Spirocyclic KRAS g12c inhibitors for treating disease

Abstract

The present disclosure relates to spirocyclic compounds targeting KRAS G12C, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.

Description

SPIROCYCLIC KRAS G12C INHIBITORS FOR TREATING DISEASE RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 761,695, filed February 21, 2025, and U. S. Provisional Application No. 63 / 715,281, filed November 1, 2024, the entire disclosure of each of which is incorporated herein by reference.TECHNICAL FIELD

[0002] The present disclosure relates to spirocyclic compounds targeting KRAS G12C, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat disease, such as cancer.BACKGROUND

[0003] Ras is a GTP-binding protein and regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. H-Ras, K-Ras, and N-Ras are the main members of Ras superfamily, which are tightly regulated by factors that switch on / off the GTPase activity. Somatic mutations at codons 12, 13, and 61 in the RAS genes are associated with about 16% of all human cancers and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-related cancers (Prior I. A. et al, A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457-2467), including 86-96% in pancreatic cancers, 40-50% in colorectal cancers, and 27-39% in lung adenocarcinomas (Kessler D. et al. Drugging an undruggable pocket on KRAS Proc Natl Acad Sci USA. 2019, 116(32): 15823-15829). Mutated RAS is locked in the constitutively activated GTP bound state and facilitates enhanced Ras signaling in cancer cells.

[0004] Direct targeting of mutant KRAS has previously proven challenging because of its high affinity for nucleotide and the lack of tractable binding pockets for small-molecule inhibitors. Recent successful inhibition of the KRAS G12C mutant by covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in KRAS G12C mutated lung cancer patients has shed light on targeting KRAS mutants for therapeutic invention. However, despite the FDA approval of sotorasib and adagrasib, certain liabilities of these compounds still exist.

[0005] Therefore, there is unmet medical need to develop novel covalent chemical modifiers that can selectively target KRAS G12C with good in vivo efficacy, safety, and predicted human oral pharmacokinetic profile for treating patients with KRAS mutant cancers.SUMMARY

[0006] In one aspect, the disclosure relates to a compound of the formula I,

[0007] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is 5- or 6-membered heteroaryl;

[0008] ring B is phenyl or 5- or 6-membered heteroaryl;

[0009] ring C is Cb-Cio aryl or 5- to 10-membered heteroaryl; provided that when ring C is a 6-membered heteroaryl, then ring B is phenyl;

[0010] X is a bond, -O-, -S-, -S(O)-, -S(O)2-, or -NR8-;

[0011] Y is a bond, -O-, -S-, or -NR10-;

[0012] each of X1, X2, and X3is independently an -O-, -S-, -S(O)2-, or -CH2-, provided that no more than one of X1, X2, and X3is a -O-, -S-, or -S(O)2-;

[0013] each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, Ci-Cg alkyl, C2-G, alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, C,-C|. aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2R‘Rb, -P(O)NRaRb, -P(O)2NRaRh, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, each R1, when present and bonded to a nitrogen atom, is deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Co alkyl, O-C alkenyl, C_-G alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, C1-C6 haloalky 1, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, -Ci-C6alkyl-C(O)ORe, Ci-Ce alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re,-OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-Cbalkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Ce alkyl-ORe, Ci-Cealkyl-SRe, Ci-Ce alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0014] R2, when covalently attached to a heteroatom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -C(=NRg)NRgRh, or an -R9, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cbcycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, -R9, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NR8S(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; or R2, when covalently attached to a carbon atom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Ciu aryl, 5- to 10-membered heteroaryl, -OR8, -OC(O)Rg, -OC(O)NRgRh, -OC(=NRg)NR8Rh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NR8Rh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgC(=NRh)NRsRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)OR8, -C(O)NRgRh, -C(=NRg)NRgRh, -PR8Rh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NR8Rh, -P(O)ORg, -P(O)2ORg, or -R9, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, -R9, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2RS, -OS(O)NR8Rh, -OS(O)2NR8Rh, -SRg, -S(O)R8, -S(O)2R8, -S(O)NRgRh, -S(O)2NR8Rh, -NR8Rh, -NR8C(O)Rh, -NR8C(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2;

[0015] each R~ and R4, when present, is independently deuterium, halogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cg-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, 5-to 10-membered heteroaryl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRaS(O)2NRaRd, -C(O)Ra, -C(O)ORC, -C(O)NRcRd, -C(=NR JNR R1, -PR R1, -P(O)RcRd, -P(O)2R R1, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2; or two R?or two R4, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl; or two R3or two R4, when present, taken together with the carbon atom to which they are attached combine to form an oxo group or a C2-Cg alkenyl group; wherein each hydrogen atom in Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, C,-C|. aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, Ci-C6haloalkyl, -ORe. -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0016] each R5, when present, is independently deuterium, halogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cs-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two R5, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to10-membered heteroaryl; wherein each hydrogen atom in Ci-Cg alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl,-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0017] R6is Ci-Ce alkyl, C2-Ce alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ct, alkylene-(4- to 10-membered heterocycloalkyl), Cg-Cio aryl, -Ci-Ce alkylene-(Cb-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(Ce-Cio aryl), 5- to 10-membered heteroaryl, and -Ci-Ce alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, -Ci-Ce alkylene-(O-Ci-C6 alkyl), -OCi-Ce alkylene-(O-Ci-C6 alkyl), -Ci-C8 alkylene-(O-Re), Ce-Cio aryl, -Ci-Ce alkylene-(Ce-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0018] R7, when present, is H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4-to 10-membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0019] R8, when present, is H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl;wherein each hydrogen atom in Ci-Ce alkyl, C2-Cg alkenyl, C2-Ce alkynyl, Ch-C. cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C& alkyl, Ci-Ce haloalkyl, Ci-C8 alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0020] R9is selected from the group consisting of -C(O)(CH=CH2), -S(O)(CH=CH2), -S(O)2(CH=CH2), -C(NH)(CH=CH2), -C(NR‘)(CH=CH2), -C(0)(OCH), -S(0)(OCH), -S(O)2(C=CH), -C(NH)(C=CH), -C(NR‘)(C=CH), -C(O)(oxiranyl), -S(O)(oxiranyl), -S(O)2(oxiranyl), -C(NH)(oxiranyl), -C(NR’)(oxiranyl), -C(O)(Ci-Ce alkyl), -S(O)(Ci-Ce alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(CI-C6alkyl), and -QNR^Ci-Ce alkyl), wherein each hydrogen atom in CH=CH2or C=CH is independently optionally substituted with deuterium, halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two hydrogen atoms on adjacent carbon atoms in CH=CH2optionally combine to form a C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein one hydrogen atom on the a- or -carbon atom of -C(O)(Ci-Ce alkyl), -S(O)(Ci-Ce alkyl), -S(O)2(Ci-Ce alkyl), -C(NH)(Ci-Ce alkyl), and -C(NR‘)(CI-C6 alkyl) is substituted with a fluoro, chloro, or CN, and the remaining hydrogen atoms in -C(O)(Ci-Ce alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(CI-C6alkyl), and - NR^Ci-Ce alkyl) are independently optionally substituted with deuterium, halogen, Ci-Ct, alkyl, C1-C0 haloalkyl, Ci-C, alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; andwherein each hydrogen atom in oxiranyl is independently optionally substituted with deuterium, halogen, Ci-Cg alkyl, Ci-Ce haloalkyl, Ci-Ce alkyl-ORe, Ci-Cg alkyl-SRe, Ci-Ce alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0021] R10, when present, is H, deuterium, Ci-C8 alkyl, C2-Ce alkenyl, C -Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-C alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0022] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, Ci-Cg alkyl, Ci-Ce alkyl-(O-Ci-C6 alkyl), C -C& alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci-Ce alkylene-tC3-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Cg-Cio aryl, C1-C0 alkylene-(Cg-Cio aryl), 5-to 10-membered heteroaryl, and Ci-C, alkylene-(5- to 10-membered heteroaryl); or two of Raand Rb, or R and Rd, or Reand Rf, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cb-Ciu aryl, or 5- to 10-membered heteroaryl; or -Reand -Rftaken together with the carbon atom to which they are attached form an oxo group or a C -C, alkenyl; wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-Ce alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, Ci-Cg alkylene-(C3-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cioaryl, Ci-Ce alkylene-(G,-Cioaryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl) is independently optionallysubstituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-Ce alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-Ce alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(Ci-Cbalkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or C1-C5 alkyl)2, -P(H or C1-C5 alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-Ce alkyl)2, -P(O)OCi-Ce alkyl, -P(O)2OCi-Ce alkyl, -CN, or -NO2, wherein each hydrogen atom in C1-C5 alkyl, Ci -Ce haloalkyl, C--C, cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;

[0023] each Rsand Rhis independently selected from the group consisting of H, deuterium, C1-C& alkyl, Ci-Cbalkyl-(O-Ci-Ce alkyl), C2-Cbalkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, Ci-Ce alkylene-(C3-Ce cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cioaryl, Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl); or two of Rgand Rh, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cioaryl, or 5- to 10-membered heteroaryl; or -Rgand -Rhtaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-C6 alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-Cb alkenyl, C2-Ce alkynyl, Cs-Ce cycloalkyl, Ci-Ce alkylene-(C3-Ce cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, Ci-Ce alky lene-(Ce-C 10 aryl), 5- to 10-membered heteroaryl, andCi-Cealkylene-(5-to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -R9, -OH, -OCi-Ce alkyl, -OR9, -OC(O)Ci-C6 alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OC(O)N(H or Ci-C6alkyl)(R9), -OS(O)Ci-C6alkyl, -OS(O)2CI-C3 alkyl, -OS(O)N(H or Ci-Ce alkyl)2, -OS(O)N(H or Ci-C6alkyl)(R9), -OS(O)2N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)(R9), -SCi-C6alkyl, -SR9, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)N(H or Ci-C6alkyl)(R9) -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)(R9), -N(H or Ci-C6alkyl)C(O)-Ci-C6alkyl, -N(H or Ci-Ce alkyl)C(O)OCi-C6alkyl, -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)S(O)Ci-C6alkyl, -N(H or Ci-C6alkyl)S(O)2Ci-C6alkyl, -N(H or Ci-C6alkyl)S(O)N(H or Ci-Ce alkyl)2, -N(H or Ci-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OC1-C alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2R9, -P(O)(H or Ci-C6alkyl)2, -P(O)(H or Ci-C6alkyl)R9, -P(O)2(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)R9, -P(O)N(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)(R9), -P(O)2N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6alkyl)(R9), -P(O)OCi-C6alkyl, -P(O)OR9, -P(O)2OCi-C6alkyl, -P(O)2R9, -CN, or -NO2. wherein each hydrogen atom in Ci-Cbalkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C,-,-C|. aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;

[0024] each R1, when bonded to a nitrogen atom, is independently Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CN, or -OH, and each R1, when bonded to a carbon atom, is independently deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-Ce alkyl, -OC(O)C1-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(O)(H or Ci-Ce alkyl), -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)?, -P(O)2N(H or Ci-Ce alkyl)2, -P(O)OCi-Ce alkyl, -P(O)2OCi-Ce alkyl, -CN, or -NO2; or two of R1, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a Ci-C cycloalkyl, 4- to 10-membered heterocycloalkyl, C,-CC aryl, or 5- to 10-membered heteroaryl; or two -R1, taken together with the carbon atom to which they are attached, form an oxo group or a C2-C6 alkenyl;

[0025] provided that R2comprises one or more R9;

[0026] ml is 0, 1, or 2;

[0027] m2 is 0, 1, 2. or 3;

[0028] m3 is 0 or 1;

[0029] nl is O, 1, 2, 3, or 4;

[0030] n2 is 0, 1, 2, 3, or 4;

[0031] p is 0, 1 or 2; and

[0032] q is 1 or 2.

[0033] In another aspect, the disclosure provides a compound of the formula II,

[0034] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, R1, R2, R3, R4, R5, R, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0036] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0037] In another aspect, the disclosure provides a compound of the formula IV,

[0038] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R1, R4, R5a, R6, R7, X, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0039] In another aspect, the disclosure provides a compound of the formula V,

[0040] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R, R7, X, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0041] In another aspect, the disclosure provides a compound of the formula VI,

[0042] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Z1, Z2, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0043] In another aspect, the disclosure provides a compound of the formula VII,

[0044] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Z1, Z2, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0045] In another aspect, the disclosure provides a compound of the formula VIII,VIII

[0046] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R6, X, Y, Z3, Z4, Y1, Y2, nl, n2, p, and q are as described herein.

[0047] In another aspect, the disclosure provides a compound of the formula IX,

[0048] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R, X, Y, Z3, Z4, Y1, Y2, nl, n2, p, and q are as described herein.

[0049] In another aspect, the disclosure provides a compound of the formula X,

[0050] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0051] In another aspect, the disclosure provides a compound of the formula XI,

[0052] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0053] In another aspect, the disclosure provides a compound of the formula XII,

[0054] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R’, X, Y1, Y2, Z1, Z2, ml, nl, n2, p, and q are as described herein.

[0055] In another aspect, the disclosure provides a compound of the formula XIII,

[0056] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, X, Y1, Y2, Z1, Z2, ml, nl, n2, p, and q are as described herein.

[0057] In another aspect, the disclosure provides a compound of the formula XIV,

[0058] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y1, Y2, Z1, Z2, Z3, Z4, nl, n2, p, and q are as described herein.

[0059] In another aspect, the disclosure provides a compound of the formula XV,

[0060] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y, Y1, Y2, Z1, Z2, Z3, Z4, nl, n2, p, and q are as described herein.

[0061] In another aspect, the disclosure provides a compound of the formula XVI,

[0062] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, R7, X, Y, ml, nl, n2, p, and q are as described herein.

[0063] In another aspect, the disclosure provides a compound of the formula XVII,

[0064] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0065] In another aspect, the disclosure provides a compound of the formula XVIII,

[0066] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0067] In another aspect, the disclosure provides a compound of the formula XIX,

[0068] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0069] In another aspect, the disclosure provides a compound of the formula XX,

[0070] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0071] In another aspect, the disclosure provides a compound of the formula XXI,

[0072] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0073] In another aspect, the disclosure provides a compound of the formula XXII,XXII

[0074] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0075] In another aspect, the disclosure provides a compound of the formula XXIII,

[0076] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R’, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0077] In another aspect, the disclosure provides a compound of the formula XXIV,

[0078] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0079] In another aspect, the disclosure provides a compound of the formula XXV,XXV

[0080] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0081] In another aspect, the disclosure provides a compound of the formula XXVI,

[0082] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R, R, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0083] In another aspect, the disclosure provides a compound of the formula XXVII,

[0084] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0085] In certain embodiments, ring C, or an isotopically labeled form thereof, is of the formula

[0086] wherein,

[0087] “ ” is a point of covalent attachment to ring A; and

[0088] Rlais H or R1.

[0089] In certain embodiments, the compound, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprises a portion of the formula

[0090] wherein is a point of covalent attachment to ring A.

[0091] In certain embodiments, the compound, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprises a portion of the formula

[0092] wherein “^~v” is a point of covalent attachment to ring A.

[0093] In certain embodiments, the compound, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprises a portion of the formula

[0094] wherein “ ■~w ’’ is a point of covalent attachment to ring A.

[0095] In certain embodiments of the above aspects, the compound of Formula (I)-(XXVII) is a compound selected from those species described or exemplified in the detailed description below.

[0096] In further aspects, the disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXVII), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof. Pharmaceutical compositions according to the disclosure may further comprise a pharmaceutically acceptable excipient.

[0097] In further aspects, the disclosure relates to a compound of Formula (I)-(XXVII), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0098] In further aspects, the disclosure relates to a method of treating disease, such as cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I)-(XXVII), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0099] In further aspects, the disclosure relates to use of a compound of Formula (I)-(XXVII), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of disease, such as cancer, and the use of such compounds and salts for treatment of such diseases.

[0100] In further aspects, the disclosure relates to a method of inhibiting a Ras, such as K-Ras, comprising contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I)-(XXVII), an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.

[0101] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0102] 1. A compound of the formula I, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,

[0103] wherein

[0104] ring A is 5- or 6-membered heteroaryl;

[0105] ring B is phenyl or 5- or 6-membered heteroaryl;

[0106] ring C is Cg-Cio aryl or 5- to 10-membered heteroaryl; provided that when ring C is a 6-membered heteroaryl, then ring B is phenyl;

[0107] X is a bond, -O-, -S-, -S(O)-, -S(O)2-, or -NR8-;

[0108] Y is a bond, -O-, -S-, or -NR10-;

[0109] each of X1, X2, and X3is independently an -O-, -S-, -S(O)2-, or -CH2-, provided that no more than one of X1, X2, and X3is a -O-, -S-, or -S(O)2-;

[0110] each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, Ci-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, each R1, when present and bonded to a nitrogen atom, is deuterium, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6 haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re. -Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf,-NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORe, Ci-Cealkyl-SRe, Ci-Ce alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0111] R2, when covalently attached to a heteroatom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -C(=NRg)NRgRh, or an -R9, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -R9, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh. -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; or R2, when covalently attached to a carbon atom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OC(=NRg)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2R8, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NR8C(=NRh)NR8Rh, -NR8S(O)Rh, -NRgS(O)2Rh, -NR8S(O)NR8Rh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -C(=NRg)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, or -R9, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -R9, -Rg, -Rh, -OR8,-OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NR8S(O)Rh, -NRgS(O)2Rh, -NR8S(O)NR8Rh, -NR8S(O)2NRgRh, -C(O)R8, -C(O)ORg, -C(O)NR8Rh, -PR8Rh, -P(O)RgRh, -P(O)2R8Rh, -P(O)NR8Rh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2;

[0112] each R3and R4, when present, is independently deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5-to 10-membered heteroaryl. -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)RC, -OS(O)2RC, -OS(O)NRcRd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2Rc, -S(O)NRcRd, -S(O)2NRcRd, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRcC(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRc)NRcRd, -PRcRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2; or two R3or two R4, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl; or two R3or two R4, when present, taken together with the carbon atom to which they are attached combine to form an oxo group or a C2-Ce alkenyl group: wherein each hydrogen atom in Ci-C8 alkyl, C2-Ce alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-C6alkyl, Ci-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0113] each R5, when present, is independently deuterium, halogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two R5, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-memberedheterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6haloalkyl, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0114] R6is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(Cs-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-C8 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, -Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and -Ci-C8 alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-C6 alkyl, -Ci-Ce alkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-C6 alkyl), -Ci-Cg alkylene-(O-Re), Cg-Cio aryl, -Ci-Cg alkylene-(Ce-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0115] R7, when present, is H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4-to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe. -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0116] R8, when present, is H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl isindependently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-Cg alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0117] R9is selected from the group consisting of -C(O)(CH=CH2), -S(O)(CH=CH2), -S(O)2(CH=CH2), -C(NH)(CH=CH2), -C(NR‘)(CH=CH2), -C(O)(C=CH), -S(O)(C=CH), -S(O)2(C=CH), -C(NH)(CCH), -C(NR')(C≡CH), -C(O)(oxiranyl), -S(O)(oxiranyl), -S(O)2(oxiranyl), -C(NH)(oxiranyl), -C(NR‘)(oxiranyl), -C(O)(Ci-Cg alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-Ce alkyl), -C(NH)(Ci-Cg alkyl), and -C(NR1)(Ci-C6 alkyl), wherein each hydrogen atom in CH=CH2or C=CH is independently optionally substituted with deuterium, halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re. -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two hydrogen atoms on adjacent carbon atoms in CH=CH2optionally combine to form a C2-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein one hydrogen atom on the a- or -carbon atom of -C(O)(Ci-Cg alkyl), -S(O)(Ci-Cg alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(Ci-Cg alkyl), and -C(NRf)(Ci-C6 alkyl) is substituted with a fluoro, chloro, or CN, and the remaining hydrogen atoms in -C(O)(Ci-Ce alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-Cg alkyl), -C(NH)(Ci-Cg alkyl), and -C(NR‘)(Ci-Cg alkyl) are independently optionally substituted with deuterium, halogen, Ci-C alkyl, Ci-C haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-Cgalkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and wherein each hydrogen atom in oxiranyl is independently optionally substituted with deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Cg alkyl-ORe, Ci-Cg alkyl-SRe, Ci-Cgalkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0118] R10, when present, is H, deuterium, Ci-C6 alkyl, C2-C6 alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-C. alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;

