Spirocyclic dihydropyran pyrimidine KRas inhibitors

Abstract

The present disclosure provides compounds of formula (A) (e.g., formula (I) (e.g., formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), formula (II) (e.g., formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), formula (III) (e.g., formula (III-1) or (III-2)), which inhibit KRas protein. Provided are compounds of Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof. These compounds are useful, for example, for treating diseases, disorders, or conditions in which increased and / or sustained KRas activation (e.g., KRas activation associated with a mutant KRas protein) contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. The present disclosure also provides compositions containing the compounds provided herein or pharmaceutically acceptable salts thereof. TIFF2025541682000773.tif91128

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is described in U.S. Provisional Patent Application No. 63 / 426,950, filed November 21, 2022; U.S. Provisional Patent Application No. 63 / 456,235, filed March 31, 2023; U.S. Provisional Patent Application No. 63 / 515,290, filed July 24, 2023; U.S. Provisional Patent Application No. 63 / 533,346, filed August 17, 2023; U.S. Provisional Patent Application No. 63 / 535,006, filed August 28, 2023; U.S. Provisional Patent Application No. 63 / 542,188, filed October 3, 2023; and U.S. Provisional Patent Application No. 63 / 545,531, filed October 24, 2023, each of which is incorporated by reference in its entirety.

[0002] Description of electronically submitted text files This application contains a Sequence Listing that has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. The XML file, created on November 3, 2023, has the filename TRLN-008-007WO1_ST26_SL.xml and is 2,080 bytes in size.

[0003] Technical Field The present disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III- In some embodiments, the KRas protein is a dysregulated KRas protein having a mutation (herein referred to as a mutated KRas protein). These compounds are useful for treating diseases, disorders, or conditions in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with mutant KRas proteins, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human).The present disclosure also provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (I

[0013] Also provided are compositions containing a compound of Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (V-c), (Vd), (V-b1), (V-a2), or (V-b2)), or a compound of Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof, as well as methods of using and making the same. [Background technology]

[0004] background The KRAS gene is frequently dysregulated (e.g., mutated or amplified) in various human cancers. Oncogenic mutations in KRas typically occur at hotspots in the protein, such as amino acid positions 12, 13, and 61. In some cases, mutations can lead to sustained KRas activation (GTP-bound state), for example, due to a lack of intrinsic GTPase activity and / or insensitivity to GTPase-activating proteins (GAPs), resulting in increased KRas signaling. Specifically, some of the most common protein mutations include mutations at position 12 (hereinafter referred to as G12X), such as G12A, G12C, G12D, G12R, G12S, and G12V, at position 13 (hereinafter referred to as G13X), such as G13C, G13D, and G13V, and at position Q61 (hereinafter referred to as Q61X), such as Q61E, Q61H, Q61K, Q61L, Q61P, and Q61R.

[0005] Although KRas is widely recognized as a target for the design and development of therapies that can specifically bind to and inhibit KRas signaling in cancer cells, it has long been considered undruggable, and currently there are few approved KRas-targeted therapies.

[0006] In some embodiments, the KRas protein is a dysregulated KRas protein having a mutation (referred to herein as a mutant KRas protein). These compounds are useful for treating diseases, disorders, or conditions in which increased and / or sustained (e.g., excessive) KRas activation, such as KRas activation associated with a mutant KRas protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). The present disclosure also provides compositions containing the same, as well as methods of using and making the same. Summary of the Invention

[0007] overview The present disclosure provides compounds of Formula (A) (e.g., compounds of Formula (I) (e.g., Formulas (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formulas (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-b), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., compounds of Formula (II ... For example, formula (III-1) or (III-2)), formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof. These compounds are useful for treating diseases, disorders, or conditions in which increased KRas activation, such as KRas activation associated with mutant KRas proteins or KRas activation associated with KRas amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human).The present disclosure also provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (I

[0013] Also provided are compositions containing a compound of Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (V-c), (Vd), (V-b1), (V-a2), or (V-b2)), or a compound of Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof, as well as methods of using and making the same.

[0008] As used herein, the term "compound of formula (A): TIFF2025541682000002.tif43128 or a pharmaceutically acceptable salt thereof, wherein E 1 are N, CH, and CR 4 and R 4 CN, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 cycloalkyl; R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000003.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of R 2a and R 2b is H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 independently selected from the group consisting of cycloalkyl; R 2a and R 2b Each carbon atom, together with the ring carbon atom to which it is attached, is C 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R 2c and R 2d H, halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 independently selected from the group consisting of cycloalkyl; R 2c and R 2d Each carbon atom, together with the ring carbon atom to which it is attached, is C 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, Ring B is TIFF2025541682000004.tif27128, wherein * is ring B and TIFF2025541682000005.tif25128 shows the ring carbon atoms common to both, X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -Rb1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0009] As used herein, the term "compound of formula (I): TIFF2025541682000006.tif38128 or a pharmaceutically acceptable salt thereof, wherein: R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000007.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7(independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Ring B is TIFF2025541682000008.tif27128, wherein * is ring B and TIFF2025541682000009.tif21128 shows the ring carbon atoms common to both X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 is selected from the group consisting of H, OH, NH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is 1 to 6 RY Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 is substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(Rf )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g But R h , C 1~3 Alkyl, and C 1~3 haloalkyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0010] As used herein, the term "compound of formula (II): TIFF2025541682000010.tif38128 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, (i) 1 to 4 R 74- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000011.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 1 or 2, Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0011] As used herein, the term "compound of formula (III)" refers to a compound of formula (III): TIFF2025541682000012.tif38128 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000013.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of R 9 , H, NR d R e , —OH, and halo; b4 is 0 or 1, Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0012] As used herein, the compound of formula (IV): TIFF2025541682000014.tif38128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 At least one of the following is CHR L or C(R L )2, Furthermore, X 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000015.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -Rb1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f)2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0013] As used herein, the term "compound of formula (V): TIFF2025541682000016.tif39128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Two or three of these are CHR independently. L or C(R L )2, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6forming a cycloalkyl ring, Each additional R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R a and R b are independently selected from the group consisting of R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000017.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and Re is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1-~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0014] As used herein, the compound of formula (VI): TIFF2025541682000018.tif38128 or a pharmaceutically acceptable salt thereof, wherein: R 1 -CN, -(C 1~3 alkylene)-CN, or -(C 3~6 cycloalkylene)-CN, wherein the heterocyclyl is a 4- to 10-membered heterocyclyl substituted with 1 to 3 R 7 may be further substituted with Each R 7 is R a and R b are independently selected from the group consisting of X 1 is S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 , H, NR d R e , —OH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(Rf )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0015] As used herein, the term "compounds of formula (A)" refers to compounds of formula (I) (e.g., formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), compounds of formula (II) (e.g., formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), compounds of formula (III) (e.g., formula (III-1) or (III-2)), compounds of formula (IV) (e.g., formula ( Also provided is a pharmaceutical composition comprising a compound of Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] Provided herein is a method for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formulas (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (III-2), Formula (III-3), Formula (III-4), Formula (III-5), Formula (III-6), Formula (III-7), Formula (III-8), Formula (III-9), Formula (III-10), Formula (III-11), Formula (III-12), Formula (III-13), Formula (III-14), Formula (III-15), Formula (III-16), Formula (III-17), Formula (III-18), Formula (III-19), Formula (III-20), Formula (III-21), Formula (III-22), Formula (III-23), Formula (III-24), Formula (III-25), Formula (III-26), Formula (III-27), Formula (III-28), Formula (III-29 ...9), Formula (III-29), Formula (III-29), Formula (III-29), Formula (III-29), Formula (III-29), Formula ( (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is provided to a subject.

[0017] Also provided is a method of treating cancer in a subject in need thereof, the method comprising: (a) determining that the cancer is KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas (b) administering to a subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV ) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a subject.

[0018] Provided herein is a method of treating a KRas-associated disease or disorder in a subject (e.g., a mutant KRas-associated disease or disorder (e.g., a KRasG12D-associated cancer, a KRasG12R-associated cancer, or a KRasG12V-associated cancer)), comprising administering to a subject identified or diagnosed with a KRas-associated disease or disorder a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formulas (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), a compound of Formula (II) (e.g., Formulas (II-a), (II-b), (II-a1), (II-b1), (II-c2), or (II-d1)). a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0019] The present disclosure also provides a method of treating a KRas-associated disease or disorder in a subject (e.g., a mutant KRas-associated disease or disorder (e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)), wherein the disease or disorder in the subject is a KRas-associated disease or disorder (e.g., a mutant KRas-associated disease or disorder (e.g., a KRas G12D-associated disease or disorder, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)). G12V-associated disease or disorder), administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) ( For example, provided are methods comprising administering to a subject a compound represented by formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0020] Further provided herein are methods of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)) in a subject, comprising administering to the subject a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer) a subject identified or diagnosed with a G12V-associated cancer) is administered a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formulas (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV ) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0021] The present disclosure also provides a method of treating a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer)) in a subject, wherein the cancer in the subject is KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V-associated cancer)). G12V mutation) and administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., For example, a compound of Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, is provided to a subject.

[0022] To facilitate understanding of the present disclosure described herein, several terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, 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 mentioned throughout this specification and the attached appendices is incorporated herein by reference in its entirety. In the event of a conflict between this disclosure and any content incorporated by reference, the present disclosure shall control.

[0023] 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 of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present disclosure provides compounds of Formula (A) (e.g., compounds of Formula (I) (e.g., Formulas (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formulas (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., Formulas (II-b), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., compounds of Formula (I) (e.g., compounds of Formula (II ... For example, formula (III-1) or (III-2)), formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof. These compounds are useful for treating diseases, disorders, or conditions associated with KRas dysregulation (e.g., KRas mutation or amplification), e.g., where increased and / or sustained (e.g., excessive) KRas activation contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). These compounds may also be useful for treating diseases, disorders, or conditions, e.g., where a mutant KRas protein (e.g., a resistance mutation) confers intrinsic resistance to one or more KRas inhibitors (e.g., KRas inhibitors selective for KRas G12C mutant proteins) or non-KRas-targeted therapeutic agents. See, e.g., Misale, et al., Nature 486.7404(2012):532-536, doi:10.1038 / nature11156 and Awad, et al., New England Journal of Medicine 384.25(2021):2382-2393, doi:10.1056 / NEJMoa2105281. The present disclosure also provides compositions containing the compounds provided herein, as well as methods of using and preparing the same.

[0025] Ras family genes (e.g., KRAS, NRAS, and HRAS) were the first oncogenes identified and are some of the most commonly mutated of all discovered oncogenes. See, for example, Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi:10.1158 / 1541-7786.MCR-15-0203. The Ras family is a group of guanine nucleotide-binding proteins typically found in the inner leaflet of the cell membrane. Wild-type Ras proteins are activated when bound to GTP but inactive when bound to GDP. Typically, growth factors bind to extracellular receptors and induce nucleotide exchange with the help of guanine nucleotide exchange factors (GEFs) (e.g., Son of sevenless Homolog 1 (SOS1)). These GEFs dissociate GDP from the Ras protein, allowing GTP to bind. When bound to GTP, Ras proteins can interact with effector proteins such as cRAF. Hydrolysis of GTP to form GDP can inactivate Ras proteins, and hydrolysis can be achieved through intrinsic GTPase activity that can be enhanced by binding to GTPase-activating proteins (GAPs). There are three major Ras proteins in humans: KRas, HRas, and NRas.

[0026] Some oncogenic KRas missense mutations prevent or delay GTP hydrolysis, which can lead to the accumulation of active KRas. KRas-related signaling pathways are persistently activated in many cancers and are involved in cell growth and proliferation, differentiation, protein synthesis, glucose metabolism, cell survival, and inflammation.

[0027] Mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity. See, e.g., Table 1, reproduced from Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi:10.1158 / 1541-7786. MCR-15-0203. These changes and other factors may contribute to increased KRas signaling in mutant KRas proteins.

[0028] [Table 1]

[0029] KRas inhibitors are described, for example, in WO 2023 / 154766, WO 2023 / 143623, WO 2022 / 240971, WO 2020 / 236940, WO 2022 / 115439, WO 2023 / 086383, WO 2021 / 093758, WO 2022 / 135546, WO 2021 / 139748, WO 2022 / 251576, and WO 2023 / 025116.

[0030] Further examples of KRas inhibitors are described, for example, in WO 2022 / 132200, WO 2022 / 133038, WO 2023 / 150284, WO 2022 / 261154, WO 2023 / 183585, WO 2023 / 099592, WO 2023 / 099623, WO 2023 / 099624, WO 2023 / 099608, WO 2023 / 099609, WO 2023 / 099610, WO 2023 / 099625, WO 2023 / 099611, WO 2023 / 099626, WO 2023 / 099612, WO 2023 / 099614, WO 2023 / 099616, WO 2023 / 099618, WO 2023 / 099619, WO 2023 / 099627, WO 2023 / 099629, WO 2023 / 099630, WO 2023 / 099640, WO 2023 / 099650, WO 2023 / 099660, WO 2023 / 099670, WO 2023 / 099680, WO 2023 / 099690, WO 2023 / 099610, WO 2023 / 099628, WO 2023 / 099629, WO 2023 / 099630, WO 2023 / 099640, W Publication No. 2022 / 250170, International Publication No. 2022 / 173870, International Publication No. 2022 / 236578, International Publication No. 2022 / 237649, International Publication No. 2022 / 248885, International Publication No. 2022 / 256459, International Publication No. 2022 / 258974, International Publication No. 2022 / 266015, International Publication No. 2023 / 018809, International Publication No. 2023 / 018810, International Publication International Publication No. 2023 / 018812, International Publication No. 2023 / 020518, International Publication No. 2023 / 020519, International Publication No. 2023 / 020521, International Publication No. 2023 / 020523, International Publication No. 2023 / 046135, International Publication No. 2023 / 061294, International Publication No. 2023 / 097227, International Publication No. 2023 / 114733, International Publication No. 2023 / 137223, International Publication No. 2 023 / 141300, WO 2023 / 138583, WO 2023 / 159086, WO 2023 / 159087, WO 2023 / 173016, WO 2023 / 173017, WO 2023 / 179703, WO 2023 / 125627, WO 2022 / 216762, and Chinese Patent No. 116143806.

