as a colorless oil (153 mg, 88%). C 16 LCMS calculated value (M+H) for C + H8F5N2O2 m / z = 355.0; found 355.0.

[0891] Step 3. N-(2-(Bromomethyl)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0892]

[0893] At 0 °C under a nitrogen atmosphere, NaBH4 (18.9 mg, 0.5 mmol) was added to a mixture of N-(3-cyano-4-fluoro-2-formylphenyl)-3-fluoro-5-(trifluoromethyl)benzamide (153 mg, 0.44 mmol) in MeOH (4 mL). The resulting mixture was stirred at the same temperature for 30 min and then quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was then dissolved in DCM (2 mL) and PBr3 (135 mg, 0.5 mmol) was added dropwise at 0 °C. The reaction mixture was then warmed to room temperature and stirred at this temperature for 2 h, then quenched with saturated NaHCO3. The mixture was extracted with DCM (2 x 10 mL). The combined organic matter was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0894] Step 4. N-(2-((2-Chloro-5-fluorophenoxy)methyl)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide

[0895]

[0896] N-(2-(Bromomethyl)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.11 mmol) was dissolved in DMF (1 mL), then 2-chloro-5-fluorophenol (29 mg, 0.2 mmol) and K2CO3 (27 mg, 0.2 mmol) were added. The resulting mixture was stirred at rt for 1 h and then diluted with water. The mixture was extracted with EtOAc (2 x 10 mL). The combined organic matter was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. C 22 H 12 The LCMS calculated value (M+H)+ m / z for ClF6N2O2 = 485.0; found 485.0.

[0897] Step 5. N-(3-Amino-4-((2-chloro-5-fluorophenoxy)methyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0898] To a mixture of N-(2-((2-chloro-5-fluorophenoxy)methyl)-3-cyano-4-fluorophenyl)-3-fluoro-5-(trifluoromethyl)benzamide (30 mg, 0.06 mmol) in n-BuOH (1 mL) was added hydrazine monohydrate (0.2 mL) at rt. The resulting mixture was stirred at 110 ° C for 1 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Sunfire prep C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.1% TFA), mobile phase B: acetonitrile; flow rate: 60 mL / min); the eluted fractions were collected and lyophilized to give the TFA salt of the desired product as a white solid. 22 H 15 LCMS calculated value (M+H)+m / z for ClF5N4O2=497.1; found 497.1.

[0899] Example 7. N-(3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0900]

[0901] Step 1. N-(4-(2-chloro-5-fluorophenoxy)-3-(1,3-dioxoisoindolin-2-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0902]

[0903] To a mixture of N-(3-amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (Example 1; 3.0 g, 6.2 mmol) in AcOH (10 mL) was added isobenzofuran-1,3-dione (1.03 g, 7.0 mmol) at room temperature. The reactants were then heated at 120 ° C for 2 h under a nitrogen atmosphere. After cooling to room temperature, the reactants were concentrated under reduced pressure. The residue was taken up in EtOAc (500 mL) and washed with saturated NaHCO 3 , brine, and the organic matter was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product precipitated out and was collected by filtration, then washed with EtOAc and dried at room temperature to give a light brown solid, which was used in the next step without further purification. C 29 H 15 LCMS calculated for ClF5N4O4 (M+H) + m / z = 613.0; found 613.0.

[0904] Step 2. N-(4-(2-Chloro-5-fluorophenoxy)-3-(1,3-dioxoisoindolin-2-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0905]

[0906] Dissolve N-(4-(2-chloro-5-fluorophenoxy)-3-(1,3-dioxoisoindolin-2-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (50 mg, 0.08 mmol) in DMF (1 mL), then add methyl iodide (14 mg, 0.1 mmol) and K2CO3 (27 mg, 0.2 mmol). Stir the resulting mixture at rt for 1 h, then dilute with water. Extract the mixture with EtOAc (2 x 10 mL). Dry the combined organic layers over anhydrous sodium sulfate, filter and concentrate under reduced pressure to give the crude product, which is used in the next step without further purification. C 30 H 17 Calculated LCMS value for ClF5N4O4 (M+H)+ m / z = 627.1; found 627.1.

