Heterocyclic inhibitors of cyclin-dependent kinases

Abstract

This disclosure provides chemical entities of formula (I) (e.g., a compound or a pharmaceutically acceptable salt thereof) that modulate (e.g., inhibit) Cyclin-dependent kinase 2 ("CDK2") activation (e.g., CCNE1 dependent CDK2 activation) and / or CDK2 complex formation and / or CDK2 complex activity. Non-limiting examples of said complexes include CDK2:cyclin complexes, e.g., CDK2:cyclin El complex (also referred to herein as CDK2:CCNE1). The chemical entities are useful, e.g., for treating a condition, disease or disorder in which (i) increased (e.g., excessive) CDK2 activation (e.g., CCNE1 dependent CDK2 activation), (ii) CDK2 complex formation and / or (iii) CDK2 complex activity contribute to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

Description

Attorney Docket No. 50006-0134WO1THERAPEUTIC AGENTS CROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of United States Provisional Application No.63 / 721,100, filed on November 15, 2024 and United States Provisional Application No.63 / 804,335, filed on May 12, 2025; each of which is incorporated herein by reference in its entirety.TECHNICAL FIELDThis disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that modulate (e.g., inhibit) Cyclin-dependent kinase 2 (“CDK2”) activation (e.g., CCNE1 dependent CDK2 activation) and / or CDK2 complex formation and / or CDK2 complex activity. Non-limiting examples of said complexes include CDK2:cyclin complexes, e.g., CDK2:cyclin El complex (also referred to herein as CDK2: CCNE1). The chemical entities are useful, e.g., for treating a condition, disease or disorder in which (i) increased (e.g., excessive) CDK2 activation (e.g., CCNE1 dependent CDK2 activation), (ii) CDK2 complex formation and / or (iii) CDK2 complex activity contribute to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.BACKGROUNDCyclin-dependent kinases (CDKs) are a family of serine / threonine kinases that are involved in regulating the cell cycle. CDKs typically work in conjunction with specific cyclin binding partners to form heterodimeric kinase complexes in order to be active and support cell division. In eukaryotic cells, there are four main phases of the cell cycle: Gl, S, G2, and M. The Gl phase prepares the cells for DNA synthesis and cell growth by upregulating expression of key proteins. The S phase is when DNA synthesis occurs, with normal cells doubling DNA content during this phase. The G2 phase is a period of rapid growth to prepare the cells for mitosis by synthesizing critical proteins. The M phase isAttorney Docket No. 50006-0134WO1when mitosis occurs, resulting in the parent cell dividing into two daughter cells (Freeman-Cook, K. 2023).The CDK2: CCNE1 complex plays a prominent role in cell cycle transition from G1 to S phase. The activated CDK2: CCNE1 complex phosphorylates the RBI tumor suppressor. RBI binds to and inhibits the E2F trancriptions factors, thus acting as a negative regulator of E2F-mediated transcription; when RBI is phosphorylated, it is released from the E2F transcription factors allowing for transcription of genes required for DNA synthesis and cell division (Asghar, 2015). In cells with CCNE1 amplification and / or overexpression, CDK2: CCNE1 hyperactivation can occur leading to cell cycle dysregulation and aberrant DNA replication; this can result in uncontrolled cell proliferation and oncogenesis. (Caldon, C. E., 2010; Fagundes, R., 2021). CCNE1 amplification and / or overexpression occurs in a number of different cancer types, including ovarian, uterine, esophagogastric, lung, breast and other indications as well (CBioPortal).SUMMARYThis disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that modulate (e.g., inhibit) Cyclin-dependent kinase 2 (“CDK2”) activation (e.g., CCNE1 dependent CDK2 activation) and / or CDK2 complex formation and / or CDK2 complex activity. Non-limiting examples of said complexes include CDK2:cyclin complexes, e.g., CDK2:cyclin El complex (also referred to herein as CDK2: CCNE1). The chemical entities are useful, e.g., for treating a condition, disease or disorder in which (i) increased (e.g., excessive) CDK2 activation (e.g., CCNE1 dependent CDK2 activation), (ii) CDK2 complex formation and / or (iii) CDK2 complex activity contribute to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.In one aspect, the disclosure features compounds of Formula (I):Attorney Docket No. 50006-0134WO1(1)or a pharmaceutically acceptable salt thereof, wherein:each of Z1and Z2is independently selected from the group consisting of N, CF, CH, CCH3, CCFH2, CCF2H, CCF3, and C-CN;Z3is N(Z4) or CH-N(R’)(-Z4), wherein Z4is a covalent warhead;X is a bond or C(RX3)(RX4);Y is a bond or C(RY3)(RY4);each of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently defined according to any one or more of (A)-(J) below:(A) one or more of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently selected from the group consisting of H; C1-3 alkyl, which is optionally substituted with from 1-6 fluoro; -CH2OCH3; CH2NR’R”; CN; CH2CN; and CH2(cyclopropyl); and cyclopropyl, wherein cyclopropyl is optionally substituted with from 1 -6 fluro;(B) RX1and RX2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selectedAttorney Docket No. 50006-0134WO1from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(C) RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(D) RY1and RY2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(E) RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(F) one of RX1and RX2and one of RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; orAttorney Docket No. 50006-0134WO1(ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(G) one of RY1and RY2and one of RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(H) one of RX1and RX2and one of RY1and RY2forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, or -C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(I) one of RX1and RX2and one of RY3and RY4forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, or -C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(J) one of RX3and RX4and one of RY1and RY2or one of RY3and RY4forms: (i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, or -C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);Attorney Docket No. 50006-0134WO1*4R”R2is -NR21R22, -OR21, orr23(Formula A); wherein:R21is:(*)l~ ( B1j - B21v- ' (F ormul a A- 1 ); or(ii) -L2-L3-B21(Formula A-2);wherein:Ring B1is:• C3-10 cycloalkylene or C3-10 cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclylene or heterocycloalkenyl ene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroarylene of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• C6-10arylene optionally substituted with from 1-4 Rc;B21is:• L1-C3-10cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;Attorney Docket No. 50006-0134WO1• L1-heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• L1-heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• L1-C6-10aryl optionally substituted with from 1-4 Rc;• Ci-io alkyl optionally substituted with from 1-6 Ra,• C(O)- Ci-io alkyl optionally substituted with from 1-6 Ra,• NR’R”; or• OR’”;R22is H; Ci-4 alkyl; -C(O)(Ci-4 alkyl); -CH2C(O)(CI-4 alkyl); -C(O)O(Ci-4 alkyl); -CH2C(O)O(CI-4 alkyl); -CONR’R”; -CH2CONR’R”; -S(O)I-2NR’R”; -CH2S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; Ci-4 alkoxy or biotinyl;each of R23and R24is independently selected from the group consisting of H; fluoro; Ci-3 alkyl, which is optionally substituted with from 1-6 fluoro; C1-3 alkoxy, which is optionally substituted with from 1-6 fluoro; OH; -CH2OCH3; CHzNR’R”; CN; CH2CN; and CH2(cyclopropyl); orR23and R24together with the carbon atom to which each is attached form C=O; or R23and R24together with the carbon atom to which each is attached form C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;L is NH, NRb, O, or a bond;L1is C(O), CH2, CH(CH3), CH(CF3), NH, NRb, O, or a bond;L2is C2-io alkylene, alkenylene, or alkynylene, each of which is optionally substituted with from 1-6 Ra, and wherein L2is optionally interrupted with an internal orAttorney Docket No. 50006-0134WO1terminal O or S atom, provided that L2and any linkages of L2to another moiety do not contain heteroatom-heteroatom bonds;L3is O, S, or a bond;R3is -B3-L4-B4;wherein:B3is:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• C6-10aryl optionally substituted with from 1-4 Rc;L4is -NHC(O)- or -C(O)NH-;B4is• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;Attorney Docket No. 50006-0134WO1• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• C6-10aryl optionally substituted with from 1-4 Rc; or• Ci-6 alkyl optionally substituted with C3-10 cycloalkyl;each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NRdRe; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;each occurrence of Rbis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(0)I-2NR’R”; - S(O)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy;each occurrence of Rcis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or Ci-4 haloalkoxy; Ci-4 haloalkoxy; -S(O)i-2(Ci-4 alkyl); -S(O)(=NH)(Ci-4 alkyl); -NRdRe; -OH; -S(O)i-2NR’R”; -Ci-4 thioalkoxy; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF5;each occurrence of Rdand Reis independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and Ci-4 alkoxy;Rpis CH3, optionally substituted cyclopropyl, phenyl, or p-tol-phenyl;Attorney Docket No. 50006-0134WO1each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C1-4 alkyl optionally substituted with 1-7 fluoro; andeach occurrence of R’” is independently selected from the group consisting of: C3-C6 cycloalkyl and C1-4 alkyl optionally substituted with C3-C6 cycloalkyl.In another aspect, this disclosure features compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:each of Z1and Z2is independently selected from the group consisting of N, CF, CH, CCH3, CCFH2, CCF2H, CCF3, and C-CN;Z3is N(Z4) or CH-N(R’)(-Z4), wherein Z4is a covalent warhead;X is a bond or C(RX3)(RX4);Y is a bond or C(RY3)(RY4);each of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently defined according to any one or more of (A)-(J) below:(A) one or more of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently selected from the group consisting of H; C1-3 alkyl, which is optionally substituted with from 1-6 fluoro; -CH2OCH3; CH2NR’R”; CN; CH2CN; CH2(cyclopropyl); and cyclopropyl, wherein cyclopropyl is optionally substituted with from 1 -6 fluoro;(B) RX1and RX2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituentsAttorney Docket No. 50006-0134WO1independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(C) RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(D) RY1and RY2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(E) RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;Attorney Docket No. 50006-0134WO1(F) one of RX1and RX2and one of RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(G) one of RY1and RY2and one of RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(H) one of RX1and RX2and one of RY1and RY2forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(I) one of RX1and RX2and one of RY3and RY4forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or -C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(J) one of RX3and RX4and one of RY1and RY2or one of R33and RY4forms:Attorney Docket No. 50006-0134WO1(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CHCCH^CH CIL)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);R24R21R2is -NR21R22, -OR21, orr23(Formula A); wherein:R21is:(i)l~ ( B1j - B21- S (F ormul a A- 1 ); or(ii) -L2-L3-B21(Formula A-2);wherein:Ring B1is:• C3-io cycloalkylene or C3-io cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclylene or heterocycloalkenylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroarylene of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; orAttorney Docket No. 50006-0134WO1Ce-io arylene optionally substituted with from 1-4 Rc;L1is C(O), CH2, CH(CH3), CH(CF3), NH, NRb, O, or a bond;L2is C2-10 alkylene, alkenylene, or alkynylene, each of which is optionally substituted with from 1-6 Ra, and wherein L2is optionally interrupted with an internal or terminal O or S atom, provided that L2and any linkages of L2to another moiety do not contain heteroatom-heteroatom bonds;L3is O, S, or a bond;B21is:• iZ-Cb-io cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• L'-heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• l heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• U-Ce-io aryl optionally substituted with from 1-4 Rc;• Ci-10 alkyl optionally substituted with from 1-6 Ra,• C(O)- Ci-10 alkyl optionally substituted with from 1-6 Ra,• NR’R”; or• OR’”;Attorney Docket No. 50006-0134WO1R22is H; Ci-4 alkyl; -C(O)(Ci-4 alkyl); -CH2C(O)(CI-4 alkyl); -C(O)O(Ci-4 alkyl); -CH2C(O)O(CI-4 alkyl); -CONR’R”; -CH2CONR’R”; -S(O)I-2NR’R”; -CH2S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; Ci-4 alkoxy or biotinyl;each of R23and R24is independently selected from the group consisting of H; fluoro; Ci-3 alkyl, which is optionally substituted with from 1-6 fluoro; C1-3 alkoxy, which is optionally substituted with from 1-6 fluoro; OH; -CH2OCH3; CH2NR’R”; CN; CH2CN; and CH2(cyclopropyl); orR23and R24together with the carbon atom to which each is attached form C=O; or R23and R24together with the carbon atom to which each is attached form C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;L is NH, NRb, O, or a bond;R3is -B3-L4-B4;wherein:B3is:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• C6-10aryl optionally substituted with from 1-4 Rc;Attorney Docket No. 50006-0134WO1L4is -NHC(O)- or -C(O)NH-;B4is• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• C6-10aryl optionally substituted with from 1-4 Rc; or• C1-6 alkyl optionally substituted with C3-10 cycloalkyl;each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NRdRe; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(Ci 4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;each occurrence of Rbis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; - S(O)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy;each occurrence of Rcis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; Ci-4 alkoxy optionally substituted with Ci-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)i-2(Ci-4 alkyl); -S(O)(=NH)(CI-4 alkyl); -NRdRe; -OH; -S(O)I-2NR’R”; -Ci-4 thioalkoxy; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF5;Attorney Docket No. 50006-0134WO1each occurrence of Rdand Reis independently selected from the group consisting of: H; Ci-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, Ci-6 alkoxy, Ci-6 haloalkoxy, and halo; -C(O)(Ci-4alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)i-2NR’R”; -S(O)i-2(Ct-4 alkyl); -OH; and C1-4 alkoxy;Rpis CH3, optionally substituted cyclopropyl, phenyl, or j>- / o / -phenyl;each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C1-4 alkyl optionally substituted with 1-7 fluoro; andeach occurrence of R’” is independently selected from the group consisting of: C3-C6 cycloalkyl and C1-4 alkyl optionally substituted with C3-C6 cycloalkyl.In a further aspect, this disclosure features compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:each of Z1and Z2is independently selected from the group consisting of N, CF, CH, CCH3, CCFH2, CCF2H, CCF3, and C-CN;Z3is N(Z4), CH-N(R’)(-Z4), N-L-(Z4), or CH-N(R’)-L-(-Z4), wherein Z4is a covalent warhead, and and L is a linker;X is a bond or C(RX3)(RX4);Y is a bond or C(RY3)(RY4);Attorney Docket No. 50006-0134WO1each of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently defined according to any one or more of (A)-(J) below:(A) one or more of RX1, RX2, RX3, RX4, Ryi, RY2, RY3, and RY4is independently selected from the group consisting of H; C1-3 alkyl, which is optionally substituted with from 1-6 fluoro; -CH2OCH3; CJhNR’R”; CN; CH2CN; CH2(cyclopropyl); cyclobutyl; and cyclopropyl, wherein cyclopropyl is optionally substituted with from 1-6 fluoro;(B) RX1and RX2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;(C) RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;(D) RY1and RY2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein theAttorney Docket No. 50006-0134WO1cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;(E) RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;(F) one of RX1and RX2and one of RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(G) one of RY1and RY2and one of RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;(H) one of RX1and RX2and one of RY1and RY2forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or -C(CH3)2C(CH3)2-;Attorney Docket No. 50006-0134WO1(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(I) one of RX1and RX2and one of RY3and RY4forms:(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);(J) one of RX3and RX4and one of RY1and RY2or one of RY3and RY4forms: (i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);*24R21^G- —R2is -NR21R22, -OR21, orr23(Formula A); wherein:R21is:(i)( B1J - B21x 7(F ormul a A- 1 ); or(ii) -L2-L3-B21(Formula A-2);wherein:Ring B1is:Attorney Docket No. 50006-0134WO1• C3-10 cycloalkylene or C3-10 cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclylene or heterocycloalkenylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)Rp, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroarylene of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• C6-10arylene optionally substituted with from 1-4 Rc;L1is C(O), CH2, CH(CH3), CH(CF3), NH, NRb, O, or a bond;L2is C2-10 alkylene, alkenylene, or alkynylene, each of which is optionally substituted with from 1-6 Ra, and wherein L2is optionally interrupted with an internal or terminal O or S atom, provided that L2and any linkages of L2to another moiety do not contain heteroatom-heteroatom bonds;L3is O, S, or a bond;B21is:• L1-C3-IO cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• L’-heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;Attorney Docket No. 50006-0134WO1• U-heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• L1-C6-10aryl optionally substituted with from 1-4 Rc;• Ci-io alkyl optionally substituted with from 1-6 Ra,• C(O)- Ci-io alkyl optionally substituted with from 1-6 Ra,• NR’R”; or• OR’”;R22is H; Ci-4 alkyl; -C(O)(Ci-4 alkyl); -CH2C(O)(CI-4 alkyl); -C(O)O(Ci-4 alkyl); -CH2C(O)O(CI-4 alkyl); -CONR’R”; -CHzCONR’R”; -S(O)i-2NR’R”; -CH2S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; Ci-4 alkoxy or biotinyl;each of R23and R24is independently selected from the group consisting of H; fluoro; Ci-3 alkyl, which is optionally substituted with from 1-6 fluoro; C1-3 alkoxy, which is optionally substituted with from 1-6 fluoro; OH; -CH2OCH3; CHzNR’R”; CN; CH2CN; and CH2(cyclopropyl); orR23and R24together with the carbon atom to which each is attached form C=O; or R23and R24together with the carbon atom to which each is attached form C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;L is NH, NRb, O, or a bond;R3is -B3-L4-B4;wherein:B3is:• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;Attorney Docket No. 50006-0134WO1• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• C6-10aryl optionally substituted with from 1-4 Rc;L4is -NHC(O)- or -C(O)NH-;B4is• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;• C6-10 aryl optionally substituted with from 1-4 Rc; or• C1-6 alkyl optionally substituted with C3-10 cycloalkyl;each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NRdRe; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;Attorney Docket No. 50006-0134WO1each occurrence of Rbis independently selected from the group consisting of: Ci-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; - S(O)i-2(Ci-4alkyl); -OH; and Ci-4 alkoxy;each occurrence of Rcis independently selected from the group consisting of: halo; cyano; Ci-io alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or Ci-4 haloalkoxy; Ci-4 haloalkoxy; -S(O)1-2(C1-4alkyl); -S(O)(=NH)(CI-4 alkyl); -NRdRe; -OH; -S(O)I-2NR’R”; -Ci-4 thioalkoxy; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF5;each occurrence of Rdand Reis independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(Ci-4alkyl); -C(O)O(Ci-4alkyl); -CONR’R”; -S(O)I-2NR’R”; -S(O)i-2(Ci-4alkyl); -OH; and Ci-4 alkoxy;Rpis CH3, optionally substituted cyclopropyl, phenyl, or j>- / o / -phenyl;each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and Ci-4 alkyl optionally substituted with 1-7 fluoro; andeach occurrence of R’” is independently selected from the group consisting of: C3-C6 cycloalkyl and Ci-4 alkyl optionally substituted with C3-C6 cycloalkylAlso provided herein is a composition, e.g., a pharmaceutical composition, that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.Attorney Docket No. 50006-0134WO1In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, exhibits a higher selectivity for CDK2 than other cyclin-dependant kinases (CDK’s) e.g., CDK1, CDK3, CDK7, and CDK9.In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, exhibits a higher selectivity for CDK2: CCNE1 than for CDK2: CCNA2.This disclosure provides methods for modulating (e.g., inhibiting) CDK2 activation (e.g., CCNE1 dependent activation), which include contacting the CDK2 with a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof.This disclosure provides methods for modulating (e g., inhibiting) CDK2 complex formation and / or kinase activity, which include contacting the CDK2 or CDK2 complex with a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. In certain embodiments, the complex is a CDK2:cyclin complex, e.g., CDK2: CCNE1.Methods include in vitro methods, e.g., contacting a sample (e.g., a biological sample) that includes one or more cells comprising CDK2 or a complex thereof with a compound of formula (I) or a pharmaceutically acceptable salt thereof.Methods can also include in vivo methods; e.g., administering a a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof, to a subject (e.g., a human) having a disease, disorder, or condition, in which increased (e.g., excessive) activation of CDK2 or a complex thereof contributes to the pathology and / or symptoms and / or progression of the disease.In some embodiments, the one or more cells are cancer cells. In certain embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, stomach cancer, melanoma, hepatocellular, and thyroid cancer (e.g., breast cancer, e.g., ovarian cancer).Attorney Docket No. 50006-0134WO1This disclosure provides methods of treating a disease or disorder associated with CDK2 activity in a subject in need thereof. The methods include administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof to the subject.In some embodiments, increased (e.g., excessive) activation of CDK2 (e.g., Cyclin El dependent CDK2 activation) or a complex thereof, contributes to the pathology and / or symptoms and / or progression of the disease or disorder.In some embodiments, the disease or disorder associated with CDK2 activity is a cancer. Accordingly, this disclosure also features methods of treating a subject with cancer, which include administering to the subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.In certain embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, stomach cancer, melanoma, hepatocellular, and thyroid cancer (e.g., breast cancer, e.g., ovarian cancer).In certain embodiments, the cancer is breast cancer, e.g.: breast invasive carcinoma (BRC ); TNBC (triple negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer); ER+HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HER2- breast cancer (human epidermal growth factor 2 negative breast cancer); HER2-low breast cancer (human epidermal growth factor 2 low breast cancer); or HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer).In certain embodiments, the cancer is ovarian cancer, (e.g., ovarian serous cystadenocarcinoma (OV)). In certain of these embodiments, the subject has CCNE1 amplified platinum-resistant or platinum-refectory ovarian cancer.Attorney Docket No. 50006-0134WO1In certain embodiments, the cancer is stomach cancer (e g., stomach adenocarcinoma (STAD)).In certain embodiments, the cancer is gastric cancer (e.g., gastrointestinal stromal tumor).In certain embodiments, the cancer is uterine cancer (e.g., uterine carcinosarcoma (UCS) or uterine corpus endometrial carcinoma (UCEC)).In certain embodiments, the cancer is endometrial cancer.In certain embodiments, the cancer is colorectal cancer.In certain embodiments, the cancer is pancreatic cancer (e.g, pancreatic adenocarcinoma (PAAD) or pancreatic ductal adenocarcinoma (PDAC)).In certain embodiments, the cancer is kidney cancer.In certain embodiments, the cancer is head and neck cancerIn certain embodiments, the cancer is liver cancer.In certain embodiments, the cancer is prostate cancer.In certain embodiments, the cancer is skin cancer.In certain embodiments, the cancer is leukemia (e.g., AML (acute myeloid leukemia)).In certain embodiments, the cancer is lymphoma (e g., B-cell lymphoma)In certain embodiments, the cancer is myelodysplastic syndromes (MDS) or my el oprol i ferati ve neoplasm s (MPN).In certain embodiments, the cancer is sarcoma (SARC).In certain embodiments, the cancer is esophageal cancer (e.g., esophageal carcinoma (ESCA)).In certain embodiments, the cancer is bladder cancer (e.g., bladder urothelial carcinoma).In certain embodiments, the cancer is lung cancer (e.g., lung squamous carcinoma and non-small cell lung cancer, e.g, EGFRm (epidermal growth factor receptor mutant)-’-non-small cell lung cancer).In certain embodiments, the cancer is cholangiocarcinoma.In certain embodiments, the cancer is adrenocortical carcinoma (ACC).In certain embodiments, the cancer is mesothelioma.Attorney Docket No. 50006-0134WO1In certain of the foregoing embodiments, the subject has CCNE1 amplified advanced / relapsed tumors.In some embodiments, the cancer is refractory to CDK4 and / or CDK4 / CDK6 inhibitors.In certain embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors is stomach / gastric cancer.In certain embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors is ovarian cancer.In certain embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors is uterine cancer.In certain embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors is lung cancer (e.g., adenocarcinoma).In certain embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors is breast cancer (e.g., BrCa resistant to CDK4 / CDK6 inhibitors).In certain embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.In certain embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1.In certain embodiments, the cancer is refractory to CDK4 and / or CDK4 / CDK6 inhibition and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1).In certain of these embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1) is stomach / gastric cancer.In certain of these embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1) is ovarian cancer.Attorney Docket No. 50006-0134WO1In certain of these embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1) is uterine cancer.In certain of these embodiments, the cancer that is refractory to the subject has, or previously and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1) is lung cancer (e.g., adenocarcinoma).In certain of these embodiments, the cancer that is refractory to CDK4 and / or CDK4 / CDK6 inhibitors and is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2 (e.g., characterized by amplification and / or overexpression of CCNE1) is breast cancer (e.g., BrCa resistant to CDK4 / 6 inhibitors).In some embodiments, the subject is being treated, or has previously been treated with one or more chemotherapies, e.g, platinum therapy.In some embodiments, the subject has, or has previously been determined to have an amplification and / or overexpression of the cyclin El (CCNE1) gene or protein, e.g., the subject has an expression level of CCNE1 that is higher than a control expression level of CCNE1.In some embodiments, the subject is being treated, or has previously been treated with one or more CDK4 and / or CDK4 / CDK6 inhibitors.For example, the subject can have ER+ HER2- breast cancer that has progressed despite treatment with one or more CDK4 / CDK6 inhibitors.As another example, the subject can have CCNE1 amplified platinu -resistant or platinum-refectory ovarian cancer.As a further example, the subject can have endometrial cancer (with prior platinum therapy, e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy).Attorney Docket No. 50006-0134WO1As a further example, the subject can have CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (which may include a prior platinum therapy) As a further example, the subject can have gastric cancer (with prior platinum therapy e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy).In some embodiments, the methods further include identifying, e.g., from a biological sample obtained from the subject, that the subject has:(a) an amplification of the cyclin El (CCNE1) gene; and / or(b) an expression level of CCNE1 that is higher than a control expression level of CCNE1.In certain of the foregoing embodiments, the subject is being treated, or has previously been treated with one or more CDK4 and / or CDK4 / CDK6 inhibitors.Accordingly, the methods can further include determining whether a subject (e.g., a human subject) is eligible or a candidate for treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof.In some embodiments, the methods can further include evaluating the response of a subject (e.g., a human subject) having said amplification and / or increased expression level of CCNE1 to a compound of formula (I) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof.In some embodiments, the subject has CCNE1 -amplified stomach / gastric cancer. In some embodiments, the subject has CCNE1 -amplified ovarian cancer.In some embodiments, the subject has CCNE1 -amplified uterine cancer.In some embodiments, the subject has CCNE1 -amplified lung cancer (e.g., adenocarcinoma).In some embodiments, the subject has CCNE1 -amplified breast cancer (e.g., BrCa resistant to CDK4 / 6 inhibitors.In certain embodiments, the methods further include administering one or more additional therapeutic agents.In some embodiments, the subject is a human.Attorney Docket No. 50006-0134WO1Other embodiments include those described in the Detailed Description and / or in the claims.DefinitionsTo facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.Covalent WarheadsThe compounds described herein include a “covalent warhead” as part of their chemical structure. In Formula I, variable “Z4” represents the covalent warhead. As used herein, the term “warhead” refers to a moiety having one or more reactive functional groups that are capable of covalently binding (e.g., irreversibly or reversibly; e.g., irreversibly) to one or more amino acid residues (e g., cysteine, lysine, serine, threonine, or histidine; for example, the one or more amino acid residues is cysteine) present in CDK2, thereby irreversibly or reversibly forming a covalent bond between the warhead and the amino acid residue. Without wishing to be bound by theory, it is believed that the formation of said covalent bond (e g., a carbon-heteroatom bond such as C-S, C-N, or C-O; e.g., C-S) between the warhead and amino acid residue can alter one or more properties associated with CDK2; e.g., can inhibit one or more functions or activities associated with CDK2.Non-limiting examples of covalent warheads include:Attorney Docket No. 50006-0134WO11) a, P unsaturated acyclic and cyclic systems (for example, Lwl-EWG, wherein LW1is alkenyl or alkynyl; and EWG is an electron withdrawing group; e.g., Michael acceptors, e.g., acrylamides, acrylates, vinyl sulfones, a, P-un saturated ketones);2) Strained heterocycles (e.g., heterocycles including from 3-4 ring atoms wherein 1 ring atom is a heteroatom selected from oxygen, nitrogen, and sulfur; e.g., epoxide, aziridine, beta-lactam, and other strained systems); optionally, the strained ring heterocycles can be linked to formula (I) via a linker, e.g., -C(O);3) Strained carbocyclic systems (e.g., cyclopropyl substituted with one or more electron-withdrawing groups); optionally, the strained ring carboocycles can be linked to formula (I) via a linker, e.g., -C(O);4) Electron-deficient arenes / heteroarenes (e.g., pyridine or fluorobenzene) which can undergo S\Ar reaction (e.g., with cysteine or lysine), e g., optionally substituted with one or more electron withdrawing groups, e g., halo, e.g., chloro;5) Sulfur-containing heteroarenes (e.g., thiadiazole);6) Styrenyl moieties (i.e., aryl / heteroaryl that is directly conjugated to an alkenyl or alkynyl); in some embodiments, the styrenyl moiety is linked to formula (I) through the conjugated double or triple bond;7) Activated ketone (e.g., halomethylketone);8) Acylating agents (e.g., carbamates, aza-peptides, acyl hydroxamates), phosphonylating agents (e.g., phosphonyl fluorides), or sulfonylation agents (e g., sulfonyl fluoride);9) Aldehydes;10) Boronic acids or boronic esters; and11) Organonitrile compounds (e.g., alkyl nitrile, cyanamide, or acyl cyanamide).Non-limiting examples of covalent warheads include W which is a moiety of Formula Aw-W’, whereinAwis an optional linker group;W’ is selected from the group consisting of:a) Lwl-EWG, whereinAttorney Docket No. 50006-0134WO1• LW1is C2-8 alkenyl, C4-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, or C2-8 alkynyl, whereino -EWG is attached to a sp2or sp hybridized carbon of LW1, thereby providing an a, P-unsaturated system;o LW1is optionally substituted with one halo (e.g., F) at the carbon atom attached to -EWG;o the sp2or sp hybridized carbons of LW1which are not attached to EWG are optionally substituted with 1 RL; and o each sp3hybridized carbon of LW1is optionally substituted with from 1-3 substituents each independently selected from halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, NH2, NH(RN), N(RN)2, and RL1; and • EWG is a divalent group selected from: -C(O)-, -S(O)2-, -C(O)O-, - C(O)NH-, -C(O)NRN-, -S(O)2NH-, and -S(O)2NRN-;b) C4-10 cycloalkenyl substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the cycloalkenyl comprises one or more Re;c) heterocycloalkenyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with 1-2 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, and from 1-3 heteroatoms each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocycloalkenyl comprises one or more Re, and the heterocycloalkenyl ring does not include an N-S bond;d) heterocyclyl including from 3-4 ring atoms wherein one ring atom is a heteroatom selected from N, NH, N(RN), NC(O)RN, NC(O)ORN, NS(O)2RN, O, and S; and 2-3 ring atoms are ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy, wherein the heterocyclyl is optionally fused to a ring including from 3-8 ring atoms, including from 1-8 ring carbon atoms each of whichAttorney Docket No. 50006-0134WO1optionally substituted 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 0-2 heteroatoms each independently selected from N, NH, N(RN), O, and S(0)o-2;e) C3-4 (e.g., C3) cycloalkyl substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy, provided that the cycloalkyl comprises one or more Re;f) Ce-io aryl substituted with from 1-4 independently selected Re, wherein the aryl is further optionally substituted with from 1-2 substituents each independently from Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy;g) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring does not include an N-S bond, and wherein the heteroaryl ring is substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the heteroaryl comprises one or more Re;h) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring includes an N-S bond, and wherein the heteroaryl ring is optionally substituted with from 1-2 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy;i) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocyclyl ring includes an N-S bond;Attorney Docket No. 50006-0134WO1j) -C(=O)(CH2)niXwlwherein Xwlis selected from -C(O)RC, -S(O)2RC, -C(O)ORC, -C(O)NHRC, -C(O)NRNRC, -S(O)2NHRC, and -S(O)2NRNRC; and nl is 0, or 1;k) -C(=O)(CH2)n2Xw2or -C(=O)CH(Xw2)-Rc, wherein Xw2is selected from ORC, SRC, S(RC)2, -OP(O)(RC)2, OC(O)RC, OC(O)ORC, O-NHC(O)RC, -OS(O)2RC, -N2, halo (e.g., F), -CN, and -NO2; and n2 is 1 or 2;l) -C(O)NH-N(RN)C(O)ORC, -C(O)NH-NHC(O)ORC, -C(O)NH-N(RN)C(O)SRC, -C(O)NH-NHC(O)SRC, -NHC(O)ORC, -N(RN)C(O)ORC, -NHC(O)SRC, -N(RN)C(O)SRC, -C(O)NH-OC(O)ORC, -C(O)N(RN)-OC(O)ORC, -C(O)NH-OC(O)SRC, and -C(O)N(RN)-OC(O)SRC;m) -P(O)(ORC)(ORC), -P(O)(NH2)(ORC), -P(O)(NHRN)(ORC), P(O)(NRNRN)(ORC), -P(O)(ORC)F, -S(O)2ORCand -S(O)2F;n) C2-4 alkenyl or C2-4 alkynyl optionally substituted with from 1-2 substituents selected from nitro and -CN;o) -B(ORC’)2;p) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, S(0)O-2, and -B(ORC’)O-, and the heteroaryl ring is optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, provided that the heteroaryl ring includes a -B(ORC’)O-;q) Lw2-EWG, wherein• LW2is C2-6 alkenyl, whereinAttorney Docket No. 50006-0134WO1o -EWG is attached to a sp2hybridized carbon of LW2, thereby providing an a, P-unsaturated system;o LW2is substituted with one RRat the carbon atom attached to - EWG; ando LW2is further optionally substituted with from 1-3 substituents each independently selected from halo, OH, Ci-6 alkoxy, Ci-6 haloalkoxy, N(RN)z, and RL2; and• EWG is a divalent group selected from: -C(O)-, -S(O)2-, -C(O)O-, - C(O)NH-, -C(O)NRN-, -S(O)2NH-, and -S(O)2NRN-;r) C(=O)H;s) Ci-6 alkyl substituted with one or more CN or -(H)N-CN; andt) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, wherein the heterocyclyl is substituted with one or more CN or -(H)N-CN; and the heterocyclyl is further optionally substituted with from 1-2 independently selected Re.Exemplary Embodiments of Covalent Warheads111In some embodiments of W, W’ is:Lwl-EWG, wherein• LW1is C2-s alkenyl, C4-10 cycloalkenyl, 5-10 membered heterocycloalkenyl, or C2-s alkynyl, whereino -EWG is attached to a sp2or sp hybridized carbon of LW1, thereby providing an a, P-unsaturated system;o LW1is optionally substituted with one halo (e.g., F) at the carbon atom attached to -EWG;Attorney Docket No. 50006-0134WO1o the sp2or sp hybridized carbons of LW1which are not attached to EWG are optionally substituted with 1 RL; and o each sp3hybridized carbon of LW1is optionally substituted with from 1-3 substituents each independently selected from halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, NH2, NH(RN), N(RN)2, and RL1; and • EWG is a divalent group selected from: -C(O)-, -S(O)2-, -C(O)O-, - C(O)NH-, -C(O)NRN-, -S(O)2NH-, and -S(O)2NRN-.In some embodiments of [1], EWG is a divalent group selected from: -C(O)-, -S(O)2-, C(O)O-, -C(O)NH-, and -S(O)2NH-. As non-limiting examples of the foregoing, EWG can be -C(O)- or -S(O)2.In some embodiments of [1], LW1is C2-3 alkenyl (e.g., C2alkenyl) optionally substituted with one halo.In certain embodiments, LW1is C2-3 alkenyl (e.g., C2alkenyl). As a non-limiting example, LW1canbeIn certain embodiments, LW1is C2-3 alkenyl (e.g., C2alkenyl) substituted with one halo at the carbon atom attached to -EWG. As a non-limiting example, LW1can beIn some embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) optionally substituted with from 1-3 halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, or N(RN)2at the sp3hybridized carbons.In certain embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) optionally substituted with from 1-3 halo at a sp3hybridized carbon.In some embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) optionally substituted with one OH, C1-6 alkoxy, or C1-6 haloalkoxy at a sp3hybridized carbon.Attorney Docket No. 50006-0134WO1In some embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) substituted with one OH, C1-6 alkoxy, or C1-6 haloalkoxy at a sp3hybridized carbon.In some embodiments of [1], L"1is C3-8 alkenyl (e.g., C3 alkenyl) optionally substituted with from one N(RN)i at a sp3hybridized carbon.In some embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) substituted with from one N(RN)i at a sp3hybridized carbon.In some embodiments of [1], LW1is C3-8 alkenyl (e.g., C3 alkenyl) optionally substituted with 1 RL1at a sp2hybridized carbon that is not attached to EWG.In some embodiments of [1], LW1is C4-10 (e.g., C4-6, e.g., C4) cycloalkenyl. As anon-limiting example, LW1can be.In some embodiments of [1], LW1is C2-8 alkynyl (e.g., C3-8) optionally substituted with from 1-3 halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, OH, or N(RN)iat the sp3carbons.In some embodiments of [1], Awis a bond.In some embodiments of [1], Awis C1-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 thioalkoxy;Attorney Docket No. 50006-0134WO17) Ce-io arylene optionally substituted with from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.[1-1]In some embodiments of [1], Awis a bond (i.e., W is W’).In some embodiments of [1-1], W or W’ is R3R4C=CR5C(=O)-, R6R7NCH2CH=CHC(=O)-, H2C=CHSO2- or R8C=CC(=O)-; wherein:R3is hydrogen;R4is hydrogen, CF3 or Z(Cl-6 alkylene)- wherein Z is H, F, Cl, Br, HO-, Cl -6 alkoxy, or fluoroCi -6 alkoxy, andR5is hydrogen, Cl -3 alkyl, fluoroCl-3 alkyl or halogen,orR4and R3together with the carbon atoms to which they are attached form a 4-8-membered carbocyclic ring;R6and R7are both methyl, or R6and R7together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen;Rsis hydrogen, C1-C3 alkyl, HO-C1-C3 alkyl or R'R" NCH2-; andR' and R" are each independently hydrogen or C1-C6 alkyl.In some embodiments of [1-1], W or W’ is R3R4C=CR5C(=O)-.In certain embodiments, R3is hydrogen.In certain embodiments, R4is hydrogen.In certain embodiments, R4is CF3.In certain embodiments, R4is ZCH2-, wherein Z is F, Cl, Br, HO- or CH3O-. In certain embodiments, R5is H.Attorney Docket No. 50006-0134WO1In certain embodiments, R5is F.In certain embodiments, R4and R5together with the carbon atoms to which they are attached form a 4-membered carbocyclic ring.As non-limiting examples to any of the foregoing embodiments (when W is R3R4C=CR5C(=O)-), W or W’ can be:In some embodiments of [1-1], W or W’ is R6R7NCH2CH=CHC(=O)-.In certain embodiments, R6and R7are both methyl.In certain embodiments, R6and R7together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally having an additional ring heteroatom which is O, wherein said ring is optionally substituted with halogen.In certain embodiments, R6and R7together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring selected from the group consisting of piperidine, morpholine, and pyrrolidine, wherein said ring is optionally substituted with halogen.As non-limiting examples to any of the foregoing embodiments (when W is R6R7NCH2CH=CHC(=O)-), W or W’ can be:Attorney Docket No. 50006-0134WO1In some embodiments of [1-1], W or W’ is R8OCC(=0)-.In certain embodiments, R8is hydrogen or methyl.In certain embodiments, R8is HOCH2-.In certain embodiments, R8is R'R" NCH2-.As non-limiting examples to any of the foregoing embodiments (when W is R8C=CC(=O)-), W or W’ can be:In some embodiments of [1-1], W or W’ is H2C=CHSC>2-.Non-limiting examples of W when W is defined according to [1-1] include:Attorney Docket No. 50006-0134WO1[1-2]In some embodiments of [1], Awis Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4)-O-;Attorney Docket No. 50006-0134WO15) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy;7) C6-10 arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy.In some embodiments of [1-2], one CH2 unit of A" is replaced by C(O).In some embodiments of [1-2], one CH2 unit of Awis replaced by -NH-.In certain embodiments of the foregoing, one CH2 unit of Awis replaced by C(O); and one CH2 unit of Awis replaced by -NH-.In some embodiments of [1-2], one CH2 unit of A" is replaced by S(O)2.In some embodiments of [1-2], one CH2 unit of Awis replaced by -NH-.In certain embodiments of the foregoing, one CH2unit of Awis replaced by S(O)2; and one CH2 unit of Awis replaced by -NH-.In some embodiments of [1-2], one CH2 unit of A" is replaced by heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy,Attorney Docket No. 50006-0134WO1and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2.OvEWG-LW1In some embodiments of [1-2], W is0-3, wherein EWG and LW1are as defined elsewhere herein, wherein LW1comprises one RL1.0RL1In certain embodiments of the foregoing, W is 0Non-limiting examples of the foregoing includes:Attorney Docket No. 50006-0134WO1O EWG— LW1In some embodiments of [1-2], W is1-3 wherein EWG and LW1are as defined elsewhere herein.Non-limiting examples of the foregoing include:Attorney Docket No. 50006-0134WO1O 0o^ rIn some embodiments of [1-2], W isH°E’3WG-,-w1wherein EWG and LW1are as defined elsewhere herein.Non-limiting examples of the foregoing include:[2] In some embodiments of W, W’ is selected from the group consisting of:C4-10 cycloalkenyl substituted with from 1-4 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, provided that the cycloalkenyl comprises one or more Re; andheterocycloalkenyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH,Attorney Docket No. 50006-0134WO1N(RN), N(Re), O, and S(0)o-2, provided that the heterocycloalkenyl comprises one or more Re, and the heterocycloalkenyl ring does not include an N-S bond.In some embodiments of W, W’ is selected from:C4-10 cycloalkenyl (e.g., C4-6) substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the cycloalkenyl comprises one or more Re.In certain embodiments of the foregoing, one or more Reis oxo.Non-limiting examples of the foregoing include:and oIn some embodiments of W, W’ is selected from:heterocycloalkenyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with 1-2 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocycloalkenyl comprises one or more Re, and the heterocycloalkenyl ring does not include an N-S bond.In certain embodiments of the foregoing, one or more Reis oxo wherein one or more oxo is conjugated to a C=C double bond.Non-limiting examples of the foregoing include:Attorney Docket No. 50006-0134WO1In some embodiments of [2], Awis a bond.In some embodiments of [2], Awis Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2wherein the heteroarylene ring is optionally substituted with from 1-2 substituents eachAttorney Docket No. 50006-0134WO1independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis Ci-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene.Non-limiting examples of W when W is as defined for [2] include:[3] In some embodiments of W, W’ is selected from:heterocyclyl including from 3-4 ring atoms wherein one ring atom is a heteroatom selected from N, NH, N(RN), NC(O)RN, NC(O)ORN, NS(O)2RN, O, and S; and 2-3 ring atoms are ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, wherein the heterocyclyl is optionally fused to a ring including from 3-8 ring atoms including from 1-8 ring carbon atoms each of which optionally substituted 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 0-2 heteroatoms each independently selected from N, NH, N(RN), O, and S(0)o-2.In some embodiments of W, W’ is selected from:Attorney Docket No. 50006-0134WO1heterocyclyl including from 3-4 ring atoms wherein one ring atom is a heteroatom selected from N, NH, N(RN), NC(O)RN, NC(O)ORN, NS(O)2RN, O, and S; and 2-3 ring atoms are ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.In some embodiments of W, W’ is selected from:heterocyclyl including from 3-4 ring atoms wherein one ring atom is a heteroatom selected from N, NH, N(RN), NC(O)RN, NC(O)ORN, NS(O)2RN, and O (e.g., O); and 2-3 ring atoms are ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci -4 thioalkoxy.In some embodiments of W, W’ is selected from:heterocyclyl including from 3 ring atoms wherein one ring atom is a heteroatom selected O; and 2 ring atoms are ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.Non-limiting examples of the foregoing include:OIn some embodiments of [3], Awis a bond.In some embodiments of [3], A" is Ci-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2units of the Ci-8 alkylene are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;Attorney Docket No. 50006-0134WO14) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci -4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci -4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene.Attorney Docket No. 50006-0134WO1Non-limiting examples of W when W is defined according to [3] include:OIn some embodiments of W, W’ is selected from:C3-4 (e.g., C3) cycloalkyl substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the cycloalkyl comprises one or more Re.In certain embodiments of the foregoing, W’ is selected from:cyclopropyl substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the cyclopropyl comprises one or more Re.In certain embodiments of the foregoing, one Reis -CN.In certain embodiments, one Reis -Q1-Q2, wherein Q1is C1-3 alkylene wherein one CH2 unit is replaced by C(O), C(O)NH, or C(O)O.Non-limiting examples of the foregoing include:In some embodiments of [4], Awis a bond.In some embodiments of [4], Awis C1-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;Attorney Docket No. 50006-0134WO14) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene.Non-limiting examples of W when W is as defined according to [4] include:OAttorney Docket No. 50006-0134WO1[5]In some embodiments of W, W’ is selected from:Ce-io aryl substituted with from 1-4 independently selected Re, wherein the aryl is further optionally substituted with from 1-2 substituents each independently from Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy; and heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring does not include an N-S bond, and wherein the heteroaryl ring is substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the heteroaryl comprises one or more Re.In some embodiments of W, W’ is selected from:Ce-io aryl substituted with from 1-4 independently selected Re, wherein the aryl is further optionally substituted with from 1-2 substituents each independently from Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.In some embodiments of W, W’ is selected from:heteroaryl including from 5-10 (e.g., 5-6) ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring does not include an N-S bond, and wherein the heteroaryl ring is substituted with from 1-4 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the heteroaryl comprises one or more Re.[5-1]In certain embodiments of [5], one or more Reis selected from halo, CN, and nitro.Non-limiting examples of the foregoing include:Attorney Docket No. 50006-0134WO1[5-2]In certain embodiments of [5], one or more Reis selected from C2 alkenyl (e.g., vinyl) and C2 alkynyl.Non-limiting examples of the foregoing include:Attorney Docket No. 50006-0134WO1[5-3]In certain embodiments of [5], one or more Reis oxo.In some embodiments of [5-3], W’ is selected from isocoumarinyl and benzoxazinones, each of which is optionally substituted as described elsewhere herein.In some embodiments of [5], Awis a bond.In some embodiments of [5], Awis Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;Attorney Docket No. 50006-0134WO16) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene.[6]In some embodiments of W, W’ is selected from:h) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring includes an N-S bond, and wherein the heteroaryl ring is optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy; andAttorney Docket No. 50006-0134WO1i) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocyclyl ring includes an N-S bond.In some embodiments of W, W’ is selected from:h) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, and S(0)o-2, wherein the heteroaryl ring includes an N-S bond, and wherein the heteroaryl ring is optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy; andi) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocyclyl ring includes an N-S bond.Non-limiting examples of the foregoing include:Attorney Docket No. 50006-0134WO1In some embodiments of [6], Awis a bond.In some embodiments of [6], Awis Ci-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;Attorney Docket No. 50006-0134WO13) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a Ci-6 alkylene (e.g., CH2).[7]In some embodiments of W, W’ is selected from:j) -C(=O)(CH2)niXwlwherein Xwlis selected from -C(O)RC, -S(O)2RC, -C(O)ORC, -C(O)NHRC, -C(O)NRNRC, -S(O)2NHRC, and -S(O)2NRNRC; and nl is 0, or 1 (e.g., 0); andk) -C(=O)(CH2)n2Xw2or -C(=O)CH(Xw2)-Rc, wherein Xw2is selected from ORC, SRC, S(RC)2, -OP(O)(RC)2, OC(O)RC, OC(O)ORC, O-NHC(O)RC, -OS(O)2RC, -N2, halo (e.g., F), -CN, and -NO2; and n2 is 1 or 2 (e.g., 1).In some embodiments of [7], Aw' is a bond.In some embodiments of [7], Awis C1-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkyl, wherein from 1-4 CH2units of the C1-8 alkylene are optionally replaced by a group selected from:l)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;Attorney Docket No. 50006-0134WO16) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of the foregoing, Awis C1-6 alkylene.Non-limiting examples of W (when W is as defined according to [7]) include:[8] In some embodiments of W, W’ is selected from:Attorney Docket No. 50006-0134WO1l) -C(O)NH-N(RN)C(O)ORC, -C(O)NH-NHC(O)ORC, -C(O)NH-N(RN)C(O)SRC, -C(O)NH-NHC(O)SRC, -NHC(O)ORC, -N(RN)C(O)ORC, -NHC(O)SRC, -N(RN)C(O)SRC, -C(O)NH-OC(O)ORC, -C(O)N(RN)-OC(O)ORC, -C(O)NH-OC(O)SRC, and -C(O)N(RN)-OC(O)SRC; andm) -P(O)(ORC)(ORC), -P(O)(NH2)(ORC), -P(O)(NHRN)(ORC), P(O)(NRNRN)(ORC), -P(O)(ORC)F, -S(O)2ORCand -S(O)2F.In some embodiments of [8], Awis a bond.In some embodiments of [8], A" is Ci-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2units of the Ci-s alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents eachAttorney Docket No. 50006-0134WO1independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene (e.g., CH2).[9]In some embodiments of W, W’ is selected from:C2-4 alkenyl or C2-4 alkynyl optionally substituted with from 1-2 substituents selected from nitro and -CN;In certain embodiments of W, W’ is selected from:C2 alkenyl and C2 alkynyl.In some embodiments of W, W’ is selected from:C2 alkenyl substituted with from 1 substituent selected from nitro and -CN;Non-limiting examples of the foregoing include:In some embodiments of [9], Awis a bond.In some embodiments of [9], Awis C1-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:Attorney Docket No. 50006-0134WO11)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2are optionally replaced by a group selected from:3) -NH-, -NRN-; andAttorney Docket No. 50006-0134WO14) -O-.In certain embodiments, Awis a Ci-6 alkylene optionally substituted with one OH. In certain embodiments, Awis a Ci-6 alkylene (e.g., CH2).Non-limiting examples of W when W is as defined for [9] include:OH