[0119] each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, Ci-C6 alkyl, Ci-C6 alkyl-(O-Ci-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci-Ce alkylene-(C2-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, Ci-Ce alkylene-(C6-Cio aryl), 5-to 10-membered heteroaryl, and Ci-Cg alkylene-(5- to 10-membered heteroaryl); or two of Raand Rb, or Rcand Rd, or Reand Rf, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; or -Reand -Rftaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-Cg alkyl, Ci-Cg alkyl-(O-Ci-C6 alkyl), C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Ci-C6 alkylene-(C3-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and Ci-C6 alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-C6alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)C1-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(O)(H or Ci-C8 alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6 alkyl)2, -P(O)2N(H or Ci-C6 alkyl)2, -P(O)OCi-C6 alkyl, -P(O)2OCi-C6 alkyl, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;

[0120] each Rgand Rhis independently selected from the group consisting of H, deuterium, Ci-C6 alkyl, Ci-C6 alkyl-(O-Ci-C6 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci-C6 alkylene-(C3-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl); or two of Rgand Rh, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or -Rgand -Rhtaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ci-C6 alkylene-(C3-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 aryl, Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5-to 10-membered heteroaryl, -R9, -OH, -OCi-Ce alkyl, -OR9, -OC(O)Ci-Ce alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OC(O)N(H or Ci-C6alkyl)(R9), -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6 alkyl)2, -OS(O)N(H or Ci-C6alkyl)(R9), -OS(O)2N(H or C1-C6 alkyl)2, -OS(O)2N(H or Ci-C6alkyl)(R9), -SCi-C6 alkyl, -SR9, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)N(H or Ci-C6alkyl)(R9) -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)(R9), -N(H or Ci-C6alkyl)C(O)-Ci-C6alkyl, -N(H or Ci-C6alkyl)C(O)OCi-C6alkyl, -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)S(O)Ci-C6alkyl, -N(H or Ci-C6alkyl)S(O)2Ci-C6 alkyl, -N(H or Ci-C6alkyl)S(O)N(H or C1-C6 alkyl)2, -N(H or Ci-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl,-C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2R9, -P(O)(H or Ci-C6alkyl)2, -P(O)(H or Ci-C6alkyl)R9, -P(O)2(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6 alkyl)R9, -P(O)N(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6 alkyl)(R9), -P(O)2N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6 alkyl)(R9), -P(O)OCi-C6alkyl, -P(O)OR9, -P(O)2OCi-C6alkyl, -P(O)2R9, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;

[0121] each Ri, when bonded to a nitrogen atom, is independently Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -CN, or -OH, and each R1, when bonded to a carbon atom, is independently deuterium, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-Ce alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6 alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-Cbalkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6 alkyl)2, -P(O)OCi-C6 alkyl, -P(O)2OCi-C6 alkyl, -CN, or -NO2; or two of R1, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or two -R1, taken together with the carbon atom to which they are attached, form an oxo group or a C2-C6 alkenyl;

[0122] provided that R2comprises one or more R9;

[0123] ml is 0, 1, or 2;

[0124] m2 is 0, 1, 2, or 3;

[0125] m3 is 0 or 1;

[0126] nl is 0, 1, 2, 3, or 4;

[0127] n2 is 0, 1, 2, 3, or 4;

[0128] p is 0, 1 or 2; and

[0129] q is 1 or 2.

[0130] 2. The compound of clause 1, having the formula II

[0131] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0132] 3. The compound of clause 1 or 2, having the formula III

[0133] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0134] 4. The compound of clause 1 or 2, having the formula IV

[0135] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0136] each R5ais independently H or R5; and

[0137] each of Z1and Z2is independently N, CH, or CR5.

[0138] 5. The compound of any one of the preceding clauses, having the formula V

[0139] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0140] each R5ais independently H or R5; and

[0141] each of Z1and Z2is independently N, CH, or CR5.

[0142] 6. The compound of any one of clauses 1, 2, or 4, having the formula VI

[0143] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0144] each R~ is independently H or R5,

[0145] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0146] each of Z1and Z2, is independently N, CH, or CR5;

[0147] m3 is 0 or 1; and1

[0148] thepresent in ring A represents the aromaticity of ring A.

[0149] 7. The compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, having the formula VII

[0150] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0151] each R5ais independently H or R5;

[0152] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0153] each of Z1and Z2is independently N, CH, or CR5;

[0154] m3 is 0 or 1; andi )

[0155] the present in ring A represents the aromaticity of ring A.

[0156] 8. The compound of any one of clauses 1, 2, 4, or 6, having the formula VIII

[0157] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0158] each R~ is independently H or R5;

[0159] each of Y1and Y2is independently N, O, S, CH, or CR', provided that at least one of Y1and Y2is N, O, or S;

[0160] each of Z1and Z2is independently N, CH, or CR5;

[0161] Z3and Z4are each independently N, CH, or CR1; andi' ')

[0162] the present in ring A and ring C represents the aromaticity of ring A and ring C.

[0163] 9. The compound of any one of the preceding clauses, having the formula IX

[0164] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0165] each R5ais independently H or R5;

[0166] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0167] each of Z1and Z2is independently N, CH, or CR5;

[0168] Z3and Z4are each independently N, CH, or CR1; and1

[0169] thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0170] 10. The compound of any one of clauses 1, 2, or 4, having the formula X

[0171] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Z1and Z2is independently N, CH, or CR5.

[0172] 11. The compound of any one of clauses 1 to 5, or 10, having the formula XI

[0173] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Z1and Z2, is independently N, CH, or CR5.

[0174] 12. The compound of any one of clauses 1, 2, 4, 6, or 10, having the formula XII

[0175] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0176] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and

[0177] each of Z1and Z2is independently N, CH, or CR5;

[0178] wherein thepresent in ring A represents the aromaticity of ring A.

[0179] 13. The compound of any one of clauses 1 to 7, or 10 to 12, having the formula XIII

[0180] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0181] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and

[0182] each of Z1and Z2is independently N, CH, or CR5;

[0183] wherein thepresent in ring A represents the aromaticity of ring A.

[0184] 14. The compound of any one of clauses 1, 2, 4, 6, 8, 10, or 12, having the formula XIV

[0185] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0186] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0187] each of Z1and Z2is independently N, CH, or CR5; and

[0188] Z3and Z4are each independently N, CH, or CR1;

[0189] wherein thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0190] 15. The compound of any one of the preceding clauses, having the formula XV

[0191] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0192] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0193] each of Z1and Z2is independently N, CH, or CR5; and

[0194] Z3and Z4are each independently N, CH, or CR1;

[0195] wherein thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0196] 16. The compound of clause 1 or 2, having the formula XVI

[0197] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R\

[0198] 17. The compound of any one of clauses 1, 2, 3, or 16, having the formula XVII

[0199] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0200] each R is independently H or R5; and

[0201] each of Z1and Z2is independently N, CH, or CR4.

[0202] 18. The compound of any one of clauses 1, 2, or 16, having the formula XVIII

[0203] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0204] each R~ is independently H or R5,

[0205] one of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and

[0206] thepresent in ring A represents the aromaticity of ring A.

[0207] 19. The compound of any one of clauses 1, 2, 3, 16, 17, or 186, or a pharmaceutically acceptable salt thereof, having the formula XIX

[0208] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0209] each R'1is independently H or R5;

[0210] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and

[0211] the present in ring A represents the aromaticity of ring A.

[0212] 20. The compound of any one of clauses 1, 2, 6, 16, or 18 having the formula XX

[0213] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0214] each R5ais independently H or R5;

[0215] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0216] Z3and Z4are each independently N, CH, or CR1; and

[0217] thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0218] 21. The compound of any one of clauses 1, 2, 3, 6, or 16 to 20, having the formula XXI

[0219] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0220] each R5ais independently H or R3;

[0221] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0222] Z3and Z4are each independently N, CH, or CR1; andi:

[0223] thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0224] 22. The compound of clause 1 or 2, having the formula XXII

[0225] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0226] 23. The compound of any one of clauses 1 to 3, having the formula XXIII

[0227] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0228] 24. The compound of any one of clauses 1, 2, or 22, having the formula XXIV

[0229] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0230] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and

[0231] wherein thepresent in ring A represents the aromaticity of ring A.

[0232] 25. The compound of any one of clauses 1 to 3, or 22 to 24, having the formula XV

[0233] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0234] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and» I

[0235] wherein thepresent in ring A represents the aromaticity of ring A.

[0236] 26. The compound of any one of clauses 1, 2, 22, or 24, having the formula XXVI

[0237] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0238] each of Y1and Y2is independently N, O, S. CH, or CR7, provided that at least one of Y1and Y2is N, O. or S;

[0239] Z3and Z4are each independently N, CH, or CR1; and

[0240] wherein thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0241] 27. The compound of clauses 1 to 3, or 22 to 26, having the formula XXVII

[0242] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein

[0243] each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;

[0244] Z3and Z4are each independently N, CH, or CR1; and

[0245] wherein thepresent in ring A and ring C represents the aromaticity of ring A and ring C.

[0246] 28. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is of the formula

[0247] wherein,” is a point of covalent attachment to ring A; and

[0249] Rlais H or R1.

[0250] 29. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is O.

[0251] 30. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is NR8.

[0252] 31. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula

[0253] 32. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8is H or methyl.

[0254] 33. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y is NR10.

[0255] 34. The compound of clause 33, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R10is H or methyl.

[0256] 35. The compound of any one of clauses 1 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula

[0257] wherein “ ” is a point of covalent attachment to ring A.

[0258] 36. The compound of clause 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

[0259] 37. The compound of clause 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is -NR8-.

[0260] 38. The compound of any one of clauses 1 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula

[0261] wherein “^wv” is a point of covalent attachment to ring A.

[0262] 39. The compound of any one of clauses 38, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8is H or methyl.

[0263] 40. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is 4- to 10-membered heterocycloalkyl, -Ci-Cc. alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(C6-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Cbalkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-C aryl, -Ci-Ce alkylene-(Ce-Cio aryl), 5-to 10-membered heteroaryl, and -Ci-Ce alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Cg alkyl, -Ci-Ce alkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-C<, alkyl), -Ci-Ce alkylene-(O-Re), Ce-Cio aryl, -Ci-Ce alkylene-(Ce-Cio aryl), haloalkyl, Cs-Ce cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf. -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0264] 41. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, -Ci-Ce alkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-Ce alkyl), -Ci-Ce alkylene-(O-Re), Ce-Cio aryl, -C1-G5 alkylene-(Cb-Cio aryl), haloalkyl, C2-Cbcycloalkyl, 5-to 10-membered heteroaryl, -Ci-Ce alkylene-(5- to 10-membered heterocycloalkyl), -ORC, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf,-NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0265] 42. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is of the formula

[0266] wherein “” is a point of covalent attachment to X.

[0267] 43. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is of the formula

[0268] wherein “•~w" is a point of covalent attachment to X.

[0269] 44. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein two R3, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C -Cbcycloalkyl.

[0270] 45. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R3, when present, is independently deuterium, halogen, Ci-Cg alkyl, -ORa, -SRa, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -CN, or -NO2, wherein each hydrogen atom in Ci-Cg alkyl, C2-Ce alkenyl, C2-C2alkynyl, C3-C6 cycloalkyl, C,-C|. aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C, alkyl, Ci-C6haloalkyl, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NRcS(O)2NRcRf, -C(O)RC, -C(O)ORC, -C(O)NRcRf, -PRcRf, -P(O)RcRf, -P(O)2RcRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0271] 46. The compound of any one of the preceding clauses, an isotopically labeled formthereof, or a pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently deuterium, halogen, -NRaRb, or -CN.

[0272] 47. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently deuterium, halogen, -NH2, or -CN.

[0273] 48. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y1, when present, is O.

[0274] 49. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y2, when present, is N.

[0275] 50. The compound of any one of clauses 1 to 47, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y1, when present, is N.

[0276] 51. The compound of any one of clauses 1 to 47, or 50, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y2, when present, is O.

[0277] 52. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein nl is 0 or 2.

[0278] 53. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein n2 is 0.

[0279] 54. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m3 is 0.

[0280] 55. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0281] 56. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0282] 57. The compound of any one of clauses 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q is 2.

[0283] 58. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Z1, when present, is N.

[0284] 59. The compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Z2, when present, is N.

[0285] 60. The compound of clause 1, selected from the group consisting of (l'R)-7'-amino-3-(4- { ( 15)- 1 -[(25)- 1 -methylpyrrolidin-2-yl]ethoxy }-6-{ [l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[ 1,2]benzoxazole-7, T-naphthalene]-8'-carbonitrile;

[0286] (TR)-7'-amino-3-(4-{[2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4 / / -spiro[[l,2]benzoxazole-7,r-naphthalene]-8’-carbonitrile;

[0287] (rS)-6'-amino-3-(4-{(lS)-l-[(2S,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6- {[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile;

[0288] (r7?)-7'-amino-3-(4-{(l. S')-l-[(2>S',4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6- {[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7,l'-naphthalene]-8'-carbonitrile;

[0289] (l'lS')-6'-amino-3-(4-{(llS')-l-[(2lS')-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2’,3',5,6-tetrahydro-4H-spiro[[ l,2]benzoxazole-7,r-indene]-7'-carbonitrile;

[0290] (riS')-6'-amino-3-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl |ethoxy lpyrimidin-2-yl j-2',3’.5,6-tetrahydr()-4 / 7-spiro[[l,2Jbenzoxazole-7,r-indene]-7'-carbonitrile;

[0291] (rS)-6’-amino-3-(4-{(lS)-l-[(2 / ?,3^)-3-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6- {[ l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile;

[0292] (l'5 6'-amino-3-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3’,5,6-tetrahydro-4H-spiro[[ l,2]benzoxazole-7, 1'-indene]-7'-carbonitrile;

[0293] (riS')-7'-amino-3-(4-{(lS)-l-[(2S,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6- {[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'77,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile;

[0294] (rS)-6’-amino-3-(4-{[(31?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile;

[0295] (lS)-6-amino-3'-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2,3-dihydro-4'H,6'H-spiro[indene-l,7'-pyrano[3,4-d] [ 1,2]oxazole]-7 -carbonitrile;

[0296] (lS)-7-amino-3'-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3,4-dihydro-2H.4'H,6'H-spiro[ naphthalene- 1,7'-pyrano[3,4- ] [ 1,2]oxazole]-8-carbonitrile;

[0297] (lS)-6-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3-dihydro-4'H,6'7 / -spiro[mdene-l,7'-pyrano[3,4- ][l,2]oxazole]-7 -carbonitrile;

[0298] 6-amino-3'-(4-{ [(31?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy }-6-{ (IS)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy]pyrimidin-2-yl)-2,3-dihydro-4’H,6'H-spiro[indene-l,7'-pyrano [3,4-d] [1,2] oxazole] -7 -carbonitrile;

[0299] (15)-7-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-3,4-dihydro-2H,4'H,6'H-spiro[naphthalene-l,7’-pyrano[3,4-6 / ][l,2]oxazole]-8-carbonitrile;

[0300] (l / ?)-6-amino-3'-(4-{[(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3,4',5'-tetrahydrospiro[indene-l,7'-pyrano[4,3-6 / ][l,2]oxazole]-7-carbonitrile; and

[0301] (l\ )-6'-amino-3-(4-{ [(31?)-l-(2-fluoroprop-2-enoyl)-2,2-dimethylazetidin-3-yl]oxy}-6-{( 1 )-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2’,3',5,6-tetrahydro-4H-spiro [ [ 1, 2]benzoxazole-7, 1 ' -indene] -7' -c arbonitrile;

[0302] or a pharmaceutically acceptable salt thereof.

[0303] 61. The compound of clause 1, selected from the group consisting of (45)-2-amino-3'-(3-{(1 )-l-[(25,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethyl]-7-{[l-(prop-2-enoyl)azetidin-3-yl ]oxy }-3H-[ l,2,3]triazolo[4,5-Z]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'77,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;

[0304] (45)-2-amino-3'-(3-{ ( 15)- 1 -[(25)- 1 -methylpyrrolidin-2-yl]ethyl } -7- { [ 1 -(prop-2-enoyl)azetidin-3-yl]amino]-377-[l,2,3]triazolo[4,5-^]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;

[0305] (45)-2-amino-3'-(7-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-3-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethyl]-377-[l,2,3]triazolo[4,5-6f|pyriniidin-5-yl)-5',6,6,,7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile:

[0306] (45)-2-amino-3'-(l-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethyl]-4-{[l-(prop-2-enoyl)azetidin-3-yl]amino}-l / 7-pyrazolo[3,4-<f|pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,577-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;

[0307] (45)-2-amino-3'-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino]-l-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethyl]-lH-pyrazolo[3,4-<f|pyrirnidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;

[0308] (45)-2-anrino-3'-(l-{(15)-l-[(25,4 / ?)-4-fhioro-l-methylpyrrolidin-2-yl]ethyl)-4-{[l-(prop-2-enoyl)azetidin-3-yl]oxy]-177-pyrazolo[3,4-<f|pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile; and

[0309] (45)-2-amino-3'-(l-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]oxy]-l / 7-pyrazolo[3,4-Z]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4' / 7,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;

[0310] an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0311] 62. A pharmaceutical composition comprising at least one compound of any one of the preceding clauses, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0312] 63. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of clauses 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to clause 62.

[0313] 64. A compound of any one of clauses 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.

[0314] 65. A compound of any one of clauses 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

[0315] 65. Use of a compound of any one of clauses 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.DETAILED DESCRIPTION

[0316] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended clauses.

[0317] For the sake of brevity, the disclosures of the publications cited in this specification, including patents, are herein incorporated by reference. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0318] As used herein and in the appended clauses, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the clauses may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of clause elements, or use of a “negative” limitation.

[0319] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-limiting sense.

[0320] To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.

[0321] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0322] Except as otherwise noted, the methods and techniques of the present embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See, e.g., Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001.

[0323] Chemical nomenclature for compounds described herein has generally been derived using the commercially-available ACD / Labs 2022.2.3 (Advanced Chemistry Development, Inc.) or ChemDraw Professional 22.2.0.3300 (PerkinElmer Informatics, Inc.).

[0324] As used herein and in connection with chemical structures depicting the various embodiments described herein, and “ AAA ” each represent a point of covalent attachment of the chemical group or chemical structure in which the identifier is shown to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure A-B, where A and B are joined by a covalent bond, in some embodiments, the portionof A-B defined by the group or chemical structure A can be represented by,<r” represents a bond to A and the point of covalent bond attachment to B. Alternatively, in some embodiments, the portionof A-B defined by the group or chemical structure B can be represented by,represents a bond to B and the point of covalent bond attachment to A.

[0325] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein.CHEMICAL DEFINITIONS

[0326] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or C1-C20 alkylene, C1-C12 alkyl or C1-C12 alkylene, or Ci-Ce alkyl or Ci-Ce alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings provided herein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CHz-h), iso-propylene ((-C(H)(CH3)CH2-)), n-butylene ((-CHo-jj), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted asdescribed herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0327] The tenn “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” to a specific range of atoms, such as C2-C20 alkenyl, C2-C12 alkenyl, or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl can be unsubstituted or substituted as described herein. An alkenyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0328] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” to a specific range of atoms, such as C2-C20 alkynyl, C2-C12 alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include acetylenyl (-C=CH) and propargyl (-CHjC=CH), but-3-yn-l,4-diyl (-OC-CH2CH2-), and the like. It will be appreciated that an alkynyl group can be unsubstituted or substituted as described herein. An alkynyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0329] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the following entities:In particular, a cyclopropyl moiety can be depicted by the structural formulabe appreciated that a cycloalkyl group can be unsubstituted or substituted as described herein.A cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0330] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0331] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CFs, -(CHajF, -CHF, -CH? Br, -CH2CF3, and -CH2CH2F.

