Macrocyclic heterocycles and uses thereof

Abstract

The present disclosure provides compounds and pharma- ceutically acceptable salts thereof, and methods of use thereof. The compounds and methods have a wide range of applications as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing the signaling output of oncogenic proteins. In certain aspects, the present disclosure provides a compound described herein, or a pharma- ceutically acceptable salt or solvate. In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt or solvate, and a pharma- ceutically acceptable excipient.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 332,794, filed April 20, 2022, U.S. Provisional Patent Application No. 63 / 404,482, filed September 7, 2022, and U.S. Provisional Patent Application No. 63 / 486,922, filed February 24, 2023, each of which is incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format, and is incorporated herein by reference in its entirety. The XML copy, created on April 18, 2023, is named 56690_748_601_SL.xml and is 7,953 bytes in size. [Background technology]

[0003] Cancer (e.g., tumors, neoplasms, metastases) is the second leading cause of death worldwide and is estimated to be responsible for approximately 10 million deaths each year. Many types of cancer harbor mutations in one or more proteins involved in various signaling pathways, leading to the uncontrolled proliferation of cancer cells. In some cases, approximately 25–30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations.

[0004] Activated by guanine nucleotide exchange factors (GEFs), Ras in its GTP-bound state interacts with many effectors. Reversion to an inactive state is driven by GTPase-activating proteins (GAPs), which downregulate active Ras by accelerating weak intrinsic GTPase activity. However, for oncogenic Ras mutants, GAP activity is impaired or greatly reduced, resulting in sustained activation and driving oncogenic Ras signaling, for example, through the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT pathways, both of which are essential for cell survival and proliferation.

[0005] The most studied GEF for Ras is the Son of Sevenless (SOS) protein, which has two known human isoforms, SOS1 and SOS2. SOS1 is the human homolog of the first identified Drosophila protein, Son of Sevenless. SOS1 has two binding sites for Ras proteins: a catalytic site that binds to GDP-bound Ras proteins and promotes guanine nucleotide exchange, and an allosteric site that binds to GTP-bound Ras proteins, further promoting Ras protein activation. Son of Sevenless 2 (SOS2) is the mammalian homolog of SOS1. Double knockout of SOS1 and SOS2 leads to rapid lethality in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). Ras proteins have long been considered "undruggable," in part due to their high affinity for their substrate, guanosine-5'-triphosphate (GTP), and / or their smooth surface with no obvious target region. The specific G12C Ras gene mutation has been identified as a druggable target, and numerous G12C-specific inhibitors have been developed. However, because the G12C mutation in Ras exhibits a much lower prevalence than other known Ras mutations, including G12D and G12V, such therapeutics remain limited in their application. Drug resistance and lack of durability pose further limitations to such therapeutics. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Baltanas et al.,Mol.Cell.Biol.,2013,33(22):4562-78 Summary of the Invention

[0007] In view of the foregoing, there remains a significant need for new designs of therapeutics and diagnostics that can specifically inhibit Ras pathway signaling, for example, by inhibiting GEFs such as SOS proteins. Such compositions and methods may be particularly useful for treating a variety of diseases, including, but not limited to, cancer and neoplastic conditions. The present disclosure addresses these needs and provides further advantages applicable to the diagnosis, prognosis, and treatment of a wide variety of diseases.

[0008] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 optionally substituted with [ka] is absent or C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b ), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R 7 )(R 7a ), and C(O), W 8 is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10 ), and C; R 1 is one or more R 11c C optionally substituted with 1-3 is alkyl, R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11 , R 11a , and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12, -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11c independently in each occurrence, a halogen, -OR 12 , and -N(R 12 )(R 13 ) and R 12independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0009] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 optionally substituted with [ka] is absent or C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b ), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R 5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R7 )(R 7a ), and C(O), W 8 is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10 ), and C; R 1 is one or more R 11c C optionally substituted with 1-3 is alkyl, R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12)(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12)(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11 and R 11a are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12)(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11c independently in each occurrence, a halogen, -OR 12 , and -N(R 12 )(R 13 ) and R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0010] The compound of formula (I) may be a compound of formula (IA): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0011] The compound of formula (I) may be a compound of formula (IB): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0012] The compound of formula (I) may be a compound of formula (IC): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0013] The compound of formula (I) may be prepared by reacting a compound of formula (ID): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0014] The compound of formula (I) may be a compound of formula (IE): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0015] For compounds of formula (I), (IA), (IB), (IC), (ID), or (IE): L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which may be selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 is covalently bonded to one of

[0016] In some embodiments, for a compound of formula (I), (IA), (IB), (IC), (ID), or (IE): [ka] is C 5-7 cycloalkyl, 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, and phenyl, each of which is selected from one or more R 11 optionally substituted with L 1 is a bond, C 1-2 Alkylene, and C 1-2 haloalkylene; R 1 is one or more R 11c C optionally substituted with 1-2 It is alkyl.

[0017] In some embodiments, for a compound of formula (I), (IA), (IB), (IC), (ID), or (IE): R 7 L 2 Bonds to halogens, -CN, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 7b L 2 Bond to, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 is optionally substituted with

[0018] For compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 may be N. In some embodiments, W 3 is N(R 3b ), N, C(R 3 ), and C(O), for example, W 3 is C(R 3 ) and C(O). In some embodiments, W 4 is N(R 4b ), N, C(R 4 ), and C(O), for example, W4 is N(R 4b ) and N. In some embodiments, W 5 is N(R 5b ), N, C(R 5 ), and C(O), for example, W 5 is N(R 5b ), N, and C(R 5 In some embodiments, W 5 is N(R 5b ) and C(R 5 In some embodiments, W 6 is C(R 6 ) and C(O). In some embodiments, W 7 is C(R 7 In some embodiments, W 8 is C(R 8 ), for example CH. In some embodiments, W 9 is C. In some embodiments, W 10 is C. In some embodiments, W 2 is N and W 3 is N(R 3b ) and W 4 , C(O) and W 9 and W 10 are each C. In some embodiments, W 2 is N and W 3 is C(O) and W 4 is N(R 4b ) and W 9 and W 10 are each C. In some embodiments, W 2 is N and W 3 is C(R 3 ) and W 4 is N and W 9 and W 10 are each C. In some embodiments, W 5 is C(R 5 ) and W 6 is C(R 6 ) and W 7 is C(R 7) and W 8 is C(R 8 ) and W 9 and W 10 are each C. In some embodiments, W 5 is N(R 5b ) and W 6 is C(O) and W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C. In some embodiments, W 5 is N and W 6 is C(R 6 ) and W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C. In some embodiments, W 2 is N and W 3 is N(R 3b ), N, C(R 3 ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), and C(O), W 5 is N(R 5b ), N, and C(R 5 ) and W 6 is C(R 6 ) and C(O), W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C. In some embodiments, W 2 is N and W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W 5 is N(R 5b ) and C(R5 ) and W 6 is C(R 6 ) and C(O), W 7 is C(R 7 ) and W 8 is CH and W 9 and W 10 are each C.

[0019] The compound of formula (IB) may be a compound of formula (I-B1) or (I-B2): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0020] The compound of formula (IC) can be prepared by reacting a compound of formula (I-C1), (I-C2), or (I-C3): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0021] The compound of formula (ID) can be a compound of formula (I-D1) or (I-D2): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0022] The compound of formula (IE) can be prepared by reacting a compound of formula (I-E1): [ka] Or it may be a pharmaceutically acceptable salt or solvate thereof.

[0023] For a compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 is the unsubstituted C1-2 In some embodiments, R 3 is hydrogen, halogen, -CN, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 3 is one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 3 is hydrogen or —CH. In some embodiments, R 3b is -CH3. In some embodiments, R 5 is hydrogen, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 5 is hydrogen. In some embodiments, R 5b is hydrogen and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 5b is -CH3. In some embodiments, R 6 is hydrogen, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 alkyl, and R 12 is C 1-6 In some embodiments, R 6 is selected from hydrogen and —OCH 3 .

[0024] For a compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12)(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -SO2N(R 12 )(R 13 ), and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 7 is C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, and —N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 10-membered heterocycloalkyl may have one, two, or three R 20 In some embodiments, R 7 is one, two, or three R 20 In some embodiments, R 7 is one, two, or three R 20 C optionally substituted with 3-10 In some embodiments, R 7 is one R 20 C optionally substituted with 3-4 In some embodiments, R 20 is -CN. In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 is one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 7 is -N(R 12 )(R 13In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is selected from.

[0025] For a compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 8 is hydrogen, halogen, and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 8 is hydrogen.

[0026] For a compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), [ka] may be selected from phenyl and 5- to 7-membered heteroaryl, each of which may be selected from one or more R 11 In some embodiments, [ka] is selected from phenyl, pyridyl, and thiophenyl, each of which is selected from one or more R 11 In some embodiments, [ka] In some embodiments, R 11 is, if present, independently in each occurrence selected from fluorine and —CH 3 .

[0027] For compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 1 is a bond and C 1-3 In some embodiments, L may be selected from haloalkylene. 1 is C 1-3 In some embodiments, L is haloalkylene. 1 is selected from -CF2-, -CF2CH2-, and -CF2CH2CH2-.

[0028] For a compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), [ka] is selected from absent, phenyl, and a 4- to 8-membered heterocycle, and the phenyl and 4- to 8-membered heterocycle are selected from one or more R 11a In some embodiments, [ka] is selected from absent, phenyl, azetidine, pyrrolidine, and piperidine, and phenyl, azetidine, pyrrolidine, and piperidine are selected from one or more R 11a In some embodiments, [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3.

[0029] For compounds of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 may, together with the atom to which it is attached, form a 16- to 36-membered macrocyclic ring. 2 together with the atoms to which it is attached form a 16- to 24-membered macrocyclic ring. 2 is C 6-15 Alkylene, C 6-15 Alkenylene, C 6-15 alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b The alkenylene and heteroalkenylene may contain one carbon-carbon double bond. The heteroalkylene and heteroalkenylene may contain at least one oxygen or nitrogen atom. In some embodiments, R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 In some embodiments, R 11b is selected from -F, =O, -CH3, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2OH, and -OH.

[0030] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R5 is hydrogen and R 5b is -CH3 and R 6 is selected from hydrogen and -OCH3, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen. In some embodiments, R 3 is hydrogen or -CH3, and R 3b is -CH3 and R 6 is selected from hydrogen and -OCH3, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen. In some embodiments, R 7 teeth, [ka] In some embodiments, R 1 is -CH3, [ka] are selected from phenyl and 5- to 7-membered heteroaryl, each of which is selected from one or more R 11 and optionally substituted with L 1 is a bond and C 1-3 haloalkylene; [ka] is selected from absent, phenyl, and a 4- to 8-membered heterocycle, and the phenyl and the 4- to 8-membered heterocycle are each independently selected from one or more R 11a and optionally substituted with L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, R 11 is fluorine, if present, and R 11a is, if present, -CH3, and R 11b If present, halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0031] A compound of formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1) is a compound having the following structure: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0032] In some embodiments, the present disclosure provides a compound of formula (I-C1), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH3; L 1 is C 1-3 haloalkylene, L 2 is one or more R 11b C optionally substituted with 5-10 is alkenylene, R 1 is -CH3, R 3 is -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen, R 11 is selected from fluorine and —CH3; R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0033] In some embodiments, the present disclosure provides a compound of formula (I-C1), or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH3; L 1 is C1-3 haloalkylene, L 2 is one or more R 11b and selected from 5- to 10-membered heteroalkylene optionally substituted with R 1 is -CH3, R 3 is hydrogen or -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen, R 11 is selected from fluorine and —CH3; R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0034] In certain aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is one or more R 11a and a 3- to 8-membered heterocycle optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11band optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 3 is N(R 3b ) and N; W 4 is C(R 4 ) and C(O), or W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W 5 is N(R 5b ), N, and C(R 5 ) and W6 is N, C(R 6 ) and C(O), W 7 is N, C(R 7 ) and C(O), R 50 is hydrogen or halogen, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , and R 5b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 11a and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0035] In certain aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is one or more R 11a and a 3- to 8-membered heterocycle optionally substituted with L 1 is a bond, C 1-6Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of W 3 is N(R 3b ) and N; W 4 is C(R 4 ) and C(O), or W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W 5 is N(R 5b ), N, and C(R 5 ) and W 6 is N, C(R 6 ) and C(O), W 7 is N, C(R 7 ) and C(O), R 50 is hydrogen or halogen, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , and R 5b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 11a is independently in each occurrence a halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15, -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CHN(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CHN(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21, -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24)C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0036] In certain aspects, the present disclosure provides a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0037] In certain aspects, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the subject is co-administered with an additional agent or therapy.