[0010] In some embodiments of W, W’ is selected from:o) -B(ORC’)2; andp) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(RN), O, S(0)O-2, and -B(ORC’)O-, and the heteroaryl ring is optionally substituted with from 1-2 substituents independently selected from Re, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, provided that the heteroaryl ring includes a -B(ORC’)O-.Non-limiting examples of the foregoing include:OH / l"B(OH)2 and.In some embodiments of

[0010] , Awis a bond.In some embodiments of

[0010] , Awis Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;Attorney Docket No. 50006-0134WO13) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy.In certain embodiments of the foregoing, A" is Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, C1-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1) -C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of the foregoing, Awis C1-8 alkylene, wherein from 1-2 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1) C(=O)Attorney Docket No. 50006-0134WO13) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a Ci-6 alkylene (e.g., CH2).Non-limiting examples of W when W is as defined for

[0010] include:

[0011] In some embodiments of W, W’ is selected from:Lw2-EWG, wherein• LW2is C2-6 alkenyl, whereino -EWG is attached to a sp2hybridized carbon of LW2, thereby providing an a, P-unsaturated system;o LW2is substituted with one RRat the carbon atom attached - EWG; ando LW2is further optionally substituted with from 1-3 substituents each independently selected from halo, OH, C1-6 alkoxy, C1-6 haloalkoxy, N(RN)i, and RL2; and• EWG is a divalent group selected from: -C(O)-, -S(O)2-, -C(O)O-, - C(O)NH-, -C(O)NRN-, -S(O)2NH-, and -S(O)2NRN-.In certain embodiments of the foregoing, LW2is C2-3 alkenyl, wherein L"2is substituted with one RRat a carbon adjacent to EWG.In certain embodiments of the foregoing, RRis independently selected from the group consisting of:(i) CN, NO2, -C(O)RC, -S(O)2RC, -C(O)ORC, -C(O)NHRC, -C(O)NR RC, -S(O)2NHRC, and -S(O)2NRNRCAs a non-limiting example of the foregoing, RRcan be -CN.Attorney Docket No. 50006-0134WO1Non-limiting examples of the foregoing include: 0 and 0In some embodiments of

[0011] , Awis a bond.In some embodiments of

[0011] , Awis Ci-8 alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and C1-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and C1-4 thioalkoxy.Attorney Docket No. 50006-0134WO1In certain embodiments of the foregoing, Awis Ci-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of the foregoing, Awis C1-6 alkylene wherein from 1-2 CH2 are optionally replaced by a group selected from:3) -NH-, -NRN-; and4) -O-.In certain embodiments, Awis a C1-6 alkylene (e.g., CH2).Non-limiting examples of W when W is as defined according to