[0332] In certain embodiments, alkenyl may be substituted. For example, the alkenyl may be substituted with halo (e.g., fluoro). Illustratively, the alkenyl substituted with halo may be a =CHF. Illustratively, a hexahydro- IH-pyrrolizinyl moiety may be substituted by halo-substituted alkenyl, for example, a substituted hexahydro- IH-pyrrolizinyl moiety can be depicted by the structural formula

[0333] The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (Ce-Ci4 aryl), or monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (C6-C10 aryl). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. It will be appreciated that an aryl group can be unsubstituted or substituted as described herein. An aryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0334] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure (e.g., heterobicyclyl or bicyclic heterocyclyl) that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples, without limitations, of mono-cyclic heterocycloalkyl groups include tetrahydrofuran, pyrrolidinyl, and morpholinyl. Polycyclic ring systems include fused,bridged, and spiro systems. In some embodiments, it can be advantageous to limit the number of atoms in a bicyclic “heterocycloalkyl” to a specific range of ring atoms, such as from 5 to 10 ring atoms (5- to 10-membered), or 6 to 10 ring atoms (6- to 10-membered). The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Examples, without limitations, of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include pyrrolizinyl, 2,5-diazabicyclo[2.2.2]octanyl, and l-oxaspiro[4.5]decanyl. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities:

[0335] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of threemembered heterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five -membered heterocyle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine,thiazolidine, 4,5-dihydro-lH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include monovalent or divalent radicals of piperidine, morpholine, 4H-l,4-thiazine, 1, 2,3,4-tetrahydropyridine, piperazine, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide.

[0336] A “heterobicyclyl” or “bicyclic heterocyclyl” refers to a heterocycle comprising a fused, bridged, or sprio bicyclic ring system that is saturated or partially saturated having one or more non-carbon ring atoms. As used herein, “heterobicyclyl” and “bicyclic heterocyclyl” can include one heterocycle ring fused to a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where the ring stem overall is saturated or partially saturated. Non-limiting examples of “heterobicyclyl” and “bicyclic heterocyclyl” include, but are not limited to, radicals of the

[0337] It will be appreciated that a heterocycloalkyl group (e.g., a heteromonocyclyl or a heterobicyclyl or a bicyclic heterocyclyl) can be unsubstituted or substituted as described herein. A heterocycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0338] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to10-membered heteroaryl. In some instances, a 5- to 10-membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0339] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or sixmembered heterocycle. A five-membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include mono-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six -membered heteroaryl can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-ri]thiophene, 177-pyrrolo[2,3- / ?]pyridine, indazole, lH-benzo[ri]imidazole, benzo [ri]oxazole, and benzo [d]thiazole.

[0340] In particular, an isoquinolin-3(2H)-onyl moiety can be depicted by the structural formula

[0341] In particular, a divalent pyridopyrimidine moiety can be depicted by the structural formula

[0342] It will be appreciated that a heteroaryl group can be unsubstituted or substituted as described herein. A heteroaryl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0343] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0344] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0345] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.

[0346] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, OH, -OCi-Ce alkyl, OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, OS(O)Ci-C6alkyl, OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6 alkyl, S(O)Ci-C6alkyl, -S(O)2CI- alkyl, S(O)N(H or Ci-C6alkyl)2, S(O)2N(H or Ci-C6alkyl)2, N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, N(CI-C6alkyl)C(O)OCi-C6alkyl, N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-Ce alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, C(O)Ci-C6alkyl, C(O)OCi-C6alkyl, C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)2, P(O)2N(H or Ci-C alkyl)2, P(O)OCiC6alkyl, P(O)2OCi-C6 alkyl, CN, or -NO2. “Optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. For example, one to three hydrogen radicals can be replaced by the optional substituent.

[0347] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.

[0348] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,13N,18O,17O,31P,32P,35S,18F,36C1, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or singlephoton emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0349] As described herein, a compound may be of a particular formula (e.g., of Formula (I)-(XXVI)), an isotopically labeled form thereof (e.g., an isotopically labeled form of the compound of Formula (I)-(XXVI)), or a pharmaceutically acceptable salt thereof (e.g., a pharmaceutically acceptable salt of the compound of Formula (I)-(XXVI) or a pharmaceutically acceptable salt of the isotopically labeled form of the compound of Formula (I)-(XXVI)).

[0350] Certain chemical entities of Formula (I)-(XXVII) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether the chemical entity exists as the tautomeric form in which it is drawn. It will be understood that the chemical entities described herein, and their constituent rings A, B, etc. can exist in different tautomeric forms. It will be readily appreciated by one of skill in the art that because of rapid interconversion, tautomers can generally be considered to be the same chemical compound. Examples of tautomers include but are not limited to enol-keto tautomers, amine-imine tautomers, and the like.Btol form Keto form Lactam form Lactim formAmide form I i ic acid form Amins form imine form

[0351] In particular, a ring option of isoquinolin-3(2H)-oneylene can exist as the followingtautomers

[0352] The nomenclature “(ATOM)i-(ATOM)j” with j > i, when applied herein to a class of substituents, is meant to refer to embodiments of this disclosure for which each and every one of the number of atom members, from i to j including i and j, is independently realized. By way of example, the term C1-C3 refers independently to embodiments that have one carbon member (Ci), embodiments that have two carbon members (C2), and embodiments that have three carbon members (C3).

[0353] The disclosure also includes pharmaceutically acceptable salts of the compounds represented by Formula (I)-(XXVII), preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0354] A “pharmaceutically acceptable salt’’ is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S. M. Berge, et al.,“Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. ©,” wherein “W©” is an inorganic counter ion (e.g., an inorganic anion) or an organic counter ion (e.g., an organic anion). In certain embodiments, W© is an anion that is complexed with a cation of a compound of the disclosure to form a pharmaceutically acceptable salt.

[0355] It will be understood that the chemical entities described herein, can exist as a salt of a free acid or base of a compound represented herein and an inorganic or organic counter ion. Illustratively, the salt can be formed during the manufacture of the compound (e.g., a salt or a pharmaceutically acceptable salt) or can substituted to a salt for further manufacture, formulation, or administration reasons. As illustrated herein, certain compounds include a “W ©,” wherein “W © ” is an inorganic counter ion (e.g., an inorganic anion) or an organic counter ion (e.g., an organic anion). In certain embodiments, W© is an anion that is complexed with a cation of a compound of the disclosure to form a pharmaceutically acceptable salt.

[0356] The term “inorganic counter ion” represents an inorganic ion that accompanies an ionic species in order to maintain electric neutrality. An inorganic counter ion may represent an anion or cation. An inorganic counterion may accompany a free acid or base of a compound represented herein. An inorganic ion may form by a reaction of an inorganic base or inorganic acid and a compound described herein that possesses a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type.

[0357] The term “organic counter ion” represents an organic counter ion that accompanies an ionic species in order to maintain electric neutrality. The organic ion may represent an anion or cation. An organic counter ion may accompany a free acid or base of a compound represented herein. An organic ion may form by a reaction of an organic base or organic acid and a compound described herein that possesses a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type.

[0358] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates,hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0359] For a compound of Formula (I)-(XXVII) that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0360] The disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of Formula (I)-(XXVII), and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula (I)-(XXVII)).

[0361] A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

[0362] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXVII), and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active productof metabolism in the body of a compound of Formula (I)-(XXVII) or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chern. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sei. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0363] As used herein, the term “KRAS inhibitor’’ includes, but is not limited to, a compound that is capable of inhibiting the protein encoded by the KRAS gene, called K-Ras, that is involved in the RAS / MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS / MAPK signaling pathway will be known and understood by one of skill in the art. It will be appreciated that KRAS mutations occur in approximately one in seven of all human metastatic cancers, and that those mutations can occur in a variety of locations in the KRAS gene coding sequence. KRAS mutations primarily occur in KRAS codons 12 and 13, and also occur in codons 18, 61, 117, and 146 at low frequencies and have distinct effects on tumor cell signaling based on the codon and missense mutation. In particular, the compounds herein can inhibit the activity of the KRAS G12C mutation. It will be understood by a person having ordinary skill in the art that reference to a inhibiting of the KRAS C12C mutations refers to inhibiting the protein encoded by the KRAS G12C gene, having a coding sequence (e.g. a guanine to cysteine substitution, at position 35 on codon 12 of the KRAS coding sequence) that produces a K-Ras G12C protein, where a glycine at position 12 of the protein sequence is replaced by am aspartic acid.REPRESENTATIVE EMBODIMENTS

[0364] In some embodiments, the disclosure relates to a compound of the formula I,

[0365] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, R1, R2, R3, R4, R5, R6, R7, X, X1, X2, X3, ml, m2, m3, nl, n2, p, and q are as described herein.

[0366] In some embodiments, the disclosure provides a compound of the formula II,

[0367] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0368] In some embodiments, the disclosure provides a compound of formula III

[0369] or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0370] In some embodiments, the disclosure provides a compound of the formula IV,

[0371] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, R7, X, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0372] In some embodiments, the disclosure provides a compound of the formula V,

[0373] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, R7, X, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0374] In some embodiments, the disclosure provides a compound of the formula VI,VI

[0375] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Z1, Z2, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0376] In some embodiments, the disclosure provides a compound of the formula VII,

[0377] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R1, R6, X, Z1, Z2, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0378] In some embodiments, the disclosure provides a compound of the formula VIII,VIII

[0379] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R6, X, Y, Z3, Z4, Y1, Y2, nl, n2, p, and q are as described herein.

[0380] In some embodiments, the disclosure provides a compound of the formula IX,IX

[0381] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R. R6, X, Y, Z3, Z4, Y1, Y2, nl, n2, p, and q are as described herein.

[0382] In some embodiments, the disclosure provides a compound of the formula X,

[0383] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0384] In some embodiments, the disclosure provides a compound of the formula XI,

[0385] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, Z1, Z2, ml, m3, nl, n2, p, and q are as described herein.

[0386] In some embodiments, the disclosure provides a compound of the formula XII,

[0387] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R, R6, X, Y1, Y2, Z1, Z2, ml, nl, n2, p, and q are as described herein.

[0388] In some embodiments, the disclosure provides a compound of formula XIII,

[0389] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, X, Y1, Y2, Z1, Z2, ml, nl, n2, p, and q are as described herein.

[0390] In some embodiments, the disclosure provides a compound of the formula XIV,XIV

[0391] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y1, Y2, Z1, Z2, Z3, Z4, nl, n2, p, and q are as described herein.

[0392] In some embodiments, the disclosure provides a compound of the formula XV,XV

[0393] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y, Y1, Y2, Z1, Z2, Z3, Z4, nl, n2, p, and q are as described herein.

[0394] In some embodiments, the disclosure provides a compound of the formula XVI,

[0395] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, R', X, Y, ml, nl, n2, p, and q are as described herein.

[0396] In some embodiments, the disclosure provides a compound of the formula XVII,

[0397] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0398] In some embodiments, the disclosure provides a compound of the formula XVIII,

[0399] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R1, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0400] In some embodiments, the disclosure provides a compound of the formula XIX,

[0401] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0402] In some embodiments, the disclosure provides a compound of the formula XX,XX

[0403] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5a, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0404] In some embodiments, the disclosure provides a compound of the formula XXI,XXI

[0405] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R. R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0406] In some embodiments, the disclosure provides a compound of the formula XXII,

[0407] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0408] In some embodiments, the disclosure provides a compound of the formula XXIII,XXIII

[0409] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, R7, X, Y, ml, m3, nl, n2, p, and q are as described herein.

[0410] In some embodiments, the disclosure provides a compound of the formula XXIV,

[0411] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0412] In some embodiments, the disclosure provides a compound of the formula XXV,

[0413] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R1, R2, R3, R4, R5, R6, X, Y, Y1, Y2, ml, nl, n2, p, and q are as described herein.

[0414] In some embodiments, the disclosure provides a compound of the formula XXVI,XXVI

[0415] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0416] In some embodiments, the disclosure provides a compound of the formula XXVII,XXVII

[0417] or a pharmaceutically acceptable salt thereof, wherein ring A, ring C, R2, R3, R4, R5, R6, X, Y, Y1, Y2, Z3, Z4, nl, n2, p, and q are as described herein.

[0418] In some embodiments, at least one hydrogen atom in the compound of the Formula (I)-(XXVII) is substituted by a deuterium. In some embodiments, at least one hydrogen atom in ring A, ring B, ring C, R1, R2, R3, R4, R5, R6, or R7in the compound of the Formula (I)-(XXVII) is substituted by a deuterium.

[0419] In some embodiments, each of X1, X2, and X3is independently an -O-, -S-, -S(O)2-, or -CH2-, provided that no more than one of X1, X2, and X1is a -O-, -S-, or -S(O)2-. In certain embodiments, the ring containing X1, X2, and X3can be substituted by R3(e.g., nl is 1, 2, 3, or 4), such that each of X1, X2, and X3is independently an -O-, -S-, -S(O)2-, -CHR3-, -C(R3)2-, or -CH2-, provided that no more than one of X1, X2, and X3is a -O-, -S-, or -S(O)2-. In some embodiments, each of X1, X2, and X is independently -CHR3-, -C(RJ)2-, or -CH -. In some embodiments, each of X1, X2, and X3is independently -CH2-.

[0420] In some embodiments, p is 0, 1 or 2. In some embodiments, p is 1 or 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1, such that the compound comprises theportion, wherein denote points of connection to the rest of the compound.

[0421] In some embodiments, q is 1 or 2. In some embodiments, q is 1 such that the compoundcomprises the portiondenote points of connection to the rest of the compound. In some embodiments, q is 2 such that the compound comprises theportiondenote points of connection to the rest of the compound.

[0422] In some embodiments, each R3and R4, when present, is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORC,or -NO2; or two R3or two R4, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a G-G, cycloalkyl or a 4- to 10-membered heterocycloalkyl; or two R3or two R4, when present, taken together with the carbon atom to which they are attached combine to form an oxo group or a C2-C6 alkenyl group; wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5-to I O-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, Ci-Ce haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe,-S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, two R3, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a Ca-Cg cycloalkyl.

[0423] In some embodiments, nl is 0, 1, 2, 3, or 4. In some embodiments, nl is 0, 1, 2, or 3. In some embodiments, nl is 0, 1, or 2. In some embodiments, nl is 1, 2, or 3. In some embodiments, nl is 1 or 2. In some embodiments, nl is 0 or 1. In some embodiments, nl is 0 or 2. In some embodiments, nl is 0 or 2. In some embodiments, nl is 0.

[0424] In some embodiments, n2 is 0, 1, 2, 3, or 4. In some embodiments, nl is 0, 1, 2, or 3. In some embodiments, n2 is 0, 1, or 2. In some embodiments, n2 is 1, 2, or 3. In some embodiments, n2 is 1 or 2. In some embodiments, n2 is 0 or 1. In some embodiments, n2 is 0.

[0425] In some embodiments, the compound comprises a portion of the formula

[0426] wherein,

[0427] is a point of covalent attachment to ring C.

[0428] In some embodiments, each of Y1and Y2is independently N, O, S, CH, or CR7, provided that one of Y1and Y2is N, O, or S. In some embodiments, each of Y1and Y2is independently N, O, S, or CH, provided that one of Y1and Y2is N, O, or S. In some embodiments, Y1is O. In some embodiments, Y2is N. In some embodiments, Y1is N. In some embodiments, Y2is O. In some embodiments, Y1is O and Y2is N, or Y1is N and Y2is O.

[0429] In some embodiments, ring A is a 5- or 6-membered heteroaryl. In some embodiments, ring A is 5-membered heteroaryl. In some embodiments, ring A is an oxazole, which may be optionally substituted by one or two R7. In some embodiments, ring A is an unsubstituted 5-or 6-membered heteroaryl (m3 of R7is 0), or a 5- or 6-membered heteroaryl substituted with 1 of R7(m3 of R7is 1). In some embodiments, ring A is an unsubstituted 5-membered heteroaryl (m3 of R' is 0). In some embodiments, ring A is an unsubstituted oxazole (m3 of R7is 0).

[0430] In some embodiments, R7, when present, is H, deuterium, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-C6alkyl, Ci-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0431] In some embodiments, m3 is 0 or 1. In some embodiments, m3 is 0. In some embodiments, m3 is 1.

[0432] In some embodiments, the compound comprises a portion of the formula

[0433] wherein,

[0434] “ ” is a point of covalent attachment to ring C.

[0435] In some embodiments, ring B is phenyl or 5- or 6-membered heteroaryl having at least one nitrogen atom. In some embodiments, ring B is phenyl or pyridyl. In some embodiments, ring B is phenyl. In some embodiments, ring B is pyridyl.

[0436] In some embodiments, the compound comprises a portion of the formula

[0437] wherein,

[0438] is a point of covalent attachment to ring C.

[0439] In some embodiments, each of Z1and Z2is independently N, CH, or CR5.In some embodiments, Z1is N. In some embodiments, Z2is N. In some embodiments, Z1is N and Z2is CH or CR5. In some embodiments, Z2is N and Z1is CH or CR5.

[0440] In some embodiments, ring B is an unsubstituted phenyl or unsubstituted 5- or 6-membered heteroaryl (m2 of R5is 0), or a phenyl or 5- or 6-membered heteroaryl substituted with 1, 2, or 3 of R3(m2 of R5). In some embodiments, ring B is an unsubstituted phenyl (m2 of R5is 0), or a phenyl substituted with 1, 2, or 3 of R3(m2 of R5). In some embodiments, ring B is an unsubstituted 5- or 6-membered heteroaryl (m2 of R5is 0), or a 5- or 6-membered heteroaryl substituted with 1, 2, or 3 of R5(m2 of R5). In some embodiments, ring B is an unsubstituted pyridyl (m2 of R5is 0), or a pyridyl substituted with 1, 2, or 3 of R5(m2 of R5).

[0441] In some embodiments, each R5, when present, is independently deuterium, halogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SR1, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two R. when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-C2alkyl, C2-C. alkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C, alkyl, Ci-C. haloalkyl. -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R3, when present, is independently deuterium, halogen, Ci-Ce alkyl, -ORa, -SRa, -NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -CN, or -NO2, wherein each hydrogen atom in Ci-Cbalkyl, C -C. alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-C6haloalkyl, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf,-P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, each R5, when present, is independently deuterium, halogen, -NRaRb, or -CN. In some embodiments, each R5, when present, is independently deuterium, halogen, -NH2, or -CN.

[0442] In some embodiments, m2 is 0, 1, 2, or 3. In some embodiments, m2 is 1, 2, or 3. In some embodiments, m2 is 2 or 3. In some embodiments, m2 is 2. In some embodiments, m2 is 3.

[0443] In some embodiments, the compound comprises a portion of the formula

[0444] wherein,

[0445] is a point of covalent attachment to ring C.

[0446] In some embodiments, X is -O-, -S-, or -NR8-, in some embodiments, X is -O-. In some embodiments, X is -NR8-.

[0447] In some embodiments, R8is H, deuterium, Ci-C8 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C -C? aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-C8 alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Cs-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf. -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re. -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc,-S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R8is H, deuterium, Ci-Cg alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Cg alkyl, C2-Ce alkenyl, C2-Cbalkynyl, C3-C6 cycloalkyl, C6-C10 aryl. 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C6alkyl, Ci-Cg haloalkyl, Ci-Ce alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R8is optionally substituted Ci-Ce alkyl, for example methyl, ethyl, propyl, or butyl. In some embodiments, R8is H or methyl.

[0448] In some embodiments, or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Cg alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cs-Cg cycloalkyl, Cb-Cio aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-Ce alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0449] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0450] In some embodiments, ring C is Cg-Cio aryl or 5- to 10-membered heteroaryl, provided that when ring C is a 6-membered heteroaryl, then ring B is phenyl. In some embodiments, ring C is Cg-Cio aryl. In some embodiments, ring C is 5- to 10-membered heteroaryl and may contain at least one or at least two heteroatoms (e.g., nitrogen). In some embodiments ring Cwherein the / vuv' represent connection points to the remaining portions of the compound.

[0451] In some embodiments, ring C is a Ce-Cio aryl or 5- to 10-membered heteroaryl substituted with 1 or 2 of R1(ml of R1). In some embodiments, ring C is 5- to 10-membered heteroaryl substituted with 1 or 2 of R1(ml of R1). In some embodiments, ring C is a Ce-Cio aryl or 5- to 10-membered heteroaryl substituted with one or more of R1. In some embodiments, ring C is 5- to 10-membered heteroaryl substituted with one or more of R1. In some embodiments, ring C is a Ce-Cio aryl or 5- to 10-membered heteroaryl without an R1(ml of R’ is O).