[0038] In certain aspects, the present disclosure provides methods for reducing Ras signaling output, comprising contacting an SOS1 protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby reducing Ras signaling output. In some embodiments, the compound disrupts the interaction between the Ras protein and SOS1. In some embodiments, the Ras protein is wild-type K-Ras or mutant K-Ras.

[0039] In certain aspects, methods are provided for inhibiting cell proliferation, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing SOS1, thereby inhibiting proliferation of the cell.

[0040] In certain aspects, the present disclosure provides methods for reducing Ras signaling output in a cell, the method comprising contacting the cell with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with an additional agent, the additional agent being selected from the group consisting of a chemotherapeutic agent, a radioactive agent, an immune modulator, and the like. or one or more targets selected from the following: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinases, topoisomerases, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1 / 2, IGF1-R, CDK9, SHC, GAB, GRB, PI3 kinase, MAPK, SHIP1, SHIP2, SHP1, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, wild-type KRas, KRas mutants (e.g., KrasG12C, KRasG12D, KRasG12S, KRasG12V, KRasG13D ... In some embodiments, the additional agent is an inhibitor of one or more targets selected from MEK, epidermal growth factor receptor (EGFR), A-Raf, B-Raf, C-Raf, SHP2, wild-type KRas, mutant KRas, and CDK4 / 6. In some embodiments, the additional agent is a chemotherapeutic agent, a radioactive agent, or an immunomodulatory agent.

[0041] In certain aspects, the present disclosure provides an SOS1 protein bound by a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the interaction between the SOS1 protein and a Ras protein is reduced compared to an SOS1 protein not bound to the compound.

[0042] In certain aspects, the present disclosure provides compounds of formula AL AB -B, wherein A is a monovalent form of a compound described herein; L AB is a covalent linker connecting A and B, B is a monovalent form of a degradation enhancer.

[0043] In some embodiments, the pro-degradation agent is selected from the group consisting of E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, PIAS5, PIAS6, PIAS7, PIAS8, PIAS9, PIAS10, PIAS11, PIAS12, PIAS13, PIAS14, PIAS15, PIAS16, PIAS17, PIAS18, PIAS19 ...9, PIAS19, PIAS19, PIAS20, PIAS21, PIAS22, PIAS23, PIAS24, PIAS25, PIAS26, PIAS27, PIAS28, PIAS29, PIAS30, PIAS31, PIAS32, 2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperone-mediated autophagy), SCFb-TRCP (Skip-Cullin-F box (beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4) CRBN) is capable of binding to a protein selected from ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. In some embodiments, the degradation-promoting agent is capable of binding to a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

[0044] In some embodiments, L AB -L AB1 -L AB2 -L AB3 -L AB4 -L AB5 - and L AB1 , L AB2 , L AB3 , L AB4 , and L AB5 are independently a bond, -O-, -N(R 100 )-, -C(O)-, -N(R 100 )C(O)-, -C(O)N(R 100 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 100 )-, -S(O)N(R 100 )-, -N(R 100 )S(O)-, -N(R 100 )S(O)2-, C 1-6 Alkylene, -(OC1-6 alkyl) z -, -(C 1-6 Alkyl-O) z -, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 selected from carbocyclene and 3- to 10-membered heterocyclene, 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Carbocyclenes and 3- to 10-membered heterocyclenes may contain one, two, or three R 20 Optionally substituted with -(OC 1-6 alkyl) z -and-(C 1-6 Alkyl-O) z -Each C 1-6 Alkyl can be one, two, or three R 20 optionally substituted with z is independently an integer from 0 to 10; Each R 100 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 -carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) can be selected from 1, 2, or 3 R 20 optionally substituted with R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0045] In some embodiments, L AB is -(O-C2 alkyl) z - and z is an integer from 1 to 10. In some embodiments, L AB is -(C2 alkyl-O-) z - and z is an integer from 1 to 10. In some embodiments, L AB is -(CH2) zz1 L AB2 (CH2O) zz2 - and L AB2 is a bond, 5- to 6-membered heterocyclene, phenylene, -C 2-4 alkynylene, —SO—, and —NH—, and zz1 and zz2 are independently integers from 0 to 10. In some embodiments, L AB is -(CH2) zz1 (CH2O) zz2 -, and zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L AB is a PEG linker. In some embodiments, B is [ka] is a monovalent form of a compound selected from

[0046] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0047] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the event of multiple definitions for terms herein, those in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated by reference. Chemical structures are named herein according to the IUPAC convention as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are merely organizational and should not be construed as limiting the subject matter described. As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0048] When used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, "C x-y " or "C x -C y " is meant to include groups containing x to y carbons in the chain. For example, "C x-y The term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups, containing x to y carbon atoms in the chain.

[0049] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched alkyl groups. An alkyl group is a group having 1 to 12 carbon atoms (e.g., C 1-12 alkyl), e.g., 1 to 8 carbon atoms (C1-8 alkyl) or 1 to 6 carbon atoms (C 1-6 The alkyl group may contain a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise expressly stated herein, the alkyl group is optionally substituted with one or more substituents, such as those described herein.

[0050] The term "haloalkyl" refers to an alkyl group that is substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0051] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group, including straight-chain and branched alkenyl groups, containing at least one double bond. Alkenyl groups are groups containing 2 to 12 carbon atoms (e.g., C 2-12 alkenyl), e.g., 2 to 8 carbon atoms (C 2-8 alkenyl) or 2 to 6 carbon atoms (C 2-6 The alkenyl group may contain an alkyl group (e.g., alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, alkenyl groups are optionally substituted with one or more substituents, such as those described herein.

[0052] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group, including straight-chain and branched alkynyl groups, containing at least one triple bond. Alkynyl groups are groups containing 2 to 12 carbon atoms (e.g., C 2-12 alkynyl), e.g., 2 to 8 carbon atoms (C 2-8alkynyl) or 2 to 6 carbon atoms (C 2-6 The alkynyl group may contain an alkynyl group (alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more substituents, such as those described herein.

[0053] An "alkylene" or "alkylene chain" refers to an alkylene group having 1 to 12 carbon atoms (e.g., C 1-12 alkylene), e.g., 1 to 8 carbon atoms (C 1-8 alkylene) or 1 to 6 carbon atoms (C 1-6 "Alkylene" refers to a substituted or unsubstituted divalent saturated hydrocarbon group, including straight-chain alkylene groups and branched alkylene groups containing an alkylene group (alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "alkynylene" refer to an alkylene group, as defined above, containing one or more carbon-carbon double or triple bonds, respectively. The point of attachment of the alkylene, alkenylene, or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0054] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, in which one or more, e.g., 1, 2, or 3, of the carbon atoms are replaced with a heteroatom such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may be optionally oxidized, and any nitrogen heteroatom may be optionally quaternized. When a numerical range is specified, it refers to the total chain length. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise herein, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein.

[0055] "Heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to substituted or unsubstituted alkylene, alkenylene, and alkynylene groups, respectively, in which one or more, e.g., 1, 2, or 3, of the carbon atoms are replaced with a heteroatom such as O, N, P, Si, S, or a combination thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may be optionally oxidized, and any nitrogen heteroatom may be optionally quaternized. When a numerical range is specified, it refers to the total chain length. For example, a 3- to 8-membered heteroalkylene group has a chain length of 3 to 8 atoms. The point of attachment of the heteroalkylene, heteroalkenylene, or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene, or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted with one or more substituents, such as those described herein.

[0056] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is a carbon atom. 3-10 Monocyclic ring, C 6-12 Bicyclic ring, C 6-12 Spirocyclic rings, and C 6-12 It may contain bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated rings, unsaturated rings, and aromatic rings. In some embodiments, a carbocycle is 6-10 C such as aryl 6-12 In some embodiments, the carbocycle is a C 6-12 In some embodiments, the carbocycle is a C 6-12 A carbocycle is a cycloalkenyl group. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, valence permitting, is included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless otherwise specified herein, carbocycles are optionally substituted with one or more substituents, such as those described herein.

[0057] "Heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms, e.g., 1, 2, or 3 heteroatoms selected from O, S, and N. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. Each ring in a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A heterocycle may be attached to the remainder of the molecule through any atom of the heterocycle, such as a carbon or nitrogen atom of the heterocycle, as long as valence permits. In some embodiments, a heterocycle is a 5- to 10-membered heteroaryl group, e.g., a 5- or 6-membered heteroaryl. In some embodiments, a heterocycle is a 3- to 12-membered heterocycloalkyl group. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Unless otherwise stated herein, heterocycles are optionally substituted with one or more substituents, such as those described herein.

[0058] "Heteroaryl" refers to a 5- to 12-membered aromatic ring containing at least one heteroatom selected from O, S, and N, e.g., 1, 2, or 3 heteroatoms. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic rings, including fused, spirocyclic, and bridged ring systems, where at least one of the rings in the ring system is aromatic. The heteroatoms in a heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, such as a carbon or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless otherwise stated herein, heteroaryls are optionally substituted with one or more substituents, such as those described herein.

[0059] Unless otherwise stated, hydrogen atoms are implied in structures drawn herein as necessary to satisfy valence requirements.

[0060] Bond or dashed bond [ka] Wavy line drawn across [ka] are used interchangeably herein to indicate where a bond break or bond occurs. For example, the structure [ka] So, R 7 but, [ka] When R is 1-cyclopropyl-1-carbonitrile, 7 teeth, [ka] It can be depicted as:

[0061] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbon or heteroatoms of the structure. It is understood that "substituted" or "substituted with" includes the implicit connotation that such substitution is in accordance with the permissible valences of the replacing atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, e.g., by rearrangement, cyclization, elimination, and the like. As used herein, the term substituted is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms, such as nitrogen, can have any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms.

[0062] The compounds disclosed herein, e.g., compounds of formula (I), may contain one or more, e.g., one, two, or three, substituents selected from the following: Halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0063] In some embodiments, compounds disclosed herein, e.g., compounds of Formula (I), contain one or more, e.g., one, two, or three, substituents selected from the following: Halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 where C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , and -N(R 22 )(R 23 Optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0064] In some embodiments, the compounds disclosed herein, e.g., compounds of Formula (I), may have one or more, e.g., one, two, or three, substituents selected from the following: halogen, oxo, ═NH, —CN, —NO, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, -CH2- (3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocycle), 3- to 10-membered heterocycle, -CH2- (3- to 10-membered heterocycle) is optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0065] It will be understood by those skilled in the art that the substituents themselves can be substituted, where appropriate. Unless specifically designated as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to a "heteroaryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0066] When divalent substituents are designated herein by their conventional chemical formula written from left to right, they are intended to encompass the isomers resulting from writing the structure from right to left, e.g., -CHO- is also intended to encompass -OCH-.

[0067] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, an "optionally substituted" group may be either unsubstituted or substituted.

[0068] The compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0069] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen is: 1 H (protium), 2 H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating drug elimination and metabolic pathways in vivo. Examples of isotopes that may be incorporated into the compounds of the present disclosure include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 36 Cl, and 18 Of particular note are compounds of formula (I) that are enriched in tritium or carbon-14, which may be used, for example, in tissue distribution studies, compounds of the present disclosure that are enriched in deuterium, particularly at metabolic sites, e.g., resulting in compounds with greater metabolic stability, and compounds of formula (I) that may be used, for example, in positron emission tomography (PET) studies. 11 C. 18 F, 15 O, and 13 A compound of formula (I) enriched in a positron-emitting isotope such as N. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0070] As used herein, the phrases "of the formula," "having the formula," or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprises" is generally used. For example, when a structure is depicted, it is understood that all stereoisomers and tautomeric forms are encompassed unless otherwise specified.