[0031] Compound Embodiments As used herein, a compound of formula (A): TIFF2025541682000020.tif43128 or a pharmaceutically acceptable salt thereof, wherein: E 1 are N, CH, and CR 4 and R 4 CN, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, and C3~6 cycloalkyl; R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000021.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of R 2a and R 2b is H, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 independently selected from the group consisting of cycloalkyl; R 2a and R 2b Each carbon atom, together with the ring carbon atom to which it is attached, is C 3~6 forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, R 2c and R 2d H, halo, CN, C 1~3 Alkyl, C 1~3 Haloalkyl, and C 3~6 independently selected from the group consisting of cycloalkyl; R 2c and R 2d Each carbon atom, together with the ring carbon atom to which it is attached, is C 3~6forming a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, Ring B is TIFF2025541682000022.tif27128, wherein * is ring B and TIFF2025541682000023.tif25128 shows the ring carbon atoms common to both X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O)1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 and n is independently selected from the group consisting of:

[0032] In some embodiments, the compound of Formula (A) has the formula (I): TIFF2025541682000024.tif38128 or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments of Formula (I), R1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000025.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Ring B is TIFF2025541682000026.tif27128, wherein * is ring B and TIFF2025541682000027.tif21128 shows the ring carbon atoms common to both X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 is selected from the group consisting of H, OH, NH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g But R h , C 1~3 Alkyl, and C 1~3haloalkyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0034] In some embodiments of Formula (I), R 1 teeth, (i) -OH on a ring carbon atom, -(C 1~3 alkylene)-OH, -CN, or -(C 1~3 alkylene)-CN, wherein the heterocyclyl is substituted with 1 to 3 R 7 heterocyclyl, optionally further substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000028.tif23128 (wherein b2 is 0, 1, or 2; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Ring B is TIFF2025541682000029.tif27128, wherein * is ring B and TIFF2025541682000030.tif21128 shows the ring carbon atoms common to both X1 is a bond, CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2 and O, with the proviso that X 1 , X 2 , and X 3 At most one of is O, b1 is 0, 1, or 2; R 9 is selected from the group consisting of H, OH, NH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, Y 2 is 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R ba 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g But R h , C 1~3 Alkyl, and C 1~3 haloalkyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0035] In some embodiments of Formula (A) (e.g., Formula (I)), X 1 If is a bond and b1 is 0, then (1)R 9 is OH or NR d R e (e.g., OH or NH), or (2) Y 2 is one R Y Optionally substituted linear C 1~6 It is alkylene.

[0036] In some embodiments of Formula (A) (e.g., Formula (I)), one or more of (1)-(4) are true: (1)R 9 is OH or NR d R e is; (2) b1 is 1 or 2; (3)X 1 is CH2; and / or (4) Y 2 is one R Y Optionally substituted linear C 1~6 It is alkylene.

[0037] In some embodiments of Formula (A) (e.g., Formula (I)), R 1 teeth, (i) -OH on a ring carbon atom, -(C 1~3 alkylene)-OH, -CN, or -(C 1~3 alkylene)-CN, wherein the heterocyclyl is substituted with 1 to 3 R 7 heterocyclyl, optionally further substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000031.tif23128 (wherein b2 is 0, 1, or 2; A 1 and A 2 are N, CH, and CR 7 and Ring B is TIFF2025541682000032.tif29128, wherein X 1 is a bond, CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2 and O, with the proviso that X 1 , X 2 , and X 3 At most one of is O, b1 is 0, 1, or 2; R 9 is selected from the group consisting of H, OH, NH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is -F, CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0038] To avoid any misunderstanding, for each option in Ring B * is of formula (A) (e.g., formula (I)) * Represents.

[0039] In some embodiments, in Formula (A) (e.g., Formula (I)), * The ring carbon atom labeled with has (S)-stereochemistry.

[0040] In some embodiments, in Formula (A) (e.g., Formula (I)), * The ring carbon atom labeled with has the (R)-stereochemistry.

[0041] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000033.tif26128.

[0042] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000034.tif26128.

[0043] In some embodiments of Formula (A) (e.g., Formula (I)), X 1 is a bond.

[0044] In some embodiments of Formula (A) (e.g., Formula (I)), X 1 , CH2, CHR L , and C(R L For example, X 1 can be CH2.

[0045] In some embodiments of Formula (A) (e.g., Formula (I)), X 2 and X 3, CH2, CHR L , and C(R L )2. For example, X 2 and X 3 can both be CH2.

[0046] In some embodiments of Formula (A) (e.g., Formula (I)), CH and X 3 is CHR L and C(R L )2.

[0047] In some embodiments of Formula (A) (e.g., Formula (I)), X 2 is CH2 and X 3 is CHR L For example, X 2 can be CH2, and X 3 can be CHMe.

[0048] In some embodiments of Formula (A) (e.g., Formula (I)), X 2 and X 3 One of them is -O-, and the other is X 2 and X 3 The other is CH2, CHR L , and C(R L For example, X 2 can be -O-, X 3 can be CH2 or CHMe.

[0049] In some embodiments of Formula (A) (e.g., Formula (I)), X 1 is CHR L and X 2 is CH2 and X 3 is CHR L and R L A pair of C, together with the ring atoms connecting them, 3~6 Forms a cycloalkyl ring (eg, a C4 cycloalkyl ring).

[0050] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000035.tif26128, where X 1 is CH2 and X 2 and X 3 , CH2, CHR L , C(R L In some embodiments, X is independently selected from the group consisting of: 2 and X 3 are both CH2. In some embodiments, X 2 is CH2 and X 3 is CHR L (e.g., CHMe).

[0051] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000036.tif26128, X 1 is CH2 and X 2 and X 3 One of the groups is -O-, and X 2 and X 3 The other is CH2, CHR L , and C(R L In some embodiments, X is selected from the group consisting of 2 is -O- and X 3 is CH2 or CHMe.

[0052] In some embodiments of Formula (A) (e.g., Formula (I)), each R L are independently 1 to 3 R c C optionally substituted with 1~3 It is alkyl.

[0053] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000037.tif26128, X 1 is CHR L and X 2 is CH2 and X 3 is CHR L and R L A pair of C, together with the ring atoms connecting them,3~6 Forms a cycloalkyl ring (e.g., a C4 cycloalkyl ring). For example, ring B is It could be TIFF2025541682000038.tif26128.

[0054] In some embodiments of Formula (A) (e.g., Formula (I)), R 9 -X 3 -It is para to.

[0055] In some embodiments, the compound of Formula (I) has the formula (I-a1): TIFF2025541682000039.tif38128 or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond or CH2, X 2 and X 3 , CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2 (for example, 0 or 1).

[0056] In some embodiments, the compound of Formula (I) has the formula (I-b1): TIFF2025541682000040.tif38128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is a bond or CH2, X 2 and X 3 -O-, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2.

[0057] In some embodiments, the compound of Formula (I) has the formula (I-b1): TIFF2025541682000041.tif38128 or a pharmaceutically acceptable salt thereof, wherein: X 1 is a bond or CH2, X 2 and X 3 -O-, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2.

[0058] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 1 is a bond.

[0059] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 1 is CH2.

[0060] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 2 and X 3 , CH2, CHR L , and C(R L )2.

[0061] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 2 and X 3 are both CH2.

[0062] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 2 is CH2 and X 3 is CHR L and C(R L For example, X 2 can be CH2, and X 3 can be CHMe.

[0063] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 1 is CH2 and X 2 and X 3 , CH2, CHR L , and C(R LIn some embodiments, X is independently selected from the group consisting of: 2 and X 3 are both CH2. In some embodiments, X 2 is CH2 and X 3 is CHR L and C(R L )2.

[0064] In some embodiments of formula (I-a1), (I-b1), or (I-c1), X 1 is CH2 and X 2 and X 3 One of the groups is -O-, and X 2 and X 3 The other is CH2, CHR L , and C(R L In some embodiments, X is selected from the group consisting of 2 is -O- and X 3 is CH2 or CHMe.

[0065] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 is selected from the group consisting of -OH, -NH2, and halo.

[0066] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 -OH, and -NR d R e is selected from the group consisting of:

[0067] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 is selected from the group consisting of -OH, and -NH2.

[0068] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R9 is -OH.

[0069] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 is -NH2.

[0070] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 is halo (e.g., -Br).

[0071] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 9 is H.

[0072] In some embodiments of Formula (A) (eg, Formula (I) (eg, Formula (I-a1), (I-b1), or (I-c1))), b1 is 0 or 1.

[0073] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), b1 is 1 or 2. For example, b1 can be 1. For example, b1 can be 2.

[0074] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), b1 is 1 or 2, and each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0075] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), b1 is 1 and R 10 In some embodiments, b1 is 1 and R 10 is R 9is ortho to R 10 is -CN.

[0076] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), b1 is 1 or 2, and each R 10 are independently -Cl or -F.

[0077] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), b1 is 1 or 2 and R 10 One or two occurrences of R 9 is ortho to each R 10 are independently —Cl or —F.

[0078] In some embodiments of Formula (A) (eg, Formula (I) (eg, Formula (I-a1), (I-b1), or (I-c1))), b1 is 0.

[0079] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000042.tif28128, wherein X 2 is —O— or —CH2—, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0080] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000043.tif28128, wherein X 2 is —O— or —CH—, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0081] In some embodiments of Formula (A) (e.g., Formula (I)), Ring B is TIFF2025541682000044.tif58128.

[0082] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 teeth, (i) -OH, -(C 1~3 alkylene)-OH, -(C 3~6 Cycloalkylene)-OH, -CN, -(C 1~3 alkylene)-CN or -(C 3~6 4-10 membered heterocyclyl substituted with cycloalkylene-CN, wherein the heterocyclyl is substituted with 1-3 R 7 heterocyclyl optionally further substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000045.tif23128 (wherein b2 is 0, 1, or 2; A 1 and A 2 are N, CH, and CR 7 and (independently selected from the group consisting of:

[0083] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 is 1 to 4 R 7 and optionally substituted 4- to 10-membered heterocyclyl.

[0084] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 represents -OH, -(C 1~3 alkylene)-OH, -CN or -(C 1~3 alkylene)-CN, and the heterocyclyl is substituted with 1 to 3 R 7 It may be further substituted with.

[0085] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 is a 4-10 (e.g., 6-, 7-, or 8-) membered heterocyclyl substituted on a ring carbon atom with —OH or —CHCN, and the heterocyclyl is substituted with 1-3 R 7 may be further substituted with Heterocyclyl is a heterocyclyl containing one ring nitrogen atom and two rings: O and S(O) 0~2 and 0 to 2 additional ring heteroatoms each independently selected from the group consisting of:

[0086] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 may further comprise 1 to 2 R 7 may be substituted with TIFF2025541682000046.tif21128. For example, R 1 teeth TIFF2025541682000047.tif21128 (e.g. TIFF2025541682000048.tif21128).

[0087] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 is 1 to 4 R 7 and 7- to 10- (eg, 7-) membered heterocyclyl optionally substituted by.

[0088] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 is a 7-10 (e.g., 7)-membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, and the 7-10-membered heterocyclyl is a 7-10-membered heterocyclyl having one to four R 7 may be substituted with.

[0089] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 is 1 to 4 R at one or more ring carbon atoms. 7 may be substituted with TIFF2025541682000049.tif21128.

[0090] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 alkyl (wherein each R c are independently selected from the group consisting of -F, -OH, and -CN.

[0091] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1is an 8- to 12-membered bicyclic heterocyclyl, the heterocyclyl containing an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl containing 1-3 R at one or more ring carbon atoms. 7 For example, R 1 teeth TIFF2025541682000050.tif26128 (e.g. TIFF2025541682000051.tif29128).

[0092] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 teeth TIFF2025541682000052.tif23128, where b2 is 0, 1, or 2; A 1 and A 2 are N, CH, and CR 7 In some embodiments, A 2 is CH.

[0093] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 teeth TIFF2025541682000053.tif27128. For example, R 1 teeth It could be TIFF2025541682000054.tif26128.

[0094] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 teeth, TIFF2025541682000055.tif26128, R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , Rb1 , and C(O)R b1 is selected from the group consisting of:

[0095] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 1 teeth TIFF2025541682000056.tif26128, R 7 teeth, (a)C(=O)N(R f )2(in the formula, each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 alkyl); (b) C(O)N(C 1~3 alkyl)R b1 or -C(O)N(H)R b1 (In the formula, R b1 is C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R g and (c)C(O)R b1 (In the formula, R b1 is 1 to 3 R g and R is a 4- to 10-membered heterocyclyl optionally substituted with b1 is attached to C(O) through a ring nitrogen atom.

[0096] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), Y 2 is -CH2-.

[0097] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 3 is R a and R b and a 4- to 10-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of:

[0098] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 3 is 1 to 6 R a and optionally substituted 7-10 membered bicyclic heterocyclyl.

[0099] In some embodiments of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-b1), or (I-c1))), R 3 is 1 to 3 R a may be substituted with TIFF2025541682000057.tif19128. For example, R 3 teeth TIFF2025541682000058.tif24128 (e.g. TIFF2025541682000059.tif23128).

[0100] In some embodiments, the compound of Formula (I) has the formula (I-a2) or (I-b2): TIFF2025541682000060.tif78128 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, TIFF2025541682000061.tif27128; X 1 is a bond or CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2 (for example, 0 or 1).

[0101] In some embodiments, the compound of Formula (I) has the formula (I-a3) or (I-b3): TIFF2025541682000062.tif77128 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 7- to 10-membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, and the 7- to 10-membered heterocyclyl is 7 may be substituted with X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2.

[0102] In some embodiments, the compound of Formula (I) has the formula (I-a4) or (I-b4): TIFF2025541682000063.tif91128 or a pharmaceutically acceptable salt thereof, wherein b3 is 0, 1, 2, or 3; X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2.

[0103] In some embodiments of Formula (I-a4) or (I-b4), b3 is 0.

[0104] In some embodiments of Formula (I-a4) or (I-b4), b3 is 1 or 2, and each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 alkyl, and each R c are independently selected from the group consisting of F, —OH, and —CN.

[0105] In some embodiments, the compound of Formula (I) has the formula (I-a5) or (I-b5): TIFF2025541682000064.tif104128 or a pharmaceutically acceptable salt thereof, wherein R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2 independently selected from the group consisting of: b1 is 0, 1, or 2.