[0907] Step 3. N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide

[0908] Add hydrazine monohydrate (0.2 mL) to a mixture of N-(4-(2-chloro-5-fluorophenoxy)-3-(1,3-dioxoisoindolin-2-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide (20 mg, 0.03 mmol) in MeOH (1 mL) at rt. Stir the resulting mixture at rt for 1 h. Concentrat...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X 1 is CR 5 , O, N or NR 6 ; X 2 is CR 7 or N; X 3 is CR 8 or N; Y is C or N; Z is C or N; n is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3, 4, 5 or 6; Ring A is C 3-14 cycloalkyl, C 6-10 aryl, 4-14 membered hetero cycloalkyl, or 5-10 membered heteroaryl; Ring B is C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; Ring C is a 5-membered heteroaryl having 2 to 3 heteroatoms selected from O and N as ring members; L 1 and L 3 each independently selected from C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -C 3-7 cycloalkylene-C 1-4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4 alkyl-, -(5- to 6-membered heteroarylene)-C 1-4 alkyl-, -O-, -S-, -N(R L ), -C(O)-, -C(O)N(R L ), -N(R L ), -N(R L ), -N(R L ), -N(R L ), -N(R L ), -S(O)2-, -N(R L ), -S(O)2N(R L ), -N(R L ), -N(R L ), where L 1 and L 3 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroarylene, C 3-7 cycloalkylene-C 1-4 alkyl, (4- to 7-membered heterocycloalkylene)-C 1-4 alkyl and (5- to 6-membered heteroarylene)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; L 2 and L 4 each independently selected from a bond, C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroaryl, -C 3-7 cycloalkylene-C 1-4 alkyl-, -(4- to 7-membered heterocycloalkylene)-C 1-4 alkyl-, -(5- to 6-membered heteroaryl)-C 1-4 alkyl-, -O-, -S-, -N(R L ), -C(O)-, -C(O)N(R L ), -N(R L ), -N(R L ), -N(R L ), -N(R L ), -N(R L ), -S(O)2-, -N(R L ), -S(O)2N(R L ), -N(R L ), and -N(R L ), where L 2 and L 4 the C 1-6 alkylene, C 1-6 haloalkylene, C 3-7 cycloalkylene, 4- to 7-membered heterocycloalkylene, 5- to 6-membered heteroaryl, C 3-7 cycloalkylene-C 1-4 alkyl, (4- to 7-membered heterocycloalkylene)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; Each R L is independently selected from H, C 1-6 alkyl and C 1-6 haloalkyl; Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1 , -SR a1 , -NR c1 R d1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR c1 R d1 , -C(O)NR c1 (OR a1 ), -OC(O)R a1 , -OC(O)NR c1 R d1 , -OC(O)OR a1 , -OS(O)2R b1 , -OS(O)2NR c1 R d1 , -NR c1 C(O)R a1 , -NR c1 C(O)OR a1 , -NR c1 C(O)NR c1 R d1 , -NR c1 S(O)2R b1 , -NR c1 S(O)2NR c1 R d1 , -NR c1 OR a1 , -NR c1 S(O)R b1 , -NR c1 S(O)NR c1 R d1 , -S(O)R b1 , -S(O)2R b1 , -S(O)NR c1 R d1 , -S(O)2NR c1 R d1 , -C(=NR e1 )R a1 , -C(=NR e1 )NR c1 R d1 , -NR c1 C(=NR e1 )R a1 , -NR c1 C(=NR e1 )NR c1 R d1 , -NR c1 S(O)(=NR e1 )R b1 , -NR c1 S(O)(=NR e1 )NR c1 R d1 , -OS(O)(=NR e1 )R b1 , -S(O)(=NR e1 )R b1 , -S(O)(=NR e1 )NR c1 R d1 , -C(O)NR c1 S(O)2R b1 , -C(O)NR c1 S(O)2NR c1 R d1 , -S(O)2NR c1 C(O)R b1 , -NR c1 S(O)NR c1 C(O)R b1 and -P(O)R f1 R g1 , wherein R 1 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Each R a1 、R b1 、R c1 and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a1 、R b1 、R c1 and R d1 of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Alternatively, any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Each R e1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f1 and R g1 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R 1A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1A , -SR a1A , -NR c1A R d1A , -C(O)R a1A , -C(O)OR a1A , -C(O)NR c1A R d1A , -C(O)NR c1A (OR a1A ), -OC(O)R a1A , -OC(O)NR c1A R d1A , -OC(O)OR a1A , -OS(O)2R b1A , -OS(O)2NR c1A R d1A , -NR c1A C(O)R a1A , -NR c1A C(O)OR a1A , -NR c1A C(O)NR c1A R d1A , -NR c1A S(O)2R b1A , -NR c1A S(O)2NR c1A R d1A , -NR c1A OR a1A , -NR c1A S(O)R b1A , -NR c1A S(O)NR c1A R d1A , -S(O)R b1A , -S(O)2R b1A , -S(O)NR c1A R d1A , -S(O)2NR c1A R d1A , -C(=NR e1A )R a1A , -C(=NR e1A )NR c1A R d1A , -NR c1A C(=NR e1A )R a1A , -NR c1A C(=NR e1A )NR c1A R d1A , -NR c1A S(O)(=NR e1A )R b1A , -NR c1A S(O)(=NR e1A )NR c1A R d1A , -OS(O)(=NR e1A )R b1A , -S(O)(=NR e1A )R b1A , -S(O)(=NR e1A )NR c1A R d1A , -C(O)NR c1A S(O)2R b1A , -C(O)NR c1A S(O)2NR c1A R d1A , -S(O)2NR c1A C(O)R b1A , -NR c1A S(O)NR c1A C(O)R b1A and -P(O)R f1A R g1A , wherein R 1A is the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a1A 、R b1A 、R c1A and R d1A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C a1A 、R b1A 、R c1A and R d1A of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c1A and R d1A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e1A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heteroalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heteroalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f1A and R g1A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R 2 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a2 , -SR a2 , -NR c2 R d2 , -C(O)R a2 , -C(O)OR a2 , -C(O)NR c2 R d2 , -C(O)NR c2 (OR a2 ), -OC(O)R a2 , -OC(O)NR c2 R d2 , -OC(O)OR a2 , -OS(O)2R b2 , -OS(O)2NR c2 R d2 , -NR c2 C(O)R a2 , -NR c2 C(O)OR a2 , -NR c2 C(O)NR c2 R d2 , -NR c2 S(O)2R b2 , -NR c2 S(O)2NR c2 R d2 , -NR c2 OR a2 , -NR c2 S(O)R b2 , -NR c2 S(O)NR c2 R d2 , -S(O)R b2 , -S(O)2R b2 , -S(O)NR c2 R d2 , -S(O)2NR c2 R d2 , -C(=NR e2 )R a2 , -C(=NR e2 )NR c2 R d2 , -NR c2 C(=NR e2 )R a2 , -NR c2 C(=NR e2 )NR c2 R d2 , -NR c2 S(O)(=NR e2 )R b2 , -NR c2 S(O)(=NR e2 )NR c2 R d2 , -OS(O)(=NR e2 )R b2 , -S(O)(=NR e2 )R b2 , -S(O)(=NR e2 )NR c2 R d2 , -C(O)NR c2 S(O)2R b2 , -C(O)NR c2 S(O)2NR c2 R d2 , -S(O)2NR c2 C(O)R b2 , -NR c2 S(O)NR c2 C(O)R b2 and -P(O)R f2 R g2 , wherein R 2 is said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 membered heterocycloalkyl, 5 - 10 membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents; Each R a2 、R b2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein R a2 、R b2 、R c2 and R d2 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents; Alternatively, any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents; Each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f2 and R g2 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R 2A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a2A , -SR a2A , -NR c2A R d2A , -C(O)R a2A , -C(O)OR a2A , -C(O)NR c2A R d2A , -C(O)NR c2A (OR a2A ), -OC(O)R a2A , -OC(O)NR c2A R d2A , -OC(O)OR a2A , -OS(O)2R b2A , -OS(O)2NR c2A R d2A , -NR c2A C(O)R a2A , -NR c2A C(O)OR a2A , -NR c2A C(O)NR c2A R d2A , -NR c2A S(O)2R b2A , -NR c2A S(O)2NR c2A R d2A , -NR c2A OR a2A , -NR c2A S(O)R b2A , -NR c2A S(O)NR c2A R d2A , -S(O)R b2A , -S(O)2R b2A , -S(O)NR c2A R d2A , -S(O)2NR c2A R d2A , -C(=NR e2A )R a2A , -C(=NR e2A )NR c2A R d2A , -NR c2A C(=NR e2A )R a2A , -NR c2A C(=NR e2A )NR c2A R d2A , -NR c2A S(O)(=NR e2A )R b2A , -NR c2A S(O)(=NR e2A )NR c2A R d2A , -OS(O)(=NR e2A )R b2A , -S(O)(=NR e2A )R b2A , -S(O)(=NR e2A )NR c2A R d2A , -C(O)NR c2A S(O)2R b2A , -C(O)NR c2A S(O)2NR c2A R d2A , -S(O)2NR c2A C(O)R b2A , -NR c2A S(O)NR c2A C(O)R b2A and -P(O)R f2A R g2A , where R 2A the C of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered hetero - cycloalkyl, 5 - 10 - membered hetero - aryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered hetero - cycloalkyl)-C 1-4 alkyl and (5 - 10 - membered hetero - aryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a2A 、R b2A 、R c2A and R d2A are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a2A 