[0011] include:0and0

[0012] In some embodiments of W, W’ is selected from:s) C1-6 alkyl substituted with one or more CN or -(H)N-CN; andt) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, wherein the heterocyclyl is substituted with one or more CN or -(H)N-CN; and the heterocyclyl is further optionally substituted with from 1-2 Re.In some embodiments of W, W’ is selected from:Attorney Docket No. 50006-0134WO1s) Ci-6 alkyl substituted with one CN or -(H)N-CN; andt) heterocyclyl including from 5-10 ring atoms including from 2-7 ring carbon atoms, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, wherein the heterocyclyl is substituted with one CN or -(H)N-CN; and the heterocyclyl is further optionally substituted with from 1-2 ReIn some embodiments of

[0012] , Awis a bond.In some embodiments of

[0012] , Awis Ci-s alkylene optionally substituted with from 1-2 substituents independently selected from OH, Ci-4 haloalkyl, Ci-4 alkoxy, and Ci-4 haloalkyl, wherein from 1-4 CH2 units of the C1-8 alkylene are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-;4) -O-;5) heterocyclylene including from 5-10 ring atoms, including from 2-7 ring carbon atoms each optionally substituted with from 1-2 substituents each independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy, and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2;6) C3-8 cycloalkylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy;7) Ce-io arylene optionally substituted with from 1-2 substituents each independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy; and8) heteroarylene including from 5-10 ring atoms and from 1-3 heteroatoms each independently each independently selected from N, NH, N(RN), O, and S(0)o-2 wherein the heteroarylene ring is optionally substituted with from 1-2 substituents eachAttorney Docket No. 50006-0134WO1independently selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxy, Ci-4 haloalkoxy, and Ci-4 thioalkoxy.In certain embodiments of the foregoing, Awis Ci-6 alkylene wherein from 1-2 CH2are optionally replaced by a group selected from:1)-C(O)-;2) -S(0)o-2;3) -NH-, -NRN-; and4) -O-.In certain embodiments of

[0012] , one CH2unit of Awis further replaced by a C(O). In certain embodiments of

[0012] , one CH2unit of A" is further replaced by — NH-or-NRNIn some embodiments of

[0012] , Awis a Ci-6 alkylene (e.g., CH2).Non-limiting examples of W when W is as defined according to

[0012] include the following:Further non-limiting examples of covalent warheads include those described in U. S. Patent Application Publication No. 2011 / 0230476 and those described in Chem. Rev. 2002, 102, 4639, each of which is incorporated by reference herein in its entirety.Other non-limiting examples of “warhead” include those described in Curr. Opin. Chem. Biol. 2016, 34, 110-116, which is incorporated by reference herein in its entirety.StereochemistryThe compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certainAttorney Docket No. 50006-0134WO1compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.The compounds generically or specifically disclosed herein include all stereoisomeric forms, including all diastereomeric and entantiomeric forms, unless it is specifically stated or the context indicates otherwise. Compounds with chiral centers can occur as racemates, individual enantiomers (e.g. as the (R) enantiomer or (S) entantiomer) or diastereomers, and mixtures thereof. All such stereoisomeric forms are included within the embodiments disclosed herein, including mixtures thereof.For certain compounds, the symbol * at a chiral center denotes that this chiral center has been resolved (i.e., is a single epimer) and is intended to indicate absolute stereochemistry in accordance with the Cahn-Ingold-Prelog priority rules.For the avoidance of doubt, and unless otherwise indicated, the use of solid and dashed wedges or lines in conjunction with all other resolved chiral centers (i.e., those not labelled with the symbol *) is intended to indicate arbitrarily assigned and / or relative stereochemistry.Other DefinitionsThe term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.Attorney Docket No. 50006-0134WO1The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed:, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed., Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.,' Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such asAttorney Docket No. 50006-0134WO1methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.The term “subject” refers to an animal, including, but not limited to, a primate (e., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, Ao-propyl, / c77-butyl, / / -hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.Attorney Docket No. 50006-0134WO1The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).The term "alkylene" refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the tworadicals can be on the same ring carbon atom (e.g., a geminal diradical such as) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinalring carbon and / or nitrogen atoms)) (e.g.,The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents.The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.Attorney Docket No. 50006-0134WO1The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclofl.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl.1.1 ]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1. l]hexane, bicyclo[3,2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromaticAttorney Docket No. 50006-0134WO1(but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- ]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[Z>][l,4]dioxine, benzo[ ][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[Z>][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupiedby non-hydrogen substituents), such as one or more of pyridone (e.g.,pyridazinone (e.g., I or -J— ), pyrazinone (e.g., —J— or I ),and imidazolone (e.g.,’), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic,Attorney Docket No. 50006-0134WO1or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[l.l.l]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyl s include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5 ] octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5 ]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5 ]decane 2,5-diazaspiro[3.6]decane, 3 -azaspiro[5.5 ]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5 ] octane, 1 -oxaspiro[3.5 ]nonane, 2-oxaspiro[3,5]nonane, 7-oxaspiro[3.5 ]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e g., 5-8 membered monocyclic, 8-12 memberedAttorney Docket No. 50006-0134WO1bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and / or bridged and / or spirocyclic rings.As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g.,[x.x. O] ring systems, in which 0 represents a zero atom bridge (e.g.,single ring atom (spiro-fused ring systems) (e.g.,or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths0) (e g-,, orAttorney Docket No. 50006-0134WO1In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compoundcontaining the moiety:encompasses the tautomeric form containing themoiety:H s. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings, and from the claims.DETAILED DESCRIPTIONThis disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt thereof) that modulate (e.g., inhibit) Cyclin-dependent kinase 2 (“CDK2”) activation (e.g., CCNE1 dependent CDK2 activation) and / or CDK2 complex formation and / or CDK2 complex activity. Non-limiting examples of said complexes include CDK2:cyclin complexes, e.g., CDK2 / cyclin El complex (also referred to herein as CDK2: CCNE1). The chemical entities are useful, e.g., for treating a condition, disease or disorder in which (i) increased (e.g., excessive) CDK2 activation (e.g., CCNE1 dependent CDK2 activation), (ii) CDK2 complex formation and / or (iii) CDK2 complex activity contribute to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). ThisAttorney Docket No. 50006-0134WO1disclosure also provides compositions containing the same as well as methods of using and making the same.Compound EmbodimentsVariables Z1and Z2, and Z3In some embodiments, each of Z1and Z2is N, and Z3is NZ4.In certain of these embodiments, Z4is C(O)-R4, S(O)-R4, or SO2-R1; wherein R1is C2-4 alkenyl, C2-4 alkynyl, C3-6 allenyl, or oxiranyl, each of which is optionally substituted with from 1-6 Ra. For example, Z4can be C(O)-R4,Variables X, Y, RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4In some embodiments, X is a bond.In some embodiments, Y is C(RY3)(RY4).In some embodiments, RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (A).In some embodiments, X is a bond, and Y is C(RY3)(RY4), and the ring containing Z3is a 6-membered ring.In some embodiments, X is a bond, and Y is C(RY3)(RY4), and the ring containing Z3is a 6-membered ring; and RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (A).In certain of the 6-membered ring embodiments, each of RX1and RX2is H.In certain of the 6-membered ring embodiments, each of RY1and RY2is H, and each of RY3and RY4is H.In certain of the 6-membered ring embodiments, each of RX1and RX2is H; each of RY1and RY2is H, and each of RY3and RY4is H.Attorney Docket No. 50006-0134WO1In certain of the 6-membered ring embodiments, one of RX1and RX2is a substituent other than H, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (5) configuration.In certain of these embodiments, each of RY1and RY2is H, and each of RY3and RY4is H.In certain of the 6-membered ring embodiments, one of RX1and RX2is Ci-3 alkyl, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (S) configuration.In certain of these embodiments, each of RY1and RY2is H, and each of RY3and RY4is H.In certain of the 6-membered ring embodiments, one of RX1and RX2is CH3, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (5) configuration.In certain of these embodiments, each of RY1and RY2is H, and each of RY3and RY4is H.In certain of the 6-membered ring embodiments, one of RY3and RY4is a substituent other than H, and the other of RY3and RY4is H, and the carbon attached to RY3and RY4is a chiral center. In certain of these embodiments, the carbon attached to RY3and RY4has the (R) configuration. In certain of these embodiments, the carbon attached to RY3and RY4has the (5) configuration.In certain of these embodiments, each of RX1and RX2is H.Attorney Docket No. 50006-0134WO1In certain of the 6-membered ring embodiments, one of RY3and RY4is C1-3 alkyl, and the other of RY3and RY4is H, and the carbon attached to RY3and RY4is a chiral center. In certain of these embodiments, the carbon attached to RY3and RY4has the (R) configuration. In certain of these embodiments, the carbon attached to RY3and RY4has the (S) configuration.In certain of these embodiments, each of RX1and RX2is H.In certain of the 6-membered ring embodiments, one of RY3and RY4is CH3, and the other of RY3and RY4is H, and the carbon attached to RY3and RY4is a chiral center. In certain of these embodiments, the carbon attached to RY3and RY4has the (R) configuration. In certain of these embodiments, the carbon attached to RY3and RY4has the (5) configuration.In certain of these embodiments, each of RX1and RX2is H.In certain embodiments, the compound has the formula:In certain embodiments, the compound has the formula:In certain of these embodiments, the carbon attached to CH3 has the (R) configuration. In certain of these embodiments, the carbon attached to CH3 has the (5) configuration.In certain of the 6-membered ring embodiments:each of RX1and RX2is H;Attorney Docket No. 50006-0134WO1each of RY1and RY2is H, andone of RY3and RY4is C1-3 alkyl, and the other of RY3and RY4is H.In certain of these embodiments, the carbon attached to RY3and RY4has the (A) configuration. In certain of these embodiments, the carbon attached to RY3and RY4has the (S) configuration.In certain of the 6-membered ring embodiments:each of RX1and RX2is H;each of RY1and RY2is H, andone of RY3and RY4is CH3, and the other of RY3and RY4is H.In certain of these embodiments, the carbon attached to RY3and RY4has the (R) configuration. In certain of these embodiments, the carbon attached to RY3and RY4has the (S) configuration.In certain embodiments, the compound has the formula:R2In certain embodiments, the compound has the formula:R2In certain of these embodiments, the carbon attached to CH3 has the (R) configuration. In certain of these embodiments, the carbon attached to CH3 has the (5) configuration.In some embodiments, Y is a bond.In some embodiments, X is a bond, and Y is a bond, and the ring containing Z3is a 5-membered ring.Attorney Docket No. 50006-0134WO1In some embodiments, RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (A).In some embodiments, X is a bond, Y is a bond, and the ring containing Z3is a 5-membered ring, and RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (A).In certain of the 5-membered ring embodiments, one of RX1and RX2is a substituent other than H, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (5) configuration.In certain of these embodiments, each of RY1and RY2is H.In certain of the 5-membered ring embodiments, one of RX1and RX2is C1-3 alkyl, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (S) configuration.In certain of these embodiments, each of RY1and RY2is H.In certain of the 5-membered ring embodiments, one of RX1and RX2is CH3, and the other of RX1and RX2is H, and the carbon attached to RX1and RX2is a chiral center. In certain of these embodiments, the carbon attached to RX1and RX2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (5) configuration.In certain of these embodiments, each of RY1and RY2is H.In certain embodiments, the compound has the formula:Attorney Docket No. 50006-0134WO1R2In certain of these embodiments, the carbon attached to CH3 has the (R) configuration. In certain of these embodiments, the carbon attached to CH3 has the (5) configuration.In certain of the 5-membered ring embodiments, one of RY1and RY2is a substituent other than H, and the other of Ryiand RY2is H, and the carbon attached to RY1and RY2is a chiral center. In certain of these embodiments, the carbon attached to RY1and RY2has the (R) configuration. In certain of these embodiments, the carbon attached to RX1and RX2has the (5) configuration.In certain of these embodiments, each of RX1and RX2is H.In certain of the 5-membered ring embodiments, one of RY1and RY2is C1-3 alkyl, and the other of RY1and RY2is H, and the carbon attached to RY1and RY2is a chiral center. In certain of these embodiments, the carbon attached to RY1and RY2has the (R) configuration. In certain of these embodiments, the carbon attached to RY1and RY2has the (S) configuration.In certain of these embodiments, each of RX1and RX2is H.In certain of the 5-membered ring embodiments, one of RY1and RY2is CH3, and the other of RY1and RY2is H, and the carbon attached to RY1and RY2is a chiral center. In certain of these embodiments, the carbon attached to RY1and RY2has the (R) configuration. In certain of these embodiments, the carbon attached to RY1and RY2has the (S) configuration.In certain of these embodiments, each of RX1and RX2is H.In certain embodiments, the compound has the formula:Attorney Docket No. 50006-0134WO1In certain of these embodiments, the carbon attached to CH3 has the (R) configuration. In certain of these embodiments, the carbon attached to CH has the (5) configuration.In certain of the 5-membered ring embodiments:one of RX1and RX2is C1-3 alkyl, and the other is H, e.g., one of RX1and RX2is CH3, and the other is H; andone of RY1and RY2is C1-3 alkyl, and the other is H, e.g., one of RY1and R2is CH3.In certain embodiments, the compound has the formula:In other 5-membered ring embodiments, each of RX1and RX2is H, and each of RY1and RY2is H, i.e., the 5-membered ring is unsubstituted.In other embodiments, two or more (e.g., two of, four of, six of, or eight of) RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are independently defined according to (B), (C), (D), (E), (F), (G), (H), (T), or (J), and the others are defined according to (A).Attorney Docket No. 50006-0134WO1For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (B), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (C), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (D), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (E), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (F), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (G), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (H), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (I), and the others are defined according to (A). In certain of theseAttorney Docket No. 50006-0134WO1embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.For example, two of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4are defined according to (J), and the others are defined according to (A). In certain of these embodiments, the ring containing Z3is a 6-membered ring. In other embodiments, the ring containing Z3is a 5-membered ring.Variable R2In some embodiments, R2is -NR21R22or -O R21.In certain embodiments, R2is -NR21R22.In other embodiments, R2is -O R21.Variable R21In certain embodiments, R21is:\ f B1) - B21x- ' (F ormul a A- 1 ).In certain of these Formula A-l embodiments, Ring B1is heterocyclylene or heterocycloalkenylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, Ring B1is heterocyclylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, Ring B1is heterocyclylene of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selectedAttorney Docket No. 50006-0134WO1from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, Ring B1is heterocyclylene of 5-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, Ring B1is heterocyclylene of 6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.For example, ring B1in (Formula A-l) can beIn certain of these embodiments, the nitrogen atom is the point of attachment to B21.As another example, ring B1can beIn certain of these embodiments, the nitrogen atom is the point of attachment to B21.In certain (Formula A-l) embodiments, ring B1is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.Attorney Docket No. 50006-0134WO1In certain of these (Formula A-l) embodiments, ring B1is C3-10 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, ring B1is C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc).In certain of these (Formula A-l) embodiments, ring B1is C5-7 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc).In certain of these (Formula A-l) embodiments, ring B1is C& cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc)In certain (Formula A-l) embodiments, B21is Ci-io alkyl optionally substituted with from 1-6 Ra.In certain of these (Formula A-l) embodiments, B21is Ci-6 alkyl optionally substituted with from 1 -6 Ra.In certain of these (Formula A-l) embodiments, B21is C1-3 alkyl optionally substituted with from 1-6 Ra.In certain of these (Formula A-l) embodiments, each occurrence of Rais fluoro. For example, B21can be -CH2CF3.As another example, B21can be -CH(CH3)CF3.As a further example, B21can be:CF CF.Attorney Docket No. 50006-0134WO1In certain (Formula A-l) embodiments, B21is L’-Cs-io cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc, optionally wherein B21is iJ-Cs-io cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, B21is Id-C^s cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).In certain of these (Formula A-l) embodiments, B21is L1-Ce cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).In certain of these (Formula A-l) embodiments, B21is L*-C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).In certain (Formula A-l) embodiments, B21is L’-heterocyclyl or L1-heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain of these (Formula A-l) embodiments, B21is L’-heterocyclyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).Attorney Docket No. 50006-0134WO1In certain of these(Formula A-l) embodiments, B21is L'-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro)In certain of these (Formula A-l) embodiments, B21is L'-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).In certain of these (Formula A-l) embodiments, B21is L^heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.In certain of these (Formula A-l) embodiments, B21is L1-heteroaryl of 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.In certain of these (Formula A-l) embodiments, B21is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 Rc.In certain (Formula A-l) embodiments, B21is NR’R”.In certain of these (Formula A-l) embodiments, each of R’ and R” is an independently selected alkyl, optionally substituted with 1-7 fluoro.In certain of the foregoing B21embodiments, L1is a bond.In certain of the foregoing B21embodiments, L1is C(O).Attorney Docket No. 50006-0134WO1In some embodiments:R21is.$ — ( B1k| - B21— " S (F ormul a A-2).Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and B21is:Ci-io alkyl optionally substituted with from 1-6 Ra;L1-C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); or L'-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).In certain of the formula A-2 embodiments, Ring B1is a saturated or partially unsaturated ring having 5-7 ring atoms (including the ring nitrogen atom attached to B21), of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.Attorney Docket No. 50006-0134WO1In certain of these formula A-2 embodiments, Ring B1is a saturated ring having 6 ring atoms (including the ring nitrogen atom attached to B21) of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.For example, ring B1in formula A-2 can beIn certain of the formula A-2 embodiments, B21is Ci-io alkyl optionally substituted with from 1-6 Ra.In certain of these formula A-2 embodiments, B21is Ci-6 alkyl optionally substituted with from 1-6 Ra.In certain of these formula A-2 embodiments, B21is C1-3 alkyl optionally substituted with from 1-6 Ra.In certain of these formula A-2 embodiments, each occurrence of Rais fluoro. For example, B21in formula A-2 can be -CH2CF3.As another example, B21in formula A-2 can be -CH(CH3)CF3.As a further example, B21in formula A-2 can be:CH3CH3CF OF.In certain of the formula A-2 embodiments, B21is L2-C4-6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc).In certain of these formula A-2 embodiments, B21is I -C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the groupAttorney Docket No. 50006-0134WO1consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc; optionally wherein each occurrence of Rcis halo, e g., fluoro).For example, B21in formula A-2 can be:In certain of these formula A-2 embodiments, L1is a bond.In certain of the formula A-2 embodiments, B21is L'-heterocyclyl of 3-10 ring atoms, optionally wherein B21is heterocyclyl of 4 ring atoms; wherein 1 ring atom is selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In some embodiments:R21is:5 — ( B1)c - B21- ' (Formula A-3).Ring B1is a saturated or partially unsaturated carbocyclic ring having 4-8 ring atoms (including the ring carbon atom attached to B21), wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; andB21is:NR’R”; orL'-hctcrocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).Attorney Docket No. 50006-0134WO1In certain of the formula A-3 embodiments, Ring B1is a saturated carbocyclic ring having 6 ring atoms (including the ring carbon atom attached to B21), wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.For example, ring B1in formula A-3 can beIn certain of the formula A-3 embodiments, B21is NR’R”.In certain of these formula A-3 embodiments, each of R’ and R” is an independently selected Ci-4 alkyl, optionally substituted with 1-7 fluoro.In certain of the formula A-3 embodiments, one of R’ and R” is unsubstituted Ci-4 alkyl, and the other is Ci-4 alkyl substituted with 1-7 fluoro.For example, B21in formula A-3 can be:CH2CHF2In certain of the formula A-3 embodiments, B21is L'-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).For example, B21in formula A-3 can be:NAttorney Docket No. 50006-0134WO1In some embodiments, R2is -OR21. In certain of these embodiments, B21can be as defined anywhere herein.In some embodiments,R2is (Formula A-4).Variable R3In some embodiments, B3is:• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or• Ce-io aryl optionally substituted with from 1-4 Rc.In certain embodiments, B3is heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.In certain embodiments, B3is heteroaryl of 6 ring atoms, wherein from 1-3 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-2 Rc.In certain embodiments, B3is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-2 Rc.For example, B3can be:In other embodiments, B3is Ce-io aryl optionally substituted with from 1-4 Rc.Attorney Docket No. 50006-0134WO1In some embodiments, B4is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain embodiments, B4is C3-10 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain embodiments, B4is C3-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.In certain embodiments, B4is C3-5 monocyclic cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.In certain embodiments, B4is cyclopentyl, which is optionally substituted with 1-4 independently selected Rc.In certain embodiments, B4is polycyclic or bicyclic C5-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.orIn certain embodiments, B4is:' / v', each of which is optionally substituted with 1-4 independently selected Rc.In certain embodiments,B4isFor example, B4can be:In some embodiments, L4is -C(O)NH-.In some embodiments, R3is:Attorney Docket No. 50006-0134WO1(Formula A-5), wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.In some of the formula A-5 embodiments, each of Y and Y* is N.In some of the formula A-5 embodiments, B4is:each of which is optionally substituted with 1-4 independently selected Rc.In certain of the formula A-5 embodiments,B4isIn certain of the formula A- 5 embodiments,B4isVariable Z4Variable Z4is a covalent warhead that can be selected as desired.In some embodiments, Z4is C(O)-R4.In some embodiments, R1is C2-4 alkenyl, which is optionally substituted with from 1-6 Ra.Attorney Docket No. 50006-0134WO1In certain embodiments, R1is C2-4 alkenyl, which is optionally substituted with from 1-2 Ra.In certain embodiments, R1is C2-4 alkenyl, which is unsubstituted.In certain of these embodiments, R1is -CH=CH2.For example, -NZ4can be -N-C(0)-CH=CH2.In other embodiments, R1is C2-4 alkenyl, which is substituted with 1-2 Ra.In certain of these embodiments, R1is C2-4 alkenyl, which is substituted with 1 RaO, RaaFor example, R1can be, jn which Raacan be, e.g., fluoro or -NR’R”. In certain of these embodiments, each of R’ and R” is independently selected from H and C1-4 alkyl. In other embodiments, Raais heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N(H), N(Rb), O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-2 Rc.abAs another example, R1can beR, in which Rabis phenyl or heteroaryl of 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the phenyl or heteroaryl is optionally substituted with 1-2 Rc, thereby forming a styrenyl moiety or the heteroaryl counterpart thereof, respectively. Representative heteroaryl groups include, e.g., pyridyl, pyrimidinyl, triazinyl, oxadiazolyl.In certain embodiments, R1is C2-4 alkenyl, which is substituted with 2 Ra.rjf- RadBy way of example, R1can be: RaRac, in which Rabis H or cyano; and each of Racand Radis independently H or an optionally substituted, non-hydrogen substituent, e.g., optionally substituted C1-C3 alkyl, optionally substituted C3-CeAttorney Docket No. 50006-0134WO1cycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl of 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, provided that two of Rab, Racand Radare other than hydrogen. Representative heteroaryl groups include, e.g., pyridyl, pyrimidinyl, triazinyl, oxadiazolyl.In still other embodiments, R1is geminally substituted C2 alkenyl, e.g., independently substituted with two substituents independently selected from those recitedin the definitions of Rab, Racand Rad. For example, R1can beIn still other embodiments, R1is a strained carbocyclic system (e.g., cyclopropyl substituted with one or more electron-withdrawing groups or bicyclofl.1.0]cy cl obutyl).In still other embodiments, R1is a strained heterocycle (e.g., a heterocycle including from 3-4 ring atoms wherein 1 ring atom is a heteroatom selected from oxygen, nitrogen, and sulfur; e.g., epoxide, aziridine, beta-lactam, and other strained systems).In some embodiments, R1is C2-6 alkynyl, which is optionally substituted with from 1-6 Ra.In certain embodiments, R1is C2-6 alkynyl, which is optionally substituted with from 1-2 Ra.XN'Z^''For example, R1canbe IIn some embodiments, Z4is heterocycloalkenyl including from 5-10 (e.g., 5 ring atoms) ring atoms including 2-7 ring carbon atoms each optionally substituted with 1-2 substituents independently selected from Re, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and Ci-4 thioalkoxy, and 1-3 heteroatoms each independently selected from N, NH, N(RN), N(Re), O, and S(0)o-2, provided that the heterocycloalkenyl comprisesAttorney Docket No. 50006-0134WO1one or more Re, and the heterocycloalkenyl ring does not include an N-S bond. For example, Z2can be:In some embodiments, Z4is RsS(O)-Rror RsS02-Rr; wherein Rsis C1-4 alkyl (e.g., CH3) or C3-5 cycloalkyl; and R1’ is divalent C2-4 alkenyl, C2-4 alkynyl, C3-6 allenyl, or oxiranyl, each of which is optionally substituted with from 1-6 Ra. For example, Z2o os< ■ < ZRIn some embodiments, Z4is an electron-deficient arene / heteroarene (e.g., pyridine or fluorobenzene) which can undergo SxAr reaction (e.g., with cysteine or lysine). Forexample, Z4can be ClNon-Limiting Combinations[A] In some embodiments:R21is.B21(Formula A-2);Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting ofAttorney Docket No. 50006-0134WO1N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and B21is:Ci-io alkyl optionally substituted with from 1-6 Ra;L1-C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); or L’-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).[B] In some embodiments:R21is( B1kl - B21- ' (Formula A-2);Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and B21is Ci-io alkyl optionally substituted with from 1-6 Ra.[C] In some embodiments:R21isAttorney Docket No. 50006-0134WO15 — ( B1k - B21— " S (Formula A-2);Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and R3is:(Rc)o-iN - B4H, wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.[D] In some embodiments:R21is.B21(Formula A-2);Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; andAttorney Docket No. 50006-0134WO1B21isCi-io alkyl optionally substituted with from 1-6 Ra;l C^s cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); or L’-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRp, P(O)Rp, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); and R3is:(Rc)o-i*Y=|=\ OH, wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.[E] In some embodiments:R21isf B1\| - B21- ' (Formula A-2);Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting ofAttorney Docket No. 50006-0134WO1N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and B21is:Ci-io alkyl optionally substituted with from 1-6 Ra; andR3is:(Rc)o-i*Y= =\ OH, wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.In some embodiments of [A], [B], [C], [D], or [E], Ring B1is a saturated or partially unsaturated ring having 5-7 ring atoms (including the ring nitrogen atom attached to B21), of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In some embodiments of [A], [B], [C], [D], or [E], Ring B1is a saturated ring having 6 ring atoms (including the ring nitrogen atom attached to B21) of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.In certain embodiments of [A], [B], [C], [D], or [E], ring B1isIn certain of these embodiments, the nitrogen atom is the point of attachment to B21.Attorney Docket No. 50006-0134WO1In some embodiments of [A], [B], [D], or [E], B21is Ci-io alkyl optionally substituted with from 1-6 Ra.In certain embodiments of [Al, [Bl, [DI, or [E], B21is Ci-6 alkyl optionally substituted with from 1-6 Ra.In certain embodiments of [A], [B], [D], or [E], n B21is Ci-3 alkyl optionally substituted with from 1-6 Ra. In certain of these embodiments, each occurrence of Rais fluoro.For example, B21can be -CH2CF3.As another example, B21can be -CH(CH )CF3.As a further example, B21can be:In certain embodiments of [A], [B], [C], [D], or [E], ring B1isthe nitrogen atom is the point of attachment to B21, and B21is C1-10 alkyl optionally substituted with from 1-6 Ra(e.g., C1-6 alkyl optionally substituted with from 1-6 Ra; C1-3 alkyl optionally substituted with from 1-6 Ra; e g., -CH2CF3; e.g., -CH(CH3)CF3; e.g.,CH3orIn some embodiments of [A], [B], [C], [D], or [E], X is a bond, and Y is C(RY3)(RY4).In certain embodiments of [A], [B], [C], [D], or [E], each of RX1and RX2is H. In certain embodiments of [A], [B], [C], [D], or [E], each of RY1and RY2is H, and each of RV3and RY4is H.Attorney Docket No. 50006-0134WO1In certain embodiments of [A], [B], [C], [D], or [E], one of RX1and RX2is C1-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H.In certain embodiments of [A], [B], [C], [D], or [E], one of RX1and RX2is C1-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H; and each of Ryi, RY2, RY3, and R14is H.In some embodiments of [A], [B], [C], [D], or [E], the compound has the formula:R2NCH3, optionally wherein Z is C(O), and R1is C2-4 alkenyl, e.g., C2-4 alkenyl. In embodiments, each of R2 and R3 can be as defined anywhere herein.In certain of these embodiments, the compound has the formula:R2'Z-RlCH3, optionally wherein Z is C(O), and R1is C2-4 alkenyl, e.g., C2-4 alkenyl. In embodiments, each of R2 and R3 can be as defined anywhere herein.In some embodiments of [C], [D], or [E], each of Y and Y* is N.In some embodiments of [C], [D], or [E], B4is:each of which is optionally substituted with 1-4 independently selected Rc.Attorney Docket No. 50006-0134WO1In certain embodiments of [C], [D], or [E], B4isFor example, B4canbeIn some of the foregoing embodiments, Z4is C(O)-R4.In certain of these embodiments, R1is C2-4 alkenyl, which is optionally substituted with from 1-6 Ra; e.g., C2 alkenyl, which is optionally substituted with from 1-2 Ra; e g., -CH=CH2.In other embodiments, R1is C3 alkenyl, which is optionally substituted with fromRa1-2 Ra; e.g., R1is *■ - ", optionally wherein Rais -NR’R”.In some embodiments, the compound is selected from the group consisting of compounds delineated in Table 1, and a pharmaceutically acceptable salt thereof.Table 1Compd.StructureNo.0X J ' • 'F / =1 || | N — 70vJ 0Attorney Docket No. 50006-0134WO1Attorney Docket No. 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A' / p -^ / itj PX12951296Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1Attorney Docket No. 50006-0134WO1The compounds of this disclosure include isotopically-labeled compounds of the disclosure. An “isotopically” or “radio-labeled” compound is a compound of the disclosure where one or more atoms are replaced or substituted by an atom having anAttorney Docket No. 50006-0134WO1atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the present disclosure include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 18F, 35S, 36C1, 82Br, 75Br, 76Br, 77Br, 1231, 1241, 1251 and 1311. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced by deuterium atoms (e.g., one or more hydrogen atoms of a Cl -6 alkyl group of Formula (I) can be optionally substituted with deuterium atoms, such as -CD3 being substituted for — CH3). In some embodiments, alkyl groups of the disclosed Formulas (e.g., Formula (I)) can be perdeuterated.Pharmaceutical Compositions and AdministrationGeneralIn some embodiments, the chemical entities described herein is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, 0, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-Attorney Docket No. 50006-0134WO1hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%- 100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).Routes of Administration and Composition ComponentsIn some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasy novi al, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.Attorney Docket No. 50006-0134WO1The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum -drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fdlers or extenders such as starches, lactose, sucrose, glucose,Attorney Docket No. 50006-0134WO1mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives.Attorney Docket No. 50006-0134WO1Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D, L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.DosagesThe dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 150 mg / Kg; from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0. 1 mg / Kg to about 200 mg / Kg; from about 0. 1 mg / Kg to about 150 mg / Kg; from about 0. 1 mg / Kg to about 100 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0. 1Attorney Docket No. 50006-0134WO1mg / Kg to about 10 mg / Kg; from about 0. 1 mg / Kg to about 5 mg / Kg; from about 0. 1 mg / Kg to about 1 mg / Kg; from about 0. 1 mg / Kg to about 0.5 mg / Kg).RegimensThe foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days,Attorney Docket No. 50006-0134WO114 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.Methods of TreatmentThis disclosure provides generally methods of treating a disease or disorder associated with CDK2 in a subject (e.g., a human patient), which include administering to the patient a therapeutically effective amount of any formula (I) compound described herein, or a pharmaceutically acceptable salt thereof.In one aspect, a compound of Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt thereof, can be used to inhibit the growth of cancerous tumors with aberrations that activate the CDK2 kinase activity. These include, but are not limited to, disease (e.g., cancers) that are characterized by amplification and / or overexpression of CCNE1 such as ovarian cancer, uterine carcinosarcoma and breast cancer and p27 inactivation such as breast cancer and melanomas. Accordingly, in some embodiments of the methods, the patient has been previously determined to have an amplification of the cyclin El (CCNE1) gene and / or an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1.Alternatively, a compound of Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt thereof, can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or of a salt thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells with CCNE1 amplification and / or overexpression in an individual or a patient.The methods include administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I) or of any of the formulasAttorney Docket No. 50006-0134WO1as described herein, or of a compound as recited in any of the claims and described herein, or a salt or a stereoisomer thereof.In some embodiments, provided herein is a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with an amplification of the cyclin El (CCNE1) gene and / or overexpression of CCNE1.In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient (in need thereof), a therapeutically effective amount of a compound of Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. In certain embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1.Cancers to be treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer (e.g, androgen receptor (AR)-dependent and AR-independent), lung cancer (e.g., NSCLC, SCLC, squamous cell carcinoma (e.g., lung squamous cell carcinoma (LUSC), or adenocarcinoma (e.g., lung adenocarcinoma (LU AD)), esophageal cancer, head and neck cancer, colorectal cancer (e.g., colon cancer, colorectal adenocarcinoma (COADREAD)), kidney cancer (e.g., RCC), liver cancer (e.g., HCC), pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), stomach (e.g, gastric) cancer, urothelial cancer, brain cancers, mesothelioma (MESO), skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, including metastasis (in particular brain metastasis) of all cancers listed.In some embodiments, the cancer is uterine cancer (e.g, uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC)), endometrial cancer (e.g., serous endometrial cancer (SEC)), breast cancer (e.g., breast invasive carcinoma (BRCA), TNBC (triple negative breast cancer), FIR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+ / HER2-Attorney Docket No. 50006-0134WO1breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast, cancer), ER+ZHER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), PR+ / HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2-low breast cancer (human epidermal growth factor 2 low breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g. ovarian serous cystadenocarcinoma (OV) and high grade serous ovarian cancer (HGSOC)); stomach cancer (including stomach adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PA AD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer (e.g., androgen receptor (AR)- dependent, AR- independent, and castration-resistant prostate cancer (CRPC)), skin cancer, leukemia (e.g, AML (acute myeloid leukemia)), lymphoma (e.g., B-cell lymphoma), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous carcinoma, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), e.g., EGFRm (epidermal growth factor receptor mutanf)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma ( ACC), or mesothelioma.In some of the foregoing embodiments of the methods provided herein, the subject is identified as having a cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, stomach adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or stomach adenocarcinoma.Attorney Docket No. 50006-0134WO1In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, stomach cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.In some of the foregoing embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification and / or overexpression of CCNE1.In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine therapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those inducedAttorney Docket No. 50006-0134WO1by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers.In some embodiments, cancers treatable with compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibitionresistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial cancer (e.g., bladder) and cancers with high microsatellite instability (MSIhigh). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, NonHodgkin lymphoma (including follicular lymphoma, including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.In some embodiments, cancers that are treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, Fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumors, hairy cell leukemia, intestinal cancer, islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectalAttorney Docket No. 50006-0134WO1cancer, renal cell carcinoma, salivary gland cancer, sinus cancer, spinal cancer, tongue cancer, tubular carcinoma, urethral cancer, and ureteral cancer.In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL) and multiple myeloma (MM).Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, and teratoma.Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.Attorney Docket No. 50006-0134WO1Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma).Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors.Exemplary nervous system cancers include cancers of the skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.Exemplary gynecological cancers include cancers of the uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).Attorney Docket No. 50006-0134WO1Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.In some embodiments, diseases and indications that are treatable using the compounds of the present disclosure include, but are not limited to, triple-negative breast cancer (TNBC), myelodysplastic syndromes, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.In some embodiments, cancers treatable with compounds of the present disclosure include Genomic Identification of Significant Targets in Cancer (GISTIC) and pheochromocytoma and paraganglioma (PCPG).In some embodiments, cancers treatable with compounds of the present disclosure include advanced / relapsed tumors; platinum-resistant or platinum-refractory ovarian cancer; endometrial cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; gastric cancer (with prior platinum therapy) that has progressed following 2 or more lines of therapies; and HR+ / HER2- BC (including both ER+ HER2- BC and PR+ / HER2- BC) that has progressed despite CDK4 / 6i. In some embodiments, cancers treatable with compounds of the present disclosure include platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer; CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies; CCNE1 amplified advanced / relapsed tumors that do not belong to the other groups; HR+ / HER2-BC that has progressed despite CDK4 / 6; and platinum-resistant or platinum-refractory CCNE1 amplified ovarian cancer. In one embodiment, the subject has CCNE1 amplified advanced / relapsed tumors. In one embodiment, the subject has CCNE1 amplified platinum-resistant or platinum -refractory ovarian cancer. In one embodiment, the subject has endometrial cancer (with prior platinum therapy, e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (including the platinum therapy). In one embodiment, the subject has CCNE1 amplified endometrial cancer that has failed 2 or more lines of therapies (which may include a prior platinum therapy). In one embodiment, the subject has gastric cancer (with prior platinum therapy e.g., wherein the patient has been previously treated with a platinum therapy) that has progressed following 2 or more lines of therapies (includingAttorney Docket No. 50006-0134WO1the platinum therapy). In one embodiment, the subject has HR+ / HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of therapies. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has pancreatic cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has PDAC that has progressed despite one or more lines of therapies. In one embodiment, the subject has CCNE1 amplified lung cancer. In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In one embodiment, the subject has CCNE1 amplified NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).In other embodiments, the cancer is breast cancer, including, e.g., ER-positive / HR- positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine therapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.In some embodiments, the compounds of Formula (I) are administered as first line therapy.In some embodiments, the compounds of Formula (I) are administered as second (or later) line therapy. In some embodiments, the compounds of Formula (I) are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor.In certain embodiments, the compounds of Formula (I) are administered as second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor.Attorney Docket No. 50006-0134WO1In some embodiments, the compounds of Formula (I) are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, e.g., an aromatase inhibitor, a SERM or a SERD (e.g., an oral SERD).In certain embodiments, the compound of Formula (I) is administered as second (or later) line therapy following treatment with a SERD (e.g., an oral SERD).In some embodiments, the compound of Formula (I) is administered as second (or later) line therapy following treatment (simultaneous or sequential) with a CDK4 / CDK6 inhibitor and with a SERD (e.g., an oral SERD).In some embodiments, the compound of the disclosure is administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, e.g., including taxanes, platinum agents, pyrimidine antagonists, and / or gemcitabine. In some embodiments, the compound of the disclosure is administered as second (or later) line therapy following treatment with HER2 targeted agents, e.g., trastuzumab. In some embodiments, the compound of the disclosure is administered as second (or later) line therapy following treatment with an EGFR inhibitor, e.g., osimertinib. In some embodiments, the compound of the disclosure is administered as second (or later) line therapy following treatment with pyrimidine antagonists (e.g., 5 -fluorouracil (5-FU)) and / or gemcitabine, and / or platinum agents (e.g., cisplatin).CombinationsIn the field of medical oncology, it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent orAttorney Docket No. 50006-0134WO1additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.One or more additional pharmaceutical agents for example, chemotherapeutics, anti-inflammatory agents, steroids, immunosuppressants, immune-oncology agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, and targeted therapies,.g., Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, SERDs, PI3K, and CDK4 / 6 kinase inhibitors are used in combination with the compounds of formula (I) for treatment of CDK2-associated diseases, disorders or conditions.In certain embodiments, CDK4 inhibitors are used in combination with the compounds of formula (I).In certain embodiments, CDK4 / 6 inhibitors are used in combination with the compounds of formula (I).In certain embodiments, endocrine agents, e.g., an aromatase inhibitor, a Selective Estrogen-Receptor Downregulator (SERD) or a Selective Estrogen Receptor Modulator (SERM), are used in combination with the compounds of formula (I).In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is fulvestrant. In still other embodiments, SERDs (e.g., oral SERDS) are used in combination with the compounds of formula (I).For example, CDK4 / 6 inhibitors and SERDs (e.g., oral SERDs) can be used in combination with the compounds of formula (I).Attorney Docket No. 50006-0134WO1Other agents such as therapeutic antibodies can be used in combination with the compounds of the present disclosure for treatment of CDK2-associated diseases, disorders, or conditions.In some embodiments, the one or more additional therapeutic agents include: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxics, immuno-oncology agents, and the like.In some embodiments, the additional anticancer agent is a PIK3CA or PI3Kalpha inhibitor including, but not limited to, alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, miransertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, STX-478, gedatolisib, and fimepinostat. In certain embodiments, the PIK3CA or PI3Kalpha inhibitor is alpelisib.In some embodiments, the additional anticancer agent is an antibody-drug conjugates including, but not limited to, Trastuzumab deruxtecan (Enhertu), Trastuzumab duocarmazine, Trastuzumab emtansine (Kadcyla), Upifitamab rilsodotin, mirvetuximab soravtansine, Tisotumab vedotin (Tivdak), Praluzatamab ravtansine, Sacituzumab govitecan or Sacituzumab Govitecan-hziy (Trodelvy), Datopotamab deruxtecan, Ladiratuzumab vedotin, Patritumab deruxtecan, STRO-002, MORab-202, DS-6000, Anetumab, avtansine, XMT-2056, Disitamab Vedotin (RC48-ADC, Aidexi).In some embodiments, the additional anticancer agent is a PLK1 inhibitor including, but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, rigosertib.In some embodiments, the additional anticancer agent is an Estrogen Receptor PROTAC (ARV-471, H3B-5942).In other embodiments, a compound of Formula (I) is administered in combination with a standard of care agent.Attorney Docket No. 50006-0134WO1In some embodiments, a compound of Formula (I) is administered in combination with endocrine therapy, e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole.In some embodiments, a compound of Formula (I) is administered in combination with a chemotherapeutic agent, e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In other embodiments, a compound of Formula (I) is administered in combination with an anti-HER2 agent, e.g., trastuzumab or pertuzumab.In some embodiments, a compound of Formula (I) is administered in combination with an effective amount of 5-FU, alpelisib, carboplatin, cisplatin, enzalutamide, fulvestrant, gemcitabine, osimertinib, ribociclib, or a combination thereof.In some embodiments, a compound of Formula (I) is administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.In some embodiments, the additional anticancer agent is an anti-angiogenesis agent, including for example VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoetin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha- v / beta-3), MMP-2 (matrix-metalloproteinase 2) inhibitors, and MMP-9 (matrix-metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP 79787), Sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdata (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Yet further anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™),Attorney Docket No. 50006-0134WO1diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Yet further antiangiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon).