[0071] Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which asymmetric centers may be defined in terms of absolute stereochemistry as (R)- or (S)-. In some embodiments, to optimize the therapeutic activity of the disclosed compounds, e.g., for treating fibrosis, it may be desirable for the carbon atoms to have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)), or to be enriched in a stereoisomeric form having such a configuration. Compounds of the present disclosure may also be provided as racemic mixtures. Accordingly, the present disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When chemical structures are depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structures. Similarly, where a particular stereoisomer is shown or named herein, those of skill in the art will understand that, unless otherwise indicated, small amounts of other stereoisomers may be present in the compositions of the present disclosure, provided that the utility of the overall composition is not obviated by the presence of such other isomers. Individual stereoisomers can be obtained by numerous methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using suitable chiral stationary phases or supports, or chemically converting them to diastereomers, separating the diastereomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomer.

[0072] Additionally, where applicable, all cis-trans or E / Z isomeric (geometric isomeric), tautomeric, and topoisomeric forms of the compounds described herein are included within the scope of the present disclosure, unless otherwise specified.

[0073] The term "pharmaceutically acceptable," as used in the subject compositions and methods, refers to a substance that is not biologically or otherwise unacceptable. For example, the term "pharmaceutically acceptable carrier" refers to a substance, such as an adjuvant, excipient, glidant, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier, that can be incorporated into a composition and administered to a patient without producing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable substances typically have met the necessary standards of toxicological and manufacturing testing and include substances identified by the U.S. Food and Drug Administration as suitable inactive ingredients.

[0074] The terms "salt" and "pharmaceutically acceptable salt" refer to a salt prepared from a base or an acid. A pharmaceutically acceptable salt is suitable for administration to a patient, such as a mammal (e.g., a salt that has acceptable mammalian safety for a given dosing regimen). Salts can be formed from inorganic bases, organic bases, inorganic acids, and organic acids. Furthermore, when a compound contains both a basic moiety, such as an amine, pyridine, or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term "salt" as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0075] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like, which retain the biological effectiveness and properties of the free base, and which are not biologically or otherwise undesirable. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Amino acid salts such as arginate, gluconate, and galacturonate are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0076] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0077] The term "effective amount" or "therapeutically effective amount" refers to an amount of an agent sufficient to produce a beneficial or desired result. A therapeutically effective amount may vary depending on one or more of the subject and condition being treated, the subject's weight and age, the severity of the condition, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or multiple doses. Components may be described herein as having at least an effective amount, or at least an effective amount as related to a particular goal or purpose as described herein. The term "effective amount" also applies to an amount that provides an image for detection with an appropriate imaging method. Specific doses may vary depending on one or more of the particular agent selected, the administration regimen to be followed, whether or not it is co-administered with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system by which the agent is delivered.

[0078] As used herein, "treating" or "treatment" refers to an approach to obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including, but not limited to: (a) preventing the occurrence of a disease or medical condition, e.g., preventing the recurrence of a disease or medical condition, or prophylactic treatment of a subject predisposed to a disease or medical condition; (b) ameliorating a disease or medical condition, e.g., eliminating or causing regression of a disease or medical condition in a subject; (c) inhibiting a disease or medical condition, e.g., slowing or halting the progression of a disease or medical condition in a subject; or (d) alleviating the symptoms of a disease or medical condition in a subject. For example, "treating cancer" includes preventing the occurrence of cancer, ameliorating cancer, inhibiting cancer, and alleviating the symptoms of cancer. A therapeutic benefit is also achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, although the subject may still be afflicted with the underlying disorder.

[0079] A "therapeutic effect," as that term is used herein, encompasses the therapeutic and / or prophylactic benefits described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0080] The terms "antagonist" and "inhibitor" are used interchangeably and refer to compounds capable of inhibiting the biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., SOS1). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. Preferred antagonists herein specifically interact (e.g., bind) with the target; however, specifically included within this definition are compounds that inhibit the biological activity of the target protein by interacting with other members of a signal transduction pathway of which the target protein is a member.

[0081] The terms "selective inhibition" or "selectively inhibit" refer to the ability of a bioactive agent to preferentially reduce target signaling activity relative to off-target signaling activity, through direct or indirect interaction with the target.

[0082] The terms "subject" and "patient" refer to animals such as mammals, e.g., humans. The methods described herein can be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal, such as a human. "Mammal" includes humans, as well as domestic animals, both laboratory animals and domestic pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife.

[0083] The terms "therapeutic agent," "therapeutic drug," or "treatment agent" are used interchangeably and refer to a molecule or compound that has some beneficial effect when administered to a subject. Beneficial effects include enabling a diagnostic determination, ameliorating a disease, symptom, disorder, or pathological condition, reducing or preventing the occurrence of a disease, symptom, disorder, or condition, and generally counteracting a disease, symptom, disorder, or pathological condition.

[0084] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to polymers of amino acids of any length. The polymers may be linear or branched, may comprise modified amino acids, and may be interrupted by non-amino acids. These terms also encompass amino acid polymers that have been modified, such as by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or conjugation with a labeling component. As used herein, the term "amino acid" refers to any natural and / or unnatural or synthetic amino acid, and includes glycine and both D- or L-optical isomers, as well as amino acid analogs and peptidomimetics.

[0085] The terms "polynucleotide," "nucleotide," "nucleotide sequence," "nucleic acid," and "oligonucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides can have any three-dimensional structure and can perform any function, known or unknown. Non-limiting examples of polynucleotides include: coding or non-coding regions of a gene or gene fragment, locus (locuses) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, small interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. Polynucleotides may contain one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNAs), morpholinos and locked nucleic acids (LNAs), glycol nucleic acids (GNAs), threose nucleic acids (TNAs), 2'-fluoro, 2'-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. Polynucleotides may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0086] As used herein, "expression" refers to the process by which a polynucleotide is transcribed from a DNA template (such as into mRNA or other RNA transcript) and / or the process by which the transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. The transcript and the encoded polypeptide may be collectively referred to as a "gene product." If the polynucleotide is derived from genomic DNA, expression may also include splicing of the mRNA in a eukaryotic cell.

[0087] An "antigen" is a moiety or molecule that contains an epitope and, as such, also specifically binds to an antibody. An "antigen-binding unit" can be the entirety of a full-length antibody or a fragment (or fragments), a structural variant thereof, a functional variant thereof, or a combination thereof. Full-length antibodies can be, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, deimmunized antibodies, humanized antibodies, and human antibodies. Examples of fragments of full-length antibodies include variable heavy chains (VH), variable light chains (VL), heavy chains (VHH or VL) found in camelids, such as camels, llamas, and alpacas. H H), heavy chains found in sharks (V-NAR domains), single domain antibodies (sdAbs, e.g., "nanobodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and "r IgG" (or half antibodies). Examples of modified antibody fragments include, but are not limited to, scFv, di-scFv, or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single-chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3), or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0088] The terms "antibody" and "antibodies" include any antigen-binding unit, including, but not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, and other epitope-binding fragments.

[0089] The term "prodrug" is intended to refer to a compound that can be converted under physiological conditions by solvolysis into a biologically active compound described herein (e.g., a compound of Formula (I)). Thus, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug is inactive when administered to a subject, but is converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., "Prodrugs as Novel Delivery Systems," (1987) ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, each of which is incorporated herein by reference in its entirety). The term "prodrug" is also meant to include any covalently bonded carrier that releases an active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds described herein may typically be prepared by modifying functional groups present in the active compound such that the modifications are cleaved to the parent active compound either by routine manipulation or in vivo. Prodrugs include compounds in which a hydroxy group, an amino group, or a mercapto group is bonded to any group that cleaves to form a free hydroxy group, a free amino group, or a free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of a hydroxy functional group in the active compound, or acetamide, formamide, and benzamide derivatives of an amine functional group.

[0090] The term "in vivo" refers to events that occur within a subject's body. The term "ex vivo" refers to events that occur initially outside a subject's body for later application in vivo within the subject's body. For example, ex vivo preparation may involve preparing cells outside a subject's body with the intent of introducing the prepared cells into the same or a different subject. The term "in vitro" refers to events that occur outside a subject's body. For example, an in vitro assay includes any assay performed outside a subject's body. In vitro assays include cell-based assays in which live or dead cells are used. In vitro assays include cell-free assays in which intact cells are not used.

[0091] The present disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Accordingly, the present disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0092] The term "Ras" or "RAS" refers to proteins of the Rat sarcoplasmic reticulum (Ras) superfamily of small GTPases, such as the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, the Rho subfamily, the Rab subfamily, the Rap subfamily, the Arf subfamily, the Ran subfamily, the Rheb subfamily, the RGK subfamily, the Rit subfamily, the Miro subfamily, and the unclassified subfamily. In some embodiments, the Ras protein is selected from the group consisting of KRAS (K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0093] The terms "mutant Ras" and "Ras mutant," used interchangeably herein, refer to a Ras protein having one or more amino acid mutations relative to a common reference sequence, such as a wild-type (WT) sequence. In some embodiments, the mutant Ras is selected from mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, the mutation can be an induced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, the mutation can be a substitution (e.g., a substituted amino acid), an insertion (e.g., an addition of one or more amino acids), or a deletion (e.g., a removal of one or more amino acids). In some embodiments, the two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, the mutation can be at any position in Ras. In some embodiments, when optimally aligned, mutations may be present at positions 12, 13, 62, 92, 95 of Ras relative to SEQ ID NO: 1, or any combination thereof. In some embodiments, mutant Ras may contain about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, mutant Ras may contain up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or less than 50 amino acids in length.In some embodiments, the mutated amino acid is a proteinogenic amino acid, a naturally occurring amino acid, a standard amino acid, a non-standard amino acid, a non-canonical amino acid, an essential amino acid, a non-essential amino acid, or a non-naturally occurring amino acid. In some embodiments, the mutated amino acid has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, the mutation comprises a reactive moiety. In some embodiments, the substituted amino acid comprises a reactive moiety. In some embodiments, the mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, the mutant Ras is a full-length or truncated polypeptide. For example, the mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of mutant RALA or mutant RALB).

[0094] compound The compounds of formula (I) disclosed herein, including compounds of formula (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), (I-E1), (II-B), (II-C), and (III), or pharmaceutically acceptable salts or solvates thereof, are SOS modulators and have a wide range of applications in therapy, diagnosis, and other biomedical research.

[0095] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 optionally substituted with [ka] is absent or C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b ), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R 5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R 7 )(R 7a ), and C(O), W 8 is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10), and C; R 1 is one or more R 11c C optionally substituted with 1-3 is alkyl, R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15, and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11 , R 11a , and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12)(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11c independently in each occurrence, a halogen, -OR 12 , and -N(R 12 )(R 13 ) and R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24)C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0096] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 optionally substituted with [ka] is absent or C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R 5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R 7 )(R 7a ), and C(O), W 8 is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10 ), and C; R 1 is one or more R 11c C optionally substituted with 1-3 is alkyl, R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8aare each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12, -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11 and R 11aare each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CHN(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CHN(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11c independently in each occurrence, a halogen, -OR 12 , and -N(R 12 )(R 13 ) and R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0097] In some embodiments, the compound of formula (I) is a compound of formula (IA): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0098] In some embodiments, the compound of formula (IA) is [ka] [ka] The compound is selected from

[0099] In some embodiments, the compound of Formula (I) is a compound of Formula (IB), for example, a compound of Formula (I-B1) or (I-B2): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0100] In some embodiments, the compound of formula (IB) is [ka] The compound is selected from:

[0101] In some embodiments, the compound of Formula (I) is a compound of Formula (IC), for example, a compound of Formula (I-C1), (I-C2), or (I-C3): [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0102] In some embodiments, the compound of formula (IC) is [ka] [ka] The compound is selected from

[0103] In some embodiments, the compound of formula (I) is a compound of formula (ID), for example, a compound of formula (I-D1) or (I-D2): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0104] In some embodiments, the compound of formula (ID) is [ka] [ka] The compound is selected from

[0105] In some embodiments, the compound of formula (I) is a compound of formula (IE), such as a compound of formula (I-E1): [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, the compound of formula (IE) is [ka] [ka] The compound is selected from

[0107] In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 is N. In some embodiments, W 3 is N(R 3b ), N, C(R 3 ), and C(O), for example, selected from NCH, N, CH, CCH, and C(O). In some embodiments, W 3 is C(R 3 ) and C(O), for example, selected from CH, CCH3, and C(O). In some embodiments, W 3is CH. In some embodiments, W 3 is CCH3. In some embodiments, W 4 is N(R 4b ), N, C(R 4 ), and C(O), for example, N(R 4b ), N, C(R 4 ), and C(O) (in this case, R 4b and R 4 are each independently, L 2 In some embodiments, W 4 is N(R 4b ) and N, for example, N(R 4b ) (in this case, R 4b L 2 In some embodiments, W 4 is N. In some embodiments, W 5 is N(R 5b ), N, C(R 5 ), and C(O), for example, N(R 5b ), NCH3, N, CH, C(R 5 ), and C(O) (in this case, R 5b and R 5 are each independently, L 2 In some embodiments, W 5 is N(R 5b ), N, and C(R 5 ), for example, N(R 5b ), NCH3, N, CH, and C(R 5 ) (in this case, R 5b and R 5 are each independently, L 2 In some embodiments, W 5 is N(R 5b ), and C(R 5 ), for example, N(R 5b ), NCH3, and CH(in this case, R 5b L 2 In some embodiments, W 5 is N(R5b In some embodiments, W 6 is C(R 6 ) and C(O), for example, COCH3, CH, C(R 6 ), and C(O) (in this case, R 6 L 2 In some embodiments, W 6 is C(O). In some embodiments, W 7 is C(R 7 ), for example, W 7 is C(R 7 ) (in this case, R 7 L 2 In some embodiments, W 7 is R 7 is not hydrogen, C(R 7 ), for example, R 7 is C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, and -OR 12 Selected from 、 C 3-10 Cycloalkyl and 3- to 10-membered heterocycloalkyl may have one, two, or three R 20 In some embodiments, W 8 is C(R 8 ), for example, W 8 is CH. In some embodiments, W 9 is C. In some embodiments, W 10 is C.