、R b2A 、R c2A and R d2A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c2A and R d2A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e2A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R f2A and R g2A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; R 3 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl, (5-6 membered heteroaryl)-C 1-4 Alkyl, -C(O)R a3 、-C(O)OR a3 、-C(O)NR c3 R d3 、-S(O)2R b3 、-S(O)2NR c3 R d3 、-S(O)(=NR e3 )R b3 and -S(O)(=NR e3 )NR c3 R d3 , where R 3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R G Substituent substitution; Alternatively, R 3 and L 3 together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a3 、R b3 、R c3 and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein the C a3 、R b3 、R c3 and R d3 of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R that is attached to the same N atom c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, where the 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 4 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, wherein R 4 said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is each optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents; R 5 Selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered hetero - cycloalkyl, 5 - 14 - membered hetero - aryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered hetero - cycloalkyl)-C 1-4 alkyl, (5 - 14 - membered hetero - aryl)-C 1-4 alkyl, - CN, - OR a5 , - SR a5 , - NR c5 R d5 , - NO2, - C(O)R a5 , - C(O)OR a5 , - C(O)NR c5 R d5 , - C(O)NR c5 (OR a5 ), - OC(O)R a5 , - OC(O)NR c5 R d5 , - OC(O)OR a5 , - OS(O)2R b5 , - OS(O)2NR c5 R d5 , - NR c5 C(O)R a5 , - NR c5 C(O)OR a5 , - NR c5 C(O)NR c5 R d5 , - NR c5 S(O)2R b5 , - NR c5 S(O)2NR c5 R d5 , - NR c5 OR a5 , - NR c5 S(O)R b5 , - NR c5 S(O)NR c5 R d5 , - S(O)R b5 , - S(O)2R b5 , - S(O)NR c5 R d5 , -S(O)2NR c5 R d5 , -C(=NR e5 )R a5 , -C(=NR e5 )NR c5 R d5 , -NR c5 C(=NR e5 )R a5 , -NR c5 C(=NR e5 )NR c5 R d5 , -NR c5 S(O)(=NR e5 )R b5 , -NR c5 S(O)(=NR e5 )NR c5 R d5 , -OS(O)(=NR e5 )R b5 , -S(O)(=NR e5 )R b5 , -S(O)(=NR e5 )NR c5 R d5 , -C(O)NR c5 S(O)2R b5 , -C(O)NR c5 S(O)2NR c5 R d5 , -S(O)2NR c5 C(O)R b5 , -NR c5 S(O)NR c5 C(O)R b5 and -P(O)R f5 R g5 , wherein R 5 is said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 - membered hetero cycloalkyl, 5 - 14 - membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 - membered hetero cycloalkyl)-C 1-4 alkyl and (5 - 14 - membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents; Each R a5 、R b5 、R c5 and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl, wherein the C a5 、R b5 、R c5 and R d5 of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents; Alternatively, any R attached to the same N atom c5 and R d5 together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl group, wherein the 4- to 14-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 5A substituents; Each R e5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f5 and R g5 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R 5A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a5A , -SR a5A , -NR c5A R d5A , -NO2, -C(O)R a5A , -C(O)OR a5A , -C(O)NR c5A R d5A , -C(O)NR c5A (OR a5A ), -OC(O)R a5A , -OC(O)NR c5A R d5A , -OC(O)OR a5A , -OS(O)2R b5A , -OS(O)2NR c5A R d5A , -NR c5A C(O)R a5A , -NR c5A C(O)OR a5A , -NR c5A C(O)NR c5A R d5A , -NR c5A S(O)2R b5A , -NR c5A S(O)2NR c5A R d5A , -NR c5A OR a5A , -NR c5A S(O)R b5A , -NR c5A S(O)NR c5A R d5A , -S(O)R b5A , -S(O)2R b5A , -S(O)NR c5A R d5A 、-S(O)2NR c5A R d5A 、-C(=NR e5A )R a5A 、-C(=NR e5A )NR c5A R d5A 、-NR c5A C(=NR e5A )R a5A 、-NR c5A C(=NR e5A )NR c5A R d5A 、-NR c5A S(O)(=NR e5A )R b5A 、-NR c5A S(O)(=NR e5A )NR c5A R d5A 、-OS(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )R b5A 、-S(O)(=NR e5A )NR c5A R d5A 、-C(O)NR c5A S(O)2R b5A 、-C(O)NR c5A S(O)2NR c5A R d5A 、-S(O)2NR c5A C(O)R b5A 、-NR c5A S(O)NR c5A C(O)R b5A and-P(O)R f5A R g5A , where R 5A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a5A 、R b5A 、R c5A and R d5A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a5A 、R b5A 、R c5A and R d5A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c5A and R d5A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e5A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f5A and R g5A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; R 6 selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 membered heterocycloalkyl)-C 1-4 alkyl, (5 - 14 membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 , -C(O)OR a6 , -C(O)NR c6 R d6 , -C(O)NR c6 (OR a6 ), -S(O)R b6 , -S(O)2R b6 , -S(O)NR c6 R d6 , -S(O)2NR c6 R d6 , -C(=NR e6 )R a6 , -C(=NR e6 )NR c6 R d6 , -S(O)(=NR e6 )R b6 , -S(O)(=NR e6 )NR c6 R d6 , -C(O)NR c6 S(O)2R b6 , -C(O)NR c6 S(O)2NR c6 R d6 and -S(O)2NR c6 C(O)R b6 , wherein R 6 the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4 - 14 membered heteroalkyl)-C 1-4 Alkyl and (5 - 14 membered heteroaryl)-C 1-4 The alkyls are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents; Each R a6 、R b6 、R c6 and R d6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein R a6 、R b6 、R c6 and R d6 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents; Alternatively, any R attached to the same N atom c6 and R d6 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents; Each R e6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered hetero cycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered hetero cycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A , -SR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -C(O)NR c6A (OR a6A ), -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -OS(O)2R b6A , -OS(O)2NR c6A R d6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -NR c6A C(O)NR c6A R d6A , -NR c6A S(O)2R b6A , -NR c6A S(O)2NR c6A R d6A , -NR c6A OR a6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A 、-S(O)2NR c6A R d6A 、-C(=NR e6A )R a6A 、-C(=NR e6A )NR c6A R d6A 、-NR c6A C(=NR e6A )R a6A 、-NR c6A C(=NR e6A )NR c6A R d6A 、-NR c6A S(O)(=NR e6A )R b6A 、-NR c6A S(O)(=NR e6A )NR c6A R d6A 、-OS(O)(=NR e6A )R b6A 、-S(O)(=NR e6A )R b6A 、-S(O)(=NR e6A )NR c6A R d6A 、-C(O)NR c6A S(O)2R b6A 、-C(O)NR c6A S(O)2NR c6A R d6A 、-S(O)2NR c6A C(O)R b6A 、-NR c6A S(O)NR c6A C(O)R b6A and-P(O)R f6A R g6A , where R 6A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a6A 、R b6A 、R c6A and R d6A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e6A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f6A and R g6A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; R 7 Selected from H, halogen group, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C 3-14 cycloalkyl group, C 6-10 aryl group, 4 - 14 - membered heterocycloalkyl group, 5 - 14 - membered heteroaryl group, C 3-14 cycloalkyl - C 1-4 alkyl group, C 6-10 aryl - C 1-4 alkyl group, (4 - 14 - membered heterocycloalkyl) - C 1-4 alkyl group, (5 - 14 - membered heteroaryl) - C 1-4 alkyl group, - CN, - OR a7 , - SR a7 , - NR c7 R d7 , - NO2, - C(O)R a7 , - C(O)OR a7 , - C(O)NR c7 R d7 , - C(O)NR c7 (OR a7 ), - OC(O)R a7 , - OC(O)NR c7 R d7 , - OC(O)OR a7 , - OS(O)2R b7 , - OS(O)2NR c7 R d7 , - NR c7 C(O)R a7 , - NR c7 C(O)OR a7 , - NR c7 C(O)NR c7 R d7 , - NR c7 S(O)2R b7 , - NR c7 S(O)2NR c7 R d7 , - NR c7 OR a7 , - NR c7 S(O)R b7 , - NR c7 S(O)NR c7 R d7 , - S(O)R b7 , - S(O)2R b7 , - S(O)NR c7 R d7 , -S(O)2NR c7 R d7 , -C(=NR e7 )R a7 , -C(=NR e7 )NR c7 R d7 , -NR c7 C(=NR e7 )R a7 , -NR c7 C(=NR e7 )NR c7 R d7 , -NR