[0159] Yet further anti-angiogenesis agents (including VEGFR / PDGFR inhibitors) include, but are not limited to, ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab.Yet further anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).In other embodiments, the additional anti-cancer agent is a signal transduction inhibitor (e.g., inhibiting how regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF 1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so called multi -targeted kinase inhibitors.Additional examples of signal transduction inhibitors which may be used in conjunction with a compound of Formula (I) include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h- R3™), panitumumab (Vectibix™), Vandetanib (Zactima™),Attorney Docket No. 50006-0134WO1pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38). Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GL4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).In other embodiments, the additional anti-cancer agent is an antineoplastic agent. Antineoplastic agents include but are not limited to hormonal modulators such as hormonal, anti-hormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomics, Topoisomerase I inhibitors, Camptothecin derivatives, Topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP- ribose) polymerase- 1 (PARP-1) inhibitor (such as, e.g., talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant derived spindle inhibitors, platinum- coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of antineoplastic agents used in combination therapy with a compound of Formula (I), optionally with one or more other agents include, but are not limited to, glucocorticoids, such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, and progestins such as medroxyprogesterone, megestrol acetate (Megace), mifepristone (RU-486), Selective Estrogen Receptor Modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene,Attorney Docket No. 50006-0134WO1arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane and CHF 4227 (Cheisi), Selective Estrogen-Receptor Downregulators (SERD’s; such as fulvestrant, LSZ102, G1T48, RAD 1901, elacestrant, GDC-9545, giredestrant, SAR439859, amcenestrant, AZD9833, camizestrant, LY3484356, Zn-c5, D-0502), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osaterone, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogen agents, such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof. Other examples of antineoplastic agents used in combination with a compound of the invention include but are not limited to suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (ranpimase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10- hydroxy camptothecin, irinotecan HC1 (Camptosar), lurtotecan, Orathecin (rubitecan, Supergen), SN- 38, topotecan, camptothecin, 10-hydroxy camptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylatingAttorney Docket No. 50006-0134WO1compounds such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.In still other embodiments, the additional anti-cancer agent is a dihydrofolate reductase inhibitor (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), pyrimidine antagonists (such as 5- fluorouracil (5-FU), Alimta (premetrexed di sodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur (UFT Orzel or Uforal and including TS-1 combination of tegafur, gimestat and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5 -azacitidine (Vidaza), decitabine, and ethynylcytidine) and other antimetabolites such as eflomithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2- methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), ING-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc) and combinations thereof.In some embodiments, the additional anti -cancer agent is a pyrimidine antagonist. In some embodiments, the pyrimidine antagonist is 5-FU.Other examples of antineoplastic cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol- Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), Ortataxel, paclitaxel (including Taxoprexin a DHA / paciltaxel conjugate), cisplatin, carboplatin, Nedaplatin, oxaliplatin (Eloxatin), Satraplatin, Camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™), Tesmilifene (DPPE enhances efficacy of cytotoxics), Theratope™ (Biomira), Tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadoliniumAttorney Docket No. 50006-0134WO1(Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamatepaclitaxel (Xyotax™) and combinations thereof.Further examples of antineoplastic agents include, but are not limited to, as Advexin (ING 201), TNFerade (GeneVec, a compound which express TNF alpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi- 4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc ), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.In other embodiments, the additional anti -cancer agent is an epigenetic modulator, for example an inhibitor or EZH2, SMARCA4, PBRM1, ARID 1 A, ARID2, ARID IB, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2 orBCL6.