[0108] In some embodiments, for compounds of formula (I), (IA), (IC), (ID), or (IE), W 2 is N and W 3 is N(R 3b ) and W 4 is C(O) and W 9 and W 10 are each C, for example, W 2 is N and W 3 is NCH3 and W 4is C(O) and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IB), (IC), (ID), or (IE), W 2 is N and W 3 is C(O) and W 4 is N(R 4b ) and W 9 and W 10 are each C, for example, W 2 is N and W 3 is C(O) and W 4 is N(R 4b ) (in this case, R 4b L 2 and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IC), (ID), or (IE), W 2 is N and W 3 is C(R 3 ) and W 4 is N and W 9 and W 10 are each C, for example, W 2 is N and W 3 is CH or CCH3, and W 4 is N and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 5 is C(R 5 ) and W 6 is C(R 6 ) and W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C, for example, W 5 is CH or C(R 5 ) (in this case, R 5 L 2 and W6 is CH or C(R 6 ) (in this case, R 6 L 2 and W 7 is C(R 7 ) and W 8 is CH and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), or (IE), W 5 is N(R 5b ) and W 6 is C(O) and W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C, for example, W 5 is NCH3 or N(R 5b ) (in this case, R 5b L 2 and W 6 is C(O) and W 7 is C(R 7 ) and W 8 is CH and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (ID), or (IE), W 5 is N and W 6 is C(R 6 ) and W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C, for example, W 5 is N and W 6 is COCH3, CH, or C(R 6 ) (in this case, R 6 L 2 and W 7 is C(R 7 ) and W 8is CH and W 9 and W 10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 is N and W 3 is N(R 3b ), N, C(R 3 ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), and C(O), W 5 is N(R 5b ), N, and C(R 5 ) and W 6 is C(R 6 ) and C(O), W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are each C, for example, W 2 is N and W 3 is selected from NCH3, N, CH, CCH3, and C(O), and W 4 is N(R 4b ), N, C(R 4 ), and C(O) (in this case, R 4b and R 4 are each independently, L 2 and W 5 is N(R 5b ), NCH3, N, CH, and C(R 5 ) (in this case, R 5b and R 5 are each independently, L 2 and W 6 COCH3, CH, C(R 6 ), and C(O) (in this case, R 6 L 2 and W 7 is C(R 7 ) and W 8 is CH and W 9 and W10 and each is C. In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), W 2 is N and W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W 5 is N(R 5b ) and C(R 5 ) and W 6 is C(R 6 ) and C(O), W 7 is C(R 7 ) and W 8 is CH and W 9 and W 10 are each C, for example, W 2 is N and W 3 is selected from CH, CCH3, and C(O), and W 4 is N(R 4b ) and N(in this case, R 4b L 2 and W 5 is N(R 5b ), NCH3, CH, and C(R 5 ) (in this case, R 5b and R 5 are each independently, L 2 and W 6 COCH3, CH, C(R 6 ), and C(O) (in this case, R 6 L 2 and W 7 is C(R 7 ) and W 8 is CH and W 9 and W 10 are each C.

[0109] In some embodiments, for compounds of formula (I): [ka] In some embodiments, [ka] [ka] [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] For example, [ka] In some embodiments, [ka] For example, [ka] In some embodiments, [ka] In some embodiments, [ka] For example, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] is.

[0110] In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-3 Alkyl, C 1-3 In some embodiments, R is selected from haloalkyl, —OH, —NH, —NHCH, and —N(CH). 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently selected from hydrogen and —CH 3 , for example selected from hydrogen.

[0111] In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 3 , R 4 , R 5 , and R 6 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 7 L 2 Bonding with C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 3 , R 4 , R 5 , and R 6 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 haloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2; R 7 L 2 Bonding with C1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 3 , R 4 , R 5 , and R 6 are each independently, L 2 a bond with R selected from hydrogen, -CH3, and -OCH3; 7 L 2 Bonding with C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 is optionally substituted with

[0112] In some embodiments, for compounds of formula (I), (IA), (IB), (IC), (ID), or (IE), R 2b and R 8b are each independently hydrogen and C 1-3 alkyl, for example, selected from hydrogen and —CH. In some embodiments, R 3b , R 4b , R5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen and C 1-3 alkyl, for example, L 2 In some embodiments, R is selected from a bond to 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 and —CH3. In some embodiments, R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 In some embodiments, R 9 and R 10 are each hydrogen.

[0113] L 2 But -L 3 -DL 4 For compounds of formula (I) where R 3 , R 4 , R 5 , R 6 , R 7 , R 3b , R 4b , R 5b , R 6b , or R 7b L for one of 2 The bond selection with -L 3 -DL 4 -with, especially L 4 For the avoidance of doubt, L 2 R, including bonds with 3 , R 4 , R 5 , R 6 , R 7 、 R 3b , R 4b , R 5b , R 6b , and / or R7b Any enumeration of "L" 4 may be considered to include "a bond with

[0114] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 is C 1-3 Alkyl and C 1-3 haloalkyl, for example, selected from -CH, -CHCH, -CH(CH), -CHF, -CHF, -CF, CHCHF, -CHCHF, and -CHCF. In some embodiments, R 1 is C 1-3 In some embodiments, R 1 is -CH3. In some embodiments, R 1 is (R)-CH. In some embodiments, R 1 is (S)-CH3.

[0115] In some embodiments, for a compound of Formula (I), (IB), (IC), (I-C1), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 3 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R13 ) are selected from each C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may independently contain 1, 2, or 3 R 20 In some embodiments, R 3 is hydrogen, halogen, -CN, C 1-3 Alkyl, C 1-3 haloalkyl, —OH, —OCH, —NH, —NHCH, —N(CH). In some embodiments, R 3 is hydrogen, halogen, -CN, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 3 is one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 3 is hydrogen or —CH. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is -CH3.

[0116] In some embodiments, for compounds of formula (I), (IB), (IC), (I-C2), (ID), or (IE), R 3b is hydrogen and C 1-3 In some embodiments, R is selected from alkyl, for example, hydrogen and —CH. 3b is -CH3. In some embodiments, R 3b is hydrogen.

[0117] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B2), (ID), (I-D2), (IE), or (I-E1), R 5 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 , -SR 12 , -N(R12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may independently contain 1, 2, or 3 R 20 In some embodiments, R 5 is hydrogen, halogen, -CN, C 1-3 Alkyl, C 1-3 haloalkyl, —OH, —OCH, —NH, —NHCH, —N(CH). In some embodiments, R 5 is hydrogen, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 5 is hydrogen or —CH. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is -CH3.

[0118] In some embodiments, for compounds of formula (I), (IA), (IB), (I-B1), (ID), or (IE), R 5b is hydrogen and C 1-3 In some embodiments, R is selected from alkyl, for example, hydrogen and —CH. 5b is hydrogen and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 5b is -CH3. In some embodiments, R 5bis hydrogen. In some embodiments, R 5b L 2 It is a combination with.

[0119] In some embodiments, for compounds of Formula (I), (IA), (IB), (I-B2), (IC), (I-C3), (IE), or (I-E1), R 6 is hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may independently contain 1, 2, or 3 R 20 In some embodiments, R 6 is hydrogen, halogen, -CN, C 1-3 Alkyl, C 1-3 haloalkyl, —OH, —OCH, —NH, —NHCH, and —N(CH). In some embodiments, R 6 is hydrogen, -OR 12 , and one, two, or three R 20 C optionally substituted with 1-6 alkyl, and R 12 is C 1-6 In some embodiments, R 6 is selected from hydrogen and —OCH. In some embodiments, R 6 is hydrogen. In some embodiments, R6 is -OCH3.

[0120] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CHN(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 In some embodiments, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 7 is C 1-6 Alkyl, C 3-10 Cycloalkyl, 3- to 10-membered heterocycloalkyl, and —N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Cycloalkyl and 3- to 10-membered heterocycloalkyl may have one, two, or three R 20 In some embodiments, R 7 is one, two, or three R 20 and optionally substituted 3- to 10-membered heterocycloalkyl, such as R 7 is one, two, or three R 20 In some embodiments, R is a 4-6 membered heterocycloalkyl optionally substituted with 7 is one, two, or three R 20 and R is a 3- to 10-membered heterocycloalkyl optionally substituted with R, wherein the heterocycloalkyl contains at least one O, N, or S, e.g., one O atom, one or two N atoms, or one S atom. 7 is one, two, or three R 20 In some embodiments, R 7 is one, two, or three R 20 C optionally substituted with 3-10 cycloalkyl, e.g., R 7 is one, two, or three R 20 C optionally substituted with 3-6 In some embodiments, R 7 is one R 20 C optionally substituted with 3-4 cycloalkyl, and optionally R 20 is -CN. In some embodiments, R 7 is one, two, or three R20 C optionally substituted with 1-6 alkyl, e.g., R 7 is one or two R 20 C replaced with 1-6 In some embodiments, R 7 is -N(R 12 )(R 13 In some embodiments, R 7 -OR 12 For example, —O(3-6 membered heterocycloalkyl). In some embodiments, R 7 is substituted with at least one -CN. In some embodiments, R 7 is unsubstituted. In some embodiments, R 7 is C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which contains 1, 2, or 3 R 20 In some embodiments, R 7 is C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from oxo, —CN, and C 1-6 In some embodiments, R is optionally substituted with 1, 2, or 3 substituents selected from alkyl. 7 is oxo, -CN, and C 1-3 In some embodiments, R is a 4- to 6-membered heterocycloalkyl substituted with 1, 2, or 3 substituents selected from alkyl. 7 is oxo, -CN, and C 1-3 C substituted with 1, 2, or 3 substituents selected from alkyl 3-4 It is cycloalkyl.

[0121] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)(NR 12 )R 15 , -S(O)2N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)(NR 12 )R 15 , and -CH2S(O)2N(R 12 )(R 13 ) and each C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 In some embodiments, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)(NR 12 )R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 7 is one, two, or three R 20and 3-6 membered heterocycloalkyl optionally substituted with S(O)(NR 12 ) is included.