[0106] In some embodiments of formula (I-a5) or (I-b5), R 7 teeth, (a)C(=O)N(R f )2(in the formula, each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 alkyl); (b) C(O)N(C 1~3 alkyl)R b1 or -C(O)N(H)R b1 (In the formula, R b1 is C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R g and (c)C(O)R b1 (In the formula, R b1 is 1 to 3 R g and R is a 4- to 10-membered heterocyclyl optionally substituted with b1 is attached to C(O) through a ring nitrogen atom.

[0107] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), X 2 and X 3 , CH2, CHR L , and C(R L )2.

[0108] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), X 2 and X 3 are both CH2.

[0109] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), X 2 is CH2 and X 3 is CHR L For example, X 2 can be CH2, and X 3 can be CH(Me).

[0110] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), X 2 is -O- and X 3 But CH2, CHR L , and C(R L For example, X 2 can be -O-, X 3 can be CH2 or CH(Me).

[0111] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), R 9 is -NH2.

[0112] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), R 9 is -OH.

[0113] In some embodiments of Formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), b1 is 1. In some embodiments of Formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), b1 is 2. In some embodiments of Formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), b1 is 0.

[0114] In some embodiments of Formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0115] In some embodiments of Formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), b1 is 1 or 2 and each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0116] In some embodiments of Formula (I-a2), (I-a3), (I-a4), or (I-a5), The TIFF2025541682000065.tif29128 part is TIFF2025541682000066.tif28128, wherein X 2is —O— or —CH—, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0117] In some embodiments of Formula (I-a2), (I-a3), (I-a4), or (I-a5), The TIFF2025541682000067.tif29128 part is TIFF2025541682000068.tif28128, wherein X 2 is —O— or —CH2, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0118] In some embodiments of Formula (I-a2), (I-a3), (I-a4), or (I-a5), The TIFF2025541682000069.tif29128 part is TIFF2025541682000070.tif58128.

[0119] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), Y 2is -CH2- and R 3 is a 4- to 10-membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, and the heterocyclyl is selected from 1-6 R a may be substituted with.

[0120] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), R 3 teeth TIFF2025541682000071.tif24128 (e.g., TIFF2025541682000072.tif23128).

[0121] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), * The ring carbon atom labeled with has the (S)-stereochemistry.

[0122] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), * The ring carbon atom labeled with has the (R)-stereochemistry.

[0123] In some embodiments of formula (I-a2), (I-b2), (I-a3), (I-b3), (I-a4), (I-b4), (I-a5), or (I-b5), The TIFF2025541682000073.tif25128 part is TIFF2025541682000074.tif26128.

[0124] In some embodiments, the compound of Formula (A) (eg, Formula (I)) is selected from the group consisting of the compounds shown in Table C1 or a pharmaceutically acceptable salt thereof.

[0125] [Table C1] TIFF2025541682000076.tif234125TIFF2025541682000077.tif234125TIFF2025541682000078.tif243125TIFF2025541682000079.tif233125TIFF2025541682000080.tif236125TIFF2025541682000081.tif213125TIFF2025541682000082.tif243123TIFF2025541682000083.tif238125TIFF2025541682000084.tif243124TIFF2025541682000085.tif222125TIFF2025541682000086.tif201125TIFF2025541682000087.tif218125TIFF2025541682000088.tif237125TIFF2025541682000089.tif234125TIFF2025541682000090.tif222125TIFF2025541682000091.tif186128TIFF2025541682000092.tif218125TIFF2025541682000093.tif216125TIFF2025541682000094.tif234125TIFF2025541682000095.tif206125TIFF2025541682000096.tif199125TIFF2025541682000097.tif222125TIFF2025541682000098.tif222125TIFF2025541682000099.tif230125TIFF2025541682000100.tif210125TIFF2025541682000101.tif232125TIFF2025541682000102.tif244122TIFF2025541682000103.tif243124TIFF2025541682000104.tif226125TIFF2025541682000105.tif243123TIFF2025541682000106.tif217125TIFF2025541682000107.tif243125TIFF2025541682000108.tif232125TIFF2025541682000109.tif212125TIFF2025541682000110.tif240125TIF F2025541682000111.tif235125TIFF2025541682000112.tif244122TIFF202554168200 0113.tif242125TIFF2025541682000114.tif213125TIFF2025541682000115.tif1991 25TIFF2025541682000116.tif243125TIFF2025541682000117.tif241125TIFF2025541 682000118.tif230125TIFF2025541682000119.tif228125TIFF2025541682000120.ti f243125TIFF2025541682000121.tif242125TIFF2025541682000122.tif226125TIFF20 25541682000123.tif213125TIFF2025541682000124.tif207125TIFF20255416820001 25.tif231125TIFF2025541682000126.tif226125TIFF2025541682000127.tif244123.

[0126] Note 1: In some compounds filed in U.S. Provisional Application No. 63 / 515,290 (e.g., Compound Nos. 143a, 143b, 149b, and 149c), the stereocenters were previously identified as * " and this stereocenter was resolved but its absolute configuration was not assigned. The compound structure is redrawn herein in enhanced stereochemical notation. See Note 2.

[0127] Note 2 In certain compounds of Table C1, one or more stereocenters are designated with "V3000 enhanced stereochemical notation" (see support.collaborativedrug.com / hc / en-us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures-Unknowns-and-Non-Tetrahedral-Chirality and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, accessed December 23, 2022, each of which is incorporated by reference in its entirety). Using this stereochemical notation, a particular stereocenter is designated with "abs," "&x," or "orx," where x is an integer (e.g., 1 or 2). For the avoidance of doubt, the stereochemical notations in Table C1 have the following meanings:

[0128] Where a structure does not contain a wedge or hash bond (i.e., each stereocenter is undefined), each stereocenter may independently have either the (R) or (S) stereochemical configuration. For the avoidance of doubt, such structures also encompass mixtures of stereoisomers. For example, TIFF2025541682000128.tif13128 is Represents TIFF2025541682000129.tif14128.

[0129] When a structure contains a stereocenter or centers, indicated by a wedge and a hash (i.e., more than one stereocenter is defined), the following notation is used: (1) If a defined stereocenter is designated by "abs" or if the defined stereocenter is not designated by an augmented stereochemical designation (e.g., "abs," "&x," or "orx"), the defined stereocenter has the absolute configuration indicated by the structural formula. For example, the structure TIFF2025541682000130.tif15128 both refer to (S)-(1-methylpyrrolidin-2-yl)methanol.

[0130] (2) When a defined stereocenter is indicated in a structural formula by "orx," the defined stereocenter is assigned, but the configuration at the defined stereocenter is not determined. For example, in the structure TIFF2025541682000131.tif13128 refers to one stereoisomer selected from the group consisting of (S)-(1-methylpyrrolidin-2-yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol.

[0131] (3) In a structural formula having at least one defined stereocenter (i.e., having a wedge bond and / or hash bond attached to at least one defined stereocenter), if the stereocenter is undefined (i.e., there are no wedge or hash bonds attached to the undefined stereocenter), a mixture of different stereoisomers at the undefined stereocenter is represented. For example, the structure TIFF2025541682000132.tif14128 is TIFF2025541682000133.tif16128 represents a mixture of the structures TIFF2025541682000134.tif24128 is Represents a mixture of TIFF2025541682000135.tif25133.

[0132] (4) When two or more defined stereocenters are indicated in a structural formula by "orx," each of these defined stereocenters is assigned, but the configuration at the defined stereocenters is not determined. a. For any pair of defined stereocenters designated by "orx" in a structural formula, if the numerical moieties in the designation are different (e.g., two defined stereocenters designated by "or1" and "or2", respectively), each defined stereocenter should be interpreted independently according to (2) above. For example, in the structure TIFF2025541682000136.tif22128 is TIFF2025541682000137.tif24130. b. For any pair of defined stereocenters designated "orx" in a structural formula, when the numerical portion of the designation is identical (e.g., two defined stereocenters are each designated "or1"), the structural formula refers to one stereoisomer having the stereochemistry relative to those stereocenters shown in the structural formula, but the absolute configuration of those stereocenters has not been determined. For example, the structure TIFF2025541682000138.tif23128 contains two "syn" stereoisomers: TIFF2025541682000139.tif24128. Another example is the structure TIFF2025541682000140.tif23128 is the "anti" stereoisomer: Points to one of the files: TIFF2025541682000141.tif24128.

[0133] (5) When two or more defined stereocenters are designated in a structural formula by "&x", the structural formula refers to a mixture of stereoisomers that differ in configuration at the defined stereocenters. Specifications: a. For any pair of defined stereocenters designated by "&x" in a structural formula, if the numerical portion of the designation is different (e.g., two defined stereocenters designated by "&1" and "&2", respectively), the structural formula refers to a mixture of stereoisomers at those two defined stereocenters, and the configuration at each defined stereocenter can vary independently of each other. For example, the structure TIFF2025541682000142.tif21128 contains four stereoisomers: Refers to a mixture of TIFF2025541682000143.tif24132. b. For any pair of defined stereocenters designated by "&x" in a structural formula, if the numerical moieties in the designation are identical (e.g., two defined stereocenters are each designated by "&1"), then the structural formula refers to a mixture of stereoisomers at those two defined stereocenters, with the relative configurations as shown in the structural formula. For example, the structure TIFF2025541682000144.tif23128 is the "syn" stereoisomer: TIFF2025541682000145.tif24128. Another example is the structure TIFF2025541682000146.tif23128 is the "anti" stereoisomer: Refers to a mixture of TIFF2025541682000147.tif24128.

[0134] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) is a compound of Formula (A) or a compound of Formula (I) described in U.S. Provisional Patent Application No. 63 / 426,950, filed November 21, 2022; U.S. Provisional Patent Application No. 63 / 456,235, filed March 31, 2023; U.S. Provisional Patent Application No. 63 / 515,290, filed July 24, 2023; U.S. Provisional Patent Application No. 63 / 533, filed August 17, 2023; No. 346; U.S. Provisional Patent Application No. 63 / 535,006, filed August 28, 2023; U.S. Provisional Patent Application No. 63 / 542,188, filed October 3, 2023; and U.S. Patent Application Publication No. 63 / 545,531, filed October 24, 2023, or a pharmaceutically acceptable salt thereof, each of which is incorporated herein by reference in its entirety.

[0135] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) has Formula (II): TIFF2025541682000148.tif38128 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000149.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of k each R 7 is R a and R b are independently selected from the group consisting of X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 1 or 2, Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms LC together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0136] In some embodiments, the compound of Formula (II) has the formula (II-a): TIFF2025541682000150.tif38128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0137] In some embodiments, the compound of Formula (II) has the formula (II-b): TIFF2025541682000151.tif38128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0138] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) has Formula (III): TIFF2025541682000152.tif38128 or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000153.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7(independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of R 9 , H, NR d R e , —OH, and halo; b4 is 0 or 1, Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each Rd and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0139] In some embodiments of Formula (III), R 9 is NR d R e In some embodiments of Formula (III), R 9 is NR d R e is.

[0140] In some embodiments of Formula (III), R 9is -NH2, and each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0141] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 is CH2 or CHR L is.

[0142] In some embodiments of Formula (II) (e.g., (II-a) or (II-b)) or Formula (III), X 2 and X 3 , CH2, CHR L , and C(R L )2.

[0143] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 is CH2 and X 2 and X 3 are both CH2.

[0144] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 , X 2 , and X 3 At least one of the following is CHR L and C(R L In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 , X 2 , and X 3 (For example, X 3 ) is CHR L and C(R L )2.

[0145] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 is CH2 and X 2 and X 3 , CH2, CHR L , and C(R L )2, independently selected from the group consisting of: X 2 and X 3 One to two (e.g., one) of the L or C(R L )2.

[0146] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 1 is CH2 and X 2 is CH2 and X 3 is CHR L In some embodiments, each R L are independently selected from the group consisting of CH3, CF3, CHF2, and CH2F.

[0147] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 2 and X 3 One of them is -O-, and the other is X 2 and X 3 The other is CH2, CHR L , and C(R L )2.

[0148] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), X 2 is -O- and X 3 , CH2, CHR L , and C(R L In some embodiments, each R L are independently selected from the group consisting of CH3, CF3, CHF2, and CH2F.

[0149] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)) or Formula (III), each R L are independently selected from the group consisting of CH3, CF3, CHF2, and CH2F.

[0150] In some embodiments of Formula (II), The TIFF2025541682000154.tif28128 part is TIFF2025541682000155.tif29128, wherein b4 is 0 or 1, X 2 is —O— or —CH—, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0151] In some embodiments of Formula (II), The TIFF2025541682000156.tif28128 part is TIFF2025541682000157.tif29159.

[0152] In some embodiments of Formula (III), The TIFF2025541682000158.tif29128 part is TIFF2025541682000159.tif28128, wherein: b4 is 0 or 1, X 2 is —O— or —CH—, X 3 is -CH2- or -CHR L - and R L But C1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0153] for example, The TIFF2025541682000160.tif29128 part is It could be TIFF2025541682000161.tif29128.

[0154] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) has Formula (IV): TIFF2025541682000162.tif33128 or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 At least one of the following is CHR L or C(R L )2, Furthermore, X 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R aand R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000163.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f)2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0155] In some embodiments of Formula (IV), R 9 OH, NR d R e and halo. For example, R 9 is NR d R e It could be.

[0156] In some embodiments, the compound of formula (IV) has formula (IV-a): TIFF2025541682000164.tif33128 or a pharmaceutically acceptable salt thereof, wherein Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0157] In some embodiments, the compound of formula (IV) has formula (IV-b): TIFF2025541682000165.tif33128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0158] In some embodiments of Formula (IV) (e.g., Formula (IV-a) or (IV-b)), X 1 is CH2.

[0159] In some embodiments of Formula (IV) (e.g., Formula (IV-a) or (IV-b)), X 2 is CH2 and X 3 is CHR L is.

[0160] In some embodiments of Formula (IV) (e.g., Formula (IV-a) or (IV-b)), X 2 is -O- and X 3 But CHR L and C(R L )2.

[0161] In some embodiments of Formula (IV) (e.g., Formula (IV-a) or (IV-b)), each R L are independently selected from the group consisting of CH3, CF3, CHF2, and CH2F.