[0166] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent, such as, but not limited to, an inhibitor of CTLA-4 (e.g., ipilimumab), PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dosterlimab), LAG-3 (e.g., relatlimab, TIM-3, TIGIT, 4-1BB, 0X40, GITR, CD40, or a CAR-T-cell therapy.In some embodiments, the additional anticancer agent is an EGFR inhibitor such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib or gefitinib or an EGFR antibody such as cetuximab, panitumumab, or necitumumab. In some embodiments, the EGFR inhibitor is osimertinib.Alternatively, a compound of Formula (I) can be administered in combination with other anti- cancer agents that are not EGFR inhibitors e.g., in combination with MEK, including mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (CDK4 / 6 inhibitors, e.g., palbociclib, riboci clib, abemacicilb, lerociclib, trilaciclib, dalpiciclib, atirmociclib, and BPL16350); anti -angiogenic agents e.g., bevacizumab,Attorney Docket No. 50006-0134WO1nintedanib; apoptosis inducers such as Bcl-2 inhibitors e.g, venetoclax, obatoclax, navitoclax and Mcl-1 inhibitors e.g., AZD-5991, AMG-176, S-64315; and mTOR inhibitors e.g, rapamycin, temsirolimus, everolimus, ridoforolimus. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib.A compound of Formula (I) can be administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemacicilb, lerociclib, trilaciclib, dalpiciclib, atirmociclib, and BPI-16350. In some embodiments, the CDK4 / 6 inhibitor is ribociclib.A compound of Formula (I) can be administered in combination with a CDK4 / 6 inhibitor and a SERD (e.g., an oral SERD).In some embodiments, a compound of Formula (I) can be administered in combination with ribociclib and fulvestrant. In some embodiments, a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein can be administered in combination with a pyrimidine antagonist and gemcitabine. In some embodiments, a compound of the disclosure can be administered in combination with a pyrimidine antagonist, gemcitabine, and a CDK4 / 6 inhibitor.In some embodiments, the combination further comprises a platinum agent. In some embodiments, a compound of the disclosure can be administered in combination with 5-FU, gemcitabine, ribociclib, and, optionally, cisplatin.In some embodiments, a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed herein can be administered in combination with an EGFR inhibitor.In some embodiments, a compound of Formula (I) can be administered in combination with osimertinib.In some embodiments, a compound of Formula (I) can be administered in combination with a PARP-1 inhibitor.In some embodiments, a compound of Formula (I) can be administered in combination with olaparib.A compound of Formula (I) can also be administered in combination with an effective amount of a second agent selected from the group consisting of palbociclibAttorney Docket No. 50006-0134WO1(e.g., ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., xeloda®), regorafenib (e.g., stivarga®), afatinib (e.g., gilotrif®), osimertinib (e.g., tagrisso®), gefitinib (e.g., iressa®), erlotinib (e.g., tarceva®), ramucirumab (e.g., cyramza®), an EGFR inhibitor, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, berzosertib, ceralasertib, SRA-737, LY2603618 (rabusertib), and trastuzumab (e.g., herceptin®), or combinations thereof. The EGFR inhibitor may be selected from afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04- 125-02, alflutinib (AST 2818), aumolertinib (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilitertinib, icotinib, JND-3229, lazertinib, nazartinib (EGF 816), avitinib, PCC-0208027, rezivertinib (BPI-7711), TQB3804, zorifertinib (AZ-3759), or DZD9008; an EGFR antibody such as cetuximab, panitumumab, necitumumab, HLX07, JMT101; or a bispecific EGFR and MET antibody (e.g., amivantamab ((JNJ-61186372, JNJ-372)).The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.Compound PreparationThe compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art or considering the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following Scheme 1, with modification for specific desired substituents..Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, andAttorney Docket No. 50006-0134WO1Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure.The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.EXAMPLESA number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the scope of the invention. Accordingly, other embodiments are within the scope of the following claims.Abbreviation of chemical termsACN = AcetonitrileDCM = DichloromethaneTHF = TetrahydrofuranNaOH = sodium hydroxideTFA = Trifluoroacetic AcidDIE A = Di isopropyl ethyl amineNa2SO4 = Sodium sulfateHPLC = High-performance liquid chromatographyLCMS = Liquid chromatography - mass spectrometryH2O = WaterpH = Potential of hydrogenDMSO = DimethylsulfoxideAttorney Docket No. 50006-0134WO1CsF = Cesium fluorideEtOAc = Ethyl acetateDMF = Dimethyl FormamideK3PO4 = Potassium phosphateNaOH = Sodium hydroxideNaHSCU = Sodium hydrogen sulfateMTBE = Methyl tert-butyl etherHATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V)m-CPBA = M-chloroperoxybenzoic acidNa2CO3 = Sodium carbonatet-AmOH = tert-amyl alcoholCS2CO3 = Cesium carbonateNaHCO3= Sodium bicarbonateTFE = TrifluoroethanolHBF4-Et2O = Tetrafluoroborate diethyl ether complexTEA = TriethylamineN2 = NitrogenH2 = HydrogenH = hourPd / C = Palladium on carbonPsi = Pounds per square inchSpeedvac = Savant SC250EXP Speedvac Concentratoraq. = Aqueous solutionLCMS analysis conditionsMethod AInstrument: Agilent LCMS system equipped with DAD and ELSD detector Ion mode: PositiveColumn: Waters X-Bridge C18, 50*2.1 mm*5 pm or equivalentMobile Phase: A: H2O (0.04% TFA); B: CH3CN (0.02% TFA)Attorney Docket No. 50006-0134WO1Gradient: 4.5 min gradient method, actual method would depend on clogP of compound.Flow Rate: 0.6 mL / min or 0.8 mL / minColumn Temp: 40 °C or 50 °CUV: 220 nmMethod BInstrument: Agilent LCMS system equipped with DAD and ELSD detector Ion mode: PositiveColumn: Waters X-Bridge ShieldRP18, 50*2.1 mm*5 pm or equivalent Mobile Phase: A: H2O (0.05% NH3·H2O) or 10 mM ammonia bicarbonate; B:CH3CNGradient: 4.5 min gradient method; actual method would depend on the clogP of the compound.Flow Rate: 0.6 mL / min or 0.8 mL / minColumn Temp: 40 °CUV: 220 nmPrep. HPLC conditionsInstrument:1. GILSON 281 and Shimadzu LCMS 2010A2. GILSON 215 and Shimadzu LC-20AP3. GILSON 215Mobile phase:A: NH4OH / H2O = 0.05% v / v; B: ACNA: FA / H2O = 0.225% v / v; B: ACNColumnXtimate Cl 8 150*25mm*5pmFlow rate: 25 mL / min or 30 mL / minMonitor wavelength: 220&254 nmGradient: actual method would depend on clog P of compoundDetector: MS Trigger or UVAttorney Docket No. 50006-0134WO1As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. The skilled artisan will also recognize that conditions and reagents described herein that can be interchanged with alternative art-recognized equivalents. For example, in many reactions, tri ethylamine can be interchanged with other bases, such as non-nucleophilic bases (e.g. diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).The skilled artisan will recognize a variety of analytical methods that can be used to characterize the compounds described herein, including, for example, 'H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The foregoing list is a subset of characterization methods available to a skilled artisan and is not intended to be limiting.To further illustrate the foregoing, the following non-limiting, exemplary synthetic schemes are included. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the invention as described, and claimed herein. The reader will recognize that the skilled artisan, provided with the present disclosure, and skill in the art is able to prepare and use the invention without exhaustive examples.Attorney Docket No. 50006-0134WO1Example 1: N-cyclopentyl-4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6- (prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (Compound 555)Step 1: To a stirred solution of fomepizole (5 g, 60.90 mmol, 1 equiv) and tert-butyl N-(3-bromopropyl)carbamate (17.40 g, 73.08 mmol, 1.2 equiv) in ACN (100 mL) were added KI (10.11 g, 60.90 mmol, 1 equiv) and CS2CO3 (29.76 g, 91.35 mmol, 1.5 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50°C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with ACN (3x30 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford tert-butyl N-[3-(4-methylpyrazol-l-yl)propyl]carbamate (13.5 g, 93%) as ayellow oil.Step 2: To a stirred solution of tert-butyl N-[3-(4-methylpyrazol-l-yl)propyl]carbamate (13 g, 54.32 mmol, 1 equiv) in THF (200 mL) was added LiAlH4 (217 mL, 1 M in THF, 4 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 70°C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (32 mL), NaOH (8 mL,15% aq) at 0°C. The resulting mixture was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in methyl [3 -(4-methylpyrazol-l -yl)propyl]amine (7 g, 84%) as a yellow solid.Step 3: To a stirred solution of methyl[3-(4-methylpyrazol-l-yl)propyl]amine (3.17 g, 20.68 mmol, 1 equiv) and tert-butyl 2,4-dichloro-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6 g, 20.68 mmol, 1.00 equiv) in THF (60 mL) and H2O (20 mL) was added NaHCCh (3.47 g, 41.36 mmol, 2 equiv) at room temperature under air atmosphere. TheAttorney Docket No. 50006-0134WO1resulting mixture was stirred for 2h at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SC>4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford tert-butyl 2-chloro-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (7 g, 83%) as a yellow oil. LC-MS: (M)+found: 407.Step 4: To a stirred solution of tert-butyl 2-chloro-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2 g, 4.92 mmol, 1 equiv) and 4-(cyclopentylcarbamoyl)phenylboronic acid (1.37 g, 5.90 mmol, 1.2 equiv) in dioxane (40 mL) and H2O (4 mL) were added CS2CO3 (3.20 g, 9.83 mmol, 2 equiv), bis(di-tert-butylphosphinous acid); dichloropalladium (0.25 g, 0.49 mmol, 0.1 equiv) and sodium 3-[2-(dicyclohexylphosphanyl)phenyl]-2,4-dimethoxybenzene-l-sulfonate hydrate (0.26 g, 0.49 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 100°C under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After fdtration, the fdtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash to afford tert-butyl 2-[4-(cyclopentylcarbamoyl)phenyl]-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.10 g, 76%) as a yellow oil. LC-MS: (M)+found: 560.Step 5: To a stirred solution of tert-butyl 2-[4-(cyclopentylcarbamoyl)phenyl]-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.20 g, 2.14 mmol, 1 equiv) in DCM (10 mL) was added trifluoroacetaldehyde (10 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for Ih at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated underAttorney Docket No. 50006-0134WO1reduced pressure to afford N-cyclopentyl-4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (0.80 g, 81%) as a yellow oil. LC-MS: (M+H)+found:460.Step 6: To a stirred solution of N-cyclopentyl-4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (120 mg, 0.26 mmol, 1 equiv) and TEA (80 mg, 0.78 mmol, 3 equiv) in DCM (2 mL) was added acryloyl chloride (24 mg, 0.26 mmol, 1 equiv) dropwise at 0°C under air atmosphere. The resulting mixture was stirred for Ih at room temperature under air atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (20 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (3x50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 7 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.5) to afford N-cyclopentyl-4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6-(prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (37 mg, 27%) as a white solid.LC-MS: (M+H)+found 514. 'H NMR (400 MHz, Chloroform-d) 58.34 (dd, J = 24.0, 7.8 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.34 (s, IH), 7.11 (s, IH), 6.52 (q, J = 5.5 Hz, 2H), 6.43 (d, J = 7.3 Hz, IH), 5.83 (dt, J = 13.1, 6.4 Hz, IH), 4.78 (d, J = 10.1 Hz, 3H), 4.70 (s, IH), 4.43 (q, J = 6.9 Hz, IH), 4.14 (t, J = 6.5 Hz, 2H), 3.69 (q, J = 13.5, 10.2 Hz, 2H), 3.20 (d, J = 14.9 Hz, 3H), 2.27 - 2.19 (m, 2H), 2.13 (dq, J = 12.7, 6.5 Hz, 2H), 2.04 (s, 3H), 1.82 - 1.63 (m, 4H), 1.56 (dd, J = 13.2, 6.6 Hz, 2H).Compounds of Formula (I) in Table C can be prepared analogously to Example 1. As the skilled person will appreciate, the compounds described herein can be prepared using variations of any one or more of the procedures described herein, e.g., substituting one or more starting materials and / or reagents for those described in one or more of the working examples.Table CAttorney Docket No. 50006-0134WO1Compd. HPLC; LCMS (M+H)+No. 'HNMRLC-MS: [M+H]+found 640.00.'HNMR (400 MHz, Chloroform-d) 58.40 (dd, J = 12.1, 8.1 Hz, 2H), 8.02 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 3H), 7.72 (dd, J = 14.2, 6.7 Hz, 2H), 7.68 (s, 1H), 7.44 568 - 7.36 (m, 2H), 7.35 - 7.28 (m, 1H), 7.30 - 7.15 (m, 2H), 7.18 - 7.10 (m, 1H), 7.09 - 6.92 (m, 1H), 6.83 (ddt, J = 15.2, 9.0, 5.3 Hz, 1H), 4.70 (s, 1H), 4.62 (s, 1H), 4.44 (dt, J = 16.5, 6.3 Hz, 2H), 3.67 (dt, J = 22.2, 6.4 Hz, 2H), 3.58 - 3.50 (m, 1H), 3.44 (d, J = 5.9 Hz, 1H), 3.13 (d, J = 2.0 Hz, 3H), 2.46 (dt, J = 24.6, 6.2 Hz, 3H).LC-MS: [M+H]+found 608.00.'H NMR (400 MHz, DMSO-d6) 5 10.33 (s, 1H), 8.45 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.52 (dt, J = 15.5, 2.3 Hz, 1H), 7.37 (t, J = 5717.9 Hz, 2H), 7.16 - 7.07 (m, 1H), 6.85 (ddq, J = 14.5, 10.7, 7.1 Hz, 1H), 4.82 (s, 1H), 4.68 (s, 1H), 3.84 - 3.72 (m, 3H), 3.63 (t, J = 7.2 Hz, 2H), 3.15 (s, 3H), 2.90 (s, 1H), 1.85 (t, J = 6.8 Hz, 2H), 1.64 - 1.39 (m, 5H).LC-MS: (M+H)+ found 472.'H NMR (400 MHz, DMSO-d6) 8 10.39 (d, J = 2.3 Hz, 1H), 8.41 (dd, J = 8.5, 3.1 Hz, 2H), 8.04 (dd, J = 8.4, 1.5 Hz, 2H), 7.86 - 7.77 (m, 2H), 7.59 (s, 1H), 7.49 (s, 402 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.21 (t, J = 8.9 Hz, 2H), 6.72 (dd, J = 16.7, 10.3 Hz, 1H), 6.27 (dd, J = 16.7, 2.4 Hz, 1H), 5.87 - 5.75 (m, 1H), 4.89 (s, 1H), 4.78 (s, 1H), 4.59 (d, J = 16.5 Hz, 2H), 4.19 - 4.12 (m, 2H), 3.52 (d, J = 6.1 Hz, 2H), 2.12 (q, J = 6.9 Hz, 2H), 1.99 (s, 3H).LC-MS: [M+H]+ found 518.00.'H NMR (400 MHz, DMSO-d6) 58.35 (t, J = 8.5 Hz, 3H), 7.90 (d, J = 8.2 Hz, 2H), 7.05 - 6.97 (m, 1H), 7.00 - 6.87 (m, 1H), 6.22 - 6.10 (m, 1H), 5.73 (t, J = 11.3 Hz, 1731H), 4.65 (s, 1H), 4.57 (s, 1H), 4.24 (q, J = 7.1 Hz, 1H), 3.90 (s, 1H), 3.85 (s, 2H), 3.58 (q, J = 6.5 Hz, 2H), 3.43 (t, J = 6.1 Hz, 2H), 1.93 - 1.87 (m, 2H), 1.83 (p, J = 6.5 Hz, 2H), 1.71 (s, 1H), 1.69 - 1.52 (m, 8H), 1.45 (s, 1H).LC-MS: (M+H)+ found: 436.645 'H NMR (400 MHz, DMSO-d6) 88.37 (dt, J = 7.2, 3.5 Hz, 3H), 7.92 (d, J = 8.2 Hz, 2H), 7.55 (dt, J = 30.9, 5.6 Hz, 1H), 6.66 (ddd, J = 45.6, 16.8, 10.3 Hz, 1H), 6.26 (dt,Attorney Docket No. 50006-0134WO1J = 16.9, 2.4 Hz, 1H), 5.80 (ddd, J = 14.8, 10.2, 2.3 Hz, 1H), 4.82 (d, J = 39.4 Hz, 2H), 4.57 (d, J = 13.5 Hz, 2H), 4.24 (q, J = 7.2 Hz, 1H), 3.71 (p, J = 5.8 Hz, 2H), 3.58 (t, J = 5.8 Hz, 2H), 3.30 (d, J = 1.6 Hz, 3H), 1.96 - 1.79 (m, 2H), 1.79 - 1.62 (m, 2H), 1.62 - 1.44 (m, 4H).LC-MS: (M+H)+ found: 585.’H NMR (400 MHz, DMSO-d6) 88.36 (d, J = 7.7 Hz, 3H), 7.92 (d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 6.72 (s, 1H), 6.16 (t, J = 13.4 Hz, 1H), 5.74 (s, 1H), 4.66 (s, 1H), 4.58 (s, 1H), 4.42 (s, 2H), 4.25 (s, 1H), 4.02 (d, J = 13.8 Hz, 1H), 3.90 (s, 1H), 3.83 (s, 1H), 3.20 (s, 1H), 2.71 (s, 2H), 1.91 (s, 4H), 1.71 (s, 3H), 1.68 - 1.61 (m, 5H), 1.55 (s, 5H), 1.33 (s, 6H), 1.19 - 1.12 (m, 1H).LC-MS: [M+H] + found 607.00’H NMR (400 MHz, DMSO-d6) 8 8.34 (s, 1H), 7.75 - 7.62 (m, 3H), 6.69 (dd, J = 16.5, 10.4 Hz, 1H), 6.29 (d, J = 17.0 Hz, 1H), 5.86 (t, J = 10.1 Hz, 1H), 4.82 (d, J = 32.0 Hz, 2H), 4.60 (d, J = 12.4 Hz, 2H), 4.39 - 4.18 (m, 2H), 3.78 (d, J = 13.6 Hz, 1H), 3.27 (t, J = 8.8 Hz, 1H), 3.10 (t, J = 12.8 Hz, 1H), 2.79 (d, J = 14.1 Hz, 5H), 2.51 (s, 3H), 1.94 (d, J = 13.4 Hz, 2H), 1.52 - 1.36 (m, 3H), 1.29 (s, 6H), 0.43 - 0.32 (m, 4H).LC-MS: [M+H] + found 599.00.’H NMR (400 MHz, DMSO-d6) 87.75 (dd, J = 8.0, 2.1 Hz, 1H), 7.67 (dd, J = 13.9, 6.2 Hz, 3H), 6.68 (ddd, J = 17.8, 10.4, 7.6 Hz, 1H), 6.28 (dt, J = 16.9, 2.7 Hz, 1H), 5.90 - 5.78 (m, 1H), 4.81 (d, J = 32.6 Hz, 2H), 4.58 (d, J = 10.1 Hz, 2H), 4.43 - 4.17 (m, 2H), 3.98 (d, J = 13.3 Hz, 1H), 3.13 (t, J = 12.8 Hz, 1H), 2.74 - 2.57 (m, 2H), 2.53 (s, 3H), 2.04 - 1.86 (m, 2H), 1.75 - 1.57 (m, 5H), 1.48 (p, J = 7.1 Hz, 2H), 1.29 (s, 12H), 0.37 (d, J = 8.7 Hz, 4H).LC-MS: [M+H]+ found 567.00.’H NMR (400 MHz, DMSO-d6) 8 9.48 - 9.42 (m, 1H), 8.77 (m, 1H), 8.17 - 8.04 (m, 3H), 7.59 - 7.50 (m, 1H), 6.91 (m, 1H), 6.78 (m, 1H), 6.63 (m, 1H), 6.26 (m, 1H), 5.79 (m, 1H), 5.29 (s, 1H), 5.03 (s, 1H), 4.88 (s, 1H), 4.74 (s, 1H), 4.59 (s, 1H), 4.54 - 4.45 (m, 2H), 3.11 - 2.90 (m, 5H), 1.82 (m, 4H), 1.47 - 1.35 (m, 1H), 1.32 (s, 6H), 0.45 - 0.38 (m, 4H).Starting material of final step was separated by Prep-Chiral-HPLC with theAttorney Docket No. 50006-0134WO1following conditions (Column: CHIRAL ART Cellulose-SZ 2*25 cm, 5 gm; Mobile Phase A: MtBE(0.5% 2MNH3-MeOH), Mobile Phase B: EtOH: DCM=11; Flow rate: 19 mL / min; Gradient: isocratic 25; Wave Length: 220 / 254 nm; RTl(min): 12.06; RT2(min): 18.01).LC-MS: (M+H)+ found:526.’H NMR (400 MHz, DMSO-d6) 8 8.59 (d, J = 3.8 Hz, 1H), 8.35 - 8.25 (m, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 7.24 (d, J = 2.5 Hz, 1H), 6.93 (ddd, J = 16.7, 10.4, 3.3 Hz, 1H), 6.20 (ddd, J = 16.9, 7.9, 2.5 Hz, 1H), 5.76 (ddd, J = 13.6, 10.4, 2.4 Hz, 1H), 4.68 (d, J = 48.5 Hz, 2H), 4.09 (t, J = 6.5 Hz, 2H), 3.77 - 3.66 (m, 2H), 3.50 (d, J = 7.2 Hz, 2H), 3.18 - 3.06 (m, 4H), 2.68 (dd, J = 18.2, 5.5 Hz, 2H), 2.12 (h, J = 6.2, 5.8 Hz, 2H), 1.98 (s, 3H), 1.26 (dd, J = 7.1, 4.9 Hz, 1H), 1.10 (t, J = 4.2 Hz, 1H), 0.98 - 0.89 (m, 2H), 0.88 -0.81 (m, 1H), 0.76 (dd, J= 10.0, 3.2 Hz, 1H). Starting material of final step was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylase-SA2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2MNH3-MeOH, Mobile Phase B: ETOH: DCM=11; Flow rate: 20 mL / min; Gradient: isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 9.9;RT2(min): 20.03)LC-MS: (M+H)+ found: 623.’H NMR (400 MHz, DMSO-d6) 88.50 (d, J = 4.2 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 11.5 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 6.95 (ddd, J = 15.3, 10.4, 4.3 Hz, 1H), 6.20 (ddd, J = 16.6, 6.1, 2.4 Hz, 1H), 5.81 - 5.71 (m, 1H), 4.78 (s, 1H), 4.65 (d, andJ = 3.6 Hz, 1H), 4.52 (d, J = 12.9 Hz, 1H), 4.26 (s, 1H), 3.87 (d, J = 13.9 Hz, 1H), 03.75 (dd, J = 11.9, 5.9 Hz, 2H), 3.31 - 3.22 (m, 2H), 3.14 (dt, J = 7.5, 3.8 Hz, 2H), 2.94 (s, 3H), 2.79 (tt, J = 23.8, 13.0 Hz, 6H), 1.76 (s, 4H), 1.26 (dd, J = 7.1, 5.0 Hz, 1H), 1.02 (t, J = 4.2 Hz, 1H), 0.97 - 0.81 (m, 3H), 0.78 (d, J = 8.2 Hz, 1H). LC-MS: (M+H)+ found: 623.’H NMR (400 MHz, DMSO-d6) 8 8.50 (d, J = 4.2 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.03 (d, J = 11.5 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 6.95 (ddd, J = 15.5, 10.4, 4.4 Hz, 1H), 6.20 (ddd, J = 16.8, 6.0, 2.4 Hz, 1H), 5.76 (ddd, J = 9.0, 6.2, 2.3 Hz, 1H), 4.78 (s, 1H), 4.65 (d, J = 3.6 Hz, 1H), 4.52 (d, J = 12.7 Hz, 1H), 4.26 (s, 1H), 3.87 (d, J = 13.5 Hz, 1H), 3.79 - 3.63 (m, 2H), 3.27 (dd, J = 8.4, 3.0 Hz, 2H), 3.14 (dt, J = 7.6,Attorney Docket No. 50006-0134WO13.9 Hz, 2H), 2.94 (s, 3H), 2.89 - 2.69 (m, 6H), 1.78 - 1.63 (m, 4H), 1.26 (dd, J = 7.1, 5.0 Hz, 1H), 1.02 (t, J = 4.3 Hz, 1H), 0.99 - 0.74 (m, 4H).Starting material of final step was separated by Prep-HPLC with the following conditions (Column: CHIRAL Amylose-SA 2*25 cm, 5 pm; Mobile Phase A:Hex(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1-HPLC; Flow rate: 20 mL / min; Gradient: to 30% B in 28 min; Wave Length: 220 / 254 nm; RTl(min): 11.86; RT2(min): 22.68).LC-MS: M+H found:583.30.’H NMR (400 MHz, Chloroform-d) 88.41 (d, J = 7.4 Hz, 2H), 7.92 - 7.78 (m, 2H), 6.61 - 6.46 (m, 2H), 6.23 (d, J = 4.6 Hz, 1H), 5.88 - 5.79 (m, 1H), 5.17 - 4.99 (m, 2H), 4.92 - 4.76 (m, 3H), 4.17 - 4.06 (m, 1H), 3.42 - 3.33 (m, 1H), 3.28 -3.17 (m, and1H), 3.15 -3.09 (m, 3H), 2.73 - 2.61 (m, 1H), 2.58 - 2.48 (m, 1H), 1.94 - 1.68 (m, 39H), 1.65 - 1.47 (m, 3H), 1.42 (t, J = 6.0 Hz, 1H), 1.28 (d, J = 8.3 Hz, 3H), 1.10 - 1.04 (m, 1H), 1.03 - 0.98 (m, 1H), 0.97 - 0.83 (m, 3H).LC-MS: M+H found:583.30.’H NMR (400 MHz, Chloroform-d) 88.40 (d, J = 8.0 Hz, 2H), 7.87 - 7.77 (m, 2H), 6.63 - 6.47 (m, 2H), 6.23 (d, J = 4.6 Hz, 1H), 5.87 - 5.77 (m, 1H), 5.17 - 5.02 (m, 2H), 4.87 (s, 3H), 4.12 (d, J = 3.4 Hz, 1H), 3.43 - 3.33 (m, 1H), 3.26 - 3.05 (m, 4H), 2.67 (t, J = 9.8 Hz, 1H), 2.58 - 2.49 (m, 1H), 1.95 - 1.67 (m, 9H), 1.60 - 1.56 (m, 3H), 1.42 (t, J = 6.0 Hz, 1H), 1.39 - 1.28 (m, 3H), 1.11 - 1.05 (m, 1H), 1.01 - 0.99 (m, 1H), 0.98 - 0.91 (m, 2H), 0.89 - 0.81 (m, 1H).LC-MS: (M+H)+ found: 587.3.’H NMR (400 MHz, DMSO-d6) 88.36 (d, J = 8.1 Hz, 3H), 7.93 (d, J = 8.2 Hz, 2H), 6.94 (ddd, J = 20.9, 16.5, 10.3 Hz, 1H), 6.80 (s, 1H), 6.26 - 6.07 (m, 1H), 5.74 (ddd, J = 13.4, 10.4, 2.3 Hz, 1H), 4.63 (d, J = 26.8 Hz, 2H), 4.44 (d, J = 13.2 Hz, 2H), 4.24 9(h, J = 7.1 Hz, 1H), 4.16 - 4.00 (m, 1H), 3.88 (dd, J = 21.1, 9.3 Hz, 4H), 3.48 - 3.41 (m, 2H), 3.22 (t, J = 12.8 Hz, 1H), 2.93 (tt, J = 11.0, 4.1 Hz, 1H), 2.74 (t, J = 12.4 Hz, 1H), 2.54 (d, J = 5.5 Hz, 2H), 2.13 - 1.83 (m, 4H), 1.71 (qd, J = 9.3, 6.2, 4.3 Hz, 2H), 1.69 - 1.31 (m, 10H).LC-MS: M+H found: 593.35.2’H NMR (400 MHz, DMSO-d6) 8 8.39 - 8.31 (m, 3H), 7.95 - 7.89 (m, 2H), 7.02 -Attorney Docket No. 50006-0134WO16.86 (m, 1H), 6.74 - 6.64 (m, 1H), 6.22 - 6.10 (m, 1H), 5.79 - 5.68 (m, 1H), 4.66 (s, 1H), 4.58 (s, 1H), 4.46 - 4.32 (m, 2H), 4.29 - 4.20 (m, 1H), 3.93 - 3.87 (m, 1H), 3.87 - 3.79 (m, 2H), 3.33 - 3.23 (m, 1H), 3.23 - 3.12 (m, 1H), 2.91 - 2.68 (m, 5H), 2.54 (d, J = 5.7 Hz, 2H), 2.03 - 1.93 (m, 2H), 1.93 - 1.83 (m, 2H), 1.78 - 1.66 (m, 2H), 1.62 - 1.51 (m, 4H), 1.51 - 1.39 (m, 2H).Starting material of final step was separated by Prep-Chiral-HPLC with the following conditions Column: (CHIRAL ART Amylase-SA2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% IPAMine)— HPLC, Mobile Phase B: ETOH: DCM=11-HPLC; Flow rate: 20 mL / min; Gradient: isocratic 25; Wave Length: 220 / 254 nm; RTl(min): 9.25; RT2(min): 14.07)LC-MS: (M+H)+ found:583.’H NMR (400 MHz, DMSO-d6) 88.50 (d, J = 3.9 Hz, 1H), 7.79 (dd, J = 8.0, 1.4 Hz, 1H), 7.76 - 7.67 (m, 2H), 7.26 (dd, J = 41.0, 7.5 Hz, 1H), 6.65 (ddd, J = 43.1, 16.8, 10.4 Hz, 1H), 6.25 (dt, J = 16.9, 2.7 Hz, 1H), 5.79 (ddd, J = 18.2, 10.3, 2.3 Hz, 1H), and 4.80 (d, J = 32.7 Hz, 2H), 4.56 (d, J = 4.0 Hz, 2H), 4.29 (dd, J = 43.7, 11.0 Hz, 2H), 6 3.96 (d, J = 13.6 Hz, 1H), 3.14 (dt, J = 7.6, 3.8 Hz, 2H), 2.74 - 2.57 (m, 2H), 2.54 (d, J = 1.7 Hz, 3H), 2.04 - 1.85 (m, 2H), 1.75 - 1.59 (m, 5H), 1.51 - 1.21 (m, 7H), 1.21 - 1.06 (m, 2H), 0.99 - 0.72 (m, 4H).LC-MS: (M+H)+ found:583.’H NMR (400 MHz, DMSO-d6) 8 8.52 (d, J = 4.0 Hz, 1H), 7.82 - 7.64 (m, 3H), 7.28 (dd, J = 39.4, 7.5 Hz, 1H), 6.66 (ddd, J = 43.6, 16.8, 10.3 Hz, 1H), 6.25 (dt, J = 16.8, 2.7 Hz, 1H), 5.80 (ddd, J = 18.2, 10.3, 2.3 Hz, 1H), 4.80 (d, J = 33.4 Hz, 2H), 4.56 (t, J = 3.5 Hz, 2H), 4.39 - 4.15 (m, 2H), 3.96 (d, J = 13.5 Hz, 1H), 3.14 (dt, J = 7.4, 3.7 Hz, 2H), 2.73 - 2.52 (m, 5H), 1.93 (dd, J = 30.9, 12.0 Hz, 2H), 1.74 - 1.59 (m, 5H), 1.50 - 1.21 (m, 7H), 1.21 - 1.06 (m, 2H), 1.00 - 0.71 (m, 4H).LC-MS: (M+H)+ found: 501.23.’H NMR (400 MHz, DMSO-d6) 89.67 (d, J = 8.1 Hz, 1H), 9.33 (d, J = 2.2 Hz, 1H), 8.71 (ddd, J = 10.6, 8.1, 2.1 Hz, 1H), 8.19 - 8.10 (m, 3H), 7.56 (dd, J = 20.1, 2.3 Hz, 01H), 6.74 - 6.54 (m, 1H), 6.28 (dt, J = 16.9, 3.0 Hz, 1H), 5.87 - 5.78 (m, 1H), 4.93 (d, J = 15.1 Hz, 2H), 4.68 (s, 2H), 3.61 (d, J = 2.4 Hz, 3H), 1.44 (p, J = 7.0 Hz, 1H), 1.34 (s, 6H), 0.43 (d, J = 6.9 Hz, 4H).Attorney Docket No. 50006-0134WO1LC-MS: M+H found: 565.30.’H NMR (400 MHz, Chloroform-d) 8 8.41 (d, J = 7.9 Hz, 2H), 8.34 (d, J = 4.7 Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H), 6.73 - 6.62 (m, 2H), 6.60 (s, 1H), 6.52 (t, J = 4.8 Hz, 1H), 5.81 - 5.73 (m, 1H), 4.82 - 4.74 (m, 4H), 4.53 (s, 1H), 3.98 (s, 1H), 3.88 (s, 1H), 3.21 (t, J = 9.7 Hz, 2H), 2.50 (s, 2H), 2.22 (d, J = 9.6 Hz, 2H), 2.08 (s, 6H), 1.54 (d, J = 9.8 Hz, 2H), 1.27 (s, 3H).LC-MS: [M+H] + found 599.00.’H NMR (400 MHz, DMSO-d6) 89.43 (d, J = 2.2 Hz, 1H), 9.17 (d, J = 4.0 Hz, 1H), 8.78 - 8.70 (m, 1H), 8.08 (d, J = 8.2 Hz, 1H), 6.94 (ddd, J = 19.4, 16.6, 10.5 Hz, 1H), 6.85 (dd, J = 13.9, 7.7 Hz, 1H), 6.22 - 6.10 (m, 1H), 5.79 - 5.68 (m, 1H), 4.67 (s, 1H), 4.59 (s, 1H), 4.35 - 4.27 (m, 1H), 3.90 (t, J = 5.8 Hz, 1H), 3.82 (d, J = 7.2 Hz, 1H), 3.62 (d, J = 13.0 Hz, 2H), 3.12 (t, J = 5.2 Hz, 4H), 2.95 - 2.84 (m, 2H), 2.54 (s, OH), 1.99 (s, 6H), 1.95 - 1.86 (m, 2H), 1.61 (dd, J = 12.1, 3.8 Hz, 1H), 1.54 (dd, J= 16.6, 4.2 Hz, 1H), 1.54 (s, 2H), 1.48 (s, 4H), 1.24 (s, 3H).LC-MS: [M+H] + found 611.35.'HNMR (400 MHz, DMSO-d6) 89.42 (s, 1H), 9.15 (d, J = 3.4 Hz, 1H), 8.74 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.11 - 6.72 (m, 2H), 6.22 - 6.10 (m, 1H), 5.74 (t, J = 11.4 Hz, 1H), 4.63 (d, J = 31.9 Hz, 2H), 4.31 (dt, J = 14.6, 5.6 Hz, 1H), 3.90 (d, J = 5.6 Hz, 5H), 3.78 (d, J = 13.4 Hz, 4H), 2.93 - 2.81 (m, 2H), 2.54 (s, 1H), 2.11 (t, J = 7.6 Hz, 4H), 1.99 (s, 6H), 1.89 (dd, J = 13.2, 3.9 Hz, 2H), 1.75 (p, J = 7.6 Hz, 2H), 1.50 (qd, J = 12.4, 4.0 Hz, 2H), 1.24 (s, 3H).LC-MS: (M+H)+ found: 594.’H NMR (400 MHz, DMSO-d6) 88.39 (t, J = 7.4 Hz, 3H), 7.96 (d, J = 8.2 Hz, 2H), 6.95 (dd, J = 16.6, 10.5 Hz, 1H), 6.18 (dt, J = 16.0, 3.8 Hz, 1H), 5.80 - 5.70 (m, 1H), 5.56 (tt, J = 7.3, 3.4 Hz, 1H), 4.82 (s, 1H), 4.73 (s, 1H), 4.25 (q, J = 7.1 Hz, 1H), 3.87 (dt, J = 22.7, 6.0 Hz, 2H), 3.73 (s, 1H), 3.59 (s, 2H), 3.50 - 3.41 (m, 1H), 3.29 (dd, J = 8.8, 3.0 Hz, 1H), 2.80 (dt, J = 15.8, 9.2 Hz, 4H), 2.68 (d, J = 16.7 Hz, 2H), 2.02 (q, J = 11.9 Hz, 2H), 1.90 (tt, J = 9.6, 3.8 Hz, 2H), 1.80 - 1.66 (m, 4H), 1.62 - 1.48 (m, 4H).LC-MS: (M+H)+ found: 581.Attorney Docket No. 50006-0134WO1’H NMR (400 MHz, DMSO-d6) 89.63 (d, J = 3.9 Hz, 2H), 8.75 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 39.4, 7.1 Hz, 1H), 6.65 (ddd, J = 48.5, 16.7, 10.3 Hz, 1H), 6.26 (ddd, J = 16.9, 6.1, 2.3 Hz, 1H), 5.80 (ddd, J = 13.7, 10.3, 2.2 Hz, 1H), 4.92 -4.71 (m, 2H), 4.58 (d, J = 22.7 Hz, 2H), 4.37 (t, J = 11.0 Hz, 2H), 4.26 (q, J = 7.1 Hz, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.33 - 3.15 (m, 2H), 2.96 - 2.69 (m, 5H), 2.08 - 1.84 (m, 4H), 1.79 - 1.68 (m, 2H), 1.59 (dq, J = 14.4, 5.4 Hz, 4H), 1.49 - 1.32 (m, 2H). LC-MS: (M+H)+found:613.35’H NMR (400 MHz, DMSO-d6) 8 8.83 (s, 1H), 7.75 - 7.54 (m, 3H), 6.86 (ddd, J = 27.0, 16.5, 10.5 Hz, 1H), 6.62 (dd, J = 16.0, 8.0 Hz, 1H), 6.09 (dd, J = 16.9, 9.6 Hz, 1H), 5.66 (t, J = 12.7 Hz, 1H), 4.52 (d, J = 31.5 Hz, 2H), 4.28 (dd, J = 45.3, 11.7 Hz, 2H), 3.96 (d, J = 13.6 Hz, 1H), 3.80 (dd, J = 26.6, 7.9 Hz, 4H), 3.33 (d, J = 18.6 Hz, 3H), 3.04 (t, J = 12.9 Hz, 1H), 2.83 (tt, J = 11.1, 4.2 Hz, 1H), 2.58 (d, J = 13.0 Hz, 1H), 2.45 - 2.41 (m, 4H), 1.90 (s, 7H), 1.78 (s, 1H), 1.58 - 1.38 (m, 5H), 1.36 - 1.27 (m, 1H), 1.17 (s, 3H).LC-MS: (M+H)+ found 582.’H NMR (400 MHz, Chloroform-d) 8 8.37 (dd, J = 17.7, 8.0 Hz, 2H), 7.81 (dd, J = 8.2, 3.4 Hz, 2H), 7.34 (d, J = 3.2 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.90 (q, J = 3.8, 2.7 Hz, 2H), 6.19 (d, J = 7.8 Hz, 1H), 4.95 (d, J = 9.5 Hz, 2H), 4.79 (d, J = 36.7 Hz, 2H), 4.43 (h, J = 6.9 Hz, 1H), 4.15 (t, J = 6.5 Hz, 2H), 3.71 (dt, J = 22.0, 7.2 Hz, 2H), 3.24 (d, J = 12.0 Hz, 3H), 2.25 (p, J = 6.7 Hz, 2H), 2.19 - 2.00 (m, 5H), 1.82 - 1.61 (m, 4H), 1.54 (dt, J = 12.8, 6.5 Hz, 2H).LC-MS: (M+H)+found 608.24.’H NMR (400 MHz, DMSO-d6) 8 10.39 (s, 1H), 8.37 (dd, J = 8.4, 4.4 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.82 (dd, J = 8.8, 5.0 Hz, 2H), 7.46 (d, J = 3.3 Hz, 1H), 7.36 - 7.17 (m, 4H), 6.92 (dp, J = 15.0, 7.4 Hz, 1H), 5.24 (s, 1H), 4.96 (d, J = 5.3 Hz, 2H), 4.60 (s, 1H), 4.13 (td, J = 6.8, 2.5 Hz, 2H), 3.68 (t, J = 7.3 Hz, 2H), 3.26 - 3.21 (m, 3H), 2.13 (h, J = 6.6 Hz, 2H), 1.98 (d, J = 2.2 Hz, 3H).LC-MS: [M+H]+ found 526.00.’H NMR (400 MHz, DMSO-d6) 8 10.32 (s, 2H), 8.45 (d, J = 8.1 Hz, 4H), 8.03 (d, J = 8.4 Hz, 4H), 7.79 (d, J = 8.0 Hz, 4H), 7.37 (t, J = 7.9 Hz, 4H), 7.11 (t, J = 7.4 Hz, 3H), 7.02 (s, 1H), 6.95 (td, J = 18.5, 17.7, 10.4 Hz, 3H), 6.16 (t, J = 14.2 Hz, 3H),Attorney Docket No. 50006-0134WO15.74 (t, J = 10.7 Hz, 2H), 4.67 (s, 2H), 4.59 (s, 2H), 3.91 (s, 2H), 3.89 - 3.82 (m, 4H), 3.59 (q, J = 6.5 Hz, 4H), 3.44 (t, J = 6.1 Hz, 4H), 1.85 (p, J = 6.4 Hz, 5H), 1.69 - 1.54 (tn, 11H), 1.47 (dd, J = 8.8, 3.7 Hz, 4H).LC-MS: (M+H)+ found 506.2.’H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 8.08 (dd, J = 2.8, 0.9 Hz, 1H), 7.76 - 7.55 (m, 4H), 7.41 - 7.27 (m, 3H), 7.16 - 7.06 (m, 2H), 6.65 (td, J = 19.1, 17.9, 10.6 Hz, 1H), 6.25 (dt, J = 16.7, 1.9 Hz, 1H), 5.79 (td, J = 10.6, 2.3 Hz, 1H), 4.94 (s, 1H), 4.79 (s, 1H), 4.70 (s, 1H), 4.51 - 4.37 (m, 3H), 3.59 (d, J = 7.5 Hz, 2H), 3.14 (s, 3H), 2.27 -2.15 (m, 2H).LC-MS: (M+H) + found 536.25.’H NMR (400 MHz, DMSO-d6) 6 8.44 - 8.26 (m, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.81 - 7.57 (m, 2H), 6.74 - 6.57 (m, 1H), 6.29 - 6.23 (tn, 1H), 5.84 - 5.71 (tn, 1H), 4.87 - 4,76 (tn, 2H), 4.62 - 4,54 (tn, 3H), 4.40 (d, J = 4.9 Hz, 2H), 4.27 (d, J = 4.5 Hz, 2H), 2.92 - 2.75 (m, 2H), 2.44 - 2.38 (m, 2H), 1.53 - 1.46 (m, 1H), 1.29 (s, 6H), 0.41 - 0.19 (m, 4H).Separated by reverse phase flash with the following conditions (Column: Xbridge BEH Shield RP18, 30*150 mm, 5pm; Mobile Phase A: Water( 1 Ommol / L NH4HC03+0.05% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / tnin; Gradient: 27% B to 57% B in 8 min; Wave Length: 220nm nm; RTl(min): 7.63)LC-MS: (M+H)+ found: 579.’H NMR (400 MHz, DMSO-d6) 6 8.36 (dt, J = 11.8, 5.5 Hz, 3H), 7.92 (d, J = 8.1 Hz, 2H), 6.97 (dq, J = 26.3, 15.7, 13.0 Hz, 2H), 6.16 (t, J = 14.6 Hz, 1H), 5.75 (d, J = 11.7 Hz, 1H), 4.92 - 4.52 (m, 3H), 4.25 (dt, J = 14.4, 7.3 Hz, 1H), 3.94 - 3.75 (m, 3H), 3.56 (dt, J = 16.5, 8.2 Hz, 2H), 3.45 (s, 2H), 3.16 (dd, J = 19.3, 10.0 Hz, 1H), 2.78 (dq, J = 17.2, 8.9 Hz, 4H), 2.56 (s, 1H), 2.23 (dt, J = 31.0, 6.3 Hz, 1H), 2.07 (dt, J = 37.0, 6.2 Hz, 1H), 1.90 (s, 2H), 1.71 (s, 2H), 1.64 - 1.44 (m, 4H).LC-MS: [M+H]+ found 545.00.’H NMR (400 MHz, DMSO-d6) 8 7.83 (dd, J = 8.0, 2.3 Hz, 1H), 7.72 - 7.62 (m, 3H), 6.78 (ddd, J = 42.8, 16.7, 10.3 Hz, 1H), 6.26 (ddd, J = 16.8, 4.5, 2.3 Hz, 1H), 5.78 (ddd, J = 10.3, 5.9, 2.3 Hz, 1H), 5.29 (s, 1H), 5.04 (d, J = 2.1 Hz, 1H), 4.85 (d, JAttorney Docket No. 50006-0134WO1= 1.9 Hz, 1H), 4.70 (s, 1H), 4.54 (d, J = 16.6 Hz, 2H), 3.93 (d, J = 13.7 Hz, 1H), 3.15 - 3.08 (m, 1H), 3.06 (d, J = 3.7 Hz, 3H), 2.57 (d, J = 1.6 Hz, 3H), 2.03 (s, 3H), 1.86 - 1.73 (m, 1H), 1.72 - 1.62 (m, 3H), 1.49 (p, J = 7.0 Hz, 1H), 1.28 (s, 6H), 0.39 - 0.29 (m, 4H).LC-MS: [M+H]+ found 566.00.'HNMR (400 MHz, DMSO-d6) 88.11 (dd, J = 4.9, 2.3 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 - 7.63 (m, 3H), 7.52 (ddt, J = 8.7, 7.0, 1.