[0122] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 teeth, [ka] where: n1 is an integer from 1 to 3, n2 is an integer from 0 to 2, n3 is an integer from 0 to 2, n4 is 0 or 1, X is -O-, -S(O2)-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR 12 )-, -CH(R 20 )-, -C(R 20 )2-, -NR 12 -, -CH(N(R 12 )(R 13 ))-, -CH(C(O)N(R 12 )(R 13 ))-, and -CH(S(O)2N(R 12 )(R 13 )-selected from R 12 , R 13 , and R 20 is as defined elsewhere herein; Optionally, two R 20 group, or R 20 and R 12 are joined together with the atoms to which they are attached to form a ring. For example, R 7 teeth, [ka] [ka] In some embodiments, X may be selected from -O-, -S(O)2-, -S(O)(NR 12 )-, -P(O)-, -CH2-, -CH(OH)-, -CH(OR 12 )-, -CH(R 20 )-, -C(R 20 )2-, -NR 12 -, -CH(N(R 12 )(R 13 ))-, -CH(C(O)N(R 12 )(R 13 ))-, and -CH(S(O)2N(R 12 )(R 13 )- is selected from.

[0123] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), or (I-D2), R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] In some embodiments, R 7 teeth, [ka] is.

[0124] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 8 is hydrogen, halogen, and one, two, or three R 20 C optionally substituted with 1-6 In some embodiments, R 8 is hydrogen.

[0125] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), [ka] is C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, for example, C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 In some embodiments, [ka] is C 5-7 cycloalkyl, 5- to 7-membered heterocycloalkyl, 5- to 7-membered heteroaryl, and phenyl, each of which is selected from one or more R 11 In some embodiments, [ka] is selected from phenyl, pyridyl, and thiophenyl, each of which is selected from one or more R 11 In some embodiments, [ka] is selected from, for example, [ka] In some embodiments, R 11 is, if present, independently selected at each occurrence from fluorine and —CH. In some embodiments, [ka] is selected from, for example, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] is.

[0126] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 1 is C 1-6 Alkylene and C 1-6 Haloalkylene, e.g., C 1-3 Alkylene and C 1-3 In some embodiments, L is selected from haloalkylene. 1 is a bond and C 1-3 In some embodiments, L is selected from haloalkylene. 1 is C 1-3 haloalkylene, for example, -CF-, -CFCH-, or -CFCHCH-. In some embodiments, L 1 is C1-2 haloalkylene, for example, -CF- or -CFCH-. In some embodiments, L 1 In some embodiments, L 1 is -CF2CH2-. In some embodiments, L 1 is -CF2CH2CH2-. In some embodiments, L 1 is a bond. In some embodiments, L 1 is a bond, -O-, -NR 12 -, -S-, C 1-6 Alkylene, C 1-6 haloalkylene, and 2- to 6-membered heteroalkylene; 1-6 Alkylene, C 1-6 Haloalkylene and 2- to 6-membered heteroalkylene are each independently one or more R 11b In some embodiments, L 1 -O-, -NR 12 -, -S-, and 2- to 6-membered heteroalkylene, wherein the 2- to 6-membered heteroalkylene is selected from one or more R 11b In some embodiments, L 1 is one or more R 11b , e.g., 1, 2, or 3 R 11b C optionally substituted with 1-6 In some embodiments, L is alkylene. 1 is a bond, -O-, -NR 12 -, -S-, C 1-3 Alkylene, C 1-3 haloalkylene, and 2- to 3-membered heteroalkylene; 1-3 Alkylene, C 1-3 Haloalkylene and 2- to 3-membered heteroalkylene are each independently one or more R 11b In some embodiments, L 1 -O-, -NR 12 -, -S-, and 2- to 3-membered heteroalkylene, wherein the 2- to 3-membered heteroalkylene is selected from one or more R 11b In some embodiments, L1 is one or more R 11b , e.g., 1, 2, or 3 R 11b C replaced with 1-3 It is alkylene.

[0127] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), [ka] is absent or C 4-8 carbocycle and 4- to 8-membered heterocycle, each of which is selected from one or more R 11a In some embodiments, [ka] are absent or selected from phenyl and 4- to 8-membered heterocycle, each of which is selected from one or more R 11a In some embodiments, [ka] are selected from phenyl and 4- to 8-membered heterocycles, each of which is selected from one or more R 11a In some embodiments, [ka] is absent or selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is selected from one or more R 11a In some embodiments, [ka] is selected from phenyl, azetidine, pyrrolidine, and piperidine, each of which is selected from one or more R 11aIn some embodiments, [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more -CH3. [ka] is one or more R 11a In some embodiments, [ka] is one or more R 11a optionally substituted with [ka] In some embodiments, [ka] In some embodiments, [ka] is one or more R 11a In some embodiments, [ka] is one or more R 11a optionally substituted with [ka] In some embodiments, [ka] In some embodiments, [ka] is one or more R 11a In some embodiments, pyrrolidine is optionally substituted with [ka] is one or more R 11a In some embodiments, the compound is piperidine, optionally substituted with [ka] is one or more R 11a optionally substituted with [ka] In some embodiments, [ka] In some embodiments, [ka] is unsubstituted. In some embodiments, [ka] is one or more R 11a , e.g., 1, 2, or 3 R 11a In some embodiments, R 11a is independently in each occurrence a halogen, -CN, C 1-6 Alkyl, C 3-6 Carbocyclic ring, 3- to 6-membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -N(R 14 )S(O)2R 15 , -C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , and -S(O)N(R 12 )(R13 ) and C 1-6 Alkyl, C 3-6 Carbocycles and 3- to 6-membered heterocycles may contain one, two, or three R 20 In some embodiments, R 11a independently in each occurrence, a halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, R is selected from haloalkyl. 11a independently in each occurrence, C 1-6 In some embodiments, R 11a is -CH3.

[0128] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 5-25 Alkylene, C 5-25 alkenylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 together with the atom to which it is attached form a 16- to 36-membered macrocyclic ring, for example a 16- to 24-membered macrocyclic ring. 2 is C 6-15 Alkylene, C 6-15 Alkenylene, C 6-15 alkynylene, 6- to 15-membered heteroalkylene, and 6- to 15-membered heteroalkenylene, each of which is selected from one or more R 11bIn some embodiments, L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 The alkenylene or heteroalkenylene of L contains one carbon-carbon double bond. 2 The heteroalkylene or heteroalkenylene of L contains at least one oxygen or nitrogen atom. 2 The heteroalkylene or heteroalkenylene of L contains at least one basic nitrogen. 2 is C 5-9 Alkylene, C 5-9 alkenylene, and 5- to 9-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 6-9 Alkylene, C 6-9 alkenylene, and 6- to 9-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 5-8 Alkylene, C 5-8 alkenylene, and 5- to 8-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 6-8 Alkylene, C 6-8 alkenylene, and 6- to 8-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 6-8 Alkylene and C 6-8 alkenylene, each of which is selected from one or more R 11bIn some embodiments, L 2 is selected from C alkylene and C alkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is selected from C7 alkylene and C7 alkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is selected from C alkylene and C alkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is -CHCHCH(CH)-. In some embodiments, L 2 is one or more R 11b In some embodiments, L is a 6- to 8-membered heteroalkylene optionally substituted with 2 is one or more R 11b In some embodiments, L is a 6-membered heteroalkylene optionally substituted with 2 is one or more R 11b In some embodiments, L is a 7-membered heteroalkylene optionally substituted with 2 is one or more R 11b In some embodiments, L is an 8-membered heteroalkylene optionally substituted with 2 is an 8-membered heteroalkylene, wherein the heteroalkylene contains one oxygen atom. 2 is -(CH2) 2-5 O(CH2) 0-5 -, for example, L 2 is -(CH2) 2-5 O(CH2) 2-5 In some embodiments, L 2 is —(CH)O(CH)—. In some embodiments, R 11b is independently in each occurrence a halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6In some embodiments, R 11b is independently in each occurrence selected from -F, =O, -CH, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHOH, and -OH. 11b is independently in each occurrence selected from —CH, —CHOH, —CHF, —CHF, and —CF, or two R 11b is bonded to =O or C 3-6 In some embodiments, R 11b is independently in each occurrence selected from —CH, —CHOH, —CHF, —CHF, and —CF, or two R 11b combine to form C 3-6 In some embodiments, R 11b is independently selected at each occurrence from —CH, —F, —CN, and —OH. 2 is -C(O)N(R 14 )- or -N(R 14 )C(O)—. In some embodiments, L 2 In some embodiments, L 2 is substituted with at least one -CH, -CHOH, -CHF, -CHF, or -CF, or two substituents are joined to form a cyclopropyl. 2 is substituted with at least one of —CH, —F, —CN, or —OH. 2 is non-substituted.

[0129] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 is -(C 1-5 alkylene)-C(O)N(R 14)-(C 1-5 alkylene)-, for example, -(C 1-5 alkylene)-C(O)N(CH3)-(C 1-5 alkylene)- or -(C 1-5 alkylene)-C(O)NH-(C 1-5 alkylene)-, and C 1-5 Alkylene is a group consisting of one or more R 11b In some embodiments, L 2 is -(C 1-2 alkylene)-C(O)N(R 14 )-(C 3-4 alkylene)-, for example -(C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, and C 1-2 Alkylene and C 3-4 Each alkylene independently has one or more R 11b In some embodiments, R 11b independently in each occurrence, a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 In some embodiments, R 11b is independently in each occurrence selected from -F, -CH, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHOH, and -OH. 11b is independently in each occurrence selected from —CH, —CHOH, —CHF, —CHF, and —CF, or two R 11b combine to form C 3-6 In some embodiments, R 11b is independently selected at each occurrence from —CH, —F, —CN, and —OH. 2 is substituted with at least one of -CH3, -F, -CN, or -OH.

[0130] In some embodiments, L 2 is -C(R 11b )(R 11b )-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH2-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkylene)-CH(R 11b )-, -CH2-(C 3-10 alkylene)-CH(R 11b )-, -C(R 11b )(R 11b )-(C 3-10 alkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkenylene)-C(R 11b )(R 11b )-, -CH2-(C 3-10 alkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkenylene)-CH(R 11b )-, -CH2-(C 3-10 alkenylene)-CH(R 11b )-, -C(R 11b )(R 11b )-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH2-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkylene)-CH(R 11b)-, -CH2-(3- to 10-membered heteroalkylene)-CH(R 11b )-, -C(R 11b )(R 11b )-(3- to 10-membered heteroalkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkenylene)-C(R 11b )(R 11b )-, -CH2-(3- to 10-membered heteroalkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkenylene)-CH(R 11b )-, and -CH2-(3- to 10-membered heteroalkenylene)-CH(R 11b In some embodiments, L 2 is -C(R 11b )(R 11b )-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH2-(C 3-10 alkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkylene)-CH(R 11b )-, and -CH2-(C 3-10 alkylene)-CH(R 11b In some embodiments, L 2 is -C(R 11b )(R 11b )-(C 3-10 alkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(C 3-10 alkenylene)-C(R 11b )(R 11b )-, -CH2-(C 3-10 alkenylene)-C(R 11b )(R11b )-, -CH(R 11b )-(C 3-10 alkenylene)-CH(R 11b )-, and -CH2-(C 3-10 alkenylene)-CH(R 11b In some embodiments, L 2 is -C(R 11b )(R 11b )-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH2-(3- to 10-membered heteroalkylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkylene)-CH(R 11b )-, and -CH2-(3- to 10-membered heteroalkylene)-CH(R 11b In some embodiments, L 2 is -C(R 11b )(R 11b )-(3- to 10-membered heteroalkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkenylene)-C(R 11b )-(R 11b )-, -CH2-(3- to 10-membered heteroalkenylene)-C(R 11b )(R 11b )-, -CH(R 11b )-(3- to 10-membered heteroalkenylene)-CH(R 11b )-, and -CH2-(3- to 10-membered heteroalkylene)-CH(R 11b )-. Any C in this paragraph is selected from 3-10 Alkylene, C 3-10 Alkenylene, 3- to 10-membered heteroalkylene, or 3- to 10-membered heteroalkenylene may be one or more R 11b In some embodiments, R 11bis independently in each occurrence a halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 In some embodiments, R 11b is independently in each occurrence selected from -F, -CH, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHOH, and -OH. 11b is independently in each occurrence selected from —CH, —CHOH, —CHF, —CHF, and —CF, or two R 11b is bonded to =O or C 3-6 It forms a cycloalkyl, for example, cyclopropyl.