[0452] In some embodiments, ring C is a Co-Cio aryl or 5- to 10-membered heteroaryl substituted with 1 or 2 of R1(ml of R1). In some embodiments, ring C is 5- to 10-membered heteroaryl substituted with 1 or 2 of R1(ml of R1). In some embodiments, ring C is Ce-Cio aryl or 5- to 10-membered heteroaryl substituted with one or more of R1. In some embodiments, ring C is 5- to 10-membered heteroaryl substituted with one or more of R1. In some embodiments, ring C is 5- to 10-membered heteroaryl without an R1(ml of R1is 0).

[0453] In some embodiments, each of Z and Z4is independently N, CH, or CR1.

[0454] In some embodiments, ring C is of the formula

[0455] wherein,

[0456] “ •~vv ” is a point of covalent attachment to ring A. In some embodiments, Rlais H or R1.

[0457] In some embodiments, the compound comprises a portion of the formula

[0458] wherein “” is a point of covalent attachment to ring A.

[0459] In some embodiments, the compound comprises a portion of the formula

[0460] wherein “ -~w ” is a point of covalent attachment to ring A.

[0461] In some embodiments, the compound comprises a portion of the formula

[0462] wherein is a point of covalent attachment to ring A.

[0463] In some embodiments, the compound comprises a portion of the formulais a point of covalent attachment to ring A.

[0465] In some embodiments, the compound comprises a portion of the formula

[0466] wherein is a point of covalent attachment to ring A.

[0467] In some embodiments, each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, Cb-C, alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C,-,-C 1 ■ aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra. -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb,-NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRh, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, each R1, when present and bonded to a nitrogen atom, is deuterium, Ci-C8 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C2-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Cg alkyl, C2-C. alkenyl, C2-Ce alkynyl, C2-Ce cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6 haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, -Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Cg alkynyl, C2-Ce cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg alkyl-ORe, Ci-Cg alkyl-SRe, Ci-Cg alkyl-NReRf. Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0468] In some embodiments, an R1and R10taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ct, alkyl, Ch-C. alkenyl, Ch-C, alkynyl, C3-C6 cycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5-to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ct, haloalkyl, Ci-Ce alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf,-NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. For example, in the portionof ring C, R1and R10taken together with the atoms to which they are attached, can combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroarylsuch aswhich may be optionally substituted.

[0469] In some embodiments, R2, when covalently attached to a heteroatom (e.g., when X is - O-, -S-, -S(O)-, -S(O)2-, or -NR8- or when covalently attached to a nitrogen in ring C), is Ci- C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -C(=NR8)NR8Rh, or an -R, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl,atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, -R9, -Rg, -Rh, -OR8, -OC(O)Rg, -OC(O)NRgRh, -OS(O)R8, -OS(O)2Rg, -OS(O)NR8Rh, -OS(O)2NR8Rh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh,-NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORS, -P(O)2ORg, -CN, or -NO2.

[0470] In some embodiments, R6is Ci-C8 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(Ce-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in Ci-Ce alkyl, C2-C6alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(Cs-Cio aryl), 5- to 10-membered heteroaryl, and -Ci-Ce alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Cg alkyl, -Ci-Cbalkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-C2alkyl), -Ci-Ce alkylene-(O-Re), Ce-Cio aryl, -Ci-C8 alkylene-(Ce-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf. -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0471] In some embodiments, R6is 4- to 10-membered heterocycloalkyl, -Ci-Ce alkylene-(4-to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-C8 alkylene-(C6-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl, -Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Ce alkylene-(C6-Cio aryl), 5- to 10-membered heteroaryl, and -Ci-Cf alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, -Ci-Ce alkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-Ce alkyl), -Ci-Ce alkylene-(O-Re), Ce-Cio aryl, -Ci-Ce alkylene-(Cs-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C -C alkylene-(5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2. In some embodiments, R6is -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl) is independentlyoptionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, -Ci-Ce alkylene-(O-Ci-Ce alkyl), -OCi-Ce alkylene-(O-Ci-Ce alkyl), -Ci-Cg alkylene-(O-Re), Ce-Cio aryl, -Ci-Ce alkylene-(C6-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0472] In some embodiments, R6is of the formula

[0473] wherein “ ” is a point of covalent attachment to X.

[0474] In some embodiments, Rbis of the formula

[0475] wherein is a point of covalent attachment to X. In some embodiments, R6is of the formula

[0476] wherein “ «w" is a point of covalent attachment to X.

[0477] In some embodiments, R6is of the formula

[0478] wherein “ JVW" is a point of covalent attachment to X.

[0479] In some embodiments, R9is selected from the group consisting of -C(O)(CH=CH2), -S(O)(CH=CH2), -S(O)2(CH=CH2), -C(NH)(CH=CH2), -C(NR1)(CH=CH2), -C(O)(C=CH), -S(O)(C=CH), -S(O)2(C=CH), -C(NH)(C=CH), -C(NR’)(C=CH), -C(O)(oxiranyl), -S(O)(oxiranyl), -S(O)2(oxiranyl), -C(NH)(oxiranyl), -CCNR'Xoxiranyl), -C(O)(Ci-C6alkyl), -S(O)(Ci-C2alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(CI-C6alkyl), and -C(NR‘)(CI-C6 alkyl), wherein each hydrogen atom in CH=CH2or C=CH is independently optionally substituted with deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, Ci-Ce alkyl-ORe, Ci-Ce alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two hydrogen atoms on adjacent carbon atoms in CH=CH2optionally combine to form a C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein one hydrogen atom on the a- or -carbon atom of -C(O)(Ci-Cg alkyl), -S(O)(Ci-Ce alkyl), -S(O)2(Ci-Ce alkyl), -C(NH)(Ci-Cg alkyl), and -CCNR'XCi-Ce alkyl) is substituted with a fluoro, chloro, or CN, and the remaining hydrogen atoms in -C(O)(Ci-Ce alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-C6alkyl). -C(NH)(CI-C6alkyl), and -C(NR‘)(CI-C6alkyl) are independently optionally substituted with deuterium, halogen, Ci-C8 alkyl, Ci-Ce haloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NRcRf, -NRcRf, -NRcC(O)Rf, -NRcC(O)ORf, -NRcC(O)NRcRf, -NRcS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and wherein each hydrogen atom in oxiranyl is independently optionally substituted with deuterium, halogen, Ci-C, alkyl, Ci-Ce haloalkyl, Ci-Ce alkyl-ORe, Ci-Ce alkyl-SRe, Ci-Ce alkyl-NReRr, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf,-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0480] In some embodiments, R9is of the formula

[0481] wherein “ -~w- ” is a point of covalent attachment to R2or X.

[0482] In some embodiments, R9is of the formula

[0483] wherein “ ” is a point of covalent attachment to R2or X.

[0484] In some embodiments, R9is of the formula

[0485] wherein “ ■'w ” is a point of covalent attachment to R2or X.

[0486] In some embodiments, R9is of the formula

[0487] wherein “” is a point of covalent attachment to R2or X.

[0488] In some embodiments, R10, when present, is H, deuterium, Ci-Ce alkyl, O-C, alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C..-C j. aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkyl-ORe, Ci-Ce alkyl-SRe, Ci-Ce alkyl-NReRf, Ci-Ce alkylene-C(O)Re, Ci-Ce alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

[0489] In some embodiments, each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-C6 alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, Ci-Ce alkylene-(C3-Ce cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, Ci-Ce alkylene-(C6-Cio aryl), 5- to 10-membered heteroaryl, and Ci-Cbalkylene-(5- to 10-membered heteroaryl); or two of Raand Rb, or R° and Rcl, or Reand Rf, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or -Reand -Rftaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-Cbalkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-C6 alkenyl, C2-C, alkynyl, C--C, cycloalkyl, C -C alkylene-(C -G. cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, Ci-Ce alkylene-(Ce-Cio aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl) isindependently optionally substituted by deuterium, halogen, Ci-Ce alkyl, C-C, haloalkyl, C3-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-C6alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C, alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-C6 alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2. -N(CI-C6alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-Ce alkyl)2, -P(H or Ci-C6alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-Cb alkyl)2, -P(O)OCi-Ce alkyl, -P(O)2OCi-Ce alkyl, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, G -C 1. aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1.

[0490] In some embodiments, each Rgand Rhis independently selected from the group consisting of H, deuterium, Ci-Cbalkyl, Ci-Ce alkyl-(O-Ci-Cbalkyl), C2-Ce alkenyl, C2-Ce alkynyl, C -C6 cycloalkyl, Ci-Ce alkylene-(C?-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), Cs-Cio aryl, Ci-Ce alkylene-(Ce-Cio aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl); or two of Rgand Rh, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or -Rgand -Rhtaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in C1-C5 alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ci-Cbalkylene-(C3-Ce cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4- to 10- membered heterocycloalkyl), Ce-Cioaryl, Ci-C6 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -R9, -OH, -OCi-Ce alkyl, -OR9, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-Ce alkyl)2, -OC(O)N(H or Ci-C6alkyl)(R9), -OS(O)Ci-C6alkyl, -OS(O)2Ci-Ce alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)N(H or Ci-C6alkyl)(R9), -OS(O)2N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)(R9), -SCi-C6alkyl, -SR9, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)N(H or Ci-Ce alkyl)(R9) -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)(R9), -N(H or Ci-C6alkyl)C(O)-Ci-C6alkyl, -N(H or Ci-C6alkyl)C(O)OCi-C6alkyl, -N(H or Ci-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl) S(O)Ci-C6alkyl, -N(H or Ci-C6alkyl)S(O)2Ci-C6alkyl, -N(H or Ci-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-Ce alkyl)2, -P(H or Ci-Ce alkyl)2R9, -P(O)(H or Ci-C8 alkyl)2, -P(O)(H or Ci-C6alkyl)R9, -P(O)2(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)R9, -P(O)N(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)(R9), -P(O)2N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6alkyl)(R9), -P(O)OCi-Cbalkyl, -P(O)OR9, -P(O)2OCi-C6alkyl, -P(O)2R9. -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce haloalkyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1.

[0491] In some embodiments, each R1, when bonded to a nitrogen atom, is independently Ci-Ce alkyl, Ci-C6haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -CN, or -OH, and each R1, when bonded to a carbon atom, is independently deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Cg-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-Ce alkyl, -OC(O)C1-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C8 alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6alkyl, -S(O)2C1-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-Cbalkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-C6alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-Ce alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6 alkyl)2, -P(O)OCi-C6 alkyl, -P(O)2OCi-Ce alkyl, -CN, or -NO2; or two of R1, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cs-Cio aryl, or 5- to 10-membered heteroaryl; or two -R1, taken together with the carbon atom to which they are attached, form an oxo group or a C2-C6 alkenyl.

[0492] In some embodiments, the compound is selected from Compound Table 1, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Examples 1-11 of Compound Table 1, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Examples 1-23 of Compound Table 1, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0493] The following in Compound Table 1 represent illustrative embodiments of compoundsof Formula (I)

[0494] Compound Table 1

[0495] isotopically labeled forms thereof, and pharmaceutically acceptable salts thereof.

[0496] In some embodiments, the compound is selected from Compound Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Examples la-1 la of Compound Table 2, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from Examples la-23a of Compound Table 2, or a pharmaceutically acceptable salt thereof.

[0497] The following in Compound Table 2 represent illustrative embodiments of compounds of Formula (I)Compound Table 2

[0498] isotopically labeled forms thereof, and pharmaceutically acceptable salts thereof.

[0499] In some embodiments, the compound is selected from the group consisting of (17?)-7'-amino-3-(4-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4’,5,6-tetrahydro-2’H,4H-spiro[[ l,2]benzoxazole-7,l'-naphthalene]-8'-carbonitrile;(l'I?)-7'-amino-3-(4-{[2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl ]ethoxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,477-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile;(r8)-6’-amino-3-(4-{(1 )-l-[(28,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / / -spiro[[ l,2]benzoxazole-7, r-indene]-7'-carbonitrile;(r7?)-7'-amino-3-(4-{(1 )-l-[(28,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy]-6-{[l-(prop- 2-enoyl)azetidin-3-yl ]oxy }pyrimidin-2-yl)-3',4’,5,6-tetrahydro-2'77,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile;(l'8)-6'-amino-3-(4-{(18)-l-[(28)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro[[l,2]benzoxazole- 7, 1 '-indene]-7’-carbonitrile;(r8)-6’-amino-3-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-6-{(18)-l-[(28)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-477-spiro [ [ 1, 2]benzox zole-7, 1 ' -indene] -7' -c arbonitrile;( 1 '8)-6'-amino-3-(4- { ( 18)- 1 -[(2 / ?,38)-3-fluoro- 1 -methylpyrrolidin-2-ylJethoxy } -6 - { [ 1 -(prop-2-enoyl)azetidin-3-yl ]oxy }pyrimidin-2-yl)-2',3’,5,6-tetrahydro-4H-spiro[[ 1,2]benzoxazole-7,r-indene]-7'-carbonitrile;( 1 '8)-6'-amino-3-(4-{ ( 1 )- 1 -[(28)- 1 -methylpy rrolidin-2-y l]ethoxy } -6-{ [ l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-477-spiro[[l,2]benzoxazole-7,r-indene]-7'-carbonitrile;(r8)-7’-amino-3-(4-{(18)-l-[(28,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl ]oxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro [ [ 1,2]benzoxazole-7, 1 '-naphthalene]-8'-carbonitrile;(r )-6'-amino-3-(4-{[(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy[-6-{(18)-l-[(28)-l-methylpyrrolidin-2-yl]ethoxy]pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro [ [ 1, 2]benzoxazole-7, 1 ’-indene] -7' -c arbonitrile;(1 )-6-amino-3'-(4-{(18)-l-[(28)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-2,3-dihydro-4'H,6' / 7-spiro[indene-l,7'-pyrano[3,4-d] [ 1,2]oxazole]-7 -carbonitrile;( 18)-7 -amino-3'-(4- { ( 1 )- 1 - [(28)- 1 -methylpyrroli din-2 -yl]ethoxy } -6- { [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy [pyri midin-2-y I )-3,4-dihydro-2 / / .47 / .67 / -spiro| naphthalene- 1,7'-pyrano[3,4-d][l,2]oxazole]-8-carbonitrile;(18)-6-amino-3'-(4-{ [(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy[-6-{(18)-l-[(28)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3-dihydro-4’H,6'H-spiro[indene-l,7'-pyrano[3,4-d][l,2]oxazole]-7-carbonitrile;(18)-7-amino-3'-(4-{[(3 / ?)-2,2-diniethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(18)-l-[(28)- l-methylpyrroh'din-2-yl|ethoxy}pymnidin-2-yl)-3.4-dihydro-27 / .4’7 / .6' / / -spiro| naphthalene-l,7'-pyrano[3,4-c?][l,2]oxazole]-8-carbonitrile;(l / ?)-6-amino-3'-(4-{[(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3,4',5'-tetrahydrospiro[indene-l,7'-pyrano[4,3-6 / ][l,2]oxazole]-7-carbonitrile; and(rS)-6'-amino-3-(4-{[(3 / ?)-l-(2-fluoroprop-2-enoyl)-2,2-dimethylazetidin-3-yl]oxy}-6-{(15)- 1-[(2S)-l-methylpyrrolidin-2-yl]ethoxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile;an isotopically labeled form thereof, or a pharmacally acceptable salt thereof.

[0500] In some embodiments, the compound is selected from the group consisting of (l'R)-T-amino-3-(4-{(15)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[ 1,2]benzoxazole-7, 1'-naphthalene]-8'-carbonitrile;(r / ?)-7'-amino-3-(4-{[2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-ylJoxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl ]ethoxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile;(l'5)-6'-amino-3-(4-{(15)-l-[(2S,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop- 2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[ l,2]benzoxazole-7,r-indene]-7’-carbonitrile;(r7?)-7'-amino-3-(4-{(15)-l-[(25,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-277,4H-spiro[[l,2]benzoxazole-7,l'-naphthalene]-8'-carbonitrile;(r5)-6'-amino-3-(4-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}-6-{ [l-(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2',3’,5,6-tetrahydro-4H-spiro[[ 1,2]benzoxazole- 7, l'-indene]-7'-carbonitrile;(l'5)-6'-amino-3-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-6-{(15)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-477-spiro[[l,2]benzoxazole-7,r-indene]-7'-carbonitrile;(rS)-6’-amino-3-(4-{(15)-l-[(2 / ?,3S)-3-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro[[l,2]benzoxazole-7, l'-indene]-7'-carbonitrile;( 1 ’5)-6'-amino-3-(4- { ( 1 S)- 1 -[(25)- 1 -methylpyrrolidin-2-yl]ethoxy } -6-{ [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[ l,2]benzoxazole-7, 1’-indene]-7'-carbonitrile;( 1 '5)-7'-amino-3-(4-{ ( 1 S )- 1 -[(2S,4 / ?)-4-fluoro- 1 -methy lpyrrolidin-2-yl]ethoxy } -6-{ [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8’-carbonitrile;(l'S)-6'-amino-3-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl Jethoxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,r-indene]-7'-carbonitrile;(lS)-6-amino-3'-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2,3-dihydro-4'H,6'H-spiro[indene-l,7'-pyrano[3,4-d] [ 1,2]oxazole] -7 -carbonitrile;(lS)-7-amino-3'-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3,4-dihydro-2H,4'H,6'H-spiro[ naphthalene- 1, 7'-pyrano[3,4-ci][l,2]oxazole]-8-carbonitrile;(lS)-6-amino-3'-(4-{[(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl Jethoxy }pyrimidin-2-yl)-2,3-dihydro-4'H,6'H-spiro[indene-l,7'-pyrano[3,4-d|[l,2JoxazoleJ-7-carbonitrile;6-amino-3’-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl Jethoxy } pyrimidin-2-yl )-2,3-di hydro-4' H,6'H-spiro[ indene- 1,7'-py rano| 3,4-d | [ 1,2]oxazole]-7 -carbonitrile;(lS)-7-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(llS')-l-[(2S)- I -methylpyrrolidin-2-yl lethoxy J pyrimidin-2-yl)-3.4-dihydr()-27 / .4’W,6' / / -spiro| naphthalene-l,7'-pyrano[3,4-c?][l,2]oxazole]-8-carbonitrile;(l / ?)-6-amino-3'-(4-{[(37?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3,4',5'-tetrahydrospiro[indene-l,7'-pyrano[4,3-r / ][l,2]oxazole]-7-carbonitrile; and(rS)-6’-amino-3-(4-{[(31?)-l-(2-fluoroprop-2-enoyl)-2,2-dimethylazetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro[[ 1,2]benzoxazole-7, 1 '-indene]-7'-carbonitrile;an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

[0501] In some embodiments, the compound is selected from the group consisting of (45)-2-amino-3'-(3-{(lS)-l-[(2S,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethyl}-7-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }-3H-[ l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'77,5H-spiro[

[0001] benzothiophene-4,7'-[ l,2]benzoxazole]-3-carbonitrile;(45)-2-amino-3'-(3-{(lb')-l-[(25)-l-methylpyrrolidin-2-yl]ethyl}-7-{[l-(prop-2-enoyl)azetidin-3-yl ]amino}-3H-[ 1,2,3]triazolo[4,5-rZ]pyrimidin-5-yl)-5',6,6',7-tetrahydro- 4'H,5H-spiro[

[0001] benzothiophene-4,7'-[ l,2]benzoxazole]-3-carbonitrile;(4S)-2-amino-3'-(7-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-3-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-377-[l,2,3]triazolo[4,5-r / ]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;(4S)-2-amino-3'-(l-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]amino}-177-pyrazolo[3,4-tZ]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;(4S)-2-amino-3'-(4-{ methyl [l-(prop-2-enoyl)azetidin-3-yl]amino}-l-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-17 -pyrazolo[3,4-d]pyrimidin-6-yl)-5’,6,6',7-tetrahydro-4'77,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;(4S)-2-amino-3'-( 1 -{ ( 1 S)- 1 - |C2. S\ 4 A* ) -4-fluo ro- 1 -methylpyrrolidin-2-y 1] ethy 1 } -4- { [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy}-lH-pyrazolo[3,4-<7]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile; and(4S)-2-amino-3'-(l-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }-17 -pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'77,5H-spiro[[l]benzothiophene-4,7'-[l,2Jbenzoxazole]-3-carbonitrile;an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.PHARMACEUTICAL COMPOSITIONS

[0502] For treatment purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients. A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti-oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste -modifying agents. In preferred embodiments, pharmaceutical compositions according to the disclosure are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0503] Sterile compositions are also contemplated by the disclosure, including compositions that are in accord with national and local regulations governing such compositions.