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 6.87 (dd, J = 8.7, 4.1 Hz, 1H), 6.71 (dd, J = 16.7, 10.3 Hz, 1H), 6.64 - 6.53 (m, 1H), 6.30 - 6.20 (m, 1H), 5.79 (ddd, J = 14.7, 10.2, 2.3 Hz, 1H), 4.85 (s, 1H), 4.75 (s, 1H), 4.55 (d, J = 9.2 Hz, 2H), 4.31 (d, J = 13.5 Hz, 3H), 3.32 (s, 1H), 2.93 (t, J = 12.4 Hz, 2H), 2.57 (d, J = 1.8 Hz, 3H), 1.95 (d, J = 12.4 Hz, 2H), 1.55 - 1.44 (m, 3H), 1.28 (s, 6H), 0.39 - 0.32 (m, 4H).LC-MS: [M+H]+ found 600.35'HNMR (400 MHz, DMSO-d6) 89.42 (s, 1H), 8.79 - 8.71 (m, 1H), 8.14 - 8.04 (m, 2H), 6.87 - 6.66 (m, 1H), 6.31 - 6.21 (m, 1H), 5.82 - 5.74 (m, 1H), 5.25 (s, 1H), 5.00 (s, 1H), 4.86 (s, 1H), 4.71 - 4.55 (m, 3H), 4.11 - 4.05 (m, 1H), 3.29 - 3.20 (m, 1H), 3.08 (s, 3H), 2.71 - 2.58 (m, 2H), 1.79 - 1.61 (m, 9H), 1.33 (s, 11H), 1.20 - 1.13 (m, 1H), 0.45 - 0.38 (m, 4H).LC-MS: (M+H)+ found: 607.’H NMR (400 MHz, DMSO-d6) 88.36 (t, J = 7.3 Hz, 3H), 7.94 (d, J = 8.2 Hz, 2H), 6.95 (dd, J = 16.6, 10.4 Hz, 1H), 6.20 (ddd, J = 16.7, 5.9, 2.3 Hz, 1H), 5.76 (dq, J = 8.9, 2.3 Hz, 1H), 4.81 - 4.62 (m, 2H), 4.53 (d, J = 12.9 Hz, 1H), 4.25 (h, J = 7.7, 7.2 Hz, 2H), 3.93 - 3.66 (m, 3H), 3.31 - 3.11 (m, 3H), 2.94 (s, 3H), 2.92 - 2.69 (m, 6H), 1.90 (tq, J = 9.8, 4.6 Hz, 2H), 1.83 - 1.62 (m, 6H), 1.55 (h, J = 6.5, 6.0 Hz, 4H). LC-MS: (M+H)+found:593.30’H NMR (400 MHz, DMSO-d6) 88.37 (d, J = 8.0 Hz, 3H), 7.92 (d, J = 8.0 Hz, 2H), 7.51 (dd, J = 13.4, 5.7 Hz, 1H), 6.96 (td, J = 19.0, 18.1, 10.4 Hz, 1H), 6.17 (t, J = 14.2 Hz, 1H), 5.75 (t, J = 11.9 Hz, 1H), 4.87 (p, J = 6.1 Hz, 1H), 4.74 - 4.56 (m, 3H), 4.20 (dt, J = 29.1, 8.0 Hz, 3H), 4.03 - 3.81 (m, 3H), 2.57 (d, J = 17.1 Hz, 2H), 2.41 (d, J = 11.6 Hz, 1H), 2.03 (d, J = 11.4 Hz, 2H), 1.90 (s, 3H), 1.81 - 1.49 (m, 11H).Attorney Docket No. 50006-0134WO1Starting material of final step was separated by the following conditions (Column: CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% IPAmine), Mobile Phase B: IPA: DCM=1: 1; Flow rate: 20 mL / min; Gradient: to 35% B in 85 min; Wave Length: 220 / 254 nm; RTl(min): 50.55; RT2(min): 59.46)LC-MS: M+H found: 605.45’H NMR (400 MHz, Chloroform-d) 57.96 (d, J = 9.1 Hz, 2H), 6.57 - 6.45 (m, 2H), 6.10 (s, 1H), 5.89 - 5.78 (m, 1H), 4.86 (s, 2H), 4.78 (d, J = 9.6 Hz, 1H), 4.69 (s, 2H), 4.64 (s, 1H), 4.42 (s, 1H), 4.00 (d, J = 9.6 Hz, 1H), 3.42 - 3.36 (m, 1H), 3.28 (t, 1H), and2.87 (d, J = 9.9 Hz, 1H), 2.52 (t, 1H), 2.25 (d, J = 8.6 Hz, 1H), 2.11 (s, 1H), 1.81 (s, 15H), 1.55-1.42 (d, J = 9.7 Hz, 4H), 1.28 (t, J = 9.2 Hz, 4H), 1.13 - 0.99 (m, 2H), 0.99 - 0.82 (m, 3H).LC-MS: M+H found: 605.35’H NMR (400 MHz, Chloroform-d) 57.95 (d, J = 9.4 Hz, 2H), 6.52 (s, 2H), 6.08 (s, 1H), 5.85 (d, J = 7.9 Hz, 1H), 4.86 - 4.78 (m, 3H), 4.69 (s, 2H), 4.42 (s, 1H), 3.99 (s, 1H), 3.40 (s, 1H), 3.28 (s, 1H), 2.86 (s, 1H), 2.50 (d, J = 8.1 Hz, 1H), 2.26 (s, 1H), 2.12 (s, 1H), 1.81 (s, 5H), 1.72 (s, 4H), 1.27 (d, J = 9.3 Hz, 4H), 1.13 - 1.06 (m, 1H), 1.02 (s, 1H), 0.90 (d, J = 5.4 Hz, 3H).LC-MS: M+H found: 621.25.’H NMR (400 MHz, DMSO-d6) 8 8.36 - 8.22 (m, 1H), 7.97 - 7.82 (m, 2H), 7.50 - 7.28 (m, 1H), 6.79 - 6.49 (m, 1H), 6.32 - 6.16 (m, 1H), 5.87 - 5.71 (m, 1H), 4.95 - 64.67 (m, 2H), 4.66 - 4.21 (m, 4H), 4.14 - 3.81 (m, 1H), 3.29 - 3.10 (m, 1H), 2.92 - 2.72 (m, 1H), 2.70 - 2.56 (m, 1H), 2.14 - 1.87 (m, 2H), 1.85 - 1.50 (m, 5H), 1.49 - 1.41 (m, 1H), 1.40 - 1.20 (m, 12H), 1.20 - 1.06 (m, 1H), 0.63 - 0.22 (m, 4H).Starting material of final step was separated by Chiral-HPLC with the following conditions (Column: Lux 5um Cellulose-22.12*25 cm, 5 pm; Mobile Phase A: Hex(0.2% IPAmine), Mobile Phase B: ETOH: MeOH=l: 2; Flow rate: 20 mL / min; and Gradient: 75% B to 25% B in 23 min; Wave Length: 220 / 254 nm; RTl(min): 17.546; 5 RT2(min): 19.989).LC-MS: [M+H] + found 550.00..’H NMR (400 MHz, Chloroform-d) 8 8.24 - 8.18 (m, 1H), 7.85 (dd, J = 13.6, 7.9 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 6.59 - 6.48Attorney Docket No. 50006-0134WO1(m, 2H), 6.16 (s, 1H), 5.81 (dd, J = 8.4, 3.4 Hz, 1H), 4.88 - 4.77 (m, 3H), 4.73 (s, 2H), 4.35 (d, J = 13.9 Hz, 4H), 3.37 (s, 1H), 3.12 (s, 2H), 2.61 (s, 3H), 2.21 (d, J = 11.8 Hz, 2H), 2.01 (s, 1H), 1.61 (d, J = 7.1 Hz, OH), 1.40 (t, J = 6.1 Hz, 1H), 1.26 (s, 2H), 1.11 - 1.04 (m, 1H), 0.99 (d, J = 4.5 Hz, 1H), 0.93 (d, J = 5.9 Hz, 1H), 0.87 (s, 3H).LC-MS: [M+H] + found 550.00.’H NMR (400 MHz, Chloroform-d) 8 8.24 - 8.18 (m, 1H), 7.85 (dd, J = 13.6, 7.9 Hz, 1H), 7.68 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 6.76 (s, 1H), 6.68 (s, 1H), 6.59 - 6.48 (m, 2H), 6.16 (s, 1H), 5.81 (dd, J = 8.4, 3.4 Hz, 1H), 4.88 - 4.77 (m, 3H), 4.73 (s, 2H), 4.35 (d, J = 13.9 Hz, 4H), 3.37 (s, 1H), 3.12 (s, 2H), 2.61 (s, 3H), 2.21 (d, J = 11.8 Hz, 2H), 2.01 (s, 1H), 1.61 (d, J = 7.1 Hz, OH), 1.40 (t, J = 6.1 Hz, 1H), 1.26 (s, 2H), 1.11 - 1.04 (m, 1H), 0.99 (d, J = 4.5 Hz, 1H), 0.93 (d, J = 5.9 Hz, 1H), 0.87 (s, 3H).’H NMR (400 MHz, DMSO-d6) 59.18 (d, J = 5.8 Hz, 1H), 8.36 (t, J = 11.1 Hz, 1H), 8.02 (s, 1H), 7.45 (d, J = 6.0 Hz, 1H), 7.25 (d, J = 4.0 Hz, 1H), 6.74 (td, J = 16.3, 10.2 Hz, 1H), 6.37- 6.18 (m, 1H), 5.79 (t, J = 10.0 Hz, 1H), 5.15 (s, 1H), 4.96 (s, 51H), 4.86 (s, 1H), 4.56 (s, 1H), 4.12 (q, J = 5.7 Hz, 2H), 3.66 (d, J = 8.3 Hz, 2H), 3.24 (s, 3H), 2.18 - 2.06 (m, 2H), 1.97 (d, J = 2.5 Hz, 3H), 1.39 (d, J = 7.0 Hz, 1H), 1.31 (s, 6H), 0.40 (d, J = 7.0 Hz, 4H).Starting material of final step was separated by Prep-Chiral-HPLC with the following conditions (Column: CHIRAL Amylose-SA 2*25 cm, 5 pm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient: to 30% B in 15 min; Wave Length: 220 / 254 nm; RTl(min): 7.864; RT2(min): 10.806)and LC-MS: (M+H)+ found 626.35.3 ’H NMR (400 MHz, DMSO-d6) 8 8.63 - 8.51 (m, 1H), 8.44 - 8.33 (m, 2H), 7.97 - 7.87 (m, 2H), 7.42 - 7.25 (m, 1H), 6.82 - 6.67 (m, 1H), 6.57 - 6.38 (m, 1H), 4.89 - 4.67 (m, 2H), 4.61 - 4.48 (m, 2H), 4.37 (s, 2H), 4.06 - 3.92 (m, 1H), 3.29 - 3.19 (m, 1H), 3.19 - 3.07 (m, 3H), 2.86 - 2.72 (m, 1H), 2.72 - 2.56 (m, 1H), 2.31 - 2.17 (m, 6H), 2.14 - 1.90 (m, 2H), 1.75 - 1.56 (m, 5H), 1.56 - 1.23 (m, 7H), 1.22 - 1.11 (m, 1H), 1.09 (t, J = 4.3 Hz, 1H), 1.02 - 0.86 (m, 2H), 0.88 - 0.72 (m, 2H).Attorney Docket No. 50006-0134WO1LC-MS: (M+H)+ found 626.40’H NMR (400 MHz, DMSO-d6) 58.58 (t, J = 3.8 Hz, 1H), 8.41 - 8.32 (m, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.44 - 7.22 (m, 1H), 6.81 - 6.68 (m, 1H), 6.59 - 6.38 (m, 1H), 4.89 - 4.68 (m, 2H), 4.61 - 4.48 (m, 2H), 4.37 (s, 2H), 4.07 - 3.92 (m, 1H), 3.28 - 3.20 (m, 1H), 3.18 - 3.05 (m, 3H), 2.78 (s, 1H), 2.62 (s, 1H), 2.37 - 2.14 (m, 6H), 2.13 - 1.90 (m, 2H), 1.77 - 1.57 (m, 5H), 1.55 - 1.28 (m, 6H), 1.28 - 1.22 (m, 1H),1.21 - 1.12 (m, 1H), 1.09 (t, J = 4.3 Hz, 1H), 1.00 - 0.88 (m, 2H), 0.88 - 0.81 (m, 1H), 0.80 - 0.72 (m, 1H).LC-MS: M+H found:611.30.’H NMR (400 MHz, Chloroform-d) 5 8.37 (d, J = 7.8 Hz, 2H), 7.95-7.71 (m, 2H), 6.81-6.58 (m, 2H), 6.43-6.38 (m, 1H), 5.81-5.77 (m, 1H), 4.93-4.72 (m, 3H), 4.37- 4.29 (m, 1H), 4.11-4.07 (m, 1H), 3.92-3.70 (m, 2H), 3.20-3.14 (m, 1H), 2.94 (d, J = 4.0 Hz, 3H), 2.81-2.78 (m, 2H), 2.68-2.59 (m, 1H), 2.55-2.47 (m, 1H), 2.07 (s, 6H), 2.01-1.86 (m, 2H), 1.84-1.69 (m, 7H), 1.63-1.48 (m, 2H), 1.28 (s, 6H).LC-MS: [M+H]+found 622.25.’H NMR (400 MHz, DMSO-d6) 88.35 (d, J = 7.8 Hz, 3H), 7.91 (d, J = 8.4 Hz, 2H), 6.95 (td, J = 17.4, 10.5 Hz, 1H), 6.73 (dd, J = 14.8, 7.5 Hz, 1H), 6.24 - 6.07 (m, 1H), 5.73 (t, J = 11.9 Hz, 1H), 4.62 (d, J = 31.5 Hz, 2H), 4.41 - 4.17 (m, 2H), 3.86 (d, J = 28.9 Hz, 2H), 3.69 (d, J = 13.0 Hz, 2H), 3.32 (s, 2H), 3.26 (d, J = 6.0 Hz, 4H), 2.96 (t, J= 12.6 Hz, 2H), 1.96 (dd, J = 29.6, 13.9 Hz, 8H), 1.69 (d, J= 12.6 Hz, 2H), 1.63 - 1.47 (m, 6H).LC-MS: M+H found: 579.30’H NMR (400 MHz, Chloroform-d) 8 8.42 (d, J = 7.9 Hz, 2H), 8.34 (d, J = 4.8 Hz, 2H), 7.83 (d, J = 7.8 Hz, 2H), 6.70 (d, J = 9.4 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 6.7 Hz, 1H), 5.81 (d, J = 9.4 Hz, 1H), 4.99 (d, J = 9.4 Hz, 2H), 4.84 (d, J = 9.0 Hz, 2H), 4.39 (s, 1H), 3.85 (s, 1H), 3.74 (s, 1H), 3.15 - 2.92 (m, 5H), 2.89 - 2.72 (m, 2H), 2.08 (s, 6H), 1.93 (s, 3H), 1.91 - 1.83 (m, 1H), 1.28 (s, 3H).LC-MS: [M+H] + found 607.00.’H NMR (400 MHz, DMSO-d6) 8 9.43 (s, 1H), 9.15 (s, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 6.96 (dd, J = 17.2, 10.5 Hz, 2H), 5.74 (t, J = 11.4 Hz, 1H), 4.67 (s, 1H), 4.59 (s, 2H), 4.34 (t, J = 13.0 Hz, 5H), 3.83 (d, J = 11.8 Hz, 4H),Attorney Docket No. 50006-0134WO13.30 (s, 1H), 2.97 (t, J = 12.4 Hz, 2H), 2.54 (s, 1H), 1.99 (s, 6H), 1.89 (d, 2H),1.52 (dt, J = 13.6, 9.9 Hz, 2H), 1.24 (s, 3H).LC-MS: [M+H]+ found 610.00.1HNMR (400 MHz, DMSO-d6) 89.43 (s, 1H), 9.17 (m, 1H), 8.75 (m, 1H), 8.08 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 6.22 -6.10 (m, 1H), 5.74 (m, 1H), 4.63 (m, 52H), 4.38 (m, 2H), 3.90 (s, 1H), 3.85 - 3.70 (m, 2H), 3.32 (m, 1H), 3.20 (m, 1H), 3.10 (m, 1H), 2.72 (m, 1H), 2.54 (s, 1H), 2.23 -2.00 (m, 6H), 1.99 (s, 6H), 1.93 (s, 2H), 1.88 - 1.77 (m, 2H), 1.81 - 1.69 (m, 2H), 1.50 - 1.35 (m, 2H), 1.24 (s, 3H). Starting material of final step was separated by Prep-Chiral HPLC with the following conditions (Column: (R, R)-WHELK-Ol-Kromasil, 2.11*25 cm, 5 pm; Mobile Phase A: Hex(0.2% 1PA), Mobile Phase B: MeOH: DCM=1: 2; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 45 min; Wave Length: 220 / 254 nm; RTl(min): 37.544; RT2(min): 41.731)LC-MS: [M+H]+found 623.25.’H NMR (400 MHz, DMSO-d6) 8 8.42 (d, J = 4.3 Hz, 1H), 7.58 (d, J = 11.2 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.03 - 6.85 (m, 1H), 6.72 (dd, J = 16.4, 7.6 Hz, 1H), 6.16 (dd, J= 16.6, 8.7 Hz, 1H), 5.73 (t, J = 12.1 Hz, 1H), 4.59 (d, J = 33.4 Hz, 2H), 4.36 (d, J = 13.1 Hz, 1H), 4.30 - 4.15 (m, 1H), 4.03 - 3.73 (m, 3H), 3.27 (dd, J = 8.6, and2.9 Hz, 3H), 3.18 - 2.99 (m, 2H), 2.94 - 2.62 (m, 5H), 2.50 (s, 3H), 1.87 (d, J = 11.7 6Hz, 2H), 1.44 (t, J = 12.8 Hz, 2H), 1.25 (dd, J = 7.1, 4.9 Hz, 1H), 1.01 (dd, J = 4.9, 3.6 Hz, 1H), 0.97 - 0.69 (m, 4H).LC-MS: [M+H]+found 623.25.’H NMR (400 MHz, DMSO-d6) 8 8.42 (dd, J = 4.2, 1.5 Hz, 1H), 7.58 (d, J = 11.3 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 6.93 (ddd, J = 24.4, 16.6, 10.5 Hz, 1H), 6.72 (dd, J = 16.2, 7.6 Hz, 1H), 6.26 - 6.09 (m, 1H), 5.83 - 5.65 (m, 1H), 4.59 (d, J = 33.3 Hz, 2H), 4.36 (d, J = 13.0 Hz, 1H), 4.25 (dt, J = 7.6, 4.1 Hz, 1H), 3.85 (dd, J = 32.9, 10.8 Hz, 3H), 3.28 (td, J = 8.6, 3.0 Hz, 3H), 3.16 - 3.01 (m, 2H), 2.88 - 2.63 (m, 5H), 2.50 - 2.33 (m, 3H), 1.88 (t, J = 11.3 Hz, 2H), 1.44 (tt, J = 11.9, 3.8 Hz, 2H), 1.25 (dd, J = 7.1, 5.0 Hz, 1H), 1.01 (dd, J = 4.9, 3.5 Hz, 1H), 0.98 - 0.72 (m, 4H). and Starting material of final step was separated by chiral Pre-HPLC (Column: 8 CHIRALPAK IE, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH),Attorney Docket No. 50006-0134WO1Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 18 mL / min; Gradient: to 50% B in 36 min; Wave Length: 220 / 254 nm; RTl(min): 17.57; RT2(min): 23.538 LC-MS: [M+H] + found 606.30.'H NMR (400 MHz, DMSO-d6) 88.52 (d, J = 4.6 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 6.93 (ddd, J = 27.0, 16.6, 10.4 Hz, 1H), 6.77 (dd, J = 16.0, 7.6 Hz, 1H), 6.16 (dd, J = 16.7, 10.1 Hz, 1H), 5.74 (t, J = 12.4 Hz, 1H), 4.61 (d, J = 32.0 Hz, 2H), 4.48 - 4.17 (m, 2H), 4.04 - 3.68 (m, 3H), 3.18 (dt, J = 7.6, 4.0 Hz, 2H), 3.09 (t, J = 12.4 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.72 (ddt, J = 25.8, 12.4, 3.1 Hz, 8H), 2.54 (s, 1H), 1.90 (s, 2H), 1.51 - 1.36 (m, 2H), 1.29 (dd, J = 7.0, 5.0 Hz, 1H), 1.20 - 1.13 (m, 1H), 1.01 - 0.94 (m, 1H), 0.94 - 0.83 (m, 2H), 0.80 (dd, J = 9.2, 4.2 Hz, 1H).LC-MS: [M+H]+found 606.25.JH NMR (400 MHz, DMSO-d6) 88.52 (d, J = 4.6 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 6.93 (ddd, J = 27.0, 16.5, 10.4 Hz, 1H), 6.77 (dd, J = 15.9, 7.7 Hz, 1H), 6.16 (dd, J = 16.7, 10.1 Hz, 1H), 5.73 (t, J = 12.5 Hz, 1H), 4.61 (d, J = 32.1 Hz, 2H), 4.46 - 4.21 (m, 2H), 4.06 - 3.59 (m, 3H), 3.27 (dd, J = 8.5, 3.0 Hz, 2H), 3.18 (dt, J = 7.6, 4.0 Hz, 1H), 3.09 (t, J = 12.7 Hz, 1H), 2.79 - 2.66 (m, 8H), 2.53 (s, 1H), 1.90 (s, 2H), 1.51 - 1.36 (m, 2H), 1.29 (dd, J = 7.0, 5.1 Hz, 1H), 1.20 - 1.13 (m, 1H), 1.02 - 0.95 (m, 1H), 0.95 - 0.85 (m, 2H), 0.80 (dd, J = 9.3, 4.2 Hz, 1H).Starting material of final step was separated by Prep-HPLC with the following conditions (Column: CHIRAL ART Amylase-SA 2*25 cm, 5 pm; Mobile Phase A: Hex(0.2% IPA), Mobile Phase B: ETOH: DCM=11; Flow rate: 20 mL / min; Gradient: isocratic 35; Wave Length: 220 / 254 nm; RTl(min): 9.43; RT2(min): 14.06)andLC-MS: [M+H]+found 622.00.1’H NMR (400 MHz, DMSO-d6) 8 9.00 (m, 1H), 8.44 (m, 1H), 8.22 (m, 1H), 6.90 (m, 2H), 6.23 - 6.11 (m, 1H), 5.74 (m, 1H), 4.64 (m, 2H), 4.41 (m, 2H), 3.91 (m, 4H), 3.84 (m, 2H), 3.31 (m, 1H),3.23 - 3.08 (m, 2H), 2.87 - 2.69 (m, 5H), 2.51 (m, 2H), 1.98 (s, 2H), 1.55 - 1.37 (m, 2H), 1.24 (m, 1H), 0.99 (m, 1H), 0.93 (m, 2H), 0.84 (m, 1H), 0.77 (m, 1H).Attorney Docket No. 50006-0134WO1LC-MS: [M+H]+ found 622.00.’H NMR (400 MHz, DMSO-d6) 89.00 (m, 1H), 8.44 (m, 1H), 8.25 - 8.19 (m, 1H), 6.95 (tn, 1H), 6.83 (m, 1H), 6.16 (m, 1H), 5.74 (m, 1H), 4.64 (m, 2H), 4.45 - 4.30 (m, 2H), 3.97 - 3.78 (m, 6H), 3.30 (m, 1H), 3.23 - 3.08 (tn, 2H), 2.95 - 2.63 (tn, 5H), 2.55 (m, 2H), 2.03 - 1.93 (m, 2H), 1.46 (m, 2H), 1.24 (m, 1H), 1.03 - 0.97 (tn, 1H), 0.93 (m, 2H), 0.84 (m, 1H), 0.77 (m, 1H).LC-MS: (M+H)+ found:595.’H NMR (400 MHz, DMSO-d6) 89.55 (d, J = 2.4 Hz, 2H), 8.68 (d, J = 7.9 Hz, 1H), 6.97 - 6.77 (m, 2H), 6.16 - 6.02 (m, 1H), 5.72 - 5.60 (m, 1H), 4.58 (d, J = 32.5 Hz, 7872H), 4.43 - 4.28 (m, 2H), 4.19 (h, J = 7.2 Hz, 1H), 3.80 (dt, J = 29.0, 5.4 Hz, 3H), 3.27 - 3.07 (tn, 3H), 2.85 - 2.63 (m, 5H), 2.48 (s, 1H), 1.97 - 1.78 (m, 4H), 1.72 - 1.60 (m, 2H), 1.60 - 1.31 (m, 6H).LC-MS: (M+H) found: 616.50’H NMR (400 MHz, DMSO-d6) 8 12.29 (s, 1H), 8.34 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 9.1 Hz, 2H), 7.05 - 6.61 (m, 3H), 6.24 - 6.08 (m, 1H), 5.81 - 5.66 (m, 1H), 4.70 - 8344.34 (tn, 4H), 4.07 (d, J = 9.8 Hz, 1H), 3.86 (s, 2H), 3.42 (s, 2H), 2.90 - 2.69 (m, 2H), 2.41 (s, 1H), 2.13 - 1.81 (m, 7H), 1.74 (d, J = 9.5 Hz, 2H), 1.65 - 1.40 (m, 4H), 0.93 - 0.76 (m, 2H), 0.73 - 0.65 (m, 2H).LC-MS: (M+H) found:677.55’H NMR (400 MHz, DMSO-d6) 89.44 (d, J = 2.2 Hz, 1H), 9.16 (d, J = 2.9 Hz, 1H), 8.82 - 8.73 (tn, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.53 - 7.34 (m, 1H), 6.82 - 6.68 (m, 471 1H), 6.48 (s, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 4.57 (d, J = 9.2 Hz, 2H), 4.40 (d, J = 9.8 Hz, 2H), 4.05 (s, 1H), 3.28 - 3.18 (m, 1H), 3.17 - 3.00 (m, 2H), 2.95 -2.71 (m, 2H), 2.22 (d, J = 7.2 Hz, 6H), 1.99 (s, 11H), 1.87 (s, 1H), 1.74 (d, J = 9.9 Hz, 2H), 1.68 - 1.55 (tn, 2H), 1.54 - 1.37 (m, 2H), 1.24 (s, 3H).Example 2: N-{bicyclo[l.l.l]pentan-l-yl}-4-(4-{methyl[3-(4-methylpyrazol-l- yl)propyl]amino}-6-(prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (Compound 543)Attorney Docket No. 50006-0134WO1Step 1: To a stirred solution of methyl[3-(4-methylpyrazol-l-yl)propyl]amine (5.32 g, 34.74 mmol, 2.5 equiv) and tert-butyl 2,4-dichloro-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (4 g, 13.79 mmol, 1 equiv) in THF (60 mb) and H2O (20 mL) was added NaHCCh (2.32 g, 27.57 mmol, 2 equiv) at room temperature under air atmosphere. The resulting mixture was stirred for 2h at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm) to afford tert-butyl 2-chloro-4-{methyl[3-(4-methylpyrazol-lyl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (3.50 g, 62%) as a yellow oil. LC-MS: [M+H]+ found 407.00.Step 2: To a stirred solution of tert-butyl 2-chloro-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (6 g, 14.75 mmol, 1 equiv) and 4-(methoxycarbonyl)phenylboronic acid (2.92 g, 16.22 mmol, 1.1 equiv) in dioxane (100 mL) and H2O (10 mL) was added Pd(dppf)C12 CH2CI2 (1.20 g, 1.47 mmol, 0.1 equiv) and CS2CO3 (14.41 g, 44.24 mmol, 3 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 1.5h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 2-[4-(methoxycarbonyl)phenyl]-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (4.50 g, 60%) as a yellow solid. LC-MS: [M+H]+ found 507.00.Attorney Docket No. 50006-0134WO1Step 3: A mixture of tert-butyl 2-[4-(methoxycarbonyl)phenyl]-4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (3 g, 5.92 mmol, 1 equiv) and trifluoroacetaldehyde (6 mL) in DCM (30 mL) was stirred for 2 h at room temperature under argon atmosphere. The resulting mixture was concentrated under reduced pressure. This resulted in methyl 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoate (3 g, 120%) as a yellow oil which was used into next step without further purification. LC-MS: [M+H]+ found 407.00.Step 4: To a stirred mixture of methyl 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-5H,6H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoate (3 g, 7.38 mmol, 1 equiv) and TEA (2.24 g, 22.14 mmol, 3 equiv) in DCM (100 mL) was added acryloyl chloride (0.80 g, 8.86 mmol, 1.2 equiv) dropwise at 0 °C under air atmosphere. The resulting mixture was stirred for 1 h at room temperature under air atmosphere. The residue was purified by silica gel column chromatography, eluted with CTLCh / MeOH (10:1) to afford methyl 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6-(prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoate (2.90 g, 85%) as a yellow solid. LC-MS: [M+H]+ found 461.00.Step 5: A mixture of methyl 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6-(prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoate (2.80 g, 6.08 mmol, 1 equiv) and trimethylstannanol (8.79 g, 48.64 mmol, 8 equiv) in Toluene (120 mL) was stirred for overnight at 120°C under nitrogen atmosphere. The reaction was quenched with KF at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure. The mixture was acidified to pH 3 with HC1 (IM aq.). The resulting mixture was extracted with CH2CI2 (100 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 100% gradient in 20 min; detector, UV 254 nm) to afford 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6-(prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoic acid (1.85 g, 68%) as a yellow solid. LC-MS: [M+H]+ found 447.00.Attorney Docket No. 50006-0134WO1Step 6: To a stirred mixture of 4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6- (prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzoic acid (80 mg, 0.18 mmol, 1 equiv), DIEA (69 mg, 0.54 mmol, 3 equiv) and bicyclo[l.l.l]pentan-l -amine (22 mg, 0.27 mmol, 1.5 equiv) in EA (2 mb) was added T3P (228 mg, 0.36 mmol, 2 equiv, 50%) in portions at room temperature under air atmosphere. The resulting mixture was stirred for 2 h at 50°C under air atmosphere. The resulting mixture was extracted with EtOAc (10 mL). The combined organic layers were washed with brine (2x5 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (10 mmol / L NH4HC03)+0.05%NH3. H20, Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 53% B in 8min; Wave Length: 254nm / 220nm; RTl(min): 9.13) to afford N- {bicyclo[l.l.l]pentan-l-yl}-4-(4-{methyl[3-(4-methylpyrazol-l-yl)propyl]amino}-6- (prop-2-enoyl)-5H,7H-pyrrolo[3,4-d]pyrimidin-2-yl)benzamide (26 mg, 28%) as an off- white solid. LC-MS: [M+H]+, found 512.25.’HNMR (400 MHz, DMSO-d6) 89.05 (s, 1H), 8.34 - 8.26 (m, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 6.3 Hz, 1H), 7.27 (d, J = 3.1 Hz, 1H), 6.80 - 6.66 (m, 1H), 6.31 - 6.21 (m, 1H), 5.84 - 5.74 (m, 1H), 5.11 (s, 1H), 4.93 (s, 1H), 4.84 (d, J = 2.2 Hz, 1H), 4.55 (s, 1H), 4.17 - 4.08 (m, 2H), 3.71 - 3.60 (m, 2H), 3.23 (s, 3H), 2.47 (s, 1H), 2.11 (s, 8H), 1.97 (d, J = 2.3 Hz, 3H).Compounds of Formula (I) in Table D can be prepared analogously to Example 2. As the skilled person will appreciate, the compounds described herein can be prepared using variations of any one or more of the procedures described herein, e g., substituting one or more starting materials and / or reagents for those described in one or more of the working examples.Table DFTPLCCompd.LCMS (M+H)+No.‘HNMR31 LC-MS: [M+H]+ found 500.00.Attorney Docket No. 50006-0134WO11H NMR (400 MHz, DMSO-d6) 88.48 (d, J = 4.3 Hz, 1H), 8.30 (dd, J = 8.3, 6.3 Hz, 2H), 7.91 - 7.85 (m, 2H), 7.45 (d, J = 6.0 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 6.73 (td, J = 15.7, 10.2 Hz, 1H), 6.26 (dt, J = 16.8, 3.0 Hz, 1H), 5.78 (ddd, J = 10.1, 7.6, 2.3 Hz, 1H), 5.12 (s, 1H), 4.96 - 4.91 (m, 1H), 4.84 (d, J = 1.9 Hz, 1H), 4.55 (s, 1H), 4.12 (td, J = 6.6, 3.6 Hz, 2H), 3.66 (q, J = 8.9, 8.4 Hz, 2H), 2.61 - 2.54 (m, 1H), 2.12 (p, J = 6.9 Hz, 2H), 1.97 (d, J = 2.2 Hz, 3H), 1.08 (d, J = 6.0 Hz, 3H), 0.96 (t, J = 5.2 Hz, 1H), 0.77 (dt, J = 8.9, 4.4 Hz, 1H), 0.50 (dt, J = 7.6, 5.4 Hz, 1H).LC-MS: [M+H]+ found 514.00.1H NMR (400 MHz, DMSO-d6) 88.44 (d, J = 8.4 Hz, 1H), 8.31 (dd, J = 8.4, 6.7 Hz, 2H), 7.96 - 7.89 (m, 2H), 7.47 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 3.4 Hz, 1H), 6.74 (td, J = 16.1, 10.2 Hz, 1H), 6.27 (dt, J = 16.8, 2.7 Hz, 1H), 5.79 (ddd, J = 10.2, 7.7, 2.3 Hz, 1H), 5.13 (s, 1H), 4.95 (s, 1H), 4.86 (s, 1H), 4.56 (s, 1H), 4.13 (td, J = 6.6, 3.6 Hz, 2H), 3.67 (d, J = 8.8 Hz, 2H), 3.50 (q, J = 7.4 Hz, 1H), 3.24 (s, 3H), 2.12 (p, J = 7.3 Hz, 2H), 1.98 (d, J = 2.1 Hz, 3H), 1.24 (d, J = 6.6 Hz, 3H), 1.01 (tq, J = 8.3, 4.7, 4.1 Hz, 1H), 0.53 - 0.26 (m, 3H), 0.21 (dt, J = 9.4, 4.6 Hz, 1H).LC-MS: [M+H]+ found 526.00.’H NMR (400 MHz, DMSO-d6) 8 8.80 (m, 1H), 8.31 (m, 2H), 7.97 - 7.91 (m, 2H), 7.46 (m, 1H), 7.28 (m, 1H), 6.81 - 6.66 (m, 1H), 6.26 (m, 1H), 5.79 (m, 1H), 5.13 (s, 1H), 4.90 (m, 2H), 4.69 - 4.51 (m, 2H), 4.21 - 4.03 (m, 2H), 3.66 (m, 2H), 3.24 (s, 3H),2.41 (m, 2H), 2.29 - 2.19 (m, 2H), 2.18 - 2.05 (m, 2H), 1.97 (m, 3H), 0.55 - 0.46 (m, 2H), 0.45 - 0.37 (m, 2H).LC-MS: [M+H]+ found 526.00.'H NMR (400 MHz, DMSO-d6) 88.55 (d, J = 7.8 Hz, 1H), 8.30 (dd, J = 8.3, 6.5 Hz, 2H), 7.95 - 7.88 (m, 2H), 7.46 (d, J = 6.0 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 6.74 (td, J = 16.0, 10.3 Hz, 1H), 6.26 (dt, J = 16.8, 2.9 Hz, 1H), 5.79 (ddd, J = 10.3, 7.8, 2.3 Hz, 1H), 5.13 (s, 1H), 4.94 (s, 1H), 4.85 (s, 1H), 4.66 (q, J = 8.0 Hz, 1H), 4.56 (s, 1H), 4.13 (td, J = 6.5, 3.5 Hz, 2H), 3.68 (t, J = 8.5 Hz, 2H), 2.37 - 2.26 (m, 1H), 2.17 - 2.02 (m, 3H), 1.97 (d, J = 2.2 Hz, 3H), 1.84 (td, J = 10.4, 9.9, 4.7 Hz, 1H), 0.63 - 0.41 (m, 3H), 0.39 - 0.29 (m, 1H).LC-MS: [M+H]+ found 528.00.‘HNMR (400 MHz, DMSO-d6) 88.58 (t, J = 5.3 Hz, 1H), 8.35 - 8.27 (m, 2H), 7.95Attorney Docket No. 50006-0134WO1- 7.89 (m, 2H), 7.46 (d, J = 5.9 Hz, 1H), 7.28 (d, J = 3.0 Hz, 1H), 6.74 (ddd, J = 16.8, 14.9, 10.3 Hz, 1H), 6.26 (ddd, J = 16.8, 3.5, 2.3 Hz, 1H), 5.79 (ddd, J = 10.3, 7.8, 2.3 Hz, 1H), 5.13 (s, 1H), 4.97 - 4.92 (tn, 1H), 4.85 (d, J = 2.2 Hz, 1H), 4.56 (s, 1H), 4.13 (td, J = 6.6, 3.4 Hz, 2H), 3.67 (q, J = 9.3, 8.7 Hz, 2H), 3.24 (s, 3H), 2.12 (p, J = 6.7 Hz, 2H), 1.98 (d, J = 2.1 Hz, 3H), 1.12 (s, 3H), 1.04 (s, 3H), 0.97 - 0.85 (m, 1H), 0.44 (dd, J = 8.6, 4.1 Hz, 1H), 0.16 (t, J = 4.9 Hz, 1H).LC-MS: (M+H) found:528.45'H NMR (400 MHz, Chloroform-d) 88.41 (d, J = 8.3 Hz, 2H), 7.84 (s, 2H), 7.34 (s, 1H), 7.09 (d, J = 6.2 Hz, 1H), 6.63 - 6.44 (m, 2H), 6.30 (s, 1H), 5.83 (s, 1H),...