[0162] In some embodiments, the compound of formula (IV) has formula (IV-c): TIFF2025541682000166.tif37128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0163] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) has Formula (V): TIFF2025541682000167.tif33128 or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond, S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Two or three of these are CHR independently. L or C(R L )2, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Each additional R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b1 is 0, 1, or 2; R 9 H, OH, NR d R e and halo; Each R 10 is R a and R b are independently selected from the group consisting of R 1 teeth, (i) 1 to 4 R 7 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl contains an endocyclic group selected from the group consisting of C(=O)NH and S(O)NH, and the heterocyclyl has 1 to 3 R at one or more ring carbon atoms. 7 8- to 12-membered bicyclic heterocyclyl optionally further substituted by (iii) TIFF2025541682000168.tif23128 (wherein b2 is 0, 1, 2, or 3; A 1 and A 2 are N, CH, and CR 7 (independently selected from the group consisting of is selected from the group consisting of Each R 7 is R a and R b are independently selected from the group consisting of Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NRd R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each R c are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1~2 (C 1~6 alkyl), S(O) 1~2 (C 1~6 haloalkyl), S(O) 1~2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 Rh C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0164] In some embodiments, the compound of Formula (V) has the formula (Va): TIFF2025541682000169.tif33128 or a pharmaceutically acceptable salt thereof, wherein Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0165] In some embodiments, the compound of Formula (V) has the formula (Vb): TIFF2025541682000170.tif33128 or a pharmaceutically acceptable salt thereof, wherein: b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0166] In some embodiments of Formula (V) (e.g., Formula (Va) or (Vb)), X 2 is —O— or —CH2— (e.g., —CH2—).

[0167] In some embodiments of Formula (V) (e.g., Formula (Va) or (Vb)), X 1 is CHR L and X 3 is CHR L and R on different ring carbon atoms L A pair of C, together with the ring atoms connecting them, 3~4 Forms a cycloalkyl ring.

[0168] In some embodiments of Formula (V) (e.g., Formula (Va) or (Vb)), X 1 is CHR L and X 3 is C(R L )2, and R on different ring carbon atoms L A pair of C, together with the ring atoms connecting them, 3~4 form a cycloalkyl ring, and the remaining R L is C optionally substituted with 1 to 3 F 1~2 It is alkyl.

[0169] In some embodiments, the compound of Formula (V) has Formula (Vc) or Formula (Vd): TIFF2025541682000171.tif77128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R L1 A pair of C, together with the ring atoms connecting them, 3~4 forming a cycloalkyl ring, R L2 is C optionally substituted with 1 to 3 F 1~2 It is alkyl.

[0170] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), Y 2 is -CH2- and R 3 is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, and the heterocyclyl is selected from 1-6 R a may be substituted with.

[0171] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), or Formula (V) (e.g., Formula (Va) or (Vb)), R 3 teeth TIFF2025541682000172.tif24128 (e.g. TIFF2025541682000173.tif23128).

[0172] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), Y 2 is CH2 and R 3 teeth TIFF2025541682000174.tif24128 (e.g., TIFF2025541682000175.tif23128).

[0173] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 teeth TIFF2025541682000176.tif23128, where b2 is 0, 1, or 2; A 1 and A 2 are N, CH and CR 7 are independently selected from the group consisting of:

[0174] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 teeth, The file is TIFF2025541682000177.tif26128.

[0175] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 teeth TIFF2025541682000178.tif26128, R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of:

[0176] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 7 teeth, (a)C(=O)N(R f )2(in the formula, each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 alkyl); (b) C(O)N(C 1~3 alkyl)R b1 or -C(O)N(H)R b1 (In the formula, R b1 is C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R g and (c)C(O)R b1 (In the formula, R b1 is 1 to 3 R g and R is a 4- to 10-membered heterocyclyl optionally substituted with b1 is attached to C(O) through a ring nitrogen atom. In some embodiments, R 7 is C(=O)N(R f )2, and each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 In some embodiments, R 7 is R b1 and R b1 is a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, each of which is 1 to 2 R g may be substituted with.

[0177] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R1 teeth TIFF2025541682000179.tif26128, where R 7a and R 7b is an independently selected R 7 is.

[0178] In some embodiments, R 7a is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of R 7b -halo, -CN, and 1 to 3 R c C optionally substituted with 1~3 It is alkyl.

[0179] In some embodiments, R 7a is the following: (a)C(=O)N(R f )2(in the formula, each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 alkyl); (b) C(O)N(C 1~3 alkyl)R b1 or -C(O)N(H)R b1 (In the formula, R b1 is C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R g and (c)C(O)R b1 (In the formula, R b1 is 1 to 3 R g and R is a 4- to 10-membered heterocyclyl optionally substituted with b1 is attached to C(O) through a ring nitrogen atom.

[0180] In some embodiments, R 7a is Rb1 and R b1 is a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, each of which is selected from 1 to 2 R g may be substituted with.

[0181] In some embodiments, R 7b is halo (e.g., —Cl).

[0182] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 is a 7-10 (e.g., 7)-membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, and the 7-10-membered heterocyclyl is a 7-10-membered heterocyclyl having one to four R 7 may be substituted with.

[0183] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 is 1 to 4 R at one or more ring carbon atoms. 7 may be substituted with TIFF2025541682000180.tif21128. For example, R 1 teeth It could be TIFF2025541682000181.tif21128.

[0184] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), each R 7 is -OH, -CN, -F, and 1 to 3 R cC optionally substituted with 1~3 alkyl (wherein each R c are independently selected from the group consisting of -F, -OH, and -CN.

[0185] In some embodiments of Formula (II) (e.g., Formula (II-a) or (II-b)), Formula (III), Formula (IV) (e.g., Formula (IV-a), (IV-b), or (IV-c)), or Formula (V) (e.g., Formula (Va), (Vb), (Vc), or (Vd)), R 1 is 1 to 4 R at one or more ring carbon atoms. 7 may be substituted with TIFF2025541682000182.tif21128, and each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 Alkyl (wherein Each R c are independently selected from the group consisting of -F, -OH, and -CN.

[0186] In some embodiments, the compound of Formula (II) has the formula (II-a1) or (II-b1): TIFF2025541682000183.tif93128 or a pharmaceutically acceptable salt thereof, wherein: b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2.

[0187] In some embodiments, the compound of formula (III) has the formula (III-1): TIFF2025541682000184.tif46128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2.

[0188] In some embodiments of formula (III-1), R 9 is NR d R e (e.g., -NH2).

[0189] In some embodiments, the compound of formula (IV) has formula (IV-a1) or (IV-b1): TIFF2025541682000185.tif93128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, b1 is 0, 1, or 2; Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X 1 is CH2, X 2 and X 3 One of them is CHR L and C(R L)2 independently selected from the group consisting of: X 2 and X 3 The other is CH2 or O.

[0190] In some embodiments of formula (IV-a1) or (IV-b1), X 2 is CH2 and X 3 is CHR L is.

[0191] In some embodiments of formula (IV-a1) or (IV-b1), R 9 is NR d R e (e.g., -NH2).

[0192] In some embodiments, the compound of Formula (V) has the formula (V-a1) or (V-b1): TIFF2025541682000186.tif93128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, b1 is 0, 1, or 2; Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X 2 is —O— or —CH—, X 1 is CHR L and X 3 is CHR L or C(R L )2, A pair of R on different ring carbon atoms L C together with the ring atoms that connect them 3~4 forming a cycloalkyl ring, If present, the remaining R L is C optionally substituted with 1 to 3 F 1~2 It is alkyl.

[0193] In some embodiments of Formula (II-a1), (II-b1), (III-1), (IV-a1), (IV-b1), (V-a1), or (V-b1), b3 is 0.

[0194] In some embodiments of Formula (II-a1), (II-b1), (III-1), (IV-a1), (IV-b1), (V-a1), or (V-b1), b3 is 1 or 2, and each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 alkyl, and each R c are independently selected from the group consisting of -F, -OH, and -CN.

[0195] In some embodiments, the compound of Formula (II) has the formula (II-a2) or (II-b2): TIFF2025541682000187.tif116128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2.

[0196] In some embodiments, the compound of formula (III) has the formula (III-2): TIFF2025541682000188.tif53128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of X 1 is CH2, X 2 and X 3 are O, CH2, CHR L , and C(R L )2.

[0197] In some embodiments of formula (III-2), R 9 is NR d R e (e.g., -NH2).

[0198] In some embodiments, the compound of Formula (IV) has the formula (IV-a2) or (IV-b2): TIFF2025541682000189.tif116128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, b1 is 0, 1, or 2; Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 7 is C(=O)N(Rf )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of X 1 is CH2, X 2 and X 3 One of them is CHR L and C(R L )2 independently selected from the group consisting of: X 2 and X 3 The other is CH2 or O.

[0199] In some embodiments of formula (IV-a2) or (IV-b2), X 2 is CH2 and X 3 is CHR L is.

[0200] In some embodiments, the compound of Formula (V) has the formula (V-a2) or (V-b2): TIFF2025541682000190.tif116128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, b1 is 0, 1, or 2; Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, R 7 is C(=O)N(R f )2, C(O)N(C 1~3 alkyl)R b1 , -C(O)N(H)R b1 , R b1 , and C(O)R b1 is selected from the group consisting of X 2 is —O— or —CH—, X 1 is CHR Land X 3 is CHR L or C(R L )2, A pair of R on different ring carbon atoms L C together with the ring atoms that connect them 3~4 forming a cycloalkyl ring, If present, the remaining R L is C optionally substituted with 1 to 3 F 1~2 It is alkyl.

[0201] In some embodiments of formula (II-a2), (II-b2), (III-2), (IV-a2), (IV-b2), (V-a2), or (V-b2), R 7 teeth, (a)C(=O)N(R f )2(in the formula, each R f are independently H or 1 to 3 R h C optionally substituted with 1~3 alkyl); (b) C(O)N(C 1~3 alkyl)R b1 or -C(O)N(H)R b1 (In the formula, R b1 is C 3~6 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R g and (c)C(O)R b1 (In the formula, R b1 is 1 to 3 R g and R is a 4- to 10-membered heterocyclyl optionally substituted with b1 is attached to C(O) through the ring nitrogen atom) is selected from the group consisting of:

[0202] In some embodiments of formula (II-a2), (II-b2), (III-2), (IV-a2), (IV-b2), (V-a2), or (V-b2), R 7 is R b1 and R b1is a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclyl, each of which is 1 to 2 R g may be substituted with.

[0203] In some embodiments of formula (II-a1), (II-b1), (III-1), (IV-a1), (IV-b1), (V-a1), (V-b1), (II-a2), (II-b2), (III-2), (IV-a2), (IV-b2), (V-a2), or (V-b2), Y 2 is -CH2- and R 3 is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, and the heterocyclyl is selected from 1-6 R a may be substituted with.

[0204] In some embodiments of formula (II-a1), (II-b1), (III-1), (IV-a1), (IV-b1), (V-a1), (V-b1), (II-a2), (II-b2), (III-2), (IV-a2), (IV-b2), (V-a2), or (V-b2), R 3 teeth, TIFF2025541682000191.tif24128 (e.g., TIFF2025541682000192.tif23128). In some embodiments, Y 2 is CH2.

[0205] In some embodiments of Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), The TIFF2025541682000193.tif28128 part is TIFF2025541682000194.tif28128.

[0206] In some embodiments, the compound of Formula (II) is selected from the group consisting of compound numbers 139, 139a, 139b, 139c, 158, 158a, 158b, 158c, 160, 160a, 161, 161a, 161b, 161c, 164, 164a, 164b, 170, 170a, 171, 171a, 171b, 171c, 176, 176a, 176b, 176c, 176d, 176e, 178, 178a, 178b, 179, 179a, 179b, 179d, 179e, 179f, 180, 180a, 180b, 180c, 181, 181a, 183, 183a, 185, 185a, 190, 190a, 190b, 190c, 191, 191a, 191b, 191c, 191d, 192, 192a, 192b, 192c, 192d, and 192e, or a pharmaceutically acceptable salt thereof. For example, the compound of formula (II) can be selected from the group consisting of compound numbers 139, 139a, 139b, 139c, 158, 158a, 158b, 158c, 160, 160a, 161, 161a, 164, 164a, 164b, 170, 170a, 171, 171a, 176, 176a, 176b, 176c, 176d, 178, 178a, 178b, 179, 179a, 180, 180a, 181, and 181a shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the compound of Formula (III) is selected from the group consisting of compound numbers 158, 158a, 158b, 158c, 161, 161a, 161b, 161c, 176, 176a, 176b, 176c, 176d, 176e, 177, 177a, 178, 178a, 178b, 179, 179a, 179b, 179d, 179e, 179f, 180, 180a, 180b, 180c, 184, 184b, 184c, 192, 192a, 192b, 192c, 192d, 192e, 194, and 194a, as shown in Table C1, or a pharmaceutically acceptable salt thereof. For example, the compound of formula (III) can be selected from the group consisting of compound numbers 158, 158a, 158b, 158c, 161, 161a, 176, 176a, 176b, 176c, 176d, 177, 177a, 178, 178a, 178b, 179, 179a, 180, and 180a shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0208] In some embodiments, the compound of formula (IV) is selected from the group consisting of compound numbers 124, 124a, 124b, 124c, 124d, 124e, 124f, 125, 125a, 130, 130a, 130b, 130c, 131, 131a, 131b, 133, 133a, 133b, 133c, 134, 134a, 138, 138a, 148, 148a, 162, 162a, 162b, 162c, 162d, 162e, 162f, 125, 125a, 130, 130a, 130b, 130c, 131, 131a, 131b, 133, 133a, 133b, 133c, 134, 134a, 138, 138a, 148, 148a, 162, 162a, 162b, 162e, 162f, 162f, 162g, 162h, 162i, 162j ... or a pharmaceutically acceptable salt thereof. For example, the compound of formula (IV) may be selected from the group consisting of compound numbers 124, 124a, 124b, 125, 125a, 130, 130a, 131, 131a, 133, 133a, 133b, 134, 134a, 138, 138a, 148, 148a, 162, 162a, 163, 163a, 175, and 175a shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0209] In some embodiments, the compound of Formula (V) is selected from the group consisting of Compound Nos. 172, 172a, 172b, and 172c shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the compound of Formula (A) (e.g., Formula (I)) has Formula (VI): TIFF2025541682000195.tif37128 or a pharmaceutically acceptable salt thereof, wherein R 1 -CN, -(C 1~3 alkylene)-CN, or -(C 3~6 cycloalkylene)-CN, wherein the heterocyclyl is a 4- to 10-membered heterocyclyl substituted with 1 to 3 R 7 may be further substituted with Each R 7 is R a and R b are independently selected from the group consisting of X 1 is S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of b1 is 0, 1, or 2; R 9 , H, NR d R e , —OH, and halo; Each R 10 is R a and R b are independently selected from the group consisting of Each R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Y 2 is a bond or 1 to 6 R Y Optionally substituted linear C 1~6 is alkylene, Each R Y are halo, cyano, -OH, oxo, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Alkyl, and C 1~6 haloalkyl; A pair of R on the same or different carbon atoms Y C together with the atoms that connect them 3~6 Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C 1~3 may be substituted with alkyl, R 3 teeth, (a)R a and R b a 4- to 15-membered heterocyclyl optionally substituted by 1 to 6 substituents independently selected from the group consisting of: (b)-NR d R e is selected from the group consisting of Each R a is independent, (a) Halo, (b) cyano, (c) -OH, (d) oxo, (e)-C 1~6 Alkoxy, (f)-C 1~6 haloalkoxy, (g)-NR d R e , (h)C(=O)C 1~6 Alkyl, (i) C(=O)C 1~6 haloalkyl, (j) C(=O)OH, (k)C(=O)OC 1~6 Alkyl, (l) C(=O)OC 1~6 haloalkyl, (m)C(=O)N(R f )2, (n)S(O) 0~2 (C 1~6 alkyl), (o)S(O) 0~2 (C 1~6 haloalkyl), (p)S(O) 1~2 N(R f )2, and (q) 1 to 6 R c each of which may be substituted with C 1~6 Alkyl, C 2~6 Alkenyl, or C 2~6 alkynyl; Each R b is -(L b ) b -R b1 and -R b1 are independently selected from the group consisting of b is 1, 2, or 3; Each-L b -O-, -N(H)-, -N(C 1~3 Alkyl)-, -S(O) 0~2 -, C(=O), and C 1~3 alkylene; Each R b1 is C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R g may be substituted with Each Rc are halo, cyano, -OH, -C 1~6 Alkoxy, -C 1~6 Haloalkoxy, -NR d R e , C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)OH, C(=O)N(R f )2, S(O) 0~2 (C 1~6 alkyl), S(O) 0~2 (C 1~6 haloalkyl), and S(O) 1~2 N(R f )2 independently selected from the group consisting of: Each R d and R e is H, C(=O)C 1~6 Alkyl, C(=O)C 1~6 Haloalkyl, C(=O)OC 1~6 Alkyl, C(=O)OC 1~6 Haloalkyl, C(=O)N(R f )2, S(O) 1-2 (C 1~6 alkyl), S(O) 1-2 (C 1~6 haloalkyl), S(O) 1-2 N(R f )2, and 1 to 3 R h C optionally substituted with 1~6 independently selected from the group consisting of alkyl, Each R f is H and 1 to 3 R h C optionally substituted with 1~6 alkyl; and Each R g is R h , C 1~3 Alkyl, C 1~3 Haloalkyl, C 3~5 independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; Each R h are halo, cyano, -OH, -C1~6 Alkoxy, -C 1~6 Haloalkoxy, -NH2, -N(H)(C 1~3 alkyl), and -N(C 1~3 alkyl)2-.