[0504] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the disclosure may be administered by a suitable route of delivery, such asoral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0505] For oral administration, the compounds the disclosure may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the disclosure may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents, and preservative agents. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include starch and gelatin. The lubricating agent, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0506] Capsules for oral administration include hard and soft gelatin capsules. To prepare hard gelatin capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0507] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0508] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the disclosure may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.Suitable aqueous vehicles include Ringer’s solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0509] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable earner. The inventive compositions may be formulated for rectal administration as a suppository.

[0510] For topical applications, the compounds of the present disclosure are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the disclosure may utilize a patch formulation to effect transdennal delivery.

[0511] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0512] The term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0513] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma,thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate -resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease. Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.

[0514] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target Ras, in particular K-Ras. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of disease caused or mediated by the KRAS G12C mutation. In preferred embodiments, methods of treating a target cancer are described.

[0515] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to the KRAS G12C mutation.

[0516] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).

[0517] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.DRUG COMBINATIONS

[0518] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present disclosure or may be included with a compound of the present disclosure in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present disclosure.

[0519] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the disclosure, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors, such as ALK inhibitors (e.g., crizotinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids. For pain indications, suitable combination agents include anti-inflammatories such as NS AIDs. The pharmaceutical compositions of the disclosure may additional comprise one or more ofIllsuch active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.CHEMICAL SYNTHESIS METHODS

[0520] The following examples are offered to illustrate but not to limit the disclosure. One of skill in the art will recognize that the following synthetic reactions and schemes may be modified by choice of suitable starting materials and reagents in order to access other compounds of Formula (I)-(XXVII).

[0521] Abbreviations: The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:

[0522] The proposed targets can be prepared via conventional chemistry or following the methods as shown below.

[0523] Intermediate synthesis

[0524] Intermediate Method 1-1 A

[0525] Preparation of 7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l, T-naphthalene]- 8'-carbonitrile (I-l-I):

[0526] Step 1. A solution of 2-diphenylphosphanylethyl(diphenyl)phosphane (576 mg, 1.45 mmol, 0.02 eq), chloroiridium (lZ,5Z)-cycloocta-l,5-diene (486 mg, 0.723 mmol, 0.01 eq) in DCM (144 mL) was degassed and purged with N2 for 3 times, and then 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.9 g, 101 mmol, 14.7 mL, 1.4 eq) and 2-allylcyclohexan-l-one (10.0 g, 72.3 mmol, 1 eq) were added sequentially via syringe. The mixture was stirred at 25 °C for 12 hours. On completion, the reaction was opened to air and methanol (100 mL) was added slowly. The mixture was stirred until gas evolution ceased, then was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 20:1 to 10:1) to give 2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propyl)cyclohexan-l-one (15.0 g, 56.3 mmol, 77% yield) as a colorless oil.

[0527] Step 2. A mixture of 2-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propyl)cyclohexan-l-one (1.35 g, 5.07 mmol, 1.1 eq), 2,3-dichloro-6-nitrobenzonitrile (1.00 g, 4.61 mmol, 1 eq), Pd(dppf)C12. CH2C12 (376 mg, 0.460 mmol, 0.1 eq), and K2CO3 (1.91 g, 13.8 mmol, 3 eq) in H2O (4 mL) and dioxane (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 12 hours under N2 atmosphere. On completion, the mixture was separated, then the organic phase was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 3:1 to 1:1) to give 2-chloro-6-nitro-3-(3-(2-oxocyclohexyl)propyl)benzonitrile (2.57 g, 7.21 mmol, 39% yield, 90% purity) as a yellow solid. ’H NMR (400 MHz, CDCL) 5 = 8.16 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 2.90 (t, J= 7.6 Hz, 2H), 2.43 - 2.36 (m, 1H), 2.35 - 2.27 (m, 2H), 2.15 - 2.05 (m, 2H), 1.92 - 1.86 (m, 2H), 1.72 - 1.61 (m, 4H), 1.46 - 1.39 (m, 1H), 1.34 - 1.27 (m, 1H). LCMS: nz / z 319.0 (M-1).

[0528] Step 3. A mixture of 2-chloro-6-nitro-3-(3-(2-oxocyclohexyl)propyl)benzonitrile (1.00 g, 3.12 mmol, 1 eq), K2CO3 (861 mg, 6.23 mmol, 2 eq), Pd(PPh3)2C12 (218 mg, 0.311 mmol, 0.1 eq) in toluene (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 12 hours under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF = 3:1 to 1:1) to give 7’-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (230 mg, 0.81 mmol, 12% yield) as a yellow solid.

[0529] Intermediate Method I- IB

[0530] Preparation of 6'-nitro-2-oxo-2',3'-dihydrospiro[cyclohexane-l,l'-indene]-7'-carbonitrile (1-1-2):

[0531] Step 1. A mixture of 2,3-dichloro-6-nitrobenzonitrile (10.0 g, 46.0 mmol, 1 eq), potassium trifluoro(vinyl)borate (6.48 g, 48.3 mmol, 1.05 eq), CS2CO3 (30.0 g, 92.1 mmol, 2 eq) and Pd(dppf)C12. CH2C12 (2.26 g, 2.76 mmol, 0.06 eq) in dioxane (100 mL) and H2O (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 60 °C for 4 hours under N2 atmosphere. On completion, the mixture was separated, then the organic phase was concentrated under vacuum to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 3:1 to 1:1) to give 2-chloro-6-nitro-3-vinylbenzonitrile (6.60 g, 31.6 mmol, 68% yield) as a yellow solid. H NMR (400 MHz, DMSO-rfo) 5 = 8.37 - 8.32 (m, 1H), 8.31 - 8.27 (m, 1H), 7.11 (dd, J = 11.2, 17.6 Hz, 1H), 6.24 (d. J = 17.6 Hz, 1H), 5.83 (d, J = 11.2 Hz, 1H).

[0532] Step 2. To a solution of allyl 2-oxocyclohexane-l -carboxylate (5.24 g, 28.7 mmol, 2 eq), 2-chloro-6-nitro-3-vinylbenzonitrile (3.00 g, 14.3 mmol, 1 eq) in THF (30 mL) was added TEA (8.73 g, 86.2 mmol, 12.0 mL, 6 eq). The mixture was stirred at 60 °C for 12 hours. On completion, the reaction mixture was diluted with water (50 mL) and was extracted with EA (30 mLx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4. filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 3:1 to 1:1) to give allyl 1 -(2-chloro-3-cyano-4-nitrophenethyl)-2-oxocyclohexane-l -carboxylate (4.10 g, 10.4 mmol, 72% yield) as a yellowsolid. LCMS: m / z 390.8 (M+l).

[0533] Step 3. Pd(PPh3)4 (591 mg, 0.511 mmol, 0.05 eq) was added followed by morpholine (4.46 g, 51.1 mmol, 4.50 mL, 5 eq) in THF (0.5 mL) to a stirring solution of allyl l-(2-chloro-3-cyano-4-nitrophenethyl)-2-oxocyclohexane-l -carboxylate (4.00 g, 10.2 mmol, 1 eq) in THF (40 mL). The reaction mixture was stirred for 2 hours at 25 °C. On completion, the reaction mixture was diluted with water (40 mL) and was extracted with EA (30 mLx3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 3:1 to 1:1) to give 2-chloro-6-nitro-3-(2-(2-oxocyclohexyl)ethyl)benzonitrile (3.10 g, 10.1 mmol, 98% yield) as a yellow solid. LCMS: m / z 305.0 (M-l); H NMR (400 MHz, DMSO-&) 5 = 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 2.90 - 2.82 (m, 2H), 2.48 - 2.36 (m. 2H), 2.25 - 2.09 (m, 2H), 2.04 - 1.94 (m, 2H), 1.85 - 1.76 (m. 1H), 1.69 - 1.55 (m, 2H), 1.48 - 1.36 (m, 2H).

[0534] Step 4. A mixture of 2-chloro-6-nitro-3-(2-(2-oxocyclohexyl)ethyl)benzonitrile (2.50 g, 8.15 mmol, 1 eq), Pd(PPh3)2C12 (572.05 mg, 0.815 mmol, 0.1 eq), K2CO3 (3.38 g, 24.5 mmol, 3 eq) in toluene (41 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 12 hours under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 2:1 to 1:1) to give 6'-nitro-2-oxo-2’,3'-dihydrospiro[cyclohexane-l,r-indene]-7'-carbonitrile (1.18 g, 4.37 mmol, 54% yield) as a yellow solid.

[0535] Intermediate Method 1-1 C

[0536] Preparation of 6-nitro-4'-oxo-2,3,5',6'-tetrahydro-2'H,4'H-spiro[indene-l,3'-pyran]-7-carbonitrile (1-1-4):

[0537] Step 1. To a solution of tetrahydropyran-4-one (10.0 g, 100 mmol, 1 eq) in THF (10 mL) was added LiHMDS (1.00 M in THF, 220 mL, 2.2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Allyl carbonochloridate (14.5 g, 120 mmol, 1.2 eq) was added into the mixture. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was slowly added into NH4CI (1000 mL) aqueous solution at 0 °C, and the aqueous phase was extracted with ethyl acetate (400 mL x 2). The combined organic phase was washed with brine (1000 mL x 2), dried over anhydrous NaaSOzi. filtered and concentrated under vacuum. The residue was purified by column chromatography CSiO:, Commercial hexanes: Ethyl acetate= 1 / 0 to 95 / 5) to give allyl 4-oxotetrahydro-2H-pyran-3-carboxylate (6.20 g, 33.7 mmol, 34% yield) as a yellow oil.NMR (400 MHz, CDCL) 5 = 11.77 (s. 1H), 6.02 - 5.86 (m, 2H), 5.41 - 5.24 (m, 4H), 4.70 - 4.62 (m, 3H), 4.55(d, J= 4.8 Hz, 1H). 4.31 (s, 2H), 4.28 - 4.20 (m, 1H), 4.17 -4.09 (m, 1H), 4.06 - 3.93 (m, 1H), 3.89 - 3.83 (m, 2H), 3.55 -3.49 (m, 1H), 2.73 - 2.65 (m, 1H), 2.62 - 2.48 (m, 1H), 2.44 - 2.37 (m, 2H).

[0538] Step 2. A mixture of allyl 4-oxotetrahydro-2H-pyran-3-carboxylate (2.47 g, 13.4 mmol, 2 eq), 2-chloro-6-nitro-3-vinylbenzonitrile (1.40 g, 6.71 mmol, 1 eq), TEA (679 mg, 6.71 mmol, 1 eq) in THF (14 mL) was degassed and purged with N? for 3 times, and then the mixture was stirred at 70 °C for 16 hours under N2 atmosphere. On completion, the mixture was concentrated under vacuum. The residue was purified by column chromatography CSiO;, Commercial hexanes: Ethyl acetate= 1 / 0 to 3 / 1) to give allyl 3-(2-chloro-3-cyano-4-nitrophenethyl)-4-oxotetrahydro-2H-pyran-3-carboxylate (1.40 g, 3.56 mmol, 53% yield) as a white solid. LCMS: m / z 393.0 (M+l).

[0539] Step 3. To a solution of allyl 3-(2-chloro-3-cyano-4-nitrophenethyl)-4-oxotetrahydro-2H-pyran-3-carboxylate (1.90 g, 4.84 mmol, 1 eq) in THF (19 mL) was added Pd(PPh3)4 (280 mg, 242 pmol, 0.05 eq) and morpholine (2.11 g, 24.2 mmol, 2.13 mL, 5 eq) in THF (1 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction was concentrated under vacuum. The residue was purified by column chromatography (SiOz, Commercial hexanes: Ethyl acetate= 1 / 0 to 60 / 40) to give 2-chloro-6-nitro-3-(2-(4-oxotetrahydro-2H-pyran-3-yl)ethyl)benzonitrile (1.40 g, 4.53 mmol, 94% yield) as a yellow solid. H NMR (400 MHz, CDCL) 5= 8.11 (s, 1H), 7.63 (d, J= 8.4 Hz, 1H), 4.21 - 4.10 (m, 2H), 3.69 (dt, J = 3.6, 11.2 Hz, 1H), 3.44 - 3.34 (m, 1H), 2.98 - 2.89 (m, 1H), 2.88 - 2.79 (m, 1H), 2.65 - 2.52 (m, 2H), 2.42 - 2.36 (m, 1H), 2.06 - 1.94 (m,lH), 1.51 - 1.39 (m, 1H).

[0540] Step 4. A mixture of 2-chloro-6-nitro-3-(2-(4-oxotetrahydro-2H-pyran-3-yl)ethyl)benzonitrile (5.00 g, 16.2 mmol, 1 eq), K2CO3 (6.72 g, 48.6 mmol, 3 eq), Pd(PPh3)2C12 (2.27 g, 3.24 mmol, 0.2 eq) in Tol. (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 hours under N2 atmosphere. On completion, the reaction was concentrated under vacuum. The residue was purified by column chromatography (SiOi, Commercial hexanes: Ethyl acetate= 1 / 0 to 70 / 30) to give 6-nitro-4'-oxo-2,3,5',6'-tetrahydro-2'H,4,H-spiro[indene-l,3'-pyran]-7-carbonitrile (2.50 g, 9.18 mmol, 57% yield) as a yellow solid.

[0541] Intermediate Table 1

[0542] Intermediate Method I-2A

[0543] Preparation of methyl l-((S)-l-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-4- (methylthio)-lH-pyrazolo[3,4-d]pyrimidine-6-carboxylate (1-2-2):> Boc

[0544] Step 1. To a solution of 4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidine (30.0 g, 158 mmol, 1 eq in THF (150 mL) was added sodium methanethiolate (17.8 g, 254 mmol, 1.6 eq) in H2O (150 mL). The mixture was stirred at 60 °C for 2 h. On completion, the reaction mixture was partitioned between EA (200 mL x 3) and water (150 mL), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOs, PE: THF= 1:0 to 4: 1) to give 6-chloro-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine (15.0 g, 74.7 mmol, 47% yield) as a white solid. LCMS: m / z 201.0 (M+l).

[0545] Step 2. To a solution of 6-chloro-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine (10.0g, 49.8 mmol, 1 eq) in 2-MeTHF (100 mL) was added tert-butyl (2S)-2-(l-hydroxyethyl)pyrrolidine-l -carboxylate (12.8 g, 60.0 mmol, 1.2 eq) and PPh (19.6 g, 74.7 mmol, 1.5 eq), then DBAD (22.9 g, 99.7 mmol, 2 eq) in 2-MeTHF (100 mL) was added at 0 °C. The mixture was stirred at 25°C for 1 h under N2. On completion, the mixture was concentrated to give a residue. The residue was purified by Prep-HPLC to give tert-butyl (S)-2-((S)-l-(6-chloro-4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)pyrrolidine-1-carboxylate (1.50 g, 3.77 mmol, 7.56% yield, minor diastereomer product) as a yellow solid. LCMS: m / z 298.1 (M+l-100).

[0546] Step 3. To a mixture of tert-butyl (S)-2-((S)-l-(6-chloro-4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)pyrrolidine-1-carboxylate (1.50 g, 3.77 mmol, 1 eq) and TEA (1.14 g, 11.3 mmol, 3 eq) in MeOH (15 mL) was added Pd(dppf)C12 (276 mg, 0.377 mmol, 0.1 eq). The resulting mixture was stirred at 70 °C under CO (50 Psi) for 24 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE: THF= 8:1) to give methyl l-((S)-l-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine-6-carboxylate (1.30 g, 3.08 mmol, 82% yield) as a yellow oil.

[0547] Intermediate Method I-2B

[0548] Preparation of methyl l-((S)-l-((2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine-6-carboxylate (1-2-3)

[0549] Step 1. To a solution of 6-chloro-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine (5.60 g, 27.9 mmol, 1 eq) and tert-butyl (2S,4R)-4-fluoro-2-((R)-l -hydroxy ethyl)pyrrolidine-l-carboxylate (7.81 g, 33.5 mmol, 1.2 eq) in THF (100 mL) was added PPh, (10.9 g, 41.8 mmol, 1.5 eq) and DBAD (12.8 g, 55.8 mmol, 2 eq). The mixture was stirred at 25 °C for 1 hour. Thereaction mixture was then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate = 1:0 to 1:1) to give tert-butyl (2S,4R)-2-((S)-l-(6-chloro-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-4-fluoropyrrolidine-l-carboxylate (15.0 g, crude) as a yellow oil. LCMS: m / z 415.9 (M+l).

[0550] Step 2. To a solution of tert-butyl (2S,4R)-2-((S)-l-(6-chloro-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)-4-fluoropyrrolidine-l-carboxylate (15.0 g, 36.0 mmol, 1 eq) in MeOH (150 mL) was added Pd(dppf)CL (2.64 g, 3.61 mmol, 0.1 eq) and TEA (108 mmol, 15.0 mL, 3 eq). The mixture was stirred at 70 °C under CO (50 psi) for 12 hours. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography CSiO\ Petroleum ether / Ethyl acetate = 1:0 to 1:1) to give methyl l-((S)-l-((2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidin-2-yl)ethyl)-4- (methylthio)-lH-pyrazolo[3,4-d]pyrimidine-6-carboxylate (15.0 g, 32.7 mmol, 90% yield) as a colorless oil.

[0551] Intermediate Method I-2C

[0552] Preparation of methyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (1-2-4):

[0553] Step 1. To a solution of methyl 4,6-dichloropyrimidine-2-carboxylate (15.1 g, 72.9 mmol, 1 eq) in DCM (150 mL) was added DIEA (18.9 g, 146 mmol, 25.4 mL, 2 eq) and (S)-l-((S)-l-methylpyrrolidin-2-yl)ethan-l-ol (14.1 g, 109 mmol, 1.5 eq). The mixture was stirred at 30 °C for 16 hours. On completion, the reaction mixture was partitioned between dichloromethane (100 mL x 3) and water (150 mL), and the combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0-100% (DCM: MeOH= 10:l) / DCM gradient @ 80 mL / min) to give methyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (12.5 g, 38.4 mmol, 53% yield, 92% purity) as a pink oil.

[0554] Intermediate Method I-2D

[0555] Preparation of 4-nitrophenyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (1-2-5):

[0556] Step 1. To a solution of methyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (1.00 g, 3.34 mmol, 1 eq) in THF (10 mL) and H2O (2 mL) was added LiOH HjO (210 mg, 5.00 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured into water (20 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylic acid (900 mg, crude) as a yellow oil. LCMS: m / z 286.0 (M+l).

[0557] Step 2. To a solution of 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylic acid (500 mg, 1.75 mmol, 1 eq) in pyridine (5 mL) was added POCI3 (805 mg, 5.25 mmol, 3 eq) and 4-nitrophenol (365 mg, 2.62 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (5 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 4-nitrophenyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (0.500 g, crude) as a yellow oil.

[0558] Intermediate Table 21SM: Starting Material(s)

[0559] Intermediate Method I-3A

[0560] Preparation of 3-(4,6-dichloropyrimidine-2-carbonyl)-7'-nitro-2-oxo-3',4’-dihydro- 2'H-spiro[cyclohexane-l, T-naphthalene]-8'-carbonitrile (1-3-1)

[0561] Methyl 4,6-dichloropyrimidine-2-carboxylate (451 mg, 2.18 mmol, 2 eq) was dissolved in dry ACN (3.1 mL) under nitrogen atmosphere. Dibromomagnesium ethoxyethane (422 mg, 1.64 mmol, 1.5 eq), 7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (310 mg, 1.09 mmol, 1 eq) and DIEA (281 mg, 2.18 mmol, 0.379 mL, 2 eq) were added, and the reaction mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was diluted with water (10 mL) and was extracted with DCM (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over NaiSO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF= 1:1 to 0:1) to give 3-(4,6-dichloropyrimidine-2-carbonyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,l'-naphthalene]-8'-carbonitrile (560 mg, 1.22 mmol, 53% yield) as a yellow solid.