Claims

1. Attorney Docket No. 50006-0134WO12.WHAT TS CLAIMED IS:

1. A compound of Formula (I):

5. 7.or a pharmaceutically acceptable salt thereof, wherein:8.each of Z1and Z2is independently selected from the group consisting of N, CF, CH, CCH3, CCFH2, CCF2H, CCF3, and C-CN;9.Z3is N(Z4), CH-N(R’)(-Z4), N-L-(Z4), or CH-N(R’)-L-(-Z4), wherein Z4is a covalent warhead, and and L is a linker;10.X is a bond or C(RX3)(RX4);11.Y is a bond or C(RY3)(RY4);12.each of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently defined according to any one or more of (A)-(J) below:13.(A) one or more of RX1, RX2, RX3, RX4, RY1, RY2, RY3, and RY4is independently selected from the group consisting of H; C1-3 alkyl, which is optionally substituted with from 1-6 fluoro; -CH2OCH3; CH2NR’R”; CN; CH2CN; CH2(cyclopropyl); cyclobutyl; and cyclopropyl, wherein cyclopropyl is optionally substituted with from 1-6 fluoro; Attorney Docket No. 50006-0134WO114.(B) RX1and RX2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;15.(C) RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;16.(D) RY1and RY2, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;17.(E) RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the Attorney Docket No. 50006-0134WO118.cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (iii) C=O;19.(F) one of RX1and RX2and one of RX3and RX4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;20.(G) one of RY1and RY2and one of RY3and RY4, together with the carbon atom to which each is attached, forms (i) C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; or (ii) heterocyclyl of 3-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;21.(H) one of RX1and RX2and one of RY1and RY2forms:22.(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;23.(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);24.(I) one of RX1and RX2and one of RY3and RY4forms:25.(i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;26.(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or Attorney Docket No. 50006-0134WO127.(iii) -C(O);28.(J) one of RX3and RX4and one of RY1and RY2or one of RY3and RV4forms: (i) -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3)-, -CH2CH2CH2-, or - C(CH3)2C(CH3)2-;29.(ii) -OCH2-, -OCH(CH3)-, -OC(CH3)2-, -CH2O-, -CH(CH3)O-, -C(CH3)2O-; or (iii) -C(O);30.R2is -NR21R22, -OR21, or (Formula A); wherein:31.R21is:

33.