c7 S(O)(=NR e7 )R b7 , -NR c7 S(O)(=NR e7 )NR c7 R d7 , -OS(O)(=NR e7 )R b7 , -S(O)(=NR e7 )R b7 , -S(O)(=NR e7 )NR c7 R d7 , -C(O)NR c7 S(O)2R b7 , -C(O)NR c7 S(O)2NR c7 R d7 , -S(O)2NR c7 C(O)R b7 , -NR c7 S(O)NR c7 C(O)R b7 and -P(O)R f7 R g7 , wherein R 7 is the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4 - 14 membered heterocycloalkyl, 5 - 14 membered heteroaryl, C 3-14 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 14 membered heterocycloalkyl)-C 1-4 alkyl and (5 - 14 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Alternatively, R 5 and R 7 together with the atom to which they are attached form a C 5-14 cycloalkyl or 5- to 14-membered heterocycloalkyl, where the C 5-14 cycloalkyl and 5- to 14-membered heterocycloalkyl are optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Alternatively, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Each R a7 、R b7 、R c7 and R d7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl, wherein R a7 、R b7 、R c7 and R d7 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Alternatively, any R attached to the same N atom c7 and R d7 together with the N atom to which they are attached form a 4- to 14-membered heterocycloalkyl, where the 4- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Each R e7 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f7 and R g7 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R 7A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7A , -SR a7A , -NR c7A R d7A , -NO2, -C(O)R a7A , -C(O)OR a7A , -C(O)NR c7A R d7A , -C(O)NR c7A (OR a7A ), -OC(O)R a7A , -OC(O)NR c7A R d7A , -OC(O)OR a7A , -OS(O)2R b7A , -OS(O)2NR c7A R d7A , -NR c7A C(O)R a7A , -NR c7A C(O)OR a7A , -NR c7A C(O)NR c7A R d7A , -NR c7A S(O)2R b7A , -NR c7A S(O)2NR c7A R d7A , -NR c7A OR a7A , -NR c7A S(O)R b7A , -NR c7A S(O)NR c7A R d7A , -S(O)R b7A , -S(O)2R b7A , -S(O)NR c7A R d7A 、 -S(O)2NR c7A R d7A 、 -C(=NR e7A )R a7A 、 -C(=NR e7A )NR c7A R d7A 、 -NR c7A C(=NR e7A )R a7A 、 -NR c7A C(=NR e7A )NR c7A R d7A 、 -NR c7A S(O)(=NR e7A )R b7A 、 -NR c7A S(O)(=NR e7A )NR c7A R d7A 、 -OS(O)(=NR e7A )R b7A 、 -S(O)(=NR e7A )R b7A 、 -S(O)(=NR e7A )NR c7A R d7A 、 -C(O)NR c7A S(O)2R b7A 、 -C(O)NR c7A S(O)2NR c7A R d7A 、 -S(O)2NR c7A C(O)R b7A 、 -NR c7A S(O)NR c7A C(O)R b7A and -P(O)R f7A R g7A , where R 7A is the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents; Each R a7A , R b7A , R c7A and R d7A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a7A , R b7A , R c7A and R d7A of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents; Alternatively, any R attached to the same N atom c7A and R d7A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7B substituents; Each R e7A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f7A and R g7A are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R 7B is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a7B , -SR a7B , -NR c7B R d7B , -NO2, -C(O)R a7B , -C(O)OR a7B , -C(O)NR c7B R d7B , -C(O)NR c7B (OR a7B ), -OC(O)R a7B , -OC(O)NR c7B R d7B , -OC(O)OR a7B , -OS(O)2R b7B , -OS(O)2NR c7B R d7B , -NR c7B C(O)R a7B , -NR c7B C(O)OR a7B , -NR c7B C(O)NR c7B R d7B , -NR c7B S(O)2R b7B , -NR c7B S(O)2NR c7B R d7B , -NR c7B OR a7B , -NR c7B S(O)R b7B , -NR c7B S(O)NR c7B R d7B , -S(O)R b7B , -S(O)2R b7B , -S(O)NR c7B R d7B 、 -S(O)2NR c7B R d7B 、 -C(=NR e7B )R a7B 、 -C(=NR e7B )NR c7B R d7B 、 -NR c7B C(=NR e7B )R a7B 、 -NR c7B C(=NR e7B )NR c7B R d7B 、 -NR c7B S(O)(=NR e7B )R b7B 、 -NR c7B S(O)(=NR e7B )NR c7B R d7B 、 -OS(O)(=NR e7B )R b7B 、 -S(O)(=NR e7B )R b7B 、 -S(O)(=NR e7B )NR c7B R d7B 、 -C(O)NR c7B S(O)2R b7B 、 -C(O)NR c7B S(O)2NR c7B R d7B 、 -S(O)2NR c7B C(O)R b7B 、 -NR c7B S(O)NR c7B C(O)R b7B and -P(O)R f7B R g7B wherein R 7B the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a7B 、R b7B 、R c7B and R d7B is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl, wherein the C a7B 、R b7B 、R c7B and R d7B of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c7B and R d7B together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e7B is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R f7B and R g7B are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; R 8 selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 10-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a8 , -SR a8 , -NR c8 R d8 , -NO2, -C(O)R a8 , -C(O)OR a8 , -C(O)NR c8 R d8 , -C(O)NR c8 (OR a8 )、-OC(O)R a8 , -OC(O)NR c8 R d8 , -OC(O)OR a8 , -OS(O)2R b8 , -OS(O)2NR c8 R d8 , -NR c8 C(O)R a8 , -NR c8 C(O)OR a8 , -NR c8 C(O)NR c8 R d8 , -NR c8 S(O)2R b8 , -NR c8 S(O)2NR c8 R d8 , -NR c8 OR a8 , -NR c8 S(O)R b8 , -NR c8 S(O)NR c8 R d8 , -S(O)R b8 , -S(O)2R b8 , -S(O)NR c8 R d8 , -S(O)2NR c8 R d8 , -C(=NR e8 )R a8 , -C(=NR e8 )NR c8 R d8 , -NR c8 C(=NR e8 )R a8 , -NR c8 C(=NR e8 )NR c8 R d8 , -NR c8 S(O)(=NR e8 )R b8 , -NR c8 S(O)(=NR e8 )NR c8 R d8 , -OS(O)(=NR e8 )R b8 , -S(O)(=NR e8 )R b8 , -S(O)(=NR e8 )NR c8 R d8 , -C(O)NR c8 S(O)2R b8 , -C(O)NR c8 S(O)2NR c8 R d8 , -S(O)2NR c8 C(O)R b8 , -NR c8 S(O)NR c8 C(O)R b8 and -P(O)R f8 R g8 , wherein R 8 is the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4 - 10 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, C 3-10 cycloalkyl - C 1-4 alkyl, C 6-10 aryl - C 1-4 alkyl, (4 - 10 - membered heterocycloalkyl)-C 1-4 alkyl and (5 - 10 - membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents; Each R a8 、R b8 、R c8 and R d8 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a8 、R b8 、R c8 and R d8 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents; Alternatively, any R attached to the same N atom c8 and R d8 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 8A substituents; Each R e8 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f8 and R g8 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; Each R 8A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl, (5-10 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a8A , -SR a8A , -NR c8A R d8A , -NO2, -C(O)R a8A , -C(O)OR a8A , -C(O)NR c8A R d8A , -C(O)NR c8A (OR a8A ), -OC(O)R a8A , -OC(O)NR c8A R d8A , -OC(O)OR a8A , -OS(O)2R b8A , -OS(O)2NR c8A R d8A , -NR c8A C(O)R a8A , -NR c8A C(O)OR a8A , -NR c8A C(O)NR c8A R d8A , -NR c8A S(O)2R b8A , -NR c8A S(O)2NR c8A R d8A , -NR c8A OR a8A , -NR c8A S(O)R b8A , -NR c8A S(O)NR c8A R d8A , -S(O)R b8A , -S(O)2R b8A , -S(O)NR c8A R d8A 、-S(O)2NR c8A R d8A 、-C(=NR e8A )R a8A 、-C(=NR e8A )NR c8A R d8A 、-NR c8A C(=NR e8A )R a8A 、-NR c8A C(=NR e8A )NR c8A R d8A 、-NR c8A S(O)(=NR e8A )R b8A 、-NR c8A S(O)(=NR e8A )NR c8A R d8A 、-OS(O)(=NR e8A )R b8A 、-S(O)(=NR e8A )R b8A 、-S(O)(=NR e8A )NR c8A R d8A 、-C(O)NR c8A S(O)2R b8A 、-C(O)NR c8A S(O)2NR c8A R d8A 、-S(O)2NR c8A C(O)R b8A 、-NR c8A S(O)NR c8A C(O)R b8A and-P(O)R f8A R g8A , where R 8A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a8A 、R b8A 、R c8A and R d8A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a8A 、R b8A 、R c8A and R d8A of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, any R attached to the same N atom c8A and R d8A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e8A is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered hetero cycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Each R f8A and R g8A is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4-10 membered heterocycloalkyl)-C 1-4 alkyl and (5-10 membered heteroaryl)-C 1-4 alkyl; and Each R G is independently selected from H, OH, CN, halo, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X 1 is N or NR 6 .