[0562] Intermediate Method I-3B

[0563] Preparation of tert-butyl (2S)-2-((lS)-l-(4-(methylthio)-6-((6S)-7-oxo-l,4-dioxadispiro[4.0.56.45]pentadecane-8-carbonyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)pyrrolidine-l -carboxylate (1-3-3)

[0564] To a first solution of methyl l-((S)-l-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidine-6-carboxylate (1.10 g, 2.61 mmol, 1 eq) in dry THF (10 mL) was added dibromomagnesium ethoxyethane (1.01 g, 3.91 mmol, 1.5 eq), and the mixture was stirred at 50 °C for 60 min. Meanwhile, to a second solution of (R)-l,4-dioxadispiro[4.0.56.45]pentadecan-7-one (878 mg, 3.91 mmol, 1.5 eq) in THF (10 mL). was added LiHMDS (1 M in THF, 6.52 mL, 2.5 eq) and stirred for 60 min. After that, the second solution was added to the first solution and stirred for 1 h at 50 °C. On completion, the mixture was quenched with sat. NH4CI (30 mL) at 0 °C and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mLx 2), dried over Na ACL. filteredand concentrated to give a residue. The residue was purified by column chromatography (SiOi, PE: THF= 5:1) to give tert-butyl (2S)-2-((lS)-l-(4-(methylthio)-6-((6S)-7-oxo-l,4-dioxadispiro[4.0.56.45]pentadecane-8-carbonyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)pyrrolidine-l -carboxylate (1.20 g, 1.96 mmol, 75% yield) as a yellow solid.

[0565] Intermediate Table 31SM: Starting Material(s)2DCM was used as the solvent3Reaction was done at 25 °C

[0566] Intermediate Method I-4A

[0567] Preparation of tert-butyl (2S)-2-(l-hydroxyethyl)pyrrolidine-l -carboxylate (1-4-3):1-4-3

[0568] Step 1. To a solution of tert-butyl (S)-2-acetylpyrrolidine-l -carboxylate (4.50 g, 21.1 mmol, 1 eq) in THF (45 mL) was added LiAlFU (2.5 M in THF, 5.00 mL, 0.6 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 hours. On completion, the reaction mixture wassequentially quenched with water (1.5 mL), 15% NaOH (1.5 mL) and H2O (4.5 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate= 10 / 1 to 3 / 1) to give tert-butyl (2S)-2-(l-hydroxyethyl)pyrrolidine-l -carboxylate (3.60 g, 16.7 mmol, 79% yield) as a yellow oil.

[0569] Intermediate Method I-4B

[0570] Preparation of tert-butyl (2S,4R)-4-fluoro-2-((R)-l-hydroxyethyl)pyrrolidine-l-carboxylate (1-4-4)

[0571] Step 1. To a solution of (2S,4R)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (20.0 g, 85.7 mmol, 1 eq) and N, O-dimethylhydroxylamine (10.0 g, 102 mmol, 1.2 eq) in DMF (200 mL) was added HATU (39.1 g, 102 mmol, 1.2 eq) and DIEA (343 mmol, 59.7 mL, 4 eq). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched by addition of H2O (500 mL) and extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase column (0.1% FA) to give tert-butyl (2S,4R)-4-fluoro-2-(methoxy(methyl)carbamoyl)pyrrolidine-l-carboxylate (29.0 g, crude) as a brown oil.

[0572] Step 2. To a solution of (2S,4R)-4-fluoro-2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (22.0 g, 79.6 mmol, 1 eq) in THF (220 mL) was added MeMgBr (3 M in THF, 34.5 mL, 1.3 eq). The mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by addition of NH4CI (100 mL) at 0 °C and extracted with EA (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1:0 to 1: 1) to give (2S,4R)-2-acetyl-4-fluoropyrrolidine-1 -carboxylate (15.0 g, 64.8 mmol, 81% yield) as a colorless oil.!H NMR (400 MHz. CDCh) 5 = 5.14 (d, J = 3.2 Hz, 1H), 5.33 - 5.04 (m, 1H), 4.62 - 4.36 (m, 1H), 4.07 - 3.75 (m, 1H), 3.69 - 3.48 (m, 1H), 2.62 - 2.41 (m, 1H), 2.24 - 2.13 (m, 3H), 2.04 - 1.74 (m,1H), 1.45 (d, J = 15.6 Hz, 9H).

[0573] Step 3. To a solution of tert-butyl (2S,4R)-2-acetyl-4-fhioropyrrolidine-l -carboxylate (10.0 g, 43.2 mmol, 1 eq) in THF (100 mL) was added (S)-(-)-2-Methyl-CBS-oxazaborolidine (2.40 g, 8.65 mmol, 0.2 eq) and BH3-Me2S (10 M in THF, 6.49 mL, 1.5 eq). The mixture was stirred at 0 °C for 0.5 hours. On completion, the reaction mixture was quenched by addition of MeOH (50 mL) at 0 °C, dissolved in water (100 mL) and extracted with EA (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiOa, Petroleum ether / Ethyl acetate = 1:0 to 1:1) to give tert-butyl (2S,4R)-4-fluoro-2-[(lR)-1 -hydroxy ethyl] pyrrolidine- 1 -carboxylate (9.50 g, 40.7 mmol, 94% yield) as a colorless oil.

[0574] Intermediate Table 41SM: Starting Material(s)

[0575] Intermediate Method I-5A

[0576] Preparation of 3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine- 2-carbonyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (1-5-1)

[0577] To a solution of 3-(4,6-dichloropyrimidine-2-carbonyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (560 mg, 1.22 mmol, 1 eq) and (S)-l-((S)-l-methylpyrrolidin-2-yl)ethan-l-ol (252 mg, 1.95 mmol, 1.6 eq) in DCM (5.6 mL) was added DIEA (472 mg, 3.66 mmol, 0.637 mL, 3 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (6 mL) and was extracted with DCM (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na SO4, filtered and concentrated to give 3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carbonyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro|cvclohexane- 1.1 '-naphthalene|-8'-carbonitiile (1 g, crude) as a brown solid.

[0578] Intermediate Method I-5B

[0579] Preparation of 5'-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine- 2-carbonyl)-6-nitro-4'-oxo-2,3,5',6'-tetrahydro-2'H,4'H-spiro[indene-l,3'-pyran]-7-carbonitrile (1-5-5)

[0580] Step 1. To a solution of 6-nitro-4'-oxo-2,3,5',6'-tetrahydro-2'H,4'H-spiro[indene-l,3'-pyran]-7-carbonitrile (2.28 g, 5.53 mmol, 1.5 eq) in THF (15 mL) was added 4-nitrophenyl 4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carboxylate (1.50 g, 3.69 mmol, 1 eq) and LiHMDS (1.00 M in THF, 9.22 mL, 2.5 eq) in THF (15 mL). The mixture was stirred at 25 °C for 0.5 hour. Then, dibromomagnesium ethoxyethane (1.43 g, 5.53 mmol, 1.5 eq) was added into the mixture. The mixture was stirred at 25 °C for 1.5 hours. On completion, the mixture was poured into NH4CI (30 mL) aqueous solution at 0 °C, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (S1O2, DCM: MeOH = 10:1) to give 5'-(4-chloro-6-((S)-l -((S)-l -methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carbonyl)-6-nitro-4'-oxo-2,3,5',6'-tetrahydro-2'H,4’H-spiro[indene-l,3'-pyran]-7-carbonitrile (1.50 g, 2.78 mmol, 75% yield) as a yellow solid.

[0581] Intermediate Table 51SM: Starting Material(s)2ACN was used as the solvent3Reaction was done at 80 °C

[0582] Intermediate Method I-6A

[0583] Preparation of 7'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7, T-naphthalene]-8'-carbonitrile (1-6-1)

[0584] Step 1. To a solution of 3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidine-2-carbonyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l, T-naphthalene]-8'-carbonitrile (1.00 g, 1.09 mmol, 1 eq) in dioxane (10 mL) was added HCOOH (104 mg, 2.17 mmol, 2 eq and hydroxylamine (143 mg, 2.17 mmol, 50% purity, 2 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (5 mL) and was extracted with DCM (5 mLx3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiOa, DCM / MeOH= 10:1 to 8:1) to give 3-((Z)-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)(hydroxyimino)methyl)-7'-nitro-2-oxo-3',4'-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (400 mg, 0.705 mmol, 64% yield) as a yellow solid. LCMS: m / z 567.3 (M+l).

[0585] Step 2. To a solution of 3-((Z)-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)(hydroxyimino)methyl)-7'-nitro-2-oxo-3',4’-dihydro-2'H-spiro[cyclohexane-l,r-naphthalene]-8'-carbonitrile (360 mg, 0.634 mmol, 1 eq) in dioxane (3.6 mL) was added HCl / dioxane (2 M, 2.54 mL, 8 eq). The mixture was stirred at 80 °C for 5 hours. On completion, the reaction mixture was diluted with water (5 mL) and was extracted with DCM (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 10:1 to 8:1) to give 3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-7'-nitro-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7,r-naphthalene]-8'-carbonitrile (160 mg, 0.291 mmol, 45% yield) as a yellow solid. LCMS: m / z 549.3 (M+l).

[0586] Step 3. To a solution of 3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-7'-nitro-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7, T-naphthalene]-8'-carbonitrile (140 mg, 0.255 mmol, 1 eq) in EtOH (7 mL) and H2O (1.16 mL) was added Fe (142 mg, 2.55 mmol, 10 eq) and AcOH (229 mg, 3.83 mmol, 0.218 mL, 15 eq). The mixture was stirred at 60 °C for 0.5 hour. On completion, the reaction mixture was diluted with water (6 mL) and was extracted with DCM (10 mLx3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH= 10:1 to 8:1) to give 7'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7,1'-naphthalene]-8'-carbonitrile (40.0 mg, 0.077 mmol, 30% yield) as a yellow solid. LCMS: m / z 519.4 (M+l).

[0587] Step 4. The above residue was purified by SFC to give (R)-7'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7, T-naphthalene]-8'-carbonitrile (16.3 mg, 0.0315 mmol, 40.9% yield) as a yellow solid (I-6-la) and (S)-7'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7, T-naphthalene]-8'-carbonitrile (12.7 mg, 0.0245 mmol, 31.8% yield) as a yellow solid (1-6- lb). Analytical data for intermediate 1-6- lb:1H NMR (400 MHz, CDCh) 6 = 7.09 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 6.61 (d, J = 8.4 Hz, 1H), 5.48 (t, J = 6.0 Hz, 1H), 4.29 (s, 2H), 3.20 (dd, J= 4.4, 16.4 Hz, 1H), 3.09 (dd, J = 5.2, 7.6 Hz, 1H), 2.93 (ddd, J = 5.6, 11.6, 16.8 Hz, 1H), 2.85 - 2.77 (m, 1H), 2.75 - 2.61 (m, 2H), 2.46 (s, 3H), 2.30 (d, J = 9.2 Hz. 2H), 2.24 - 2.17 (m, 1H), 2.11 - 2.02 (m, 3H), 1.95 - 1.85 (m, 4H), 1.79 - 1.71 (m. 3H), 1.36 (d, J = 6.4 Hz, 3H): LCMS: m / z 519.3 (M+l).

[0588] Intermediate Method L6B

[0589] Preparation of (4S)-2-amino-3'-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylsulfinyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (1-6-5):

[0590] Step 1. To a solution of tert-butyl (2S)-2-((lS)-l-(4-(methylthio)-6-((6S)-7-oxo-l,4-dioxadispiro[4.0.56.45]pentadecane-8-carbonyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)ethyl)pyrrolidine-l -carboxylate (1.16 g, 1.89 mmol, 1 eq) in dioxane (10 mL) was added hydroxylamine (187 mg, 2.83 mmol, 50% purity, 1.5 eq) and HCOOH (272 mg, 5.67 mmol, 3 eq). The mixture was stirred at 40 °C for 1 h. On completion, the reaction mixture was adjusted to pH 7 by aq. NaHCO3 and then partitioned between EA (10 mL x 3) and water (10 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl (S)-2-((S)-l-(6-((S)-5,6-dihydro-4H-dispiro[benzo[d]isoxazole-7, T-cyclohexane-2',2"-[l,3]dioxolan]-3-yl)-4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)pyrrolidine-1-carboxylate (1.10 g, crude) as a yellow oil. LCMS: m / z 611.3 (M+l).

[0591] Step 2. To a solution of tert-butyl (S)-2-((S)-l-(6-((S)-5,6-dihydro-4H-dispiro[benzo[d]isoxazole-7, T-cyclohexane-2',2"-[l,3]dioxolan]-3-yl)-4-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)pyrrolidine-1-carboxylate (1.00 g, 1.59 mmol, 1 eq) in DCM (10 mL) was added TFA (40.4 mmol, 3.3 mL, 25 eq. The mixture was stirred at 25 °Cfor 1 h. On completion, the mixture was concentrated to give (S)-3-(4-(methylthio)-l-((S)-l-((S)-pyrrolidin-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,r-cyclohexan]-2'-one (1.50 g, crude) as a yellow oil. LCMS: m / z 467.3 (M+l).

[0592] Step 3. To a solution of (S)-3-(4-(methylthio)-l-((S)-l-((S)-pyrrolidin-2-yl)ethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,r-cyclohexan]-2'-one (500 mg, 1.07 mmol, 1 eq) in MeOH (5 mL) was added (CHO)n (161 mg, 5.36 mmol, 5 eq) and AcOH (64.3 mg, 1.07 mmol, 1 eq) at 0 °C, and the mixture was stirred at 0.5 h. Then NaBH3CN (134 mg, 2.14 mmol, 2 eq) was added at 0°C. The mixture was stirred at 25 °C for 2.5 h. On completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH= 1:0 to 10:1) to give (S)-3-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,1'-cyclohexan]-2'-one (170 mg, 0.354 mmol, 33% yield) as a yellow solid. LCMS: m / z 481.4 (M+l).

[0593] Step 4. To a solution of (S)-3-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5,6-dihydro-4H-spiro[benzo[d]isoxazole-7,l'-cyclohexan]-2'-one (170 mg, 0.354 mmol, 1 eq) in EtOH (1.7 mL) was added Sulfur (13.0 mg, 0.406 mmol, 1.15 eq), NH4OAc (30.0 mg, 0.389 mmol, 1.1 eq), followed by propanedinitrile (49.1 mg, 0.742 mmol, 2.1 eq) under N2. The mixture was stirred at 40 °C for 24 h. On completion, the mixture was quenched with aq. NaOH (1 mL) at 0 °C and extracted with EA (2 mL x 3). The combined organic layers were washed with brine (3 mLx 2), dried over Na2SO4 filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH= 1:0 to 10:1) to give (S)-2-amino-3'-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (120 mg, 0.214 mmol, 60% yield) as a yellow solid. LCMS: m / z 561.3 (M+l).

[0594] Step 5. To a solution of (S)-2-amino-3'-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylthio)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (60.0 mg, 0.107 mmol, 1 eq) in THF (1.2 mL) and H2O (1.2 mL) was added Oxone (98.7 mg, 0.161 mmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by addition of Na2SO3 (10 mL) at 0 °C, then diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give (4S)-2-amino-3'-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylsulfinyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (50.0 mg, 0.0867 mmol, 81% yield) as a yellow solid.

[0595] Intermediate Table 61SM: Starting Material(s)2Preparative HPLC was done in Step 43DCE was used as the solvent in Step 34Step 1 time was 12 hours5No SFC separation was performed

[0596] Intermediate Method L7A

[0597] Preparation of l-(3-hydroxyazetidin-l-yl)prop-2-en-l-one (1-7-1)

[0598] A solution of azetidin-3-ol (100 mg, 0.913 mmol, 1 eq, HCI salt) and K2CO3 (278 mg, 2.01 mmol, 2.2 eq) in H2O (0.7 mL) was stirred at 25 °C for 0.5 hour, then to the mixture was added acryloyl chloride (91.0 mg, 1.00 mmol, 0.082 mL, 1.1 eq) in DCM (1 mL) at 0 °C. Themixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was diluted with water (5 mL) and extracted with EA (5 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give l-(3-hydroxyazetidin-l-yl)prop-2-en-l-one (40.0 mg, 0.315 mmol, 34% yield, 100% purity) as a white solid.

[0599] Intermediate Method I-7B

[0600] Preparation of l-(3-aminoazetidin-l-yl)prop-2-en-l-one (1-7-3)

[0601] Step 1. To a solution of tert-butyl azetidin-3-ylcarbamate (300 mg, 1.74 mmol, 1 eq) in THF (3 mL) was added NaHCO3 (439 mg, 5.23 mmol, 3 eq), then to the mixture was added acryloyl chloride (173 mg, 1.92 mmol, 0.156 mL, 1.1 eq). The mixture was stirred at 0 °C for 0.5 hour. On completion, the reaction mixture was added to H2O (10 mL) and extracted with EA (10 mL x3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl (1-acryloylazetidin-3-yl)carbamate (390 mg, 1.55 mmol, 89 % yield, 90% purity) as a white solid. LCMS: m / z 227.0 (M+l)

[0602] Step 2. To a solution of tert-butyl (l-acryloylazetidin-3-yl)carbamate (30.0 mg, 0.133 mmol, 1 eq) in DCM (0.5 mL) was added TFA (154 mg, 1.35 mmol, 0.1 mL, 10.2 eq). The mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuum to give l-(3-aminoazetidin-l-yl)prop-2-en-l-one (30.0 mg, crude) as a colorless oil.

[0603] Intermediate Table 71SM: Starting Material(s)2Step 1 was done at room temperature3Step 1 warmed to 18 °C and stirred for 15 minutes

[0604] General Method A

[0605] Preparation of (17?)-7'-amino-3-(4-{(15)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6- {[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3’,4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile (Ex. la)

[0606] To a solution of (R)-7’-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[benzo[d]isoxazole-7,l'-naphthalene]-8'-carbonitrile (5.00 mg, 0.00963 mmol, 1 eq) in DMF (0.5 mL) was added CS2CO3 (9.42 mg, 0.0289 mmol, 3 eq) and l-(3-hydroxyazetidin-l-yl)prop-2-en-l-one (3.67 mg, 0.0289 mmol, 3 eq). The mixture was stirred at 60 °C for 2 hours. On completion, the reaction solution was filtered to remove the CS2CO3. The filtrate was purified by prep-HPLCto give (TR)-7’-amino-3-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[ 1,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile (5.23 mg, 0.00789 mmol, 81.92% yield, 98.94% purity, FA salt) as a yellow solid (Ex. la). Analytical data for Ex. la can be found in the table below.

[0607] General Method B

[0608] Preparation of (l'S)-6’-amino-3-(4-{(lS)-l-[(2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile (Ex. 3a)

[0609] Step 1. To a solution of 6'-amino-3-(4-chloro-6-((S)-l-((2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[benzo[d]isoxazole-7, T-indene]-7'-carbonitrile (50.0 mg, 0.0956 mmol, 1 eq) in DMF (0.5 mb) was added CS2CO3 (93.5 mg, 0.287 mmol, 3 eq) and l-(3-hydroxyazetidin-l-yl)prop-2-en-l-one (97.2 mg, 0.765 mmol, 8 eq). The mixture was stirred at 60 °C for 12 hours. On completion, the mixture was filtered. The filtrate was purified by prep-HPLC to give 3-(4-(( 1-acryloylazetidin-3-yl)oxy)-6-((S)-l-((2S,4R)-4-fluoro-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-6’-amino-2’,3',5,6-tetrahydro-4H-spiro[benzo[d]isoxazole-7,r-indene]-7'-carbonitrile (35.0 mg, 0.057 mmol, 60% yield) as a white solid. LCMS: m / z 614.2 (M+l).