34. (Formula A-l); or35.(ii) -L2-L3-B21(Formula A-2);36.wherein:37.Ring B1is:38.• C3-10 cycloalkylene or C3-10 cycloalkenylene, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;39.• heterocyclylene or heterocycloalkenylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; Attorney Docket No. 50006-0134WO140.• heteroarylene of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or41.• C6-10arylene optionally substituted with from 1-4 Rc;42.L1is C(O), CH2, CH(CH3), CH(CF3), NH, NRb, O, or a bond;43.L2is C2-10 alkylene, alkenylene, or alkynylene, each of which is optionally substituted with from 1-6 Ra, and wherein L2is optionally interrupted with an internal or terminal O or S atom, provided that L2and any linkages of L2to another moiety do not contain heteroatom-heteroatom bonds;44.L3is O, S, or a bond;45.B21is:46.• l -io cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;47.• L1-heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;48.• L'-heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;49.• L1-C6-10aryl optionally substituted with from 1-4 Rc;50.• Ci-10 alkyl optionally substituted with from 1-6 Ra,51.• C(O)- Ci-10 alkyl optionally substituted with from 1-6 Ra,52.• NR’R”; or53.. OR’”; Attorney Docket No. 50006-0134WO154.R22is H; Ci-4 alkyl; -C(O)(Ci-4 alkyl); -CH2C(O)(CI-4 alkyl); -C(O)O(Ci-4 alkyl); -CH2C(O)O(CI-4alkyl); -CONR’R”; -CH2CONR’R”; -S(O)I-2NR’R”; -CH2S(O)I-2NR’R”; -S(O)I-2(CI-4 alkyl); -OH; Ci-4 alkoxy or biotinyl;55.each of R23and R24is independently selected from the group consisting of H; fluoro; Ci-3 alkyl, which is optionally substituted with from 1-6 fluoro; C1-3 alkoxy, which is optionally substituted with from 1-6 fluoro; OH; -CH2OCH3; CH2NR’R”; CN; CH2CN; and CH2(cyclopropyl); or56.R23and R24together with the carbon atom to which each is attached form C=O; or R23and R24together with the carbon atom to which each is attached form C3-5 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;57.L is NH, NRb, O, or a bond;58.R3is -B3-L4-B4;59.wherein:60.B3is:61.• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;62.• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;63.• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or64.• C6-10aryl optionally substituted with from 1-4 Rc; Attorney Docket No. 50006-0134WO165.L4is -NHC(O)- or -C(O)NH-;66.B4is:67.• C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;68.• heterocyclyl or heterocycloalkenyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc;69.• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc;70.• C6-10aryl optionally substituted with from 1-4 Rc; or71.• C1-6 alkyl optionally substituted with C3-10 cycloalkyl;72.each occurrence of Rais independently selected from the group consisting of: -OH; -halo; -NRdRe; C1-4 alkoxy; C1-4 haloalkoxy; -C(=O)O(Ci-4 alkyl); -C(=O)(Ci-4 alkyl); -C(=O)OH; -CONR’R”; -S(O)I-2NR’R”; -S(O)1-2(C1-4alkyl); and cyano;73.each occurrence of Rbis independently selected from the group consisting of: C1-6 alkyl optionally substituted with from 1-3 independently selected Ra; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)I-2NR’R”; - S(O)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy;74.each occurrence of Rcis independently selected from the group consisting of: halo; cyano; C1-10 alkyl which is optionally substituted with from 1-6 independently selected Ra; C2-6 alkenyl; C2-6 alkynyl; C1-4 alkoxy optionally substituted with C1-4 alkoxy or C1-4 haloalkoxy; C1-4 haloalkoxy; -S(O)i-2(Ci-4 alkyl); -S(O)(=NH)(CI-4 alkyl); - Attorney Docket No. 50006-0134WO175.NRdRe; -OH; -S(O)I-2NR’R”; -Ci-4 thioalkoxy; -NO2; -C(=0)(Ci-io alkyl); -C(=O)O(Ci-4 alkyl); -C(=O)OH; -C(=O)NR’R”; and -SF5;76.each occurrence of Rdand Reis independently selected from the group consisting of: H; C1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R”, -OH, C1-6 alkoxy, C1-6 haloalkoxy, and halo; -C(O)(Ci-4 alkyl); -C(O)O(Ci-4 alkyl); -CONR’R”; -S(O)i-2NR’R”; -S(O)1-2(C1-4alkyl); -OH; and C1-4 alkoxy;77.Rpis CH3, optionally substituted cyclopropyl, phenyl, or / t- / o / -phenyl;78.each occurrence of R’ and R” is independently selected from the group consisting of: H; -OH; and C1-4 alkyl optionally substituted with 1-7 fluoro; and79.each occurrence of R’” is independently selected from the group consisting of: C3-C6 cycloalkyl and C1-4 alkyl optionally substituted with C3-C6 cycloalkyl.

2. The compound of claim 1, wherein each of Z1and Z2is N, and Z3is NZ4.

3. The compound of claim 1 or 2, wherein Z4is C(O)-R4, S(O)-R4, or SO2-R1; wherein R1is C2-4 alkenyl, C2-4 alkynyl, C3-6 allenyl, or oxiranyl, each of which is optionally substituted with from 1-6 Ra.

4. The compound of any one of claims 1-3, wherein X is a bond.

5. The compound of any one of claims 1-4, wherein Y is C(RY3)(RY4).

6. The compound of any one of claims 1-5, wherein X is a bond, and Y is C(RY3)(RY4).Attorney Docket No. 50006-0134WO17. The compound of any one of claims 1-6, wherein each of RX1and RX2is H.

8. The compound of any one of claims 1-7, wherein each of RY1and RY2is H, and each of RY3and RY4is H.

9. The compound of any one of claims 1-6, wherein one of RX1and RX2is Ci-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H.

10. The compound of any one of claims 1-6 and 9, wherein one of RY3and RY4is C1-3 alkyl, and the other is H, optionally wherein.one of RY3and RY4is CH3, and the other is H.

11. The compound of any one of claims 1-6, 9, or 10, wherein one of RY1and RY2is C1-3 alkyl, and the other is H, optionally wherein.one of RY1and RY2is CH3, and the other is H.

12. The compound of any one of claims 1-6, and 9, wherein one of RX1and RX2is C1-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H; and each of RY1, RY2, RY3, and RY4is H.

13. The compound of any one of claims 1-6 and 9 or 12, wherein the compound has the formula:

93.

14. The compound of any one of claims 1-6, 9, 12, or 13, wherein the compound has the formula:Attorney Docket No. 50006-0134WO196.R297.l\K99.

15. The compound of any one of claims 1-6, 10, or 11, wherein each of RX1and RX2is H, and one of RY1, RY2, RY3, and RY4is C1-3 alkyl, and the other three are H, optionally wherein each of RX1and RX2is H, and one of RY1, RY2, RV3, and RY4is CH3, and the other three are H.

16. The compound of any one of claims 1-6, 10 or 15, wherein:103.each of RX1and RX2is H;104.each of RY1and RY2is H, and105.one of RY3and RY4is C1-3 alkyl, and the other of RY3and RY4is H; optionally wherein:106.each of RX1and RX2is H;107.each of RY1and RY2is H, and108.one of RY3and RY4is CH3, and the other of RY3and RY4is H.

17. The compound of any one of claims 1-6, 10, 15, or 16, wherein the compound has the formula:110.R2111.CH3112.N114.

18. The compound of any one of claims 1-6, 10, or 15-17, wherein the compound has the formula:Attorney Docket No. 50006-0134WO1117.R2118.CH3119.N^R1121.

122. R3N19. The compound of any one of claims 1-3, wherein Y is a bond.

20. The compound of any one of claims 1, 2, or 19, wherein X is a bond, and Y is a bond.

21. The compound of any one of claims 1, 2, 19 or 20, wherein one of RX1and RX2is C1-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H.

22. The compound of any one of claims 1, 2, 19, 20, or 21, wherein the compound has the formula:127.R2R2129.

23. The compound of any one of claims 1-4, 19 or 20, wherein one of Ryiand R¥2is C1-3 alkyl, and the other is H, optionally wherein one of RY1and RY2is CH3, and the other is H.

24. The compound of any one of claims 1-4 and 19, 20, or 23, wherein the compound has the formula:133.i2135.

136. Attorney Docket No. 50006-0134WO125. The compound of any one of claims 1-4, 19, or 20, wherein:138.one of RX1and RX2is Ci-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H; and139.one of RY1and RY2is C1-3 alkyl, and the other is H, optionally wherein one of RY1and RY2is CH3.

26. The compound of any one of claims 1-4, 19, 20, or 25, wherein the compound has the formula:

142.

27. The compound of claim 19 or 20, wherein each of RX1and RX2is H, and each of RY1and R¥2is H.

28. The compound of any one of claims 1-27, wherein R2is -NR21R22or O R21, optionally wherein R2is -NR21R22.

29. The compound of any one of claims 1-28, wherein R21is:

148.

149. (Formula A-l).

30. The compound of any one of claims 1-29, wherein Ring B1is heterocyclylene or heterocycloalkenylene of 3-10 ring atoms, wherein from 1-3 ringAttorney Docket No. 50006-0134WO1151.atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

31. The compound of any one of claims 1-30, wherein Ring B1is heterocyclylene of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

32. The compound of any one of claims 1-31, wherein Ring B1is heterocyclylene of 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

33. The compound of any one of claims 1-32, wherein Ring B1is heterocyclylene of 5-7 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

34. The compound of any one of claims 1-33, wherein Ring B1is heterocyclylene of 6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), P(O)RP, O, and S(0)o-2, and wherein the heterocyclylene is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.Attorney Docket No. 50006-0134WO135. The compound of any one of claims 1-34, wherein ring B1is158.

36. The compound of claim 35, wherein the nitrogen atom is the point of attachment to B21.

37. The compound of any one of claims 1-34, wherein ring B1is163.

38. The compound of claim 37, wherein the nitrogen atom is the point of attachment to B21.

39. The compound of any one of claims 1-29, wherein ring B1is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

40. The compound of any one of claims 1-29 and 39, wherein ring B1is C3-10 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

41. The compound of any one of claims 1-27 and 39-40, wherein ring B1is C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc).

42. The compound of any one of claims 1-27 and 39-41, wherein ring B1is C5-7 cycloalkyl, which is optionally substituted with 1-4 substituents independentlyAttorney Docket No. 50006-0134WO1170.selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc)43. The compound of any one of claims 1-27 and 39-42, wherein ring B1is Ce cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc)44. The compound of any one of claims 1-27 and 39-43, wherein ring B1is174.

45. The compound of any one of claims 1-44, wherein B21is Ci-io alkyl optionally substituted with from 1-6 Ra.

46. The compound of any one of claims 1-45, wherein B21is Ci-6 alkyl optionally substituted with from 1-6 Ra.

47. The compound of any one of claims 1-46, wherein B21is C1-3 alkyl optionally substituted with from 1-6 Ra.

48. The compound of any one of claims 45-47, wherein each occurrence of Rais fluoro.

49. The compound of any one of claims 1-48, wherein B21is -CH2CF3.

50. The compound of any one of claims 1-48, wherein B21is -CH(CH3)CF3.

51. The compound of any one of claims 1-48, wherein B21is:Attorney Docket No. 50006-0134WO1184.

52. The compound of any one of claims 1-44, wherein B21is -Cs-io cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc, optionally wherein B21is l Ca-io cycloalkyl optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

53. The compound of any one of claims 1-44 or 52, wherein B21is L1-C4-s cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

54. The compound of any one of claims 1-44 and 52-53, wherein B21is L1-Ce cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

55. The compound of any one of claims 1-44 and 52-54, wherein B21is I?-C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

56. The compound of any one of claims 1 -44, wherein B21is L’-heterocyclyl or L'-hctcrocycloalkcnyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl isAttorney Docket No. 50006-0134WO1191.optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

57. The compound of any one of claims 1-44 and 56, wherein B21is L1-heterocyclyl of 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

58. The compound of any one of claims 1-44 and 56-57, wherein B21is L1-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro)59. The compound of any one of claims 1-44 and 56-58, wherein B21is L1-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

60. The compound of any one of claims 1-44, wherein B21is L'-heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.Attorney Docket No. 50006-0134WO161. The compound of any one of claims 1-44 and 60, wherein B21is L1-heteroaryl of 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.

62. The compound of any one of claims 1-44 and 60-61, wherein B21is heteroaryl of 5 ring atoms, wherein from 1-3 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-4 Rc.

63. The compound of any one of claims 1-44, wherein B21is NR’R”.

64. The compound of claim 63, wherein each of R’ and R” is an independently selected alkyl, optionally substituted with 1-7 fluoro.

65. The compound of any one of claims 1-64, wherein L1is a bond.

66. The compound of any one of claims 1-64, wherein L1is C(O).

67. The compound of any one of claims 1-44, wherein203.R21is.204.( B1kl - B21206.

207. - (F ormul a A-2).208.Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and Attorney Docket No. 50006-0134WO1209.B21is210.Ci-io alkyl optionally substituted with from 1-6 Ra;211.L1-C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); or L’-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRp, P(O)Rp, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

68. The compound of claim 67, wherein Ring B1is a saturated or partially unsaturated ring having 5-7 ring atoms (including the ring nitrogen atom attached to B21), of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

69. The compound of claim 67 or 68, wherein Ring B1is a saturated ring having 6 ring atoms (including the ring nitrogen atom attached to B21) of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

70. The compound of any one of claims 67-69, wherein ring B1is216.

217. Attorney Docket No. 50006-0134WO171. The compound of any one of claims 67-70, wherein B21is Ci-io alkyl optionally substituted with from 1-6 Ra.

72. The compound of any one of claims 67-71, wherein B21is Ci-6 alkyl optionally substituted with from 1-6 Ra.

73. The compound of any one of claims 67-72, wherein B21is C1-3 alkyl optionally substituted with from 1-6 Ra.

74. The compound of any one of claims 71-73, wherein each occurrence of Rais fluoro.

75. The compound of any one of claims 67-74, wherein B21is -CH2CF3.

76. The compound of any one of claims 67-75, wherein B21is -CH(CH3)CF3.

77. The compound of any one of claims 67-76, wherein B21is:225.CF227.

78. The compound of any one of claims 67-70, wherein B21is L1-C4-6 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc).

79. The compound of any one of claims 67-70 and 78, wherein B21is I?-C4 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4Attorney Docket No. 50006-0134WO1231.independently selected Rc; optionally wherein each occurrence of Rcis halo, e g., fluoro);232.optionally wherein B21is:

233.

80. The compound of claim 78 or 79, wherein L1is a bond.

81. The compound of any one of claims 67-70, wherein B21is L'-heterocyclyl of 3-10 ring atoms, optionally wherein B21is heterocyclyl of 4 ring atoms; wherein 1 ring atom is selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

82. The compound of any one of claims 1-44, wherein239.

240. (Formula A-2).241.Ring B1is a saturated or partially unsaturated carbocyclic ring having 4-8 ring atoms (including the ring carbon atom attached to B21), wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and242.B21is:243.NR’R”; or244.L'-hctcrocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro). Attorney Docket No. 50006-0134WO183. The compound of claim 82, wherein Ring B1is a saturated carbocyclic ring having 6 ring atoms (including the ring carbon atom attached to B21), wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

84. The compound of claim 82 or 83, wherein ring B1is247.

85. The compound of any one of claims 82-84, wherein B21is NR’R”.

86. The compound of any one of claims 82-85, wherein each of R’ and R” is an independently selected Ci-4 alkyl, optionally substituted with 1-7 fluoro.

87. The compound of any one of claims 82-86, wherein one of R’ and R” is unsubstituted Ci-4 alkyl, and the other is Ci-4 alkyl substituted with 1-7 fluoro.

88. The compound of any one of claims 82-84, wherein B21is:

254.

255. CH2CHF289. The compound of any one of claims 82-84, wherein B21is L1-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro).

90. The compound of any one of claims 82-84 and 89, wherein B21is:Attorney Docket No. 50006-0134WO1259.

91. The compound of any one of claims 1-27, wherein R2is -OR21.

92. The compound of any one of claims 1-27, wherein R2is R24R21263.\^C\ —265. 266.r23(Formula A).

93. The compound of any one of claims 1-92, wherein B3is:268.• heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc; or269.• Ce-io aryl optionally substituted with from 1-4 Rc.

94. The compound of any one of claims 1-93, wherein B3is heteroaryl of 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), O, and S(0)o-2, and wherein the heteroaryl is optionally substituted with 1-4 Rc.

95. The compound of any one of claims 1-94, wherein B3is heteroaryl of 6 ring atoms, wherein from 1-3 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-2 Rc.

96. The compound of any one of claims 1-95, wherein B3is heteroaryl of 6 ring atoms, wherein 1-2 ring atoms are N, and wherein the heteroaryl is optionally substituted with 1-2 Rc.Attorney Docket No. 50006-0134WO197. The compound of any one of claims 1-96, wherein B3is:

275.

98. The compound of any one of claims 1-93, wherein B3is Ce-io aryl optionally substituted with from 1-4 Re.

99. The compound of any one of claims 1-98, wherein B4is C3-10 cycloalkyl or C3-10 cycloalkenyl, each of which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

100. The compound of any one of claims 1-99, wherein B4is C3-10 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

101. The compound of any one of claims 1-100, wherein B4is C3-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.

102. The compound of any one of claims 1-101, wherein B4is C3-5 monocyclic cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.

103. The compound of claim 102, wherein B4is cyclopentyl, which is optionally substituted with 1-4 independently selected Rc.

104. The compound of any one of claims 1-101, wherein B4is polycyclic or bicyclic C5-8 cycloalkyl, which is optionally substituted with 1-4 independently selected Rc.Attorney Docket No. 50006-0134WO1105. The compound of any one of claims 1-101 and 104, wherein B4is:

286.

287. , each of which is optionally substituted with 1-4 independently selected Rc.

106. The compound of any one of claims 1-101 and 104-105, wherein B4is290.

107. The compound of any one of claims 1-101 and 104-106, wherein B4is294.

108. The compound of any one of claims 1-107, wherein L4is -C(O)NH-.

109. The compound of any one of claims 1-108, wherein R3is:

299.

300. , wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.

110. The compound of claim 109, wherein each of Y and Y* is N.Attorney Docket No. 50006-0134WO1111. The compound of any one of claims 109-110, wherein B4is:303.* - or \ / 305.

306. 'nj' v, each of which is optionally substituted with 1-4 independently selected Rc.

112. The compound of any one of claims 109-111, wherein308.

309. B4is310.Cl^ / 113. The compound of any one of claims 109-112, wherein312.

313. B4is ' / v'114. The compound of any one of claims 3-113, wherein Z4is C(O)-R4115. The compound of any one of claims 3-114, wherein R1is C2-4 alkenyl, which is optionally substituted with from 1-6 Ra.

116. The compound of any one of claims 3-115, wherein R1is C2 alkenyl, which is optionally substituted with from 1-2 Ra.

117. The compound of any one of claims 3-116, wherein R1is -CH=CH2.

118. The compound of any one of claims 3-117, wherein R1is C3 alkenyl, which is optionally substituted with from 1-2 Ra.Attorney Docket No. 50006-0134WO1119. The compound of any one of claims 1-116 and 118, wherein R1is321.

322. 5 _^-Ra323., optionally wherein Rais -NR’R’ ’.

120. The compound of any one of claims 1-29, wherein325.R2is NR21R22;326.R21is:327.f B1\| - B21329.

330. — '' (F ormul a A-2).331.Ring B1is a saturated or partially unsaturated ring having 4-8 ring atoms (including the ring nitrogen atom attached to B21), of which 1-3 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc; and B21is:332.Ci-io alkyl optionally substituted with from 1-6 Ra;333.L1-C4-8 cycloalkyl, which is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(e.g., optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); or L’-heterocyclyl of 3-7 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rb), PRP, P(O)RP, O, and S(0)o-2, and wherein the heterocyclyl is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc(optionally substituted with 1-4 independently selected Rc, optionally wherein each Rcis fluoro); and R3is: Attorney Docket No. 50006-0134WO1334.(Rc)o-i336.

337. , wherein each of Y and Y* is independently N, CH, or CF; Rcis F; and B4is optionally substituted C3-C4 monocyclic cycloalkyl or optionally substituted C5-C7 bicyclic or polycyclic cycloalkyl.

121. The compound of claim 120, wherein Ring B1is a saturated or partially unsaturated ring having 5-7 ring atoms (including the ring nitrogen atom attached to B21), of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

122. The compound of claim 120 or 121, wherein Ring B1is a saturated ring having 6 ring atoms (including the ring nitrogen atom attached to B21) of which 1-2 of the ring atoms (including the nitrogen atom attached to B21) are ring heteroatoms, wherein any additional ring heteroatom(s) are independently selected from the group consisting of N(H), N(Rb), O, P(O)RP, and S(0)o-2; and wherein Ring B1is optionally substituted with 1-4 substituents independently selected from the group consisting of oxo and Rc.

123. The compound of any one of claims 120-122, wherein ring B1is341.l~<^ / N~l343.

124. The compound of claim 123, wherein the nitrogen atom is the point of attachment to B21.Attorney Docket No. 50006-0134WO1125. The compound of any one of claims 120-124, wherein B21is C1-10 alkyl optionally substituted with from 1-6 Ra.

126. The compound of any one of claims 120-125, wherein B21is C1-6 alkyl optionally substituted with from 1-6 Ra.

127. The compound of any one of claims 120-126, wherein B21is C1-3 alkyl optionally substituted with from 1-6 Ra.

128. The compound of any one of claims 125-127, wherein each occurrence of Rais fluoro.

129. The compound of any one of claims 120-128, wherein B21is -CH2CF3.

130. The compound of any one of claims 120-128, wherein B21is - CH(CH3)CF3.

131. The compound of any one of claims 120-128 and 130, wherein B21is:353.CH3354.or356.

132. The compound of any one of claims 120-131, wherein X is a bond, and Y is C(RY3)(RY4).

133. The compound of any one of claims 120-132, wherein each of RX1and RX2is H.

134. The compound of any one of claims 120-133, wherein each of Riand RY2is H, and each of RY3and RY4is H.Attorney Docket No. 50006-0134WO1135. The compound of any one of claims 120-134, wherein one of RX1and RX2is Ci-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H.

136. The compound of any one of claims 120-135, wherein one of RX1and RX2is C1-3 alkyl, and the other is H, optionally wherein one of RX1and RX2is CH3, and the other is H; and each of RY1, RY2, RY3, and RY4is H.

137. The compound of any one of claims 120-132, wherein the compound has the formula:

365.

138. The compound of any one of claims 120-132 and 137, wherein the compound has the formula:

369.

139. The compound of any one of claims 120-138, wherein each of Y and Y* is N.Attorney Docket No. 50006-0134WO1140. The compound of any one of claims 120-139, wherein B4is:

374.

375. independently selected Rc.376.RC-s 141. The compound of any one of claims 120-140, wherein377.

378. B4is379.Cl^ / 142. The compound of any one of claims 120-141, wherein381.

382. B4is ' / v'143. The compound of any one of claims 120-142, wherein Z4is C(O)-R4144. The compound of claim 143, wherein R1is C2-4 alkenyl, which is optionally substituted with from 1-6 Ra.

145. The compound of claim 143 or 144, wherein R1is C2 alkenyl, which is optionally substituted with from 1-2 Ra.

146. The compound of any one of claims 143-145, wherein R1is -CH=CH2.

147. The compound of any one of claims 143-145, wherein R1is C3 alkenyl, which is optionally substituted with from 1-2 Ra.Attorney Docket No. 50006-0134WO1148. The compound of any one of claims 142-144 and 146, wherein R1is390.

391. 5 _^-Ra392., optionally wherein Rais -NR’R’ ’.

149. The compound of any one of claims 1-148, wherein the compound is selected from the group consisting of compounds delineated in Table 1, and a pharmaceutically acceptable salt thereof.

150. A pharmaceutical composition comprising a compound of any one of claims 1-148 and one or more pharmaceutically acceptable excipients.

151. A method for modulating CDK2 activity, the method comprising contacting the CDK2 and / or a complex of CDK2 with Cyclin El with a compound or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-149; or a pharmaceutical composition as defined in claim 150.

152. The method of claim 151, wherein modulating CDK2 activity comprises inhibiting CDK2 activity.

153. The method of claim 151 or 152, which is carried out in vitro.

154. The method of any one of claims 151-153, wherein the method comprises contacting a sample comprising one or more cells comprising CDK2 with the compound.

155. The method of any one of claims 151-154, wherein the one or more cells are one or more cancer cells.

156. The method of claim 155, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidneyAttorney Docket No. 50006-0134WO1401.cancer, liver cancer, pancreatic cancer, gastric cancer, stomach cancer, melanoma and thyroid cancer.

157. The method of claim 151 or 152, which is carried out in vivo.

158. A method of treating a disease or disorder associated with CDK2 activity in a subject in need thereof, the method comprising administering a compound of any one of claims 1-149 or a pharmaceutical composition of claim 150.

159. The method of claim 158, wherein increased (e.g., excessive) CDK2 activity contributes to the pathology and / or symptoms and / or progression of the disease or disorder.

160. The method of claim 158 or 159, wherein the disease or disorder associated with CDK2 activity is a cancer.

161. The method of claim 161, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, stomach cancer, melanoma and thyroid cancer.

162. The method of claim 160 or 161, wherein the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

163. The method of any one of claims 160-162, wherein the cancer is characterized by amplification and / or overexpression of CCNE1.

164. The method of any one of claims 160-163, wherein the cancer is refractory to CDK4 and / or CDK4 / CDK6 inhibition.Attorney Docket No. 50006-0134WO1165. The method of any one of claims 160-164, wherein the method further comprises administering one or more additional therapeutic agents.

166. The method of any one of claims 158-165, wherein the subject is a human.

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