[0211] In some embodiments of Formula (VI), R 1 is -CN or -(C 1=3 alkylene)-CN, and the heterocyclyl is substituted with 1 to 3 R 7 It may be further substituted with.

[0212] In some embodiments of Formula (VI), R 1 is -CN or -(C 1~3 alkylene)-CN-substituted 6- to 8-membered heterocyclyl, Heterocyclyl has one ring nitrogen atom and 0 to 1 ring oxygen atoms; Heterocyclyl is one to three R 7 It may be further substituted with.

[0213] In some embodiments of Formula (VI), each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0214] In some embodiments of Formula (VI), R 1 teeth, TIFF2025541682000196.tif26128, wherein b3 is 0, 1, or 2. In some embodiments, each R 7 is -OH, -CN, -F, and 1 to 3 R c C optionally substituted with 1~3 Alkyl (e.g., C optionally substituted with 1 to 3 -F) 1~3 In some embodiments, b3 is 0.

[0215] For example, R 1 is in formula (VI) It could be TIFF2025541682000197.tif26128.

[0216] In some embodiments of Formula (VI), R 9 is NR d R e or OH (e.g., —NH2).

[0217] In some embodiments, the compound of formula (VI) has formula (VI-a): TIFF2025541682000198.tif38128 or a pharmaceutically acceptable salt thereof, wherein: Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0218] In some embodiments of Formula (VI-a), b1 is 1 or 2.

[0219] In some embodiments, the compound of formula (VI) has formula (VI-b): TIFF2025541682000199.tif38128 or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0220] In some embodiments of Formula (VI-b), R 9 Ha-NR d R e is.

[0221] In some embodiments, the compound of formula (VI) has formula (VI-c): TIFF2025541682000200.tif38128 or a pharmaceutically acceptable salt thereof, wherein: b4 is 0 or 1, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0222] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 or CHR L is.

[0223] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 2 and X 3 , CH2, CHR L , and C(R L )2.

[0224] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 and X 2 and X 3 are both CH2.

[0225] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 , X 2 and X 3 At least one (e.g., one) of L and C(R L )2.

[0226] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 and X 2 and X 3 , CH2, CHR L, and C(R L )2, independently selected from the group consisting of: X 2 and X 3 One or two of these are independently CHR L or C(R L )2.

[0227] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 and X 2 is CH2 and X 3 is CHR L is.

[0228] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 and X 2 and X 3 One of the groups is -O-, and X 2 and X 3 The other is CH2, CHR L , and C(R L )2.

[0229] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), X 1 is CH2 and X 2 is -O- and X 3 , CH2, CHR L , and C(R L )2.

[0230] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), or (VI-c)), each R L are independently selected from the group consisting of CH3, CF3, CHF2, and CH2F.

[0231] In some embodiments, the compound of formula (VI) has formula (VI-d): TIFF2025541682000201.tif33128 compound or a pharmaceutically acceptable salt thereof, wherein: X 1 is S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3 At least one of the following is CHR L or C(R L )2, Furthermore, however, X 1 , X 2 , and X 3 Not more than one of O and S(O) 0~2 is selected from the group consisting of Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0232] In some embodiments, the compound of formula (VI) has formula (VI-e): TIFF2025541682000202.tif33128 or a pharmaceutically acceptable salt thereof, wherein X 1 is S(O) 0~2 , CH2, CHR L , C(R L )2, and O; X 2 and X 3 , CH2, CHR L , C(R L )2, O, and S(O) 0~2 are independently selected from the group consisting of: 1 , X 2 , and X 3Two or three of these are CHR independently. L or C(R L )2, A pair of R on the same or different ring carbon atoms L C together with the ring atoms that connect them 3~6 forming a cycloalkyl ring, Each additional R L is C 1~3 Alkoxy, -F, CN, and 1 to 3 R c C optionally substituted with 1~3 independently selected from the group consisting of alkyl, Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0233] In some embodiments of formula (VI-d) or (VI-e), R 9 is NH2.

[0234] In some embodiments of formula (VI-d) or (VI-e), b1 is 1 or 2.

[0235] In some embodiments of formula (VI-d) or (VI-e), The TIFF2025541682000203.tif27128 part is TIFF2025541682000204.tif29128, wherein b4 is 0 or 1, X 2 is —O— or —CH—, X 3 is -CH2- or -CHR L - and R L But C 1~3 alkyl (e.g., methyl); Each R 10 is -Cl, -F, -CN, and 1 to 3 R c C optionally substituted with 1~3 alkyl.

[0236] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), Y 2 is -CH2- and R 3 is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, and the heterocyclyl is selected from 1-6 R a may be substituted with.

[0237] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), R 3 teeth TIFF2025541682000205.tif24128 (e.g. TIFF2025541682000206.tif25128).

[0238] In some embodiments of Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), The TIFF2025541682000207.tif28128 part is TIFF2025541682000208.tif28128.

[0239] In some embodiments, the compound of Formula (VI) is selected from the group consisting of compound numbers 149, 149a, 149b, 149c, 173, 173a, 174, 174a, 186, 186a, 186b, 186c, 187a, 187a, 188, 188a, 189, 189a, 191, 191a, 191b, 191c, 191d, 192, 192a, 192b, 192c, 192d, 192e, 195, and 195a shown in Table C1, or a pharmaceutically acceptable salt thereof.

[0240] Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b ), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) were synthesized using methods involving resolution of a stereoisomeric mixture (e.g., SFC separation of stereoisomers). In Table C1, the resolved stereocenters in these compounds are labeled with the enhanced stereochemical annotation of "or1" and / or "or2." In some cases, stereoisomeric resolution is performed during the final step of the synthesis, thereby providing individual stereoisomers of a compound of Formula (A). Alternatively, in some other cases, resolution may be performed on an intermediate or starting material, where each of the constituent stereoisomers of the intermediate or starting material may be separately subjected to subsequent steps of the synthesis to provide each compound of Formula (A) as a separate stereoisomer. Those skilled in the art will appreciate that under any approach to stereoisomeric resolution, stereoisomers having both the (R) and (S) configurations at the resolved stereocenters are provided. See Table C3 (in Table C1, compounds whose stereoisomers include or1 and / or or2 stereochemical designations are provided in the unstereoformed form, followed by the respective stereoisomers having the (R)- and (S)-configurations).

[0241] [Table C3] TIFF2025541682000210.tif221102TIFF2025541682000211.tif243101TIFF2025541682000212.tif239102TIFF2025541682000213.tif203102TIFF2025541682000214.tif242102TIFF2025541682000215.tif243102TIFF2025541682000216.tif239102TIFF2025541682000217.tif228102TIFF2025541682000218.tif238102TIFF2025541682000219.tif243102TIFF2025541682000220.tif242102TIFF2025541682000221.tif93128

[0242] As used herein, the term "compounds of formula (A)" refers to compounds of formula (I) (e.g., formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), compounds of formula (II) (e.g., formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), compounds of formula (III) (e.g., formula (III-1) or (III-2)), compounds of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), Also provided is a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein)) non-covalently linked to a compound of Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof. In some embodiments, Gly10 of the KRas protein is represented by Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula a compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, 1 via hydrogen bonds between the OH group of Gly10 and the NH group of R 1 via water-mediated interactions between the OH groups of 1Without wishing to be bound by theory, in some embodiments, Gly10 of the KRas protein interacts non-covalently with a group represented by Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (I R of a compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof 1 The interaction between the groups promotes inhibition of the interaction between the KRas protein and Raf-RBD. In some embodiments, Arg68 of the KRas protein is selected from the group represented by Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or ( III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof; 1 groups (e.g., guanidine at Arg68 and R 1Without wishing to be bound by theory, in some embodiments, the interaction between Arg68 of the KRas protein and Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) ( For example, R of a compound of formula (III-1) or (III-2)), formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof 1 promotes the inhibition of the interaction between the KRas protein and Raf-RBD.

[0243] chemical definition The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0244] The term "oxo" refers to a divalent double-bonded oxygen atom (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0245] The term "alkyl" refers to a saturated acyclic hydrocarbon radical, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10indicates that the group may have 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, and n-hexyl. The term "saturated," as used in this context, means that only single bonds exist between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein.

[0246] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).

[0247] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0248] 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 the avoidance of doubt, in "cycloalkylene" and "heterocyclylene", the two radicals may be on the same ring carbon atom (e.g., TIFF2025541682000222.tif20128), or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., TIFF2025541682000223.tif20128).

[0249] The term "alkenyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups may be either unsubstituted or substituted with one or more substituents.

[0250] The term "alkynyl" refers to an acyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups may be either unsubstituted or substituted with one or more substituents.

[0251] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which at least one ring in the system is aromatic (e.g., a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system), and in which 0, 1, 2, 3, or 4 atoms of each ring can be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0252] The term "cycloalkyl" as used herein refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated hydrocarbon group, e.g., having 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3 to 10 ring carbons or 3 to 6 ring carbons, where the cycloalkyl group may be substituted. The term "saturated" as used in this context means that only single bonds exist between the constituent carbon atoms. Examples of saturated cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyls can have any degree of unsaturation, provided that one or more double bonds are present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group as a whole is not fully saturated. Examples of partially unsaturated cycloalkyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which two rings are connected through exactly one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like.

[0253] The term "heteroaryl" as used herein means a monocyclic, bicyclic, tricyclic, or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms, wherein at least one ring in the system is selected from the group consisting of N, O, S( TIFF2025541682000224.tif16128), and P( TIFF2025541682000225.tif15128), and at least one ring in the system is aromatic (but need not be a heteroatom-containing ring, e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be either 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, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, and pyrido[2,3-d]pyrimidinyl. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazolyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, where each ring nitrogen adjacent to the carbonyl is a pyridonyl (e.g., TIFF2025541682000226.tif24128), pyrimidonyl (e.g., TIFF2025541682000227.tif24128), pyridazinonyl (e.g., TIFF2025541682000228.tif20128), pyrazinonyl (e.g., TIFF2025541682000229.tif20128), and imidazolonyl (e.g., TIFF2025541682000230.tif16128), and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of the following:

[0254] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic saturated or partially unsaturated ring system having 3 to 15 ring atoms (e.g., a 5- to 8-membered monocyclic, an 8- to 12-membered bicyclic, or an 11- to 15-membered tricyclic ring system) having 1 to 3 heteroatoms if monocyclic, 1 to 6 heteroatoms if bicyclic, or 1 to 9 heteroatoms if tricyclic or polycyclic, wherein the heteroatoms are O, N, S ( TIFF2025541682000231.tif16128), and P( TIFF2025541682000232.tif16128) (e.g., carbon atoms and 1 to 3, 1 to 6, or 1 to 9 N, O, S, or P heteroatoms, respectively, in the case of monocyclic, bicyclic, or tricyclic rings), where 0, 1, 2, or 3 atoms in each ring can be replaced by substituents. The term "saturated," as used in this context, means that only single bonds exist between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups can have any degree of unsaturation, provided that one or more double bonds are present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl.

[0255] Heterocyclyl may contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyl include 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2-azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2-azabicyclo[2.2.2]octyl, Heterocyclyl includes 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2-oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5-oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7-oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2-oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, etc. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected through only one atom).Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4-azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2-azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl, 2,5-diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2 .2]pentyl, 4-oxaspiro[2.5]octyl, 1-oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6-oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1-oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl, and the like.