[0610] Step 2. The above crude product (35.0 mg, 0.0570 mmol, 1 eq) was purified by SFC to give (T5)-6’-amino-3-(4-{ (15)-l-[(2S',4R)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{ [1-(prop-2-enoyl)azetidin-3-yl ]oxy }pyrimidin-2-yl)-2',3’,5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7,r-indene]-7'-carbonitrile (10.33 mg, 0.0154 mmol, 27.01% yield, 91.53% purity) as a yellow solid (Ex. 3a) and (l'7,)-6'-amino-3-(4-{(15')-l-[(2S,47,)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[ 1,2]benzoxazole-7, 1 '-indene]-7'-carbonitrile (10.33 mg, 0.0154 mmol, 27.01% yield, 91.53% purity) as a yellow solid (Ex. 3b). The analytical data for Ex. 3a can be found in the table below. Analytical data for Ex. 3b: H NMR (400 MHz, MeOD-7v) 5 = 7.25 (d, J= 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.42 - 6.31 (m, 1H), 6.28 (s, 1H), 6.27 -6.21 (m, 1H), 5.74 (d, 7= 10.0 Hz, 1H), 5.62 (s, 1H), 5.44 (t, 7= 6.4 Hz, 1H), 5.25 - 5.02 (m, 1H), 4.82 - 4.73 (m, 1H), 4.57 - 4.47 (m, 1H), 4.40 - 4.25 (m, 1H), 4.18 - 4.05 (m, 1H), 3.52 -3.34 (m, 1H), 3.21 - 3.10 (m, 1H), 3.09 - 3.00 (m, 1H), 2.99 - 2.81 (m, 3H), 2.75 - 2.59 (m, 1H), 2.53 (s, 3H), 2.38 (d, 7 = 8.0 Hz, 2H), 2.26 - 2.11 (m, 2H), 2.09 - 2.03 (m, 1H), 1.99 -1.81 (m, 3H), 1.35 (d, 7 = 6.0 Hz, 3H). LCMS: mlz 614.1 (M+l).

[0611] General Method C

[0612] Preparation of (lA)-6'-amino-3-(4-{(27?)-2-[(2S)-l-methylpyrrolidin-2-yl]propyl}-6-{[l-(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile (Ex. 6a)

[0613] (S)-6'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[benzo[d]isoxazole-7,r-indene]-7'-carbonitrile (26.7 mg, 0.0528 mmol, 1 eq), l-(3-aminoazetidin-l-yl)prop-2-en-l-one (20.0 mg, 0.158 mmol, 3 eq) and DIEA (41.0 mg, 0.317 mmol, 0.055 mL, 6 eq) were taken into a microwave tube in DMSO (0.5 mL). The sealed tube was heated at 60 °C for 4 hours under microwave. On completion, the mixture was filtered. The filtrate was purified by prep-HPLC to give (l'5)-6'-amino-3-(4-{(2 / ?)-2-[(25)-l-methylpyrrolidin-2-yl]propyl}-6-{[l-(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2’,3',5,6-tetrahydro-4 / 7-spiro[[l,2]benzoxazole-7, T-indene]-7'-carbonitrile (0.580 mg, 0.000905 mmol, 1.71% yield, 100% purity, FA salt) as a yellow solid (Ex. 6a). Analytical data for Ex. 6a can be found in the table below.

[0614] General Method D

[0615] Preparation of (4S)-2-amino T-(l-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-4-{[l- (prop-2-enoyl)azetidin-3-yl]amino}-l H-pyrazolo[3,4-rZ]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'77,5 / 7-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile (Ex. 13a)

[0616] To a solution of (4S)-2-amino-3'-(l-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethyl)-4-(methylsulfinyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[benzo[b]thiophene-4,7'-benzo[d]isoxazole]-3-carbonitrile (20.0 mg, 0.034 mmol, 1 eq) and l-(3-aminoazetidin-l-yl)prop-2-en-l-one (8.75 mg, 0.0694 mmol, 2 eq) in DMSO (0.4 mL) was added DIEA (13.5 mg, 0.104mmol, 0.018 mL, 3 eq). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was filtered to give a residue. The residue was purified by prep-HPLC to give (45)-2-amino-3'-(l-{(15')-l-[(25')-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]amino}-lH-pyrazolo[3,4-r / ]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4' / 7,577-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile (2.05 mg, 0.00284 mmol, 8.19% yield, 94.92% purity, FA salt) as a brown solid (Ex. 13a). Analytical data for Ex. 13a can be found in the table below.

[0617] General Method E

[0618] Preparation of (l'S)-6’-amino-3-(4-{[(3. R)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(l> S')-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro- 4H-spiro[[l,2]benzoxazole-7,l'-indene]-7'-carbonitrile (Ex. 17a)

[0619] To a solution of (R)-l-(3-hydroxy-2,2-dimethylazetidin-l-yl)prop-2-en-l-one (1.02 g, 6.60 mmol, 2 eq) in THF (10 mL) was added NaH (528 mg, 13.2 mmol, 60% purity, 4 eq) at 0 °C, and the suspension was stirred at 25 °C for 10 min. Then, a solution of (S)-6'-amino-3-(4-chloro-6-((S)-l-((S)-l-methylpyrrolidin-2-yl)ethoxy)pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[benzo[d]isoxazole-7, T-indene]-7'-carbonitrile (1.70 g, 3.30 mmol, 1 eq) in THF (10 mL) was added, and the mixture and stirred at 25 °C for 0.5 hours. On completion, the mixture was added into a saturated solution of NH4CI (30 mL) dropwise under N2 atmosphere at 0-10 °C. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC to give (l'S)-6'-amino-3-(4-{ [(3 / ?)- 2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2- yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-477-spiro[[l,2]benzoxazole-7, T-indene]-7'- carbonitrile (881.14 mg, 1.39 mmol, 42.16% yield, 98.449% purity) as a yellow solid (Ex.17a). Analytical data for Ex. 17a can be found in the table below.

[0620] Example Table 1.1ACN was used as the solvent2Reaction was carried out for 12 hours3Reaction was carried out for 0.5 hours4DMF was used as the solvent

[0621] Cell proliferation assay:

[0622] For the 3-day anti-proliferation assay, one thousand KRAS mutant cells per well were seeded in 384-well white plate and then treated with indicated compounds for 72 hours at 37 °C and 5% CO2. Compounds were added using the Tecan D300e Digital Dispenser in a 1:3 titration for 9 doses, starting from 1000 nM. At the end of the study, cell viability was measured by CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) using 18 pL per well following the manufacturer's protocol. Luminescence was measured by Tecan Spark multimode microplate reader and IC50 values were calculated using non-linear regression analysis (four parameter variable slope) with GraphPad Prism version 10.1.2 (GraphPad Software LLC, San Diego, CA).

[0623] For the 5-day anti-proliferation assay, KRAS mutant cells were inoculated to 96-well plates at a cell density of 2000 cells per well and treated with indicated compounds for 5 days at 37°C and 5% CO2 Compounds were added using the Tecan D300e Digital Dispenser in a 1:3 titration for 9 doses, starting from 300 nM. At the end of the study, cell viability was measured by CellTiter-Glo 2.0 luciferase-based ATP detection assay (Promega, Madison, WI) using 30 pL per well following the manufacturer’s protocol. Luminescence was measured by Tecan Spark multimode microplate reader and IC50 values were calculated using non-linear regression analysis (four parameter variable slope) with GraphPad Prism version 10.1.2 (GraphPad Software LLC, San Diego, CA).

[0624] Bioassay Table 1.GP2D and SW620 were 3-day assays while H358 was a 5-day assay

Claims

1. WHAT IS CLAIMED IS:

1. A compound of the formula I, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof,4. 6.wherein7.ring A is 5- or 6-membered heteroaryl;8.ring B is phenyl or 5- or 6-membered heteroaryl;9.ring C is Ce-Cio aryl or 5- to 10-membered heteroaryl; provided that when ring C is a 6-membered heteroaryl, then ring B is phenyl;10.X is a bond, -O-, -S-, -S(O)-, -S(O)2-, or -NR8-;11.Y is a bond, -O-, -S-, or -NR10-;12.each of X1, X2, and X3is independently an -O-, -S-, -S(O)2-, or -CH2-, provided that no more than one of X1, X2, and X3is a -O-, -S-, or -S(O)2-;13.each R1, when present and bonded to a carbon atom, is independently deuterium, halogen, Ci-Ce alkyl, C2-Cbalkenyl, C2-C& alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cioaryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rb, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2, each R1, when present and bonded to a nitrogen atom, is deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-C. alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-Ce alkyl, O-C. alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, C -Craryl. 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-C6haloalky 1, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, -Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylene-(5- to 10-membered heteroaryl), and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Cealkyl-ORe, Ci-Ce alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;14.R2, when covalently attached to a heteroatom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C -Craryl, 5- to 10-membered heteroaryl, -C(O)Rg, -C(O)OR8, -C(O)NR8Rh, -C(=NR8)NR8Rh, or an -R9, wherein each hydrogen atom in Ci-C8 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, -R9, -Rg, -Rh, -OR8, -OC(O)RS, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NR8Rh, -OS(O)2NRgRh, -SRg, -S(O)R8, -S(O)2R8, -S(O)NR8Rh. -S(O)2NRgRh, -NR8Rh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2; or R2, when covalently attached to a carbon atom, is Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, 4-to 10-membered heterocycloalkyl, C6-Cioaryl, 5- to 10-membered heteroaryl, -15.

16. -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, or -R9, wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C -C alkynyl, C -C cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, -R9, -Rg, -Rh, -ORg, -OC(O)Rg, -OC(O)NRgRh, -OS(O)Rg, -OS(O)2Rg, -OS(O)NRgRh, -OS(O)2NRgRh, -SRg, -S(O)Rg, -S(O)2Rg, -S(O)NRgRh, -S(O)2NRgRh, -NRgRh, -NRgC(O)Rh, -NRgC(O)ORh, -NRgC(O)NRgRh, -NRgS(O)Rh, -NRgS(O)2Rh, -NRgS(O)NRgRh, -NRgS(O)2NRgRh, -C(O)Rg, -C(O)ORg, -C(O)NRgRh, -PRgRh, -P(O)RgRh, -P(O)2RgRh, -P(O)NRgRh, -P(O)2NRgRh, -P(O)ORg, -P(O)2ORg, -CN, or -NO2;17.each R3and R4, when present, is independently deuterium, halogen, Ci-Ce alkyl, C -C, alkenyl, C2-Cb alkynyl, C2-Cb cycloalkyl, 4- to 10-membered heterocycloalkyl, Cb-Cio aryl, 5- to 10-membered heteroaryl, -ORC, -OC(O)RC, -OC(O)NRcRd, -OC(=NRc)NRcRd, -OS(O)Ra. -OS(O)2RC, -OS(O)NR Rd, -OS(O)2NRcRd, -SRC, -S(O)RC, -S(O)2RC, -S(O)NRcRd, -S(O)2NRcRd, -NR Rd, -NRcC(O)Rd, -NRcC(O)ORd, -NR C(O)NRcRd, -NRcC(=NRd)NRcRd, -NRcS(O)Rd, -NRcS(O)2Rd, -NRcS(O)NRcRd, -NRcS(O)2NRcRd, -C(O)RC, -C(O)ORC, -C(O)NRcRd, -C(=NRc)NRcRd, -PRRd, -P(O)RcRd, -P(O)2RcRd, -P(O)NRcRd, -P(O)2NRcRd, -P(O)ORC, -P(O)2ORC, -CN, or -NO2; or two R3or two R4, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C2-Ce cycloalkyl or a 4- to 10-membered heterocycloalkyl; or two R3or two R4, when present, taken together with the carbon atom to which they are attached combine to form an oxo group or a C2-Ce alkenyl group; wherein each hydrogen atom in Ci-Ce alkyl, C2-Ce alkenyl, C2-C, alkynyl, C3-C6 cycloalkyl, Cs-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-C6alkyl, Ci-C6haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf. -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; each R5, when present, is independently deuterium, halogen, Ci-Ce alkyl, C -C,, alkenyl, C2-Ce alkynyl, C2-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cwaryl, 5-to 10-membered heteroaryl, -ORa, -OC(O)Ra, -OC(O)NRaRb, -OC(=NRa)NRaRb, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRaRb, -OS(O)2NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -S(O)2NRaRb, -NRaRb, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)NRaRb, -NRaC(=NRa)NRaRb, -NRaS(O)Rb, -NRaS(O)2Rh, -NRaS(O)NRaRb, -NRaS(O)2NRaRb, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(=NRa)NRaRb, -PRaRb, -P(O)RaRb, -P(O)2RaRb, -P(O)NRaRb, -P(O)2NRaRb, -P(O)ORa, -P(O)2ORa, -CN, or -NO2; or two R5, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-C alkyl, C2-C6 alkenyl, C>-C alkynyl, C -C.. cycloalkyl, Cg-Cioaryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cg haloalkyl, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;18.R6is Ci-Cb alkyl, C2-C6 alkenyl, C2-Cg alkynyl, Cs-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-C alkylene-(4- to 10-membered heterocycloalkyl), Cg-Cioaryl, -Ci-Cg alkylene-(Cg-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), C -Cio aryl, -Ci-Ce alkylene-(Cg-Cio aryl), 5- to 10-membered heteroaryl, and -Ci-Ce alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Cg alkyl, -Ci-Cgalkylene-(O-Ci-Cg alkyl), -OCi-Cg alkylene-(O-Ci-C6 alkyl), -Ci-Cg alkylene-(O-Re), Cg-Cioaryl, -Ci-Cg alkylene-(Cg-Cio aryl), haloalkyl, Cs-Cg cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;19.R7, when present, is H, deuterium, C1-C0 alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, or 5- to 10-membered heteroaryl, wherein each hydrogen atom in Ci-C alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cs-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Cg alkyl, Ci-C haloalkyl, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; R8, when present, is H, deuterium, Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-C<, alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Cghaloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf. -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re. -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;20.R9is selected from the group consisting of -C(0)(CH=CH2), -S(0)(CH=CH2), -S(O)2(CH=CH2), -C(NH)(CH=CH;), -C(NR1)(CH=CH2), -C(O)(C=CH), -S(O)(C=CH), -S(0)2(OCH), -C(NH)(C≡CH), -C(NR')(C=CH), -C(O)(oxiranyl), -S(O)(oxiranyl), -S(O)2(oxiranyl), -C(NH)(oxiranyl), -C(NR')(oxiranyl), -C(O)(Ci-C6alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(CI-C6alkyl), and -QNR^Ci-Ce alkyl), wherein each hydrogen atom in CH=CH2 or C=CH is independently optionally substituted with deuterium, halogen, Ci-Ce alkyl, Ci-Cehaloalkyl, Ci-Cg alkyl-ORe, Ci-Ce alkyl-SRe, Ci-C(, alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe. -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf. -NReC(O)Rf. -NReC(O)ORf.21.-NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; or two hydrogen atoms on adjacent carbon atoms in CH=CH2optionally combine to form a C3-C6 cycloalkyl, 3- to 10-membered heterocycloalkyl; wherein one hydrogen atom on the a- or f)-carbon atom of -C(O)(Ci-C8 alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-C(, alkyl), -C(NH)(CI-C6alkyl), and -CfNR'jfCi-Ce alkyl) is substituted with a fluoro, chloro, or CN, and the remaining hydrogen atoms in -C(O)(Ci-C6alkyl), -S(O)(Ci-C6alkyl), -S(O)2(Ci-C6alkyl), -C(NH)(CI-C6alkyl), and -C(NR‘)(CI-C6 alkyl) are independently optionally substituted with deuterium, halogen, C1-C6 alkyl, Ci-Cehaloalkyl, Ci-C6alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl-C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf. -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2; and wherein each hydrogen atom in oxiranyl is independently optionally substituted with deuterium, halogen, Ci-Cg alkyl, Ci-Cghaloalkyl, Ci-Cg alkyl-ORe, Ci-C6alkyl-SRe, Ci-C6alkyl-NReRf, Ci-C6alkyl -C(O)Re, Ci-C6alkyl-C(O)ORe, -Ci-C6alkyl-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;22.R10, when present, is H, deuterium, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, or 5- to 10-membered heteroaryl; or an R1and R10, when present, taken together with the atoms to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl; wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-Cg alkyl, Ci-Cshaloalkyl, Ci-Cgalkyl-ORe, Ci-Cg alkyl-SRe, Ci-Cgalkyl-NReRf, Ci-Cg alkylene-C(O)Re, Ci-C6alkylene-C(O)ORe, -Ci-C6alkylene-C(O)NReRf, -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2;23.each Ra, Rb, Rc, Rd, Re, and Rfis independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, Ci-Cg alkyl-(O-Ci-Cg alkyl), C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Ci-Cg alkylene-(Cs-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), Cg-Cio aryl, Ci-Cg alkylene-(C6-Cio aryl), 5-to 10-membered heteroaryl, and C1-C0 alkylene-(5- to 10-membered heteroaryl); or two of Raand Rb, or Rcand Rd, or Reand Rf, taken together with the atom or atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cm aryl, or 5- to 10-membered heteroaryl; or -Reand -Rftaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-Cg alkyl, Ci-Cbalkyl-(0-Ci-Co alkyl), C2-Cbalkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Ci-Cg alkylene-(C3-Cg cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), Cg-Cioaryl, Ci-C(,alkylene-(C6-Cioaryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, Ci-Ce haloalkyl, Cs-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Cs-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-C6alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)2, -SCi-C6alkyl, -S(O)Ci-C6 alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2. -N(CI-C6alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(CI-C6alkyl)C(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)Ci-C6alkyl, -N(CI-C6alkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl) S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-Ce alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C8 alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6alkyl)2, -P(O)OCi-C6alkyl, -P(O)2OCi-Ce alkyl, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, Ci-Cr, haloalkyl, C -C cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;24.each Rsand Rhis independently selected from the group consisting of H, deuterium, Ci-Ce alkyl, Ci-Ce alkyl-(O-Ci-Ce alkyl), C2-Ce alkenyl, C2-Ce alkynyl, C-C, cycloalkyl, Ci-Cg alkylene-(C2-C6 cycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Ce alkylene-(4-to 10-membered heterocycloalkyl), Cs-Cio aryl, Ci-Ce alky lene-(Cb-Cio aryl), 5- to 10-membered heteroaryl, and Ci-Ce alkylene-(5- to 10-membered heteroaryl); or two of Rsand Rh, taken together with the atom or atoms to which they are attached, combine to form a C2-Ce cycloalkyl, 4- to 10-membered heterocycloalkyl, Ce-Cio aryl, or 5- to 10-membered heteroaryl; or -Rgand -Rhtaken together with the carbon atom to which they are attached form an oxo group or a C2-C6 alkenyl; wherein each hydrogen atom in Ci-Ce alkyl, Ci-Ce alkyl-(O-Ci-C6 alkyl), C2-Ce alkenyl, C2-Ce alkynyl, C3-C6 cycloalkyl, Ci-Cealkylene-(C3-Cbcycloalkyl), 4- to 10-membered heterocycloalkyl, Ci-Cg alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, Ci-Cc alkylene-(C6-Cio aryl), 5- to 10-membered heteroaryl, and Ci-Ct, alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted by deuterium, halogen, Ci-Ce alkyl, -C, haloalkyl. C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-Cioaryl, 5- to 10-membered heteroaryl, -R9, -OH, -OC1-C6 alkyl, -OR9, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-C6alkyl)2, -OC(O)N(H or Ci-C6alkyl)(R9), -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-C6alkyl)2, -OS(O)N(H or Ci-C6alkyl)(R9), -OS(O)2N(H or Ci-C6alkyl)2, -OS(O)2N(H or Ci-C6alkyl)(R9), -SCi-C6alkyl, -SR9, -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-C6alkyl)2, -S(O)N(H or Ci-C6 alkyl)(R9) -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-Cg alkyl)2, -N(H or Ci-C6alkyl)(R9), -N(H or Ci-C6alkyl)C(O)-Ci-Cg alkyl, -N(H or Ci-Cg alkyl)C(O)OCi-C6alkyl, -N(H or Ci-Cg alkyl)C(O)N(H or Ci-Cbalkyl)2, -N(H or Ci-C alkyl)S(O)Ci-Cg alkyl, -N(H or Ci-C6alkyl)S(O)2Ci-C6alkyl, -N(H or Ci-Cg alkyl)S(O)N(H or Ci-Cg alkyl)2, -N(H or Ci-C6alkyl)S(O)2N(H or Ci-Cg alkyl)2, -C(O)Ci-C6alkyl, -C(O)OCi-Cg alkyl, -C(O)N(H or Ci-Cg alkyl)2, -P(H or Ci-Cg alkyl)2, -P(H or Ci-Cg alkyl)2R9, -P(O)(H or Ci-Cg alkyl)2, -P(O)(H or Ci-Cg alkyl)R9, -P(O)2(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)R9, -P(O)N(H or Ci-C6 alkyl)2, -P(O)N(H or Ci-C6alkyl)(R9), -P(O)2N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6alkyl)(R9), -P(O)OCi-C6alkyl, -P(O)OR9, -P(O)2OCi-Cg alkyl, -P(O)2R9, -CN, or -NO2, wherein each hydrogen atom in Ci-C6 alkyl, Ci-C6 haloalkyl, Cj-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cioaryl, and 5- to 10-membered heteroaryl, is optionally substituted with one or more deuterium, halogen, or R1;25.each R1, when bonded to a nitrogen atom, is independently Ci-C, alkyl. Ci-Cg haloalkyl, Cs-Cg cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cioaiyl, 5- to 10-membered heteroaryl, -CN, or -OH, and each R1, when bonded to a carbon atom, is independently deuterium, halogen, C -C alkyl, Ci-Cg haloalkyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, 5- to 10-membered heteroaryl, -OH, -OCi-C. alkyl, -OC(O)Ci-C6alkyl, -OC(O)N(H or Ci-Cg alkyl)2, -OS(O)Ci-C6alkyl, -OS(O)2Ci-C6alkyl, -OS(O)N(H or Ci-Cg alkyl)2, -OS(O)2N(H or Ci-Cg alkyl)2, -SCi-C6alkyl, -S(O)Ci-Cg alkyl, -S(O)2Ci-C6alkyl, -S(O)N(H or Ci-Cg alkyl)2, -S(O)2N(H or Ci-C6alkyl)2, -N(H or Ci-C6alkyl)2, -N(Ci-Cg alkyl)C(O)-Ci-C6alkyl, -N(CI-C6alkyl)C(O)OCi-C6alkyl, -N(Ci-Cbalkyl)C(O)N(H or Ci-C6alkyl)2, -N(Ci-Cg alkyl)S(O)Ci-Cg alkyl, -N(CI-C6alkyl)S(O)2Ci-C6alkyl, -N(CI-C6alkyl)S(O)N(H or Ci-C6alkyl)2, -N(CI-C6alkyl)S(O)2N(H or Ci-C6alkyl)2, -C(O)Ci-Cg alkyl, -C(O)OCi-C6alkyl, -C(O)N(H or Ci-C6alkyl)2, -P(H or Ci-Cg alkyl)2, -P(O)(H or Ci-C6alkyl)2, -P(O)2(H or Ci-C6alkyl)2, -P(O)N(H or Ci-C6alkyl)2, -P(O)2N(H or Ci-C6alkyl)2, -P(O)OCi-C6alkyl, -P(O)2OCi-C6 alkyl, -CN, or -NO2; or two of R1, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, Cg-Cio aryl, or 5-to 10-membered heteroaryl; or two -R1, taken together with the carbon atom to which they are attached, form an oxo groups or a C2-Cg alkenyl;26.provided that R2comprises one or more R9;27.ml is 0, 1, or 2;28.m2 is 0, 1, 2, or 3;29.m3 is 0 or 1;30.nl is 0, 1, 2, 3, or 4; n2 is 0, 1, 2, 3, or 4;31.p is 0, 1 or 2; and32.q is 1 or 2.