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 6-membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 and -S(O)2R b6 , wherein R 6 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents; and Each R a6 and R b6 are independently selected from H and C 1-6 alkyl groups.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -C(O)R a6 and -S(O)2R b6 , wherein R 6 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 6A substituents; and Each R a6 and R b6 are independently selected from H and C 1-6 alkyl groups.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 6 is selected from H, C 1-6 alkyl, -C(O)R a6 and -S(O)2R b6 , wherein the C 6 alkyl of R 1-6 is optionally substituted by 1, 2, 3 or 4 independently selected R 6A substituents; and Each R a6 and R b6 is independently selected from H and C 1-3 alkyl groups.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, methyl, ethyl, methylcarbonyl and methylsulfonyl, wherein the methyl and ethyl of R 6 are optionally substituted by 1 or 2 independently selected R 6A substituents.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A , -SR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -NR c6A C(O)NR c6A R d6A , -NR c6A S(O)2R b6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R ; d6A and -S(O)2NR c6A R d6A , wherein the C 6A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 Naphthenic-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is each optionally substituted by 1, 2, 3 or 4 independently selected R G substituents; and Each R a6A , R b6A , R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl; Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents.

8. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 1-6 haloalkyl, 4- to 7-membered heterocycloalkyl, -CN, -OR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein the C 6A alkyl, C 1-6 haloalkyl and 4- to 7-membered heterocycloalkyl of R 1-6 are each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; and Each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl; Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents.

9. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein each R 6A is independently selected from CN, 4-7 membered heterocycloalkyl, and -C(O)NR c6A R d6A ; and Each R c6A and R d6A are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl and C 2-6 alkynyl; Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents.

10. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein each R 6A is independently selected from CN, azetidinyl, aminocarbonyl, methylaminocarbonyl and morpholinocarbonyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein X 2 is CR 7 .

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R 7 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 14-membered heteroaryl)-C 1-4 alkyl and -C(O)NR c7 R d7 , wherein R 7 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, C 3-14 cycloalkyl-C 1-4 alkyl, C 6-10 0aryl-C 1-4 alkyl, (4- to 14-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 14-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents; and Each R c7 and R d7 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl, (5- to 6-membered heteroaryl)-C 1-4 alkyl and -C(O)NR c7 R d7 wherein the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R 7A substituents; and Each R c7 and R d7 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 ycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, 5- to 6-membered heteroaryl, and -C(O)NR c7 R d7 , wherein each of said C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 ycloalkyl, phenyl, 4- to 10-membered heterocycloalkyl, and 5- to 6-membered heteroaryl is optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and Each R c7 and R d7 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

15. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, 5-6 membered heteroaryl, and -C(O)NR c7 R d7 , wherein the C 7 of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, 8-10 membered heterocycloalkyl, and 5-6 membered heteroaryl are each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents; and Each R c7 and R d7 are independently selected from H and C 1-6 alkyl groups.

16. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein each R 7 is H, chloro, bromo, methyl, ethyl, vinyl, ethynyl, propynyl, dimethylpropynyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, phenyl, pyrazolyl, pyridyl, triazolyl, pyrimidinyl, and ethylaminocarbonyl, wherein R 7 of said methyl, ethyl, vinyl, ethynyl, propynyl, dimethylpropynyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, phenyl, pyrazolyl, pyridyl, triazolyl, and pyrimidinyl is each optionally substituted with 1, 2, 3, or 4 independently selected R 7A substituents.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each R 7A are independently selected from oxo, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl, (5-10 membered heteroaryl)-C 1-4 Alkyl, CN, OR a7A 、-NR c7A R d7A and C(O)NR c7A R d7A , where R 7A The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 Cycloalkyl-C 1-4 Alkyl, C 6-10 Aryl-C 1-4 Alkyl, (4-10 membered heterocycloalkyl)-C 1-4 Alkyl and (5-10 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3 or 4 independently selected R 7B Substituents are substituted; and Each R a7A 、R c7A and R d7A are independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each R 7A independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, CN, OR a7A 、-NR c7A R d7A and C(O)NR c7A R d7A , where R 7A The C 1-6 Alkyl, C 3-7 Cycloalkyl, 4-7 membered heterocycloalkyl and 5-6 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B Substituents are substituted; and Each R a7A , R c7A and R d7A is independently selected from H and C 1-6 alkyl groups.

19. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein each R 7A is independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, CN, OR a7A , -NR c7A R d7A and C(O)NR c7A R d7A , wherein the C 7A alkyl, C 1-6 cycloalkyl, 4- to 7-membered heterocycloalkyl and 5- to 6-membered heteroaryl of R 3-7 are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B substituents; and Each R a7A , R c7A and R d7A is independently selected from H and C 1-3 alkyl groups.

20. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein each R 7A is independently selected from methyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, imidazolyl, pyrazolyl, pyridinyl, cyano, hydroxy, amino and aminocarbonyl, wherein the 7A methyl, isopropyl, cyclopropyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, imidazolyl, pyrazolyl and pyridinyl of R 7B are each optionally substituted by 1, 2, 3 or 4 independently selected R 7B substituents.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each R 7B is independently selected from C 1-6 alkyl, OR a7B , NR c7B R d7B , C(O)R a7B and -C(O)NR c7B R d7B , wherein the C 1-6 alkyl is optionally substituted with OH; and Each R a7B , R c7B and R d7B is independently selected from H and C 1-3 alkyl groups.

22. The compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein each R 7B is independently selected from methyl, hydroxymethyl, hydroxy, amino, methylcarbonyl and methylaminocarbonyl.

23. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, chloro, bromo, methyl, hydroxymethyl, cyanomethyl, hydroxyethyl, cyanoethyl, pyridylethyl, cyanovinyl, pyridylvinyl, ethynyl, cyclopropyl ethynyl, (hydroxycyclopropyl)ethynyl, (hydroxymethylcyclopropyl)ethynyl, (aminocyclopropyl)ethynyl, (hydroxy)(dimethyl)propynyl, (amino)(dimethyl)propynyl, (methyloxetanyl)ethynyl, tetrahydropyranyl ethynyl, (methylcarbonylpiperidyl)ethynyl, (methylaminocarbonylpiperidyl)ethynyl, pyridyl ethynyl, (methylpyrazolyl)ethynyl, (methylimidazolyl)ethynyl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, pyrimidinyl, isopropylpyrazolyl, tetrahydrofuranylpyrazolyl, methyltriazolyl, phenyl, aminocarbonylphenyl, ethylaminocarbonyl, methylpyrazolyl, pyridyl and morpholinomethyl.

24. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, chloro, bromo, methyl, 25. The compound according to any one of claims 1, 2 and 11 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 together with the atoms to which they are attached form a 5- to 14-membered heterocycloalkyl, wherein the 5- to 14-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 and 11, wherein R 6 and R 7 together with the atoms to which they are attached form a 5- to 14-membered heterocycloalkyl selected from ​ 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein X 3 is CR 8 .

28. The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, X 3 is CH.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein Y is C.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein Z is C.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein Z is N.

33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 ; and Each R c3 and R d3 are independently selected from H and C 1-6 alkyl groups.

34. The compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, C 1-6 alkyl and -C(O)NR c3 R d3 ; and Each R c3 and R d3 are independently selected from H and C 1-3 alkyl groups.

35. The compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, methyl and aminomethylcarbonyl.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein R 4 is selected from H, C 1-6 alkyl and C 1-6 haloalkyl.

37. The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein R 4 is H or methyl.

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein L 1 is -N(R L )C(O)- or -N(R L ).

39. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 37, wherein L 1 is -NHC(O)-.

40. The compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond.

41. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from C 1-6 alkylene, -O-, and -N(R L ).

42. The compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from methylene, -O- and -NH-.

43. The compound according to any one of claims 1 to 42 or a pharmaceutically acceptable salt thereof, wherein L 4 is a bond or -O-.

44. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein ring A is C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered hetero cycloalkyl or 5- to 10-membered heteroaryl.

45. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein ring A is phenyl, 8- to 10-membered heterocycloalkyl or 8- to 10-membered heteroaryl.

46. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein ring A is phenyl, benzo[b]thienyl or indolinyl.

47. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 46, wherein n is 0, 1, 2, 3 or 4.

48. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, wherein each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN and -OR a1 ; and Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

49. The compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and OR a1 ; and Each R a1 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.

50. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 47, wherein each R 1 is independently selected from fluoro, chloro, trifluoromethyl and hydroxy.

51. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 50, wherein ring B is C 3-7 cycloalkyl, phenyl, 4- to 7-membered hetero cycloalkyl or 5- to 6-membered heteroaryl.

52. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 50, wherein ring B is phenyl or 5- to 6-membered heteroaryl.

53. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 50, wherein ring B is phenyl or pyridyl.

54. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 53, wherein m is 0, 1, 2 or 3.

55. The compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

56. The compound according to any one of claims 1 to 54 or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from a halogen group.

57. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 54, wherein each R 2 is independently chloro or fluoro.

58. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X 1 is CR 5 , N or NR 6 ; X 2 is CR 7 or N; X 3 is CR 8 or N; Y is C or N; Z is C or N; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; L 1 is -NHC(O)- or -NH-; L 2 is a key; L 3 selected from C 1-6 alkylene, -O-, and -NH-; L 4 is a bond or -O-; Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a1 , -SR a1 , -NR c1 R d1 , -C(O)R a1 , -C(O)OR a1 , -C(O)NR c1 R d1 , -C(O)NR c1 (OR a1 ), -OC(O)R a1 , -OC(O)NR c1 R d1 , -OC(O)OR a1 , -OS(O)2R b1 , -OS(O)2NR c1 R d1 , -NR c1 C(O)R a1 , -NR c1 C(O)OR a1 , -NR c1 C(O)NR c1 R d1 , -NR c1 S(O)2R b1 , -NR c1 S(O)2NR c1 R d1 , -NR c1 OR a1 , -NR c1 S(O)R b1 , -NR c1 S(O)NR c1 R d1 , -S(O)R b1 , -S(O)2R b1 , -S(O)NR c1 R d1 , -S(O)2NR c1 R d1 、 -C(=NR e1 )R a1 、 -C(=NR e1 )NR c1 R d1 、 -NR c1 C(=NR e1 )R a1 、 -NR c1 C(=NR e1 )NR c1 R d1 、 -NR c1 S(O)(=NR e1 )R b1 、 -NR c1 S(O)(=NR e1 )NR c1 R d1 、 -OS(O)(=NR e1 )R b1 、 -S(O)(=NR e1 )R b1 、 -S(O)(=NR e1 )NR c1 R d1 、 -C(O)NR c1 S(O)2R b1 、 -C(O)NR c1 S(O)2NR c1 R d1 、 -S(O)2NR c1 C(O)R b1 、 -NR c1 S(O)NR c1 C(O)R b1 and -P(O)R f1 R g1 , wherein each of the R 1 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Each R a1 、R b1 、R c1 and R d1 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl, wherein the C a1 、R b1 、R c1 and R d1 of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Alternatively, any R attached to the same N atom c1 and R d1 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 1A substituents; Each R e1 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; Each R f1 and R g1 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; Each R 1A is independently selected from H, OH, CN, a halogen group, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino; Each R 2 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl, (5-6-membered heteroaryl)-C 1-4 alkyl, -CN, -OR a2 , -SR a2 , -NR c2 R d2 , -C(O)R a2 , -C(O)OR a2 , -C(O)NR c2 R d2 , -C(O)NR c2 (OR a2 ), -OC(O)R a2 , -OC(O)NR c2 R d2 , -OC(O)OR a2 , -OS(O)2R b2 , -OS(O)2NR c2 R d2 , -NR c2 C(O)R a2 , -NR c2 C(O)OR a2 , -NR c2 C(O)NR c2 R d2 , -NR c2 S(O)2R b2 , -NR c2 S(O)2NR c2 R d2 , -NR c2 OR a2 , -NR c2 S(O)R b2 , -NR c2 S(O)NR c2 R d2 , -S(O)R b2 , -S(O)2R b2 , -S(O)NR c2 R d2 , -S(O)2NR c2 R d2 、-C(=NR e2 )R a2 、-C(=NR e2 )NR c2 R d2 、-NR c2 C(=NR e2 )R a2 、-NR c2 C(=NR e2 )NR c2 R d2 、-NR c2 S(O)(=NR e2 )R b2 、-NR c2 S(O)(=NR e2 )NR c2 R d2 、-OS(O)(=NR e2 )R b2 、-S(O)(=NR e2 )R b2 、-S(O)(=NR e2 )NR c2 R d2 、-C(O)NR c2 S(O)2R b2 、-C(O)NR c2 S(O)2NR c2 R d2 、-S(O)2NR c2 C(O)R b2 、-NR c2 S(O)NR c2 C(O)R b2 and-P(O)R f2 R g2 , where R 2 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 3-7 Cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 Cycloalkyl-C 1-4 Alkyl, phenyl-C 1-4 Alkyl, (4-7 membered heterocycloalkyl)-C 1-4 Alkyl and (5-6 membered heteroaryl)-C 1-4 Each alkyl group is optionally replaced by 1, 2, 3, 4, 5 or 6 independently selected R 2A Substituent substitution; Each R a2 、R b2 、R c2 and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl, wherein R a2 、R b2 、R c2 and R d2 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7-membered heterocycloalkyl, 5-6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7-membered heterocycloalkyl)-C 1-4 alkyl and (5-6-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents; Alternatively, any R attached to the same N atom c2 and R d2 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl, wherein the 4- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 2A substituents; Each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; Each R f2 and R g2 are independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; Each R 2A is independently selected from H, OH, CN, a halogen group, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, sulfanyl, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino; R 3 Selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C(O)R a3 , -C(O)OR a3 , -C(O)NR c3 R d3 , -S(O)2R b3 , -S(O)2NR c3 R d3 , -S(O)(=NR e3 )R b3 and -S(O)(=NR e3 )NR c3 R d3 , wherein R 3 the C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Alternatively, R 3 and L 3 together with the atom to which they are attached form a 5- to 10-membered heterocycloalkyl, wherein the 5- to 10-membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R a3 、R b3 、R c3 and R d3 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; Alternatively, any R attached to the same N atom c3 and R d3 together with the N atom to which they are attached form a 4- to 7-membered heterocycloalkyl group, wherein the 4- to 7-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R G substituents; Each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy; R 4 selected from H, C 1-6 alkyl and C 1-6 haloalkyl; R 8 selected from H, a halogen group, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy; and Each R G is independently selected from H, OH, CN, a halogen group, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

59. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: X 1 is N or NR 6 ; X 2 is CR 7 ; X 3 is CR 8 ; Y is C or N; Z is C or N; n is 0, 1, 2, 3 or 4; m is 0, 1, 2, 3 or 4; ring A is phenyl, 8- to 10-membered heterocycloalkyl or 8- to 10-membered heteroaryl; ring B is phenyl or 5- to 6-membered heteroaryl; ring C is a 5-membered heteroaryl having 2 to 3 nitrogen atoms as ring members; L 1 is -N(R L )C(O)- or -N(R L )-; L 2 is a key; L 3 Selected from C 1-6 alkylene, -O-, and -N(R L )-; L 4 is a bond or -O-; Each R L is independently selected from H and C 1-6 alkyl; Each R 1 is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, -CN and -OR a1 ; Each R a1 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; Each R 2 is independently selected from a halogen group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; R 3 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and -C(O)NR c3 R d3 ; Each R c3 and R d3 are independently selected from H and C 1-6 alkyl; R 4 selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; R 6 selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 alkyl, -C(O)R a6 , -C(O)OR a6 , -C(O)NR c6 R d6 , -C(O)NR c6 (OR a6 ), -S(O)R b6 , -S(O)2R b6 , -S(O)NR c6 R d6 , -S(O)2NR c6 R d6 , -C(=NR e6 )R a6 , -C(=NR e6 )NR c6 R d6 , -S(O)(=NR e6 )R b6 , -S(O)(=NR e6 )NR c6 R d6 , -C(O)NR c6 S(O)2R b6 , -C(O)NR c6 S(O)2NR c6 R d6 and -S(O)2NR c6 C(O)R b6 , wherein R 6 the said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl and (5-6 membered heteroaryl)-C 1-4 each alkyl is optionally substituted by 1, 2, 3 or 4 independently selected R 6A substituents; Each R a6 、R b6 、R c6 and R d6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl, wherein the C a6 、R b6 、R c6 and R d6 of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents; Alternatively, any R attached to the same N atom c6 and R d6 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, wherein the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 6A substituents; Each R e6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, C 6-10 aryl-C 1-4 alkyl, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 10-membered heteroaryl)-C 1-4 alkyl; Alternatively, R 6 and R 7 together with the atom to which they are attached form a 5- to 14-membered heterocycloalkyl group, wherein the 5- to 14-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, 4, 5 or 6 independently selected R 7A substituents; Each R 6A is independently selected from oxo, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4-7 membered heterocycloalkyl)-C 1-4 alkyl, (5-6 membered heteroaryl)-C 1-4 alkyl, -CN, -OR a6A , -SR a6A , -NR c6A R d6A , -NO2, -C(O)R a6A , -C(O)OR a6A , -C(O)NR c6A R d6A , -OC(O)R a6A , -OC(O)NR c6A R d6A , -OC(O)OR a6A , -NR c6A C(O)R a6A , -NR c6A C(O)OR a6A , -NR c6A C(O)NR c6A R d6A , -NR c6A S(O)2R b6A , -NR c6A S(O)R b6A , -NR c6A S(O)NR c6A R d6A , -S(O)R b6A , -S(O)2R b6A , -S(O)NR c6A R d6A and -S(O)2NR c6A R d6A , wherein the C 6A of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heteroalkyl)-C 1-4 alkyl and (5- or 6-membered heteroaryl)-C 1-4 each of the alkyls is optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; Each R a6A 、R b6A 、R c6A and R d6A is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl, where the C a6A 、R b6A 、R c6A and R d6A of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, (4- to 7-membered heterocycloalkyl)-C 1-4 alkyl and (5- to 6-membered heteroaryl)-C 1-4 alkyl is each optionally substituted with 1, 2, 3 or 4 independently selected R G substituents; or Alternatively, any R attached to the same N atom c6A and R d6A together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl group, where the 4- to 10-membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; R 8 selected from H, a halogen group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; and Each R G is independently selected from H, OH, CN, halogen, oxo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, cyano-C 1-4 alkyl, HO-C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heteroalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamoyl, C 1-3 alkylcarbamoyl, di(C 1-3 alkyl)carbamoyl, carboxyl, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, aminocarbonyloxy, C 1-3 alkylaminocarbonyloxy, di(C 1-3 alkyl)aminocarbonyloxy, C 1-3 alkylsulfonylamino, sulfamoyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, sulfamoylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino and di(C 1-3 alkyl)aminocarbonylamino.