[0256] As used herein, when a ring is described as "partially unsaturated," it means that the ring has one or more additional degrees of unsaturation (e.g., one or more double or triple bonds between constituent ring atoms in addition to the degree of unsaturation due to the ring itself), provided that the ring is not aromatic. Examples of such rings include cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0257] For the avoidance of doubt, unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form bicyclic or higher ring systems (e.g., tricyclic, polycyclic ring systems), such rings and cyclic groups are defined as those in which the points of fusion are (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 is a 0 atom bridge (e.g., TIFF2025541682000233.tif12128), (ii) a single ring atom (spiro-fused ring system) (e.g., TIFF2025541682000234.tif20128), or (iii) a sequence of consecutive ring atoms (bridged ring systems with all bridge lengths > 0) (e.g., It is understood that the present invention encompasses those having fused rings, including those located at positions (e.g., TIFF2025541682000235.tif16128).

[0258] Additionally, atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include 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 include 13 C and 14 Contains C.

[0259] Additionally, compounds disclosed generically or specifically herein are intended to include all tautomeric forms. Thus, by way of example, the moiety: The compound containing TIFF2025541682000236.tif17128 is the moiety: TIFF2025541682000237.tif19128. Similarly, pyridinyl or pyrimidinyl moieties described as optionally substituted with hydroxyl encompass the pyridone or pyrimidone tautomeric forms.

[0260] The compounds provided herein can include various stereochemical forms.The compounds also include diastereomers and optical isomers, for example, mixtures of enantiomers, including racemic mixtures, and individual enantiomers and diastereomers resulting from structural asymmetry in a particular compound.Unless otherwise indicated, the disclosed compounds are named or depicted by structure without specifying stereochemistry, and if they have one or more chiral centers, it is understood that they represent all possible stereoisomers of the compound.

[0261] Treatment method Indications Provided herein is a method for inhibiting KRas protein. Provided herein is an inhibitor of KRas protein (e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) that is useful for treating or preventing a disease or disorder associated with KRas dysregulation (i.e., a KRas-related disease or disorder), such as, for example, cardiovascular disease, inflammatory disease and / or autoimmune disease, or cancer (e.g., a KRas-related cancer).

[0262] As used herein, the term "KRas-associated disease or disorder" refers to a disease or disorder associated with or involving dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them (e.g., one or more) (e.g., any of the types of dysregulation of the expression, activity, or levels of the KRAS gene, KRas protein, or any of them described herein). Non-limiting examples of KRas-associated diseases or disorders include, for example, cancer, cardiovascular disease (e.g., arteriovenous malformation), endometritis, and inflammatory and / or autoimmune diseases (e.g., autoimmunity and non-malignant syndromes of abnormal leukocyte homeostasis). See, e.g., Adashek et al. Genome Med. 2020;12:16, doi:10.1186 / s13073-020-0714-y; Niemela et al. Blood. 2011;117(10):2883-6, doi:10.1182 / blood-2010-07-295501; Nosan et al. Croat Med J. 2013, 54(6):574-578, doi:10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5(2020):312-319, 10.1080 / 21541248.2018.1502591.

[0263] As used herein, the term "mutated KRas-associated disease or disorder" refers to a disease or disorder associated with or involving a KRas mutation (e.g., a KRAS gene and / or a KRas protein having a mutation corresponding to a mutation in the KRas protein). Non-limiting examples of mutant KRas-associated diseases or disorders include, for example, cancer, cardiovascular disease (e.g., arteriovenous malformation), endometritis, and inflammatory and / or autoimmune diseases (e.g., autoimmunity and non-malignant syndromes of abnormal leukocyte homeostasis). See, e.g., Adashek et al. Genome Med. 2020;12:16, doi:10.1186 / s13073-020-0714-y; Niemela et al. Blood. 2011;117(10):2883-6, doi:10.1182 / blood-2010-07-295501; Nosan et al. Croat Med J. 2013, 54(6):574-578, doi:10.3325 / cmj.2013.54.574; and Messina et al. Small GTPases 11.5(2020):312-319, 10.1080 / 21541248.2018.1502591.

[0264] The phrase "dysregulated expression or activity or levels of the KRAS gene, KRas protein, or any of them" refers to a genetic mutation (e.g., a mutation in the KRAS gene that results in the expression of a KRas protein comprising at least one amino acid deletion compared to the wild-type KRas protein, a mutation in the KRAS gene that results in the expression of a KRas protein having one or more point mutations compared to the wild-type KRas protein, a mutation in the KRAS gene that results in the expression of a KRas protein having at least one inserted amino acid compared to the wild-type KRas protein, a gene duplication that results in an increased level of the KRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of the KRas protein in a cell), an alternatively spliced ​​version of KRas mRNA that results in a KRas protein having at least one amino acid deletion in the KRas protein compared to the wild-type KRas protein, or an increased expression (e.g., increased levels) of wild-type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As one example, the dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them can be a mutation in the KRAS gene that encodes a KRas protein with reduced GTPase activity and / or increased signaling activity compared to a protein encoded by a KRAS gene that does not contain the mutation. As another example, the dysregulation of the expression, activity, or level of the KRAS gene, KRas protein, or any of them can be KRas amplification. In some embodiments, the KRas amplification is amplification of wild-type KRas. In some embodiments, the KRas amplification is amplification of mutant KRas.

[0265] As used herein, a "dysregulated KRas protein" refers to (i) a KRas protein having a mutation (e.g., a deletion of at least one amino acid compared to the wild-type KRas protein, one or more point mutations compared to the wild-type KRas protein, or an insertion of at least one amino acid compared to the wild-type KRas protein), (ii) a KRas protein that results, for example, from a gene duplication event of a gene encoding a KRas protein (e.g., a wild-type KRas protein), thus resulting in an increased level and / or activity of the KRas protein (e.g., a wild-type KRas protein) in a cell, (iii) a KRas protein that results from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that may also result in an increased level and / or activity of the KRas protein (e.g., a wild-type KRas protein) in a cell, or (iv) a KRas protein that results in a KRas protein having a deletion of at least one amino acid in the KRas protein compared to the wild-type KRas protein. (v) refers to a KRas protein resulting from an alternatively spliced ​​version of mRNA, or (v) a KRas protein resulting from increased expression (e.g., increased levels) of wild-type KRas protein in mammalian cells due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). In some embodiments, the dysregulated KRas protein is a dysregulated human KRas protein.

[0266] As used herein, a "mutant KRas protein" refers to a KRas protein that contains substitutions, insertions, deletions, truncations, and / or fusions relative to the wild-type human KRas sequence shown in SEQ ID NO: 1. For example, a mutant human KRas protein contains a substitution at any amino acid position (relative to SEQ ID NO: 1).

[0267] As used herein, "KRas G12X mutant protein" refers to a KRas protein that includes a substitution of glycine at the 12th amino acid position (relative to SEQ ID NO: 1) with any other amino acid.

[0268] As used herein, "KRas G12A mutant protein" refers to a KRas protein containing a glycine to alanine substitution at amino acid position 12 (relative to SEQ ID NO: 1).

[0269] As used herein, a "KRas G12C mutant protein" refers to a KRas protein that contains a glycine to cysteine ​​substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0270] As used herein, "KRas G12D mutant protein" refers to a KRas protein that contains a glycine to aspartic acid substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0271] As used herein, "KRas G12R mutant protein" refers to a KRas protein containing a glycine to arginine substitution at amino acid position 12 (relative to SEQ ID NO: 1).

[0272] As used herein, a "KRas G12S mutant protein" refers to a KRas protein that contains a glycine to serine substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0273] As used herein, a "KRas G12V mutant protein" refers to a KRas protein that contains a glycine to valine substitution at the 12th amino acid position (relative to SEQ ID NO: 1).

[0274] As used herein, "KRas G13X mutant protein" refers to a KRas protein that includes a substitution of glycine at the 13th amino acid position (relative to SEQ ID NO: 1) with any other amino acid.

[0275] As used herein, a "KRas G13C mutant protein" refers to a KRas protein containing a glycine to cysteine ​​substitution at amino acid position 13 (relative to SEQ ID NO: 1).

[0276] As used herein, "KRas G13D mutant protein" refers to a KRas protein that contains a glycine to aspartic acid substitution at the 13th amino acid position (relative to SEQ ID NO: 1).

[0277] As used herein, a "KRas G13V mutant protein" refers to a KRas protein that contains a glycine to valine substitution at the 13th amino acid position (relative to SEQ ID NO: 1).

[0278] As used herein, "KRas Q61X mutant protein" refers to a KRas protein that contains a substitution of glutamine at amino acid position 61 (relative to SEQ ID NO: 1) with any other amino acid.

[0279] As used herein, "KRas Q61E mutant protein" refers to a KRas protein containing a glutamine to glutamic acid substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0280] As used herein, "KRas Q61H mutant protein" refers to a KRas protein containing a glutamine to histidine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0281] As used herein, "KRas Q61K mutant protein" refers to a KRas protein containing a glutamine to lysine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0282] As used herein, "KRas Q61L mutant protein" refers to a KRas protein containing a glutamine to leucine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0283] As used herein, "KRas Q61P mutant protein" refers to a KRas protein containing a glutamine to proline substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0284] As used herein, "KRas Q61R mutant protein" refers to a KRas protein containing a glutamine to arginine substitution at amino acid position 61 (relative to SEQ ID NO: 1).

[0285] As used herein, a "KRas inhibitor" includes any compound that exhibits KRas protein inactivation activity (e.g., inhibits or reduces KRas signaling activity). In some embodiments, the KRas inhibitors described herein have an IC of 1 μM or less in the nucleotide exchange assay described herein. 50 value, IC of 1 μM or less in the Raf kinase interaction assay described herein 50In some embodiments, the KRas inhibitor inhibits the signaling activity of a wild-type KRas protein. In some embodiments, the KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein, resulting in a decrease in other downstream effectors, such as activated Raf or ERK. In some embodiments, the KRas inhibitor inhibits the signaling activity of a mutant KRas protein. In some embodiments, the KRas inhibitor inhibits both the signaling activity of a wild-type KRas protein and the signaling activity of one or more mutant KRas proteins and may be referred to as a "pan-KRas inhibitor." In some embodiments, the KRas inhibitor inhibits one or more mutant KRas proteins, and such a KRas inhibitor may be referred to as a "mutant KRas inhibitor" or by the mutant it inhibits. For example, a KRas inhibitor that inhibits a KRas G12R mutant protein may be referred to as a "KRas G12R inhibitor." As another example, a KRas inhibitor that inhibits both KRas G12C and KRas G12D mutant proteins may be referred to as a "KRas G12C inhibitor" and / or a "KRas G12D inhibitor." In some embodiments, a "mutant KRas inhibitor" inhibits more than one mutant KRas protein and may be referred to as a "pan-mutant KRas inhibitor." In some embodiments, the pan-mutated KRas inhibitor inhibits two or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.For example, a "KRas G12X inhibitor" may inhibit two or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, and a KRas G12V mutant protein. As yet another example, a KRas inhibitor that inhibits a KRas G13D mutant protein may be referred to as a "KRas G13D inhibitor." In some embodiments, a KRas inhibitor may inhibit a KRas protein having one or more mutations, and such a KRas inhibitor may be referred to as a "mutant KRas inhibitor," regardless of whether the mutant KRas inhibitor also inhibits a wild-type KRas protein. In some embodiments, the KRas inhibitor is a mutant KRas inhibitor. In some embodiments, the KRas inhibitor is an allosteric inhibitor.

[0286] Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula ( A compound of Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof, is a KRas inhibitor. In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof, is a mutant KRas inhibitor.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, or a combination thereof. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of Formula IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12R mutant protein, KRas G12V mutant protein, or both. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12V mutant protein.

[0287] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of Formula IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof is a KRas G12X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits four or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits five or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits four or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRAS G12V mutant protein, or both.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12A mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12C mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof does not inhibit KRas G12C mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof does not inhibit KRas G12D mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12S mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12V mutant protein.

[0288] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of Formula IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof is a KRas G13X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G13C mutant protein, KRas G13D mutant protein, and KRas G13V mutant protein.In some embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (I The compound of formula (V) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G13C mutant protein, KRas G13D mutant protein, and KRas G13V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G13C mutant protein, KRas G13D mutant protein, and KRas G13V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G13C mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G13D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G13V mutant protein.

[0289] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of Formula IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof is a KRas Q61X inhibitor. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits four or more mutant KRas proteins selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits five or more mutant KRas proteins selected from the group consisting of KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61E mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61K mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61P mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas Q61R mutant protein.

[0290] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2) ), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant human KRas proteins selected from the group consisting of KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12X mutant protein, KRas G13X mutant protein, and KRas Q61X mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and mutant KRas Q61R protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits four or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof, KRas Five or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. It inhibits KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. It inhibits KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and KRas Q61R mutant protein.

[0291] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12V mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), The compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) ( For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, is useful for treating bladder cancer.

[0292] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2) ), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2) ), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2) ), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12V mutant protein, and KRas G13D mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), The compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both.In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) ( For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, is useful for treating cervical cancer.

[0293] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof, is useful for treating colorectal cancer.

[0294] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2) ), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof, is a KRas The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein.In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof, is useful for treating endometrial cancer.

[0295] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, and KRas Q61H mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein, KRas G12V mutant protein, or both.In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof is useful for treating esophageal cancer or gastric cancer.

[0296] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13V mutant protein, a KRas Q61E mutant protein, a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61E mutant protein, KRas Q61H mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, KRas Q61P mutant protein, and mutant KRas Q61R protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof is useful for treating leukemia.

[0297] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G13D mutant protein, KRas G13V mutant protein, KRas Q61K mutant protein, KRas Q61L mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)), or a pharmaceutically acceptable salt thereof, is useful for inhibiting KRas G12C mutant protein, KRas G12D mutant protein, and KRas In some embodiments, the compound of formula (I) (e.g., formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), formula (II) (e.g., formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), formula (III) (e.g., , Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12C mutant protein, KRas G12D mutant protein, and KRas G12R mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas G12D mutant protein and KRas G12R mutant protein, or both.In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) ( For example, a compound of formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, is useful for treating melanoma.

[0298] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas G13D mutant protein, KRas Q61H mutant protein, and KRas Q61L mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula (IV-a), (IV-b) , (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))) or a pharmaceutically acceptable salt thereof inhibits KRasG12A mutant protein, KRasG12D mutant protein, and KRasG12V mutant protein.In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) (e.g., Formula The compounds of Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, are useful for treating lung cancer (e.g., non-small cell lung cancer).