[0131] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), L 2 -L 3 -DL 4 - in which L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b and D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d and optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11bAs noted above, alkenylene and alkynylene groups each contain one or more carbon-carbon double or triple bonds (i.e., for example, C 2-10 Alkenylene, C 2-10 Alkynylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 5-25 Alkenylene, C 5-25 Alkynylene, C 6-15 Alkenylene, C 6-15 Alkynylene, C 5-10 Alkenylene, and C 5-10 Similarly, heteroalkenylene groups contain one or more carbon-carbon double bonds (i.e., two or more carbon atoms and one or more heteroatoms, such as in 3- to 10-membered heteroalkenylene, 3- to 8-membered heteroalkenylene, 5- to 25-membered heteroalkenylene, 6- to 15-membered heteroalkenylene, and 5- to 10-membered heteroalkenylene. In some embodiments, L 2 -L 3 -DL 4 - in which L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b and D is optionally substituted with C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d and optionally substituted with L 4 is absent. In some embodiments, L 2 -L 3 -DL 4 - in which L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b and D is absent or C 3-10carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d and optionally substituted with L 4 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 -L 3 -DL 4 - in which L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b and D is optionally substituted with C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d and optionally substituted with L 4 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, R 11b is independently in each occurrence a halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 In some embodiments, R 11b is independently in each occurrence selected from -F, -CH, -CHF, -CHF, -CF, -CHCHF, -CHCHF, -CHOH, and -OH. 11b is independently in each occurrence selected from —CH, —CHOH, —CHF, —CHF, and —CF, or two R 11b is bonded to =O or C 3-6In some embodiments, D is selected from phenyl and 5-8 membered heteroaryl, such as triazole and imidazole. In some embodiments, D is unsubstituted. In some embodiments, D is selected from one or more R 11d , e.g., 1, 2, or 3 R 11d is replaced by .

[0132] In some embodiments, for compounds of formula (I), L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 Covalently bonded to one of the following: 2 is W 3 may be covalently bonded to, in which case R 3b or R 3 is, as shown in formula (IA), L 2 In some embodiments, L 2 is W 4 In this case, R 4b or R 4 is expressed as L 2 In some embodiments, L 2 is W 5 In this case, R 5b or R 5 is expressed as L 2 In some embodiments, L 2 is W 6 In this case, R 6b or R 6 As shown in formula (ID), L 2In some embodiments, L 2 is W 7 In this case, R 7b or R 7 is expressed as L 2 It is a combination with.

[0133] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , and -N(R 22 )(R 23 Optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0134] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 20 is independently in each occurrence a halogen, oxo, ═NR 22 , -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R25 , -S(O)(NR 22 )R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NR 22 , -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , and -N(R 22 )(R 23 Optionally substituted with 1, 2, or 3 groups independently selected from:

[0135] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 20 is independently in each occurrence a halogen, oxo, =NH, -CN, -NO2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, -CH2- (a 3- to 10-membered heterocyclic ring), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10carbocycle), 3- to 10-membered heterocycle, -CH2- (3- to 10-membered heterocycle) is optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0136] In some embodiments, for compounds of Formula (I-B1), R 5b is -CH3 and R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen. In some embodiments, for compounds of formula (I-B2), R 5 is hydrogen and R 6 is selected from hydrogen and -OCH3, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen.

[0137] In some embodiments, for compounds of Formula (I-C1), R 3 is hydrogen or -CH3, and R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen. In some embodiments, for compounds of formula (I-C2), R 3b is -CH3 and R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen. In some embodiments, for compounds of formula (I-C3), R 3 is hydrogen or -CH3, and R 6 is selected from hydrogen and -OCH3, R 7 is C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3- to 10-membered heterocyclic ring, -N(R 12 )(R 13 ), -C(O)R15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 8 is hydrogen.

[0138] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 is -CH3, [ka] are selected from phenyl and 5- to 7-membered heteroaryl, each of which is selected from one or more R 11 and optionally substituted with L 1 is a bond and C 1-3 haloalkylene; [ka] is selected from absent, phenyl, and a 4- to 8-membered heterocycle, and the phenyl and the 4- to 8-membered heterocycle are each independently selected from one or more R 11a and optionally substituted with L 2 But C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b In some embodiments, R 11 is fluorine, if present, and R 11a is, if present, -CH3, and R 11b If present, halogen, oxo, C 1-6 Alkyl, C 1-6Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0139] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] is one or more R 11a optionally replaced with [ka] and L 2 is C 6-8 Alkylene, C 6-8 alkenylene, and 6- to 8-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, R 1 is -CH3, [ka] and L 1 is C 1-2 haloalkylene, [ka] and L 2 is one or more R 11b In some embodiments, R is a 6- to 8-membered heteroalkylene optionally substituted with 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] is one or more R 11a optionally replaced with [ka] and L 2 is C 6-8 Alkylene and C 6-8 alkenylene, each of which is selected from one or more R 11b In some embodiments, R 1 is -CH3, [ka] and L 1 is C 1-2 haloalkylene, [ka] and L 2 is one or more R 11b C optionally substituted with 6-8 In some embodiments, R is alkenylene. 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] is one or more R 11a optionally replaced with [ka] and L 2 is -(C 1-2alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, and C 1-2 Alkylene and C 3-4 Each alkylene independently has one or more R 11b In some embodiments, R 11a is, if present, -CH3, and R 11b If present, halogen, -CN, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, (C 1-3 alkyl)-OH, and -OH.

[0140] In some embodiments, for a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), or (I-E1), R 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] and L 2 is C 6-8 Alkylene, C 6-8 alkenylene, and 6- to 8-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, R 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] and L 2 is C 6-8 Alkylene and C 6-8 alkenylene, each of which is selected from one or more R 11b In some embodiments, R 1 is -CH3, [ka] Selected from L 1 is C 1-2 haloalkylene, [ka] and L 2 is -(C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, and C 1-2 Alkylene and C 3-4 Each alkylene independently has one or more R 11b In some embodiments, R 11b If present, halogen, -CN, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, (C 1-3 alkyl)-OH, and -OH.

[0141] In some embodiments, the compound of formula (I) is a compound of the following formula: [ka] where R 50 is hydrogen or R 11 and R 51 is hydrogen or halogen.

[0142] In some embodiments, the compound of formula (I) is a compound of the following formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (IA) is a compound of the following formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (IB) is a compound of the following formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (IC) is a compound of the formula: [ka] [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (IC) is a compound of the formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (ID) is a compound of the following formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, the compound of formula (IE) is a compound of the formula: [ka] where R 50 is hydrogen or fluoro. In some embodiments, L 1 is C 1-3Haloalkylene, e.g., C 1-2 Haloalkylene or C 1-2 In some embodiments, L is fluoroalkylene. 2 is C 6-8 Alkylene, C 6-8 alkenylene, and 6- to 8-membered heteroalkylene, each of which is selected from one or more R 11b In some embodiments, L 2 is C 6-8 Alkylene and C 6-8 alkenylene, each of which is selected from one or more R 11b In some embodiments, L 2 is -(C 1-2 alkylene)-C(O)N(CH3)-(C 3-4 alkylene)- or -(C 1-2 alkylene)-C(O)NH-(C 3-4 alkylene)-, and C 1-2 Alkylene and C 3-4 Each alkylene independently has one or more R 11b In some embodiments, R 11b If present, halogen, -CN, C 1-3 Alkyl, C 1-3 Haloalkyl, (C 1-3 In some embodiments, R 50 is hydrogen. In some embodiments, R 50 is fluoro.

[0143] In certain aspects, the present disclosure provides a compound of formula (I-C1): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH3; L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with R 1 is -CH3, R 3 is hydrogen or -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen, R 11 is selected from fluorine and —CH3; R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0144] In certain aspects, the present disclosure provides a compound of formula (I-C1): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine; L 1 is selected from -CF2-, -CF2CH2-, and -CF2CH2CH2-; L 2 is C 5-10 Alkylene, C 5-10 selected from alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene; R 1 is -CH3, R 3 is hydrogen or -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen.

[0145] In certain aspects, the present disclosure provides a compound of formula (I-C1): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH3; L 1 is C 1-3 haloalkylene, L 2 is one or more R 11b C optionally substituted with 5-10 is alkenylene, R 1 is -CH3, R 3 is -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen, R 11 is selected from fluorine and —CH3; R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0146] In certain aspects, the present disclosure provides a compound of formula (I-C1): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is selected from [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is optionally substituted with one or more —CH3; L 1 is C 1-3 haloalkylene, L 2 is one or more R 11b and selected from 5- to 10-membered heteroalkylene optionally substituted with R 1 is -CH3, R 3 is hydrogen or -CH3, R 7 teeth, [ka] is selected from R 8 is hydrogen, R 11 is selected from fluorine and —CH3; R 11b is halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 alkyl)-OH, and -OH.

[0147] In certain aspects, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] are selected from phenyl and 5- to 7-membered heteroaryl, each of which is selected from one or more R 11 optionally substituted with [ka] are absent or selected from phenyl and 4- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond and C 1-3 haloalkylene; L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 2 is N, W 3 is N(R 3b ), N, C(R 3 ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), and C(O), W 5 is N(R 5b ), N, and C(R 5 ) and W 6 is C(R 6 ) and C(O), W 7 is C(R 7 ) and W 8 is C(R 8 ) and W 9 and W 10 are C, respectively, R 1 is -CH3, R 2 , R2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently selected from hydrogen and —CH; R 3 , R 4 , R 5 , and R 6 are each independently L 2 Bonds with hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 selected from haloalkyl, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2; R 7 L 2 Bonding with C 1-6 Alkyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -N(R 12 )(R 13 ), -C(O)R 15 , -C(O)N(R 12 )(R 13 ), -S(O)R 15 , and -SO2N(R 12 )(R 13 ) and C 1-6 Alkyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 3b , R 4b , and R 5b are each independently, L 2 Bonds with hydrogen and C 1-3 alkyl, R 11 , R 11a , and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17atogether with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21, -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0148] In certain aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is one or more R 11a and a 3- to 8-membered heterocycle optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 3 is N(R 3b ) and N; W 4 is C(R 4 ) and C(O), or W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W5 is N(R 5b ), N, and C(R 5 ) and W 6 is N, C(R 6 ) and C(O), W 7 is N, C(R 7 ) and C(O), R 50 is hydrogen or halogen, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , and R 5b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 11a and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17)(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0149] In certain aspects, the present disclosure provides a compound of formula (III): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is one or more R 11a and a 3- to 8-membered heterocycle optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of W 3 is N(R 3b ) and N; W 4 is C(R 4 ) and C(O), or W 3 is C(R 3 ) and C(O), W 4 is N(R 4b ) and N; W 5 is N(R 5b ), N, and C(R 5 ) and W 6 is N, C(R 6 ) and C(O), W 7 is N, C(R 7 ) and C(O), R 50 is hydrogen or halogen, R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , and R 5b are each independently, L 2 Bonds with hydrogen, -CN, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 11a is independently in each occurrence a halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0150] In some embodiments, the compound of formula (III) is a compound of the following formula: [ka] [ka] is.

[0151] In some embodiments, the compound of formula (III) is a compound of the following formula: [ka] is.

[0152] In some embodiments, for compounds of formula (III): [ka] is selected from azetidine, pyrrolidine, and piperidine, each of which is selected from one or more R 11a In some embodiments, [ka] each of which contains one or more R 11a In some embodiments, [ka] is one or more R 11a optionally replaced with [ka] In some embodiments, L 1 is C 1-3 In some embodiments, L is haloalkylene. 2 is C 5-10 alkylene, C 5-10 Alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from the group consisting of one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of the L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b and D is optionally substituted with C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d and optionally substituted with L 4 is C 1-8 Alkylene, C 1-8alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b is optionally substituted with

[0153] In certain aspects, the present disclosure provides compounds of the following formula: [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-8 Alkylene, C 1-8alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b ), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R 5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R 7 )(R 7a ), and C(O), W 8 is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10 ), and C; R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7bare each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11d is independently in each occurrence a halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0154] In certain aspects, the present disclosure provides a compound of formula (II-B) or (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is absent or has one or more R 11a is a 4- to 8-membered heterocycle optionally substituted with L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10 alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b or L 2 But -L 3 -DL 4 - and L 3 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with D is C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-8 Alkylene, C 1-8 alkenylene, 2- to 8-membered heteroalkylene, and 2- to 8-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with R 3 and R 8 are each independently selected from hydrogen and —CH; R 7 is C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which contains 1, 2, or 3 R 20 optionally substituted with R 5b is hydrogen and C 1-3 alkyl, R 50 is selected from hydrogen and halogen; R11a and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, hydrogen and C 1-6 alkyl, R 24 independently in each occurrence, hydrogen and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0155] In some embodiments, the present disclosure provides a compound of formula (II-B) or (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is absent or has one or more R 11a is a 4- to 8-membered heterocycle optionally substituted with L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with R 3 , R 5b , and R 8 are each independently selected from hydrogen and —CH; R 7 is C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which contains 1, 2, or 3 R 20 optionally substituted with R 50 is selected from hydrogen and halogen; R 11a independently in each occurrence, a halogen, C 1-3 Alkyl, and C 1-3 haloalkyl; R 11b is independently in each occurrence halogen, oxo, -CN, C 1-3 alkyl, and —OH; R 20 is independently in each occurrence halogen, oxo, -CN, and C 1-6 alkyl.