2. The compound of claim 1, having the formula II36.

37. an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, having the formula III40.

41. an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or 2, having the formula IV44.

45. an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5; and46.each of Z1and Z2is independently N, CH, or CR5.

5. The compound of any one of the preceding claims, having the formula V49. 51.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5; and52.each of Z1and Z2is independently N, CH, or CR5.

6. The compound of any one of claims 1, 2, or 4, having the formula VI55. 57.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5,58.each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;59.each of Z1and Z2, is independently N, CH, or CR5;60.m3 is 0 or 1; and62.the63.

64. present in ring A represents the aromaticity of ring A.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, having the formula VII66. 68.VII69.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R;70.each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;71.each of Z1and Z2is independently N, CH, or CR5;72.m3 is 0 or 1; and73.the74.

75. present in ring A represents the aromaticity of ring A.

8. The compound of any one of claims 1, 2, 4, or 6, having the formula VIII78. 80.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R3;81.each of Y1and Y2is independently N, O, S, CH, or CR', provided that at least one of Y1and Y2is N, O, or S;82.each of Z1and Z2is independently N, CH, or CR5;83.Z3and Z4are each independently N, CH, or CR1; and84.the present in ring A and ring C represents the aromaticity of ring A and ring C.

9. The compound of any one of the preceding claims, having the formula IX86. 88.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5;89.each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;90.each of Z1and Z2is independently N, CH, or CR5;91.Z3and Z4are each independently N, CH, or CR1; and93.the94.

95. present in ring A and ring C represents the aromaticity of ring A and ring C.

10. The compound of any one of claims 1, 2, or 4, having the formula X98. 100.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Z1and Z2is independently N, CH, or CR'.

11. The compound of any one of claims 1 to 5, or 10, having the formula XI102. 104.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Z1and Z2, is independently N, CH, or CR3.

12. The compound of any one of claims 1, 2, 4, 6, or 10, having the formula XII107. 109.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR, provided that at least one of Y1and Y2is N, O, or S; and110.each of Z1and Z2is independently N, CH, or CR5;112.wherein the113.

114. present in ring A represents the aromaticity of ring A.

13. The compound of any one of claims 1 to 7, or 10 to 12, having the formula XIII117. 119.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR provided that at least one of Y1and Y2is N, O, or S; and120.each of Z1and Z2is independently N, CH, or CR5;121.wherein the122.

123. present in ring A represents the aromaticity of ring A.

14. The compound of any one of claims 1, 2, 4, 6, 8, 10, or 12, having the formula XIV126. 128.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;129.each of Z1and Z2is independently N, CH, or CR5; and130.Z3and Z4are each independently N, CH, or CR1;132.wherein the133.

134. present in ring A and ring C represents the aromaticity of ring A and ring C.

15. The compound of any one of the preceding claims, having the formula XV137. 139.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; each of Z1and Z2is independently N, CH, or CR5; and140.Z3and Z4are each independently N, CH, or CR1;142.wherein the143.

144. present in ring A and ring C represents the aromaticity of ring A and ring C.

16. The compound of claim 1 or 2, having the formula XVI147. 149.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each RSais independently H or R5.

17. The compound of any one of claims 1, 2, 3, or 16, having the formula XVII152. 154.XVII155.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently H or R5; and156.each of Z1and Z2is independently N, CH, or CR5.

18. The compound of any one of claims 1, 2, or 16, having the formula XVIII159. 161.XVIII162.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5,163.one of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and165. 167.the present in ring A represents the aromaticity of ring A.

19. The compound of any one of claims 1, 2, 3, 16, 17, or 186, or a pharmaceutically acceptable salt thereof, having the formula XIX170. 172.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently H or R5;173.each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and174.the present in ring A represents the aromaticity of ring A.

20. The compound of any one of claims 1, 2, 6, 16, or 18 having the formula XX176. 178.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently H or R5;179.each of Y1and Y2is independently N, O, S, CH, or CR, provided that at least one of Y1and Y2is N, O, or S;180.Z3and Z4are each independently N, CH, or CR1; and182.the183.

184. present in ring A and ring C represents the aromaticity of ring A and ring C.

21. The compound of any one of claims 1, 2, 3, 6, or 16 to 20, having the formula XXI187. 189.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R~ is independently H or R5;190.each of Y1and Y2is independently N, O, S, CH, or CR, provided that at least one of Y1and Y2is N, O, or S;191.Z3and Z4are each independently N, CH, or CR1; and193.the194.

195. present in ring A and ring C represents the aromaticity of ring A and ring C.

22. The compound of claim 1 or 2, having the formula XXII197. 199.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

23. The compound of any one of claims 1 to 3, having the formula XXIII202. 204.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 1, 2, or 22, having the formula XXIV207. 209.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S; and211.wherein the212.

213. present in ring A represents the aromaticity of ring A.

25. The compound of any one of claims 1 to 3, or 22 to 24, having the formula XV215. 217.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR', provided that at least one of Y1and Y2is N, O, or S; and219. 221.» I222.wherein the223.

224. present in ring A represents the aromaticity of ring A.

26. The compound of any one of claims 1, 2, 22, or 24, having the formula XXVI227. 229.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O. or S;230.Z3and Z4are each independently N, CH, or CR1; and232.wherein the233.

234. present in ring A and ring C represents the aromaticity of ring A and ring C.

27. The compound of claims 1 to 3, or 22 to 26, having the formula XXVII236. 238.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each of Y1and Y2is independently N, O, S, CH, or CR7, provided that at least one of Y1and Y2is N, O, or S;239.Z3and Z4are each independently N, CH, or CR1; and241.wherein the242.

243. present in ring A and ring C represents the aromaticity of ring A and ring C.

28. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is of the formula246.

248.

249. “ ^wv- ” is apoint of covalent attachment to ring A; and250.R^is H orR1.

29. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is O.

30. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is NR8.

31. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula255.

257. 259.wherein “ •~w ” is a point of covalent attachment to ring A.

32. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8is H or methyl.

33. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y is NR10.

34. The compound of claim 33, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R10is H or methyl.

35. The compound of any one of claims 1 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula266. 268.wherein “^w" is a point of covalent attachment to ring A.

36. The compound of claim 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

37. The compound of claim 35, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein X is -NR8-.

38. The compound of any one of claims 1 to 16, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, comprising a portion of the formula273.

275. 277.wherein is a point of covalent attachment to ring A.

39. The compound of any one of claims 38, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R8is H or methyl.

40. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is 4- to 10-membered heterocycloalkyl, -Ci-C6alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cioaryl, -Ci-Cg alkylene-(Cs-Cio aryl), 5- to 10-membered heteroaryl, or -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in 4- to 10-membered heterocycloalkyl, -Ci-Cb alkylene-(4- to 10-membered heterocycloalkyl), Ce-Cio aryl, -Ci-Cbalkylene-(C6-Cioaryl), 5- to 10-membered heteroaryl, and -Ci-Ct, alkylene-(5- to 10-membered heteroaryl), is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-Ce alkyl, -Ci-Ce alky lene-(O-Ci-Ce alkyl), -0C1-C& alkylene-(0-Ci-C6 alkyl), -Ci-C, alkylene-(O-Re), Ce-Cio aryl, -Ci-C8 alkylene-(C6-Cio aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -Ci-Ce alkylene-(5- to 10-membered heterocycloalkyl), -ORe,280.-OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

41. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -Ci-Ce alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted by deuterium, halogen, -Re, -Rf, Ci-C, alkyl, -Ci-Cbalkylene-(O-Ci-C6 alkyl), -OCi-Cbalkylene-(O-Ci-C6 alkyl), -Ci-Ce alkylene-(O-Re), Cs-Cioaryl, -Ci-C6alkylene-(Cb-Cio aryl), haloalkyl, Cs-Ce cycloalkyl, 5-to 10-membered heteroaryl, -Ci-Ce alkylene-(5- to 10-membered heterocycloalkyl), -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReC(=NRf)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

42. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is of the formula284.

285. wherein “ ww ” is a point of covalent attachment to X.

43. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein R6is of the formula287.

44. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein two R3, when present, taken together with the carbon atom or carbon atoms to which they are attached, combine to form a C3-C6 cycloalkyl.

45. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R5, when present, is independently deuterium, halogen, Ci-Ce alkyl, -ORa, -SRa, -NRaRh, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -CN, or -NO2, wherein each hydrogen atom in Ci-Ce alkyl, C2-C6 alkenyl, Co-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cio aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, Ci-C alkyl, Ci-C6haloalkyl. -Re, -Rf, -ORe, -OC(O)Re, -OC(O)NReRf, -OS(O)Re, -OS(O)2Re, -OS(O)NReRf, -OS(O)2NReRf, -SRe, -S(O)Re, -S(O)2Rc, -S(O)NReRf, -S(O)2NReRf, -NReRf, -NReC(O)Rf, -NReC(O)ORf, -NReC(O)NReRf, -NReS(O)Rf, -NReS(O)2Rf, -NReS(O)NReRf, -NReS(O)2NReRf, -C(O)Re, -C(O)ORe, -C(O)NReRf, -PReRf, -P(O)ReRf, -P(O)2ReRf, -P(O)NReRf, -P(O)2NReRf, -P(O)ORe, -P(O)2ORe, -CN, or -NO2.

46. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R, when present, is independently deuterium, halogen, -NRaRb, or -CN.

47. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein each R'. when present, is independently deuterium, halogen, -NH2, or -CN.

48. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y1, when present, is O.

49. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y2, when present, is N.

50. The compound of any one of claims 1 to 47, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y1, when present, is N.

51. The compound of any one of claims 1 to 47, or 50, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Y2, when present, is O.

52. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein nl is 0 or 2.

53. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein n2 is 0.

54. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein m3 is 0.

55. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

56. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q is 1.

57. The compound of any one of claims 1 to 55, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein q is 2.

58. The compound of any one of the preceding claims, or an isotopically labeled form thereof, a pharmaceutically acceptable salt thereof, wherein Z1, when present, is N.

59. The compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, wherein Z2, when present, is N.

60. The compound of claim 1, selected from the group consisting of (l' / ?)-7'-amino-3-(4-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7, T-naphthalene]-8'-carbonitrile;304.(T7?)-7'-amino-3-(4-{[2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl Jethoxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[ l,2]benzoxazole-7, l'-naphthalene]-8'-carbonitrile;305.(T5)-6'-amino-3-(4-{(1 )-l-[(25,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl ]oxy }pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[ 1,2]benzoxazole-7, T-indene]-7'-carbonitrile;306.(T / ?)-7'-amino-3-(4-{(1 )-l-[(25,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-ylJoxy}pyrimidin-2-yl)-3',4',5,6-tetrahydro-2' / / ,4 / / -spiro[[l,2]benzoxazole-7,r-naphthalene]-8’-carbonitrile;307.( 1 '5)-6'-amino-3-(4- { ( 1 )-l - [ (25) - 1 -methylpyrrolidin-2-y l]ethoxy } -6- { [ 1 -(prop-2-enoyl)azetidin-3-yl]amino}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4H-spiro[[ 1,2]benzoxazole-7, l'-indene]-7'-carbonitrile;308.(T5)-6'-amino-3-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-4 / 7-spiro [ [ 1, 2]benzoxazole-7, 1 ’-indene] -7' -c arbonitrile;309.( 1 '5)-6'-amino-3-(4-{ ( 15) - 1 -[(2 / ?,35)-3-fluoro- l-methylpyrrolidin-2-yl]ethoxy } -6-{ [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-47 / -spiro[[l,2]benzoxazole-7, 1 '-indene]-7'-carbonitrile;310.(T )-6'-amino-3-(4-{(15)-l-[(2 )-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2',3'.5,6-tetrahydro-4H-spiro[[l,2]benzoxazole-7, T-indene]-7'-carbonitrile;311.( 1 '5)-7'-amino-3-(4-{ ( 15)- 1 -[(25,4 / ?)-4-fluoro- 1 -methylpyrrolidin-2-yl]ethoxy } -6-{ [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy }pyrimidin-2-yl)-3',4',5,6-tetrahydro-2'H,4H-spiro[[l,2]benzoxazole-7,r-naphthalene]-8'-carbonitrile;312.(l'5)-6'-amino-3-(4-{[(3 / )-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2',3',5,6-tetrahydro-477-spiro[[l,2]benzoxazole-7,r-indene]-7'-carbonitrile;313.( 15)-6-amino-3'-(4- { (1 )- 1 - [(25)- 1 -methylpyrrolidin-2-yl]ethoxy } -6- { [ 1 -(prop-2-enoyl)azetidin-3-yl]oxy}pyrimidin-2-yl)-2,3-dihydro-4'H,6'H-spiro[indene-l,7'-pyrano[3,4-d] [ 1,2]oxazole]-7 -carbonitrile; (lS)-7-amino-3'-(4-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}-6-{[l-(prop-2-enoy l)azetidin-3-yl ]oxy } pyrimidin-2-yl)-3,4-dihydro-2H,4'H,6'H-spiro[ naphthalene- 1,7'-pyrano[3,4-d][l,2]oxazole]-8-carbonitrile;314.(15)-6-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3-dihydro-4'7 / ,6'77-spiro[indene-l,7'-pyrano[3,4-d][l,2]oxazole]-7-carbonitrile;315.6-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3-dihydro-4' / 7,6' / 7-spiro[indene-l,7'-pyrano[3,4-d][l,2]oxazole]-7-carbonitrile;316.(lS)-7-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-yl]oxy}-6-{(lS)-l-[(2S)- 1 -methylpyrrolidin-2-yl ]ethoxy}pyrimidin-2-yl)-3,4-dihydro-2H,4'H,6'77-spiro[ naphthalcne-l,7'-pyrano[3,4-d][l,2]oxazole]-8-carbonitrile;317.(17?)-6-amino-3'-(4-{[(3 / ?)-2,2-dimethyl-l-(prop-2-enoyl)azetidin-3-ylJoxy}-6-{(lS)-l-L(2S')-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2,3,4',5'-tetrahydrospiro[indene-l,7'-pyrano[4,3-d][l,2]oxazole]-7-carbonitrile; and318.(TS)-6'-amino-3-(4-{[(3 / ?)-l-(2-fluoroprop-2-enoyl)-2,2-dimethylazetidin-3-yl]oxy}-6-{(lS)-l-[(25)-l-methylpyrrolidin-2-yl]ethoxy}pyrimidin-2-yl)-2'.3',5,6-tetrahydro-4H-spiro [ [ 1, 2]benzoxazole-7, 1 ’-indene] -7' -c arbonitrile;319.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

61. The compound of claim 1, selected from the group consisting of (4S)-2-amino-3'-(3-{(lS)-l-[(2S,47?)-4-fhjoro-l-methylpyrrolidin-2-yl]ethyl}-7-{ [l-(prop-2-enoyl)azetidin-3-yl ]oxy } -3 / 7-11,2,3]triazolo[4,5-d]pyrimidin-5-yl)-5’,6,6',7-tetrahydro-4'H,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;321.(4S)-2-amino-3'-(3- { ( 1 S)- 1 - [(25')- 1 -methy lpyrrolidin-2-y 1] e thy 1 } -7- { [ 1 -(prop-2-enoyl)azetidin-3-yl]amino}-3 / 7-[l,2,3]triazolo[4,5-rf]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'H,5H-spiro[[ 1 ]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;322.(4S)-2-amino-3'-(7-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-3-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-3H-[l,2,3]triazolo[4,5-d]pyrimidin-5-yl)-5',6,6',7-tetrahydro-4'77,5H-spiro[[ 1 ]benzothiophene-4,7'-[ l,2]benzoxazole]-3-carbonitrile:323.(45)-2-amino-3'-(l-{(15)-l-[(25)-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]amino}-l / 7-pyrazolo[3,4-d]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4' / 7,577-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;324.(4S)-2-amino-3'-(4-{methyl[l-(prop-2-enoyl)azetidin-3-yl]amino}-l-{(lS)-l-[(2S)-l-methylpyrrolidin-2-yl]ethyl}-l / 7-pyrazolo[3,4-<f|pyrimidin-6-yl)-5',6,6',7-tetrahydro-4' / 7,5H- spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;325.(4S)-2-amino-3'-(l-{(lS)-l-[(2S,4 / ?)-4-fluoro-l-methylpyrrolidin-2-yl]ethyl}-4-{[l-(prop-2-enoyl)azetidin-3-yl]oxy }-177-pyrazolo[3,4-6 / ]pyrimidin-6-yl)-5',6,6',7-tetrahydro-4'77,5 / 7-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile; and326.(4S)-2-amino-3'-(l -{ (1S)-1 -[(2S)-1 -methylpyrrolidin-2-yl]ethyl }-4-{ [1 -(prop-2-enoyl)azetidin-3-yl]oxy}-177-pyrazolo[3,4-J]pyrimidin-6-yl)-5’,6,6',7-tetrahydro-4'77,5H-spiro[[l]benzothiophene-4,7'-[l,2]benzoxazole]-3-carbonitrile;327.an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof.

62. A pharmaceutical composition comprising at least one compound of any one of the preceding claims, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

63. A method of treating disease, such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any one of claims 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 62.

64. A compound of any one of claims 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.

65. A compound of any one of claims 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.

66. Use of a compound of any one of claims 1 to 61, an isotopically labeled form thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.

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