[0299] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The present invention inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, KRas G12V mutant protein, KRas G13C mutant protein, KRas Q61H mutant protein, and KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12C mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), The compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12D mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some such embodiments, the compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula (IV) ( For example, a compound of Formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or Formula (V) (e.g., Formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or Formula (VI) (e.g., Formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e))), or a pharmaceutically acceptable salt thereof, is useful for treating pancreatic cancer.

[0300] In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits one or more mutant KRas proteins selected from the group consisting of a G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits two or more mutant KRas proteins selected from the group consisting of a G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula (IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits KRas. The compound inhibits three or more mutant KRas proteins selected from the group consisting of a G12A mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, a KRas G12V mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( A compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits two or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits three or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, KRas G12S mutant protein, and KRas G12V mutant protein.In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2), (I-b3), (I-b4), (I-b5), or (I-c1)), Formula (II) (e.g., Formula (II-a), (II-b), (II-a1), (II-b1), (II-a2), or (II-b2)), Formula (III) (e.g., Formula (III-1) or (III-2)), Formula ( The compound of formula IV) (e.g., formula (IV-a), (IV-b), (IV-c), (IV-a1), (IV-b1), (IV-a2), or (IV-b2)), or formula (V) (e.g., formula (Va) or (Vb), (V-a1), (Vc), (Vd), (V-b1), (V-a2), or (V-b2)), or formula (VI) (e.g., formula (VI-a), (VI-b), (VI-c), (VI-d), or (VI-e)) or a pharmaceutically acceptable salt thereof inhibits one or more mutant KRas proteins selected from the group consisting of KRas G12A mutant protein, KRas G12R mutant protein, and KRas G12V mutant protein. In some embodiments, a compound of Formula (A) (e.g., Formula (I) (e.g., Formula (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b1), (I-b2)...

Claims

1. Formula (III): or a pharmaceutically acceptable salt thereof: During the ceremony, R １ teeth, (i) 1 to 4 R ７ 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl is selected from C(=O)NH and S(O) ２ NH, and said heterocyclyl has 1 to 3 R ７ 8- to 12-membered bicyclic heterocyclyl, optionally further substituted by (iii) (Wherein b2 is 0, 1, 2, or 3; A １ and A ２ are N, CH, and CR ７ (independently selected from the group consisting of is selected from the group consisting of Each R ７ is R ａ and R ｂ are independently selected from the group consisting of X １ is a bond, S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At most one of O and S(O) ０～２ is selected from the group consisting of R ９ , H, NR ｄ R ｅ , —OH, and halo; b4 is 0 or 1; Each R １０ is R ａ and R ｂ are independently selected from the group consisting of Each R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

2. R ９ Ga-NH ２ and each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ 10. The compound of claim 1, wherein each of the aryl groups is independently selected from the group consisting of alkyl.

3. Formula (II): or a pharmaceutically acceptable salt thereof: During the ceremony, R １ teeth, (i) 1 to 4 R ７ 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl is selected from C(=O)NH and S(O) ２ NH, and said heterocyclyl has 1 to 3 R ７ 8- to 12-membered bicyclic heterocyclyl, optionally further substituted by (iii) (Wherein b2 is 0, 1, 2, or 3; A １ and A ２ are N, CH, and CR ７ (independently selected from the group consisting of is selected from the group consisting of Each R ７ is R ａ and R ｂ are independently selected from the group consisting of X １ is a bond, S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At most one of O and S(O) ０～２ is selected from the group consisting of b1 is 1 or 2; Each R １０ is R ａ and R ｂ are independently selected from the group consisting of Each R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

4. The compound has the formula (II-a): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (II-b): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound of claim 3.

5. X １ But CH ２ or CHR Ｌ The compound according to any one of claims 1 to 4,

6. X ２ and X ３ But CH ２ , CHR Ｌ , and C(R Ｌ ) ２ The compound of any one of claims 1 to 5, independently selected from the group consisting of:

7. X １ is CH ２ and X ２ and X ３ Both are CH ２ is, or X １ , X ２ , and X ３ At least one (e.g., one) of Ｌ and C(R Ｌ ) ２ or X １ is CH ２ and X ２ and X ３ But CH ２ , CHR Ｌ , and C(R Ｌ ) ２ are independently selected from the group consisting of: ２ and X ３ One or two of these are independent, CHR Ｌ or C(R Ｌ ) ２ is, or X １ is CH ２ and X ２ is CH ２ and X ３ is CHR Ｌ That is, The compound according to any one of claims 1 to 6.

8. X ２ and X ３ is —O—, and X ２ and X ３ The other is CH ２ , CHR Ｌ , and C(R Ｌ ) ２ is selected from the group consisting of Optionally, X ２ is —O—, and X ３ But CH ２ , CHR Ｌ , and C(R Ｌ ) ２ selected from the group consisting of The compound according to any one of claims 1 to 5.

9. Each R Ｌ But CH ３ , C.F. ３ , CHF ２ , and C.H. ２ The compound of any one of claims 1 to 8, independently selected from the group consisting of F.

10. A part comprising: wherein: b4 is 0 or 1; X ２ is —O— or —CH ２ - and X ３ But -CH ２ -or-CHR Ｌ -, where R Ｌ is C １～３ alkyl (e.g., methyl), and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, Optionally, The part is, selected from the group consisting of The compound of claim 3.

11. Formula (IV): or a pharmaceutically acceptable salt thereof: During the ceremony, X １ is a bond, S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At least one of the following is CHR Ｌ or C(R Ｌ ) ２ and Furthermore, however, X １ , X ２ , and X ３ At most one of O and S(O) ０～２ is selected from the group consisting of b1 is 0, 1, or 2; R ９ is H, OH, NR ｄ R ｅ and halo; Each R １０ is R ａ and R ｂ are independently selected from the group consisting of Each R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R １ teeth, (i) 1 to 4 R ７ 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl is selected from C(=O)NH and S(O) ２ NH, and said heterocyclyl has 1 to 3 R ７ 8- to 12-membered bicyclic heterocyclyl, optionally further substituted by (iii) (Wherein b2 is 0, 1, 2, or 3; A １ and A ２ are N, CH, and CR ７ (independently selected from the group consisting of is selected from the group consisting of Each R ７ is R ａ and R ｂ are independently selected from the group consisting of Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

12. The compound has the formula (IV-a): or a pharmaceutically acceptable salt thereof, wherein Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (IV-b): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (IV-c): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound of claim 11.

13. Formula (V): or a pharmaceutically acceptable salt thereof: During the ceremony, X １ is a bond, S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ Two or three of these are CHR independently. Ｌ or C(R Ｌ ) ２ and A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, and Each additional R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, b1 is 0, 1, or 2; R ９ is H, OH, NR ｄ R ｅ and halo; Each R １０ is R ａ and R ｂ are independently selected from the group consisting of R １ teeth, (i) 1 to 4 R ７ 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl is selected from C(=O)NH and S(O) ２ NH, and said heterocyclyl has 1 to 3 R ７ 8- to 12-membered bicyclic heterocyclyl, optionally further substituted by (iii) (Wherein b2 is 0, 1, 2, or 3; A １ and A ２ are N, CH, and CR ７ (independently selected from the group consisting of is selected from the group consisting of Each R ７ is R ａ and R ｂ are independently selected from the group consisting of Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

14. The compound has the formula (V-a): or a pharmaceutically acceptable salt thereof, wherein Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (IV-b): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound represented by formula (V-c) or (V-d): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R Ｌ１ said pair together with the ring atoms connecting them form a C ３～４ forming a cycloalkyl ring, and R Ｌ２ is C optionally substituted with 1 to 3 F １～２ is alkyl, The compound of claim 13.

15. Y ２ Ga-CH ２ - and R ３ is a 4- to 10-membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, said heterocyclyl being selected from 1-6 R ａ and optionally, R ３ teeth, (for example, 15. The compound according to any one of claims 1 to 14, wherein

16. R １ but wherein b2 is 0, 1, or 2; １ and A ２ N, CH, and CR ７ or independently selected from the group consisting of R １ but, That is, A compound according to any one of claims 1 to 15.

17. R １ but and R ７ C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ The compound according to any one of claims 1 to 16, selected from the group consisting of:

18. R ７ but, (a) C(=O)N(R ｆ ) ２ (In the formula, each R ｆ are independently H or 1 to 3 R ｈ C optionally substituted with １～３ alkyl); (b)C(O)N(C １～３ alkyl)R ｂ１ or -C(O)N(H)R ｂ１ (In the formula, R ｂ１ is C ３～６ cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R ｇ and (c) C(O)R ｂ１ (In the formula, R ｂ１ is 1 to 3 R ｇ 4-10 membered heterocyclyl optionally substituted by R ｂ１ is attached to C(O) through a ring nitrogen atom) or optionally, R ７ is C(=O)N(R ｆ ) ２ where each R ｆ are independently H or 1 to 3 R ｈ C optionally substituted with １～３ 18. The compound of claim 17, wherein the compound is alkyl.

19. R １ but wherein R ７ａ and R ７ｂ are independently selected R ７ The compound according to any one of claims 1 to 16,

20. R ７ａ C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ and R ７ｂ is -halo, -CN, and 1 to 3 R ｃ C optionally substituted with １～３ is alkyl, or R ７ａ but, (a) C(=O)N(R ｆ ) ２ (In the formula, each R ｆ are independently H or 1 to 3 R ｈ C optionally substituted with １～３ alkyl); (b)C(O)N(C １～３ alkyl)R ｂ１ or -C(O)N(H)R ｂ１ (In the formula, R ｂ１ is C ３～６ cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R ｇ and (c) C(O)R ｂ１ (In the formula, R ｂ１ is 1 to 3 R ｇ 4-10 membered heterocyclyl optionally substituted by R ｂ１ is attached to C(O) through a ring nitrogen atom) selected from the group consisting of 20. The compound of claim 19.

21. R １ is a 7-10 (e.g., 7) membered heterocyclyl having one ring nitrogen atom, one ring oxygen atom, and no additional ring heteroatoms, wherein said 7-10 membered heterocyclyl is selected from 1-4 R ７ The compound according to any one of claims 1 to 15, optionally substituted with

22. R １ has 1 to 4 R at one or more ring carbon atoms ７ may be substituted with (e.g., R １ teeth 22. The compound of claim 21 , wherein

23. Each R ７ is —OH, —CN, —F, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, In the formula, each R ｃ are independently selected from the group consisting of —F, —OH, and —CN; 23. The compound of claim 22.

24. The compound has the formula (III-1): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X １ is CH ２ and X ２ and X ３ is O, CH ２ , CHR Ｌ , and C(R Ｌ ) ２ Independently selected from the group consisting of: The compound of claim 1.

25. R ９ But NR ｄ R ｅ (For example, -NH ２ 25. The compound of claim 24, wherein

26. The compound has the formula (II-a1) or (II-b1): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X １ is CH ２ and X ２ and X ３ is O, CH ２ , CHR Ｌ , and C(R Ｌ ) ２ Independently selected from the group consisting of: The compound of claim 3.

27. The compound has the formula (IV-a1) or (IV-b1): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; b1 is 0, 1, or 2; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X １ is CH ２ and X ２ and X ３ One of them is CHR Ｌ and C(R Ｌ ) ２ and X ２ and X ３ The other is CH ２ or O, The compound of claim 11.

28. X ２ is CH ２ and X ３ is CHR Ｌ 28. The compound of claim 27, wherein:

29. The compound has the formula (V-a1) or (V-b1): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; b1 is 0, 1, or 2; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, b3 is 0, 1, 2, or 3; X ２ is —O— or —CH ２ - and X １ is CHR Ｌ and X ３ is CHR Ｌ or C(R Ｌ ) ２ where: A pair of R on different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～４ forming a cycloalkyl ring, and If present, the remaining R Ｌ is C optionally substituted with 1 to 3 F １～２ is alkyl, The compound of claim 13.

30. b3 is 0 or b3 is 1 or 2, and each R ７ is —OH, —CN, —F, and 1 to 3 R ｃ C optionally substituted with １～３ alkyl, wherein each R ｃ is independently selected from the group consisting of -F, -OH, and -CN.

31. The compound has the formula (III-2): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R ７ is C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ is selected from the group consisting of X １ is CH ２ and X ２ and X ３ is O, CH ２ , CHR Ｌ , and C(R Ｌ ) ２ Independently selected from the group consisting of: The compound of claim 1.

32. R ９ But NR ｄ R ｅ (For example, -NH ２ 32. The compound of claim 31 , wherein

33. The compound has the formula (II-a2) or (II-b2): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R ７ is C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ is selected from the group consisting of X １ is CH ２ and X ２ and X ３ is O, CH ２ , CHR Ｌ , and C(R Ｌ ) ２ Independently selected from the group consisting of: The compound of claim 3.

34. The compound has the formula (IV-a2) or (IV-b2): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; b1 is 0, 1, or 2; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R ７ is C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ is selected from the group consisting of X １ is CH ２ and X ２ and X ３ One of them is CHR Ｌ and C(R Ｌ ) ２ and X ２ and X ３ The other is CH ２ or O, The compound of claim 11.

35. X ２ is CH ２ and X ３ is CHR Ｌ 35. The compound of claim 34, wherein:

36. The compound has the formula (V-a2) or (V-b2): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1; b1 is 0, 1, or 2; Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, R ７ is C(=O)N(R ｆ ) ２ , C(O)N(C １～３ alkyl)R ｂ１ , -C(O)N(H)R ｂ１ , R ｂ１ , and C(O)R ｂ１ is selected from the group consisting of X ２ is —O— or —CH ２ - and X １ is CHR Ｌ and X ３ is CHR Ｌ or C(R Ｌ ) ２ where: A pair of R on different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～４ forming a cycloalkyl ring, and If present, the remaining R Ｌ is C optionally substituted with 1 to 3 F １～２ is alkyl, The compound of claim 13.