[0156] In some embodiments, the present disclosure provides a compound of formula (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is absent or has one or more R 11a is a 4- to 8-membered heterocycle optionally substituted with L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with R 3 is hydrogen, R 8 is selected from hydrogen and —CH3; R 7 teeth, [ka] is selected from R 50 is selected from hydrogen and halogen; R 11a independently in each occurrence, a halogen, C 1-3 Alkyl, and C 1-3 haloalkyl; R 11b is independently in each occurrence halogen, oxo, -CN, C 1-3 alkyl, and —OH; R 20 is independently in each occurrence halogen, oxo, -CN, and C 1-6 alkyl.

[0157] In some embodiments, the present disclosure provides a compound of formula (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is one or more R 11a is a 4- to 8-membered heterocycle optionally substituted with L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10alkenylene, 5- to 10-membered heteroalkylene, and 5- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with R 3 is selected from hydrogen and —CH3; R 8 is selected from hydrogen and —CH3; R 7 teeth, [ka] is selected from R 50 is selected from hydrogen and halogen; R 11a independently in each occurrence, a halogen, C 1-3 Alkyl, and C 1-3 haloalkyl; R 11b is independently in each occurrence halogen, oxo, -CN, C 1-3 alkyl, and —OH.

[0158] In some embodiments, the present disclosure provides a compound of formula (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] is a 4- to 6-membered heterocycle, L 1 is C 1-3 haloalkylene, L 2 is C 5-10 Alkylene, C 5-10 selected from alkenylene, and 5- to 10-membered heteroalkylene; R 3 is selected from hydrogen and —CH3; R 8 is hydrogen, R 7 teeth, [ka] is selected from R 50 is selected from hydrogen and halogen.

[0159] In some embodiments, the present disclosure provides a compound of formula (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] and L 1 is -CF2CH2-, L 2 is a 5- to 10-membered heteroalkylene, the heteroalkylene containing one oxygen atom; R 3 is selected from hydrogen and —CH3; R 8 is hydrogen, R 7 teeth, [ka] is selected from R 50 is selected from hydrogen and halogen.

[0160] In some embodiments, the present disclosure provides a compound of formula (II-C): [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein: [ka] and L 1 is -CF2-, L 2 is C5-10 alkenylene; R 3 is selected from hydrogen and —CH3; R 8 is hydrogen, R 7 teeth, [ka] is selected from R 50 is selected from hydrogen and halogen.

[0161] In some embodiments, the compound of formula (II-B) is a compound of the following formula: [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro. In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is hydrogen. In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is fluoro. In some embodiments, R 7 teeth, [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is hydrogen and R 7 teeth, [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50is fluoro and R 7 teeth, [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] In some embodiments, R 5b is -CH3 and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] is.

[0162] In some embodiments, the compound of formula (II-C) is a compound of the following formula: [ka] [ka] In some embodiments, the compound of formula (II-C) is a compound of the following formula: [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8is hydrogen and R 50 is selected from hydrogen and fluoro. In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is hydrogen. In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is fluoro. In some embodiments, R 3 is hydrogen and R 8 is hydrogen and R 50 is hydrogen. In some embodiments, R 3 is hydrogen and R 8 is hydrogen and R 50 is fluoro. In some embodiments, R 3 is -CH3 and R 8 is hydrogen and R 50 is hydrogen. In some embodiments, R 3 is -CH3 and R 8 is hydrogen and R 50 is fluoro. In some embodiments, R 7 teeth, [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is hydrogen and R 7 teeth, [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is fluoro and R 7 teeth, [ka] In some embodiments, R 3 is hydrogen and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] In some embodiments, R 3 is hydrogen and R 8 is hydrogen and R 50 is hydrogen and R 7 teeth [ka] In some embodiments, R 3 is hydrogen and R 8 is hydrogen and R 50 is fluoro and R 7 teeth, [ka] In some embodiments, R 3 is -CH3 and R 8 is hydrogen and R 50 is hydrogen and R 7 teeth, [ka] In some embodiments, R 3 is -CH3 and R 8 is hydrogen and R 50 is fluoro and R 7 teeth, [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] In some embodiments, R 3 is selected from hydrogen and —CH3, and R 8 is hydrogen and R 50 is selected from hydrogen and fluoro; R 7 teeth, [ka] is.

[0163] Embodiments disclosed herein that refer to compounds of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), and / or (I-E1) are intended to also apply to compounds of Formula (II-B), (II-C), and (III), unless the context of the embodiment expressly dictates otherwise (e.g., an embodiment may refer to a variable, e.g., R), that is not present in compounds of Formula (II-B), (II-C), or (III). 1 only mentions

[0164] Also, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Also provided is a compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

[0165] Also, [ka] [ka] [ka] [ka] Also provided is a compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

[0166] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0167] In some embodiments, the present disclosure provides: [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0168] In some embodiments, the present disclosure provides: [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0169] In some embodiments, the present disclosure provides: [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0170] In some embodiments, the present disclosure provides: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0171] In some embodiments, the compound of formula (I) is a compound of the following formula: [ka] [ka] or a salt or solvate thereof.

[0172] In some embodiments, a compound of Formula (I), such as a compound of Formula (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), (I-E1), (II-B), (II-C), or (III), is provided as a substantially pure stereoisomer. In some embodiments, the stereoisomer is provided in at least 80% enantiomeric excess, e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9% enantiomeric excess.

[0173] In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0174] In some embodiments, the compounds described herein possess acidic or basic groups and thus react with any of a number of inorganic or organic bases or acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified compound in free form with the appropriate acid or base and isolating the salt thus formed.

[0175] In some embodiments, the compounds described herein exist as solvates. In some embodiments, there are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0176] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during the process of crystallization using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0177] In certain aspects, the present disclosure provides compounds of formula AL AB -B, wherein A is a monovalent form of a compound described herein; L AB is a covalent linker connecting A and B, B is a monovalent form of a degradation enhancer.

[0178] A "degradation-promoting agent" is a compound capable of binding to a ubiquitin ligase protein (e.g., an E3 ubiquitin ligase protein) or a protein capable of binding to a ubiquitin ligase protein to form a protein complex that can conjugate the ubiquitin protein to a target protein. In some embodiments, a degradation-promoting agent is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In some embodiments, a degradation-promoting agent is capable of binding to an E2 ubiquitin-conjugating enzyme. In some embodiments, a degradation-promoting agent is capable of binding to a protein complex comprising an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.

[0179] In some embodiments, the pro-degradation agent is selected from the group consisting of E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, PIAS5, PIAS6, PIAS7, PIAS8, PIAS9, PIAS10, PIAS11, PIAS12, PIAS13, PIAS14, PIAS15, PIAS16, PIAS17, PIAS18, PIAS19 ...9, PIAS19, PIAS19, PIAS20, PIAS21, PIAS22, PIAS23, PIAS24, PIAS25, PIAS26, PIAS27, PIAS28, PIAS29, PIAS30, PIAS31, PIAS32, 2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperone-mediated autophagy), SCFb-TRCP (Skip-Cullin-F box (beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4) CRBN) is capable of binding to a protein selected from ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885. In some embodiments, the degradation-promoting agent is capable of binding to a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1. In some embodiments, the degradation promoter is a compound described in Ishida and Ciulli, SLAS Discovery 2021, Vol. 25(4) 484-502, such as VH032, VH101, VH298, thalidomide, bestatin, methylbestatin, nutlin, idasanutlin, bardoxolone, bardoxolone methyl, indisulam (E7070), E7820, chloroquinoxaline sulfonamide (CQS), nimbolide, KB02, ASTX660, lenalidomide, or pomalidomide, which is incorporated by reference in its entirety for all purposes.

[0180] In some embodiments, the degradation promoter is selected from the group consisting of US2018 / 0050021, WO2016 / 146985, WO2018 / 189554, WO2018 / 119441, WO2018 / 140809, WO2018 / 119448, WO2018 / 119357, WO2018 / 118598, WO2018 / 102067, WO2018 / 98280, WO2018 / 89736, WO 2018 / 81530, WO2018 / 71606, WO2018 / 64589, WO2018 / 52949, WO2017 / 223452, WO2017 / 204445, WO2017 / 19 7055, WO2017 / 197046, WO2017 / 180417, WO2017 / 176958, WO2017 / 11371, WO2018 / 226542, WO2018 / 223909 , WO2018 / 189554, WO2016 / 169989, WO2016 / 146985, CN105085620B, CN106543185B, US10040804, US99383 02, US10144745, US10145848, US9938264, US9632089, US9821068, US9758522, US9500653, US9765019, US and US2014 / 0356322, each of which is incorporated by reference in its entirety for all purposes.

[0181] In some embodiments, L AB -L AB1 -L AB2 -L AB3 -L AB4 -L AB5 - and L AB1 , L AB2 , L AB3 , L AB4 , and L AB5 are each independently a bond, -O-, -N(R 100 )-, -C(O)-, -N(R 100)C(O)-, -C(O)N(R 100 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 100 )-, -S(O)N(R 100 )-, -N(R 100 )S(O)-, -N(R 100 )S(O)2-, C 1-6 Alkylene, -(OC 1-6 alkyl) z -, -(C 1-6 Alkyl-O) z -, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 carbocyclene, and 3- to 10-membered heterocyclene; 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 1-6 Haloalkylene, C 3-12 Carbocyclenes and 3- to 10-membered heterocyclenes may contain one, two, or three R 20 Optionally substituted with -(OC 1-6 alkyl) z -and-(C 1-6 Alkyl-O) z -Each C 1-6 Alkyl can be one, two, or three R 20 optionally substituted with each z is independently an integer from 0 to 10; R 100 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 -carbocycle), 3- to 10-membered heterocycle, and -CH2- (3- to 10-membered heterocycle) can be selected from 1, 2, or 3 R20 optionally substituted with R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22)(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 It is optionally substituted with 1, 2, or 3 groups independently selected from carbocycle and 3- to 10-membered heterocycle.

[0182] In some embodiments, L AB is -(O-C2 alkyl) z - and z is an integer from 1 to 10. In some embodiments, L AB is -(C2 alkyl-O-) z - and z is an integer from 1 to 10. In some embodiments, L AB is -(CH2) zz1 L AB2 (CH2O) zz2 - and L AB2 is a bond, 5- to 6-membered heterocyclene, phenylene, -C 2-4 alkynylene, —SO—, or —NH—, and zz1 and zz2 are independently integers from 0 to 10. In some embodiments, L AB is -(CH2) zz1 (CH2O) zz2 -, and zz1 and zz2 are each independently an integer from 0 to 10. In some embodiments, L AB is a PEG linker (e.g., a bivalent linker of 1 to 10 ethylene glycol subunits). In some embodiments, B is [ka] [ka] In some embodiments, B is a monovalent form of a compound selected from: [ka] is a monovalent form of a compound selected from

[0183] Also, [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof. [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0184] The chemicals described herein can be synthesized according to one or more of the exemplary schemes herein and / or techniques known in the art. Materials used herein are commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are used for illustrative purposes. Various steps are described and illustrated in Schemes 1-8 and Examples 1-36, although in some cases, steps may be performed in an order different from that shown in Schemes 1-8 and Examples 1-36. Various modifications to these synthetic reaction schemes may be made and will be suggested to those of skill in the art upon review of this disclosure. The numbering or R groups in each scheme typically have the same meaning as defined elsewhere herein, unless otherwise indicated.