60. The compound according to claim 1, wherein the compound of formula I is a compound of formula II: or a pharmaceutically acceptable salt thereof.

61. The compound according to claim 1, wherein the compound of formula I is a compound of formula IIa: or a pharmaceutically acceptable salt thereof.

62. The compound according to claim 1, wherein the compound of formula I is a compound of formula III: or a pharmaceutically acceptable salt thereof.

63. The compound according to claim 1, wherein the compound of formula I is a compound of formula IIIa: or a pharmaceutically acceptable salt thereof.

64. The compound according to claim 1, wherein the compound of formula I is a compound of formula IV: or a pharmaceutically acceptable salt thereof.

65. The compound according to claim 1, wherein the compound of formula I is a compound of formula IVa: or a pharmaceutically acceptable salt thereof.

66. The compound according to claim 1, selected from: N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(4-(2-Chloro-5-fluorophenoxy)-3-(methylamino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-((5-chloropyridin-3-yl)oxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-((2-chloro-5-fluorophenyl)amino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorobenzyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-((2-chloro-5-fluorophenoxy)methyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-ethyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-morpholino-2-oxoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-methyl-1H-pyrazol-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(pyridin-3-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-phenyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)benzo[b]thiophene-3-carboxamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-5-fluoro-3-hydroxy-3-(trifluoromethyl)indoline-1-carboxamide; N-(3-Amino-5-(2-chloro-5-fluorophenoxy)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(morpholinomethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; and N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; or a pharmaceutically acceptable salt thereof.

67. The compound according to claim 1, selected from: N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(hydroxymethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(1-isopropyl-1H-pyrazol-4-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-(4-carbamoylphenyl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(pyrimidin-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(cyanomethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(6-Amino-7-(2-chloro-5-fluorophenoxy)-2-oxo-2,3-dihydro-1H-pyrazolo[1,5,4-de]quinoxalin-8-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-1-(2-amino-2-oxoethyl)-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-(2-cyanoethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-(2-Aminoacetamido)-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-8-oxo-6,7,8,9-tetrahydro-[1,4]diazeto [6,7,1-hi]indazol-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(pyridin-2-ylethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((tetrahydro-2H-pyran-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-(3-amino-3-methylbut-1-yn-1-yl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((tetrahydrofuran-3-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(cyclopropylethynyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-((1-hydroxycyclopropyl)ethynyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-((1-(hydroxymethyl)cyclopropyl)ethynyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-((1-aminocyclopropyl)ethynyl)-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((3-methyloxetan-3-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-ethynyl-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methyl-1H-pyrazol-3-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(3-hydroxyprop-1-yn-1-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methyl-1H-imidazol-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-((1-methylpiperidin-4-yl)ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-((1-acetylpiperidin-4-yl)ethynyl)-3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-Chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-3-(methylamino)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-Chloro-4-(2-chloro-5-fluorophenoxy)-3-(dimethylamino)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-1-(2-(azetidin-1-yl)ethyl)-7-chloro-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (E)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethenyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (Z)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethenyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-cyanoethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-chloro-5-fluorobenzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-(trifluoromethyl)benzamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)nicotinamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)benzo[b]thiophene-3-carboxamide; N-(3-Amino-7-chloro-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)indoline-1-carboxamide; 3-Amino-4-(2-chloro-5-fluorophenoxy)-N-ethyl-5-(3-fluoro-5-(trifluoromethyl)benzamido)-1-methyl-1H-indazole-7-carboxamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-7-(2-hydroxyethyl)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-(2-hydroxyethyl)-7-(pyridin-2-yl ethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-methyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-cyclopropyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(2-Amino-3-(2-chloro-5-fluorophenoxy)-7-cyclobutyl-8-oxo-7,8-dihydro-6H-pyrazolo[4,5,1-ij]quinazolin-4-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-7,8,9,10-tetrahydrocyclopenta[c]pyrazolo[4,5,1-ij]quinolin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(4-Amino-3-(2-chloro-5-fluorophenoxy)-7-oxo-8,9,10,11-tetrahydro-7H-pyrazolo[4,5,1-de]phenanthridin-2-yl)-3-fluoro-5-(trifluoromethyl)benzamide; (E)-N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(2-(pyridin-2-yl)vinyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(2-(pyridin-2-yl)ethyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(3-Amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-7-(piperidin-2-ylethynyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; N-(7-((1-Acetylpiperidin-2-yl)ethynyl)-3-amino-4-(2-chloro-5-fluorophenoxy)-1-methyl-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; 2-((3-Amino-4-(2-chloro-5-fluorophenoxy)-5-(3-fluoro-5-(trifluoromethyl)benzamidoyl)-1-methyl-1H-indazol-7-yl)ethynyl)-N-methylpiperidine-1-carboxamide N-(3-Amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1-(methylsulfonyl)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; and N-(1-Acetyl-3-amino-7-bromo-4-(2-chloro-5-fluorophenoxy)-1H-indazol-5-yl)-3-fluoro-5-(trifluoromethyl)benzamide; or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising the compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

69. A method of inhibiting the activity of PI3Kα kinase, which comprises contacting the kinase with the compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof.

70. A method of treating a PI3Kα-mediated disease or disorder in a patient, which comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof.

71. The method according to claim 70, wherein the disease or disorder is cancer.

72. The method according to claim 71, wherein the cancer is selected from breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, and head and neck cancer.

73. The method according to claim 70, wherein the disease or disorder is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis / skeletal and spinal syndrome) or PIK3CA-related overgrowth syndrome (PROS).

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