37. R ７ but, (a) C(=O)N(R ｆ ) ２ (In the formula, each R ｆ are independently H or 1 to 3 R ｈ C optionally substituted with １～３ alkyl); (b)C(O)N(C １～３ alkyl)R ｂ１ or -C(O)N(H)R ｂ１ (In the formula, R ｂ１ is C ３～６ cycloalkyl or 4- to 6-membered heterocyclyl, each of which is selected from 1 to 3 R ｇ and (c) C(O)R ｂ１ (In the formula, R ｂ１ is 1 to 3 R ｇ 4-10 membered heterocyclyl optionally substituted by R ｂ１ is attached to C(O) through a ring nitrogen atom) The compound of any one of claims 31 to 36, selected from the group consisting of:

38. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (III) is selected from the group consisting of compound numbers 158, 158a, 158b, 158c, 161, 161a, 161b, 161c, 176, 176a, 176b, 176c, 176d, 176e, 177, 177a, 178, 178a, 178b, 179, 179a, 179b, 179d, 179e, 179f, 180, 180a, 180b, 180c, 184, 184b, 184c, 192, 192a, 192b, 192c, 192d, 192e, 194, and 194a, as shown in Table C1.

39. The compounds of formula (II) are compound numbers 139, 139a, 139b, 139c, 158, 158a, 158b, 158c, 160, 160a, 161, 161a, 161b, 161c, 164, 164a, 164b, 170, 170a, 171, 171a, 171b, 171c, 176, 176a, 176b, 176c, 176d, 176e, 178, 178a, 178b, 179, 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, selected from the group consisting of 179a, 179b, 179d, 179e, 179f, 180, 180a, 180b, 180c, 181, 181a, 183, 183a, 185, 185a, 190, 190a, 190b, 190c, 191, 191a, 191b, 191c, 191d, 192, 192a, 192b, 192c, 192d, and 192e.

40. The compound of formula (IV) is compound Nos. 124, 124a, 124b, 124c, 124d, 124e, 124f, 125, 125a, 130, 130a, 130b, 130c, 131, 131a, 131b, 133, 133a, 133b, 133c, 134, 134a, 138, 138a, 148, 148a, 162, 162a, 162b, 162c, 162d, 162e, 162f, 162f, 162g, 162h, 162h, 162i, 162j, 162j, 162j, 162j, 162k ...

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 163a, 163b, 175, 175a, 176, 176a, 176b, 176c, 176d, 176e, 177, 177a, 178, 178a, 178b, 179, 179a, 179b, 179d, 179e, 179f, 182, 182a, 182b, 182c, 182d, 193, and 193a.

41. 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (V) is selected from the group consisting of compound numbers 172, 172a, 172b, and 172c shown in Table C1.

42. Formula (VI): or a pharmaceutically acceptable salt thereof: During the ceremony, R １ represents -CN, -(C １～３ alkylene)-CN, or -(C ３～６ 4-10 membered heterocyclyl substituted with 1-3 R ７ may be further substituted with Here, each R ７ is R ａ and R ｂ are independently selected from the group consisting of X １ is S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At most one of O and S(O) ０～２ is selected from the group consisting of b1 is 0, 1, or 2; R ９ , H, NR ｄ R ｅ , —OH, and halo; Each R １０ is R ａ and R ｂ are independently selected from the group consisting of Each R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

43. R １ is -CN or -(C １～３ alkylene)-CN, wherein the heterocyclyl is substituted with 1 to 3 R ７ and optionally further substituted with R １ is -CN or -(C １～３ alkylene)-CN substituted 6-8 membered heterocyclyl, the heterocyclyl has one ring nitrogen atom and 0 to 1 ring oxygen atoms, and The heterocyclyl is selected from 1 to 3 R ７ and optionally, each R ７ is —OH, —CN, —F, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, 43. The compound of claim 42.

44. R １ but, 44. The compound of claim 42 or 43, wherein b3 is selected from the group consisting of:

45. Each R ７ are independently —OH, —CN, —F, and 1 to 3 R ｃ C optionally substituted with １～３ Alkyl (e.g., C optionally substituted with 1 to 3 —F) １～３ 45. The compound of claim 44, wherein the compound is selected from the group consisting of: alkyl.

46. 46. ​​The compound of claim 44 or 45, wherein b3 is 0.

47. R ９ But, -NR ｄ R ｅ or OH (e.g., —NH ２ 47. The compound according to any one of claims 42 to 46, wherein

48. The compound of formula (VI) may be a compound of formula (VI-a): or a pharmaceutically acceptable salt thereof, wherein Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound of formula (VI) may be a compound of formula (VI-b): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound of formula (VI) may be a compound of formula (VI-c): or a pharmaceutically acceptable salt thereof, wherein b4 is 0 or 1, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (VI-d): or a pharmaceutically acceptable salt thereof, wherein X １ is S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At least one of the following is CHR Ｌ or C(R Ｌ ) ２ and Furthermore, however, X １ , X ２ , and X ３ At most one of O and S(O) ０～２ and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound has the formula (VI-e): or a pharmaceutically acceptable salt thereof, wherein X １ is S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ Two or three of these are CHR independently. Ｌ or C(R Ｌ ) ２ and A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, and Each additional R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ alkyl, and Each R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, The compound according to any one of claims 42 to 47.

49. 43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (VI) is selected from the group consisting of compound numbers 149, 149a, 149b, 149c, 173, 173a, 174, 174a, 186, 186a, 186b, 186c, 187a, 187a, 188, 188a, 189, 189a, 191, 191a, 191b, 191c, 191d, 192, 192a, 192b, 192c, 192d, 192e, 195, and 195a shown in Table C1.

50. Y ２ Ga-CH ２ - and R ３ is a 4- to 10-membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatoms selected from the group consisting of oxygen and nitrogen, wherein said heterocyclyl is selected from 1-6 R ａ and optionally, R ３ but, (for example, 50. The compound according to any one of claims 24 to 37 or 42 to 49, wherein

51. A portion comprising:

51. The compound of any one of claims 1 to 37, 42 to 48, or 50, wherein

52. 52. A pharmaceutical composition comprising a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

53. 52. A method for treating a KRas-associated cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52.

54. 52. A method for treating a KRas-associated cancer in a subject in need thereof, comprising: (a) determining that the cancer in the subject has KRas dysregulation; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52.

55. 52. A method of treating a KRas-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a cancer with KRas dysregulation a therapeutically effective amount of a compound of any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 52.

56. 1. A method of treating a KRas-associated cancer in a subject, comprising: (a) determining that the cancer in the subject has KRas dysregulation; (b) administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 52; The method comprising:

57. The method of any one of claims 53 to 56, wherein the KRas-associated cancer is a mutant KRas-associated cancer.

58. the mutant KRas-associated cancer is a KRas G12A-associated cancer, a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12R-associated cancer, a KRas G12S-associated cancer, or a KRas G12V-associated cancer; or the mutant KRas-associated cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer; or the mutant KRas-associated cancer is a KRas G12D-associated cancer; or the mutant KRas-associated cancer is a KRas G12R-associated cancer; or The mutant KRas-associated cancer is a KRas G12V-associated cancer.

58. The method of claim 57.

59. 57. The method of any one of claims 54 or 56, wherein the step of determining that the cancer in the subject has KRas dysregulation comprises performing an assay to detect the KRas dysregulation (e.g., KRas mutation) in a tumor sample from the subject.

60. 60. The method of claim 59, wherein detecting the KRas dysregulation comprises detecting a KRAS gene having a mutation corresponding to a substitution of glycine 12 in the KRas protein and / or a KRas protein having a substitution of glycine 12.

61. the substitution of glycine 12 is with alanine, cysteine, aspartic acid, arginine, serine, or valine; or the substitution of glycine 12 with aspartic acid; or the substitution of glycine 12 with arginine; or the substitution of glycine 12 with valine; 61. The method of claim 60.

62. the KRas-associated cancer is selected from the group consisting of blood cancer, soft tissue cancer, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, gastric cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and combinations thereof; Optionally, the KRas-associated cancer is pancreatic cancer. Optionally, the KRas-associated cancer is selected from the group consisting of blood cancer, brain cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, gastric cancer, thymic cancer, urothelial cancer, and uterine cancer. Optionally, the KRas-associated cancer is selected from the group consisting of blood cancer, bladder cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous cancer, ovarian cancer, pancreatic cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer (e.g., seminoma), thymic cancer, and uterine cancer; or Optionally, the KRas-associated cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal or gastric cancer, leukemia, lung cancer (e.g., NSCLC), pancreatic cancer, and renal cancer.

62. The method of any one of claims 53 to 61.

63. 63. The method of any one of claims 53 to 62, comprising administering an additional therapy or therapeutic agent to the subject.

64. 64. The method of claim 63, wherein the additional therapy or therapeutic agent is selected from the group consisting of a Ras pathway targeted therapeutic agent, a kinase targeted therapeutic agent, an mTORC1 inhibitor or degrader, a YAP inhibitor or degrader, a proteasome inhibitor or degrader, an HSP90 inhibitor or degrader, a farnesyltransferase inhibitor or degrader, a PTEN inhibitor or degrader, a signal transduction pathway inhibitor or degrader, a checkpoint inhibitor, a modulator of an apoptosis pathway, a chemotherapeutic agent, an angiogenesis targeted therapy, an immune targeting agent, radiation therapy, and combinations thereof.

65. Formula (SII-a2), (SIV-a2), (SV-a2), (SVI-a2), or (SVII-a2): or a salt thereof: During the ceremony, ns is 0, 1, or 2; R Ｓ is R ｃ and R ｂ１ C optionally substituted with 1 to 3 substituents independently selected from the group consisting of １～６ is alkyl, R １１ is NH ２ , NHPg, and N(Pg) ２ is selected from the group consisting of R １１ａ is NHPg and N(Pg) ２ is selected from the group consisting of each Pg is an independently selected nitrogen protecting group; R １２ is selected from the group consisting of halo (e.g., —Br) and CN; b4 is 0 or 1; R １０ is —Cl, —F, —CN, and 1 to 3 R ｃ C optionally substituted with １～３ is selected from the group consisting of alkyl, X １ is a bond, S(O) ０～２ , C.H. ２ , CHR Ｌ , C(R Ｌ ) ２ and O; X ２ and X ３ is CH ２ , CHR Ｌ , C(R Ｌ ) ２ , O, and S(O) ０～２ are independently selected from the group consisting of: １ , X ２ , and X ３ At most one of O and S(O) ０～２ is selected from the group consisting of Each R Ｌ is C １～３ Alkoxy, —F, CN, and 1 to 3 R ｃ C optionally substituted with １～３ independently selected from the group consisting of alkyl, A pair of R on the same or different ring carbon atoms Ｌ together with the ring atoms that connect them form C ３～６ forming a cycloalkyl ring, R １ teeth, (i) 1 to 4 R ７ 4- to 10-membered heterocyclyl optionally substituted by (ii) 8- to 12-membered bicyclic heterocyclyl, wherein the heterocyclyl is selected from C(=O)NH and S(O) ２ NH, and said heterocyclyl has 1 to 3 R ７ 8- to 12-membered bicyclic heterocyclyl, optionally further substituted by (iii) (Wherein b2 is 0, 1, 2, or 3; A １ and A ２ are N, CH, and CR ７ (independently selected from the group consisting of is selected from the group consisting of Each R ７ is R ａ and R ｂ are independently selected from the group consisting of Y ２ is a bond or 1 to 6 R Ｙ A linear C optionally substituted with １～６ is alkylene, Each R Ｙ is halo, cyano, -OH, oxo, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Alkyl, and C １～６ haloalkyl; A pair of R on the same or different carbon atoms Ｙ together with the atoms that connect them form C ３～６ Form a cycloalkyl ring or a 4- to 6-membered heterocyclyl ring, each of which is selected from 1 to 3 independently selected C １～３ may be substituted with alkyl, R ３ teeth, (a) R ａ and R ｂ a 4- to 15-membered heterocyclyl optionally substituted with 1 to 6 substituents independently selected from the group consisting of: (b)-NR ｄ R ｅ is selected from the group consisting of Each R ａ is independent, (a) halo, (b) cyano, (c) —OH, (d) oxo, (e)-C １～６ Alkoxy, (f)-C １～６ haloalkoxy, (g)-NR ｄ R ｅ 、 (h) C(=O)C １～６ Alkyl, (i) C(=O)C １～６ haloalkyl, (j)C(=O)OH, (k)C(=O)OC １～６ Alkyl, (l)C(=O)OC １～６ haloalkyl, (m)C(=O)N(R ｆ ) ２ 、 (n) S(O) ０～２ (C １～６ alkyl), (o)S(O) ０～２ (C １～６ haloalkyl), (p)S(O) １～２ N (R ｆ ) ２ , and (q) 1 to 6 R ｃ C, each of which may be substituted with １～６ Alkyl, C ２～６ Alkenyl, or C ２～６ Alkynyl is selected from the group consisting of Each R ｂ Is -(L ｂ ) ｂ -R ｂ１ and -R ｂ１ and independently selected from the group consisting of: b is 1, 2, or 3; Each -L ｂ is -O-, -N(H)-, -N(C １～３ alkyl)-, -S(O) ０～２ -, C(=O), and C １～３ alkylene; and Each R ｂ１ is C ３～１０ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１０ aryl, and 5- to 10-membered heteroaryl, each of which is independently selected from the group consisting of 1 to 3 R ｇ may be substituted with Each R ｃ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NR ｄ R ｅ , C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)OH, C(=O)N(R ｆ ) ２ , S(O) ０～２ (C １～６ alkyl), S(O) ０～２ (C １～６ haloalkyl), and S(O) １～２ N (R ｆ ) ２ are independently selected from the group consisting of Each R ｄ and R ｅ is H, C(=O)C １～６ Alkyl, C(=O)C １～６ Haloalkyl, C(=O)OC １～６ Alkyl, C(=O)OC １～６ Haloalkyl, C(=O)N(R ｆ ) ２ , S(O) １～２ (C １～６ alkyl), S(O) １～２ (C １～６ haloalkyl), S(O) １～２ N (R ｆ ) ２ , and 1 to 3 R ｈ C optionally substituted with １～６ independently selected from the group consisting of alkyl, Each R ｆ is H and 1 to 3 R ｈ C optionally substituted with １～６ alkyl; and Each R ｇ is R ｈ , C １～３ Alkyl, C １～３ Haloalkyl, C ３～５ independently selected from the group consisting of cycloalkyl, and 4- to 5-membered heterocyclyl; and Each R ｈ is halo, cyano, -OH, -C １～６ Alkoxy, -C １～６ Haloalkoxy, —NH ２ , -N(H)(C １～３ alkyl), and —N(C １～３ alkyl) ２ - are independently selected from the group consisting of:

66. Any of the foregoing compounds, compositions, combinations, pharmaceutical compositions, methods, uses and processes substantially as provided herein.

Images