[0185] Unless specified to the contrary, reactions described herein are conducted at atmospheric pressure and generally within a temperature range of −10° C. to 200° C. Furthermore, unless otherwise specified, reaction times and conditions are approximate and are intended to be conducted, for example, at about atmospheric pressure within a temperature range of about −10° C. to about 110° C., for a period of about 1 to about 24 hours, with reactions left overnight having an average duration of about 16 hours.

[0186] In general, the compounds of the present disclosure can be prepared by the following reaction schemes. [ka]

[0187] In some embodiments, compounds of formula 1e can be prepared according to Scheme 1. For example, heteroarylamine 1b can be formed from chloride 1a via a nucleophilic aromatic substitution reaction. Lactam displacement can proceed under basic conditions to give diene 1c, which can undergo a cross-metathesis reaction, such as a Grubbs cross-metathesis reaction, to form macrocycle 1d. Optionally, 1d can be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide compounds of formula 1e. [ka]

[0188] Similarly, in some embodiments, compounds of formula 2e can be prepared according to Scheme 2. For example, heteroarylamine 2b can be formed from chloride 2a via a nucleophilic aromatic substitution reaction. Lactam displacement can proceed under basic conditions to give diene 2c, which can undergo a cross-metathesis reaction, such as a Grubbs cross-metathesis reaction, to form macrocycle 2d. Optionally, 2d can be subjected to one or more subsequent reactions, such as a hydrogenation reaction, to provide compounds of formula 2e. [ka]

[0189] In some embodiments, compounds of formula 3e can be prepared according to Scheme 3. For example, heteroaryl amine 3b can be formed from chloride 3a via a substitution reaction. Lactam displacement can provide protected amine 3c. Ester hydrolysis can form carboxylic acid 3d, which undergoes deprotection and peptide coupling to provide macrocycles of formula 3e. [ka]

[0190] Similarly, in some embodiments, compounds of formula 4e can be prepared according to Scheme 4. For example, heteroaryl amine 4b can be formed from chloride 4a via a substitution reaction. Lactam displacement can provide protected amine 4c. Ester hydrolysis can form carboxylic acid 4d, which undergoes deprotection and peptide coupling to provide macrocycles of formula 4e. [ka]

[0191] In some embodiments, compounds of formula 5g can be prepared according to Scheme 5. For example, heteroarylamine 3c can be formed by coupling chloride 5a with amine 5b. Oxidation of the alcohol can provide aldehyde 5d, which can be followed by displacement of the phenol to provide 5e. Removal of the amine protecting group can provide 5f, which can undergo reductive amination to form the macrocycle of formula 5g. [ka]

[0192] In some embodiments, compounds of formula 6f can be prepared according to Scheme 6. For example, heteroarylamine 6c can be formed by coupling chloride 1a with amine 6b. After substitution of phenol with olefin 6d, a second olefin can be introduced to give diene 6e. After a cross-metathesis reaction, such as a Grubbs cross-metathesis reaction, the resulting double bond can be hydrogenated to provide macrocycles of formula 6f. [ka]

[0193] In some embodiments, compounds of formula 7e can be prepared according to Scheme 7. For example, heteroarylamine 7b can be formed by coupling chloride 7a with amine 5b. Displacement of the phenol affords 7c. Ester hydrolysis and amine deprotection can afford 7d, which can be cyclized via a peptide coupling reaction to form the macrocycle of formula 7e. [ka]

[0194] In some embodiments, compounds of formula 8g can be prepared according to Scheme 8. For example, lactam 8a can be substituted with a suitable bromodioxolane (8b) to afford acetal 8c. Nucleophilic aromatic substitution with amine 8d can provide heteroarylamine 8e, which can be treated with a suitable acid, such as HCl, to remove the Boc protecting group and expose the aldehyde. Finally, cyclization of 8f can proceed via reductive amination conditions to afford macrocycles of formula 8g.

[0195] In some embodiments, compounds of the present disclosure, for example, compounds of the formulas given in Table 1, were synthesized according to one of the general routes outlined in Schemes 1-8, Examples 1-36, or by methods generally known in the art. In some embodiments, exemplary compounds can include, but are not limited to, compounds selected from Table 1, or salts or solvates thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34]

[0196] In some embodiments, compounds of the present disclosure exhibit one or more functional properties disclosed herein. For example, a subject compound can reduce Ras signaling output. In some cases, a subject compound can disrupt Ras-SOS interaction, including disrupting the interaction or binding between mutant Kras (e.g., Kras G12C) and SOS1, or between wild-type Kras and SOS1, thereby reducing Ras signaling output. In some embodiments, a subject compound specifically binds to SOS proteins, including SOS1. In some embodiments, the subject compounds (including those shown in Table 1) have an IC50 against SOS proteins of less than about 5 μM, less than about 1 μM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in in vitro assays known in the art or exemplified herein.

[0197] A reduction in Ras signaling output can be evidenced by one or more of the following: (i) an increase in steady-state levels of GDP-bound Ras protein, (ii) a reduction in steady-state levels of GTP-bound Ras protein, (iii) a reduction in phosphorylated AKTs473, (iv) a reduction in phosphorylated ERKT202 / y204, (v) a reduction in phosphorylated S6S235 / 236, (vi) a reduction (e.g., inhibition) of cell proliferation in Ras-driven tumor cells (e.g., derived from a tumor cell line disclosed herein), or (vii) interference with or disruption of the interaction or binding between an SOS protein (e.g., SOS1) and a Ras protein, e.g., wild-type or mutant Ras. In some cases, a reduction in Ras signaling output can be evidenced by two, three, four, five, six, or all of (i)-(vii) above.

[0198] It is understood that different aspects of the present invention can be evaluated individually, collectively, or in combination with one another. The various aspects of the present invention described herein can be applied to any of the specific uses disclosed herein. In the composition section of this disclosure, a composition of matter, including a compound of any formula disclosed herein, can be utilized in the method section, including the methods of use and manufacture disclosed herein, and vice versa.

[0199] method In certain aspects, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor or a hematological cancer. In some embodiments, the subject is administered an additional agent or additional therapy.

[0200] In certain aspects, the present disclosure provides methods for reducing Ras signaling output, comprising contacting an SOS1 protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby reducing Ras signaling output. In some embodiments, the compound disrupts the interaction between the Ras protein and SOS1. In some embodiments, the Ras protein is wild-type K-Ras or mutant K-Ras.

[0201] In certain aspects, methods are provided for inhibiting cell proliferation, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing SOS1, thereby inhibiting proliferation of the cell.

[0202] In certain aspects, the present disclosure provides a method of reducing Ras signaling output in a cell, the method comprising contacting the cell with an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, in combination with an additional agent, wherein the additional agent is a chemotherapeutic agent, a radioactive agent, an immunomodulator, or one or more targets selected from the group consisting of MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinases, topoisomerases, ALK, and the like. and AKT, wild-type KRas, KRas mutants (e.g., KrasG12C, KRasG12D, KRasG12S, KRasG12V, KRasG13D, KRasG13C, or KRasG13V), ROS1, CDK4 / 6, and mutants of one or more targets thereof, wherein the compound of formula (I) has the following structure: [ka] and During the ceremony, [ka] is C 5-7 carbocycle and 5- to 7-membered heterocycle, each of which is selected from one or more R 11 optionally substituted with [ka] is absent or C 3-8 carbocycle and 3- to 8-membered heterocycle, each of which is selected from one or more R 11a optionally substituted with L 1 is a bond, C 1-6 Alkylene, and C 1-6 haloalkylene; L 2 is C 5-25 Alkylene, C 5-25 Alkenylene, C 5-25 alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is selected from one or more R 11b and optionally substituted with L 2 is W 3 , W 4 , W 5 , W 6 , or W 7 or L 2 -L 3 -DL 4 - and L 4 But, W 3 , W 4 , W 5 , W 6 , or W 7 covalently bonded to one of L 3 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R11b optionally substituted with D is absent or C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which is selected from one or more R 11d optionally substituted with L 4 is C 1-10 Alkylene, C 1-10 Alkenylene, C 1-10 alkynylene, 2- to 10-membered heteroalkylene, and 2- to 10-membered heteroalkenylene, each of which is selected from one or more R 11b optionally substituted with W 2 is N(R 2b ), N, C(R 2 ), C(R 2 )(R 2a ), and C(O), W 3 is N(R 3b ), N, C(R 3 ), C(R 3 )(R 3a ), and C(O), W 4 is N(R 4b ), N, C(R 4 ), C(R 4 )(R 4a ), and C(O), W 5 is N(R 5b ), N, C(R 5 ), C(R 5 )(R 5a ), and C(O), W 6 is N(R 6b ), N, C(R 6 ), C(R 6 )(R 6a ), and C(O), W 7 is N(R 7b ), N, C(R 7 ), C(R 7 )(R 7a ), and C(O), W 8is N(R 8b ), N, C(R 8 ), C(R 8 )(R 8a ), and C(O), W 9 is N, C(R 9 ), and C; W 10 is N, C(R 10 ), and C; R 1 is one or more R 11c C optionally substituted with 1-3 is alkyl, R 2 , R 2a , R 3a , R 4a , R 5a , R 6a , R 7a , R 8 , and R 8a are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 3 , R 4 , R 5 , R 6 , and R 7 are each independently, L 2 Bonds with hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may independently contain 1, 2, or 3 R 20 optionally substituted with R 2b and R 8b are each independently hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15, -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected from 1, 2, or 3 R 20 optionally substituted with R 3b , R 4b , R 5b , R 6b , and R 7b are each independently, L 2 Bonds with hydrogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -S(O)R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , and -CH2S(O)2N(R 12 )(R 13 ) are selected from each C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10The carbocycle and the 3- to 10-membered heterocycle may independently contain 1, 2, or 3 R 20 optionally substituted with R 9 and R 10 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), a 3- to 10-membered heterocyclic ring, and —CH—(3- to 10-membered heterocyclic ring), 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2-(3- to 10-membered heterocyclic ring) are independently selected from 1, 2, or 3 R 20 optionally substituted with R 11 , R 11a , and R 11d are each independently in each occurrence halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R 12 )(R 13 ), -N(R 14)C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11b is independently in each occurrence halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic ring, 3-10 membered heterocyclic ring, -OR 12 , -SR 12 , -N(R 12 )(R 13 ), -C(O)OR 12 , -OC(O)N(R 12 )(R 13 ), -N(R 14 )C(O)N(R 12 )(R 13 ), -N(R 14 )C(O)OR 15 , -N(R 14 )S(O)2R 15 , -C(O)R 15 , -S(O)R 15 , -OC(O)R 15 , -C(O)N(R 12 )(R 13 ), -C(O)C(O)N(R12 )(R 13 ), -N(R 14 )C(O)R 15 , -S(O)2R 15 , -S(O)2N(R 12 )(R 13 ), -S(=O)(=NH)N(R 12 )(R 13 ), -CH2C(O)N(R 12 )(R 13 ), -CH2N(R 14 )C(O)R 15 , -CH2S(O)2R 15 , -CH2S(O)2N(R 12 )(R 13 ), -CH2N(R 12 )S(O)2(R 13 ), and -P(O)(R 17 )(R 17a ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 11c independently in each occurrence, a halogen, -OR 12 , and -N(R 12 )(R 13 ) and R 12 independently in each occurrence, hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 13 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6haloalkyl, or R 12 and R 13 together with the nitrogen atom to which they are attached, form one, two, or three R 20 forming a 3- to 10-membered heterocycle optionally substituted with R 14 independently in each occurrence, hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 15 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycles and 3- to 10-membered heterocycles may contain one, two, or three R 20 optionally substituted with R 17 and R 17a are each independently in each occurrence, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Cycloalkyl can have one, two, or three R 20 or R 17 and R 17a together with the phosphorus atom to which they are attached form a 3- to 10-membered heterocyclic ring, R 20 is independently in each occurrence halogen, oxo, =NH, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 carbocyclic ring), 3- to 10-membered heterocyclic ring, -CH2- (3- to 10-membered heterocyclic ring), -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22, -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25 , -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), -OCH2C(O)OR 22 , and -OC(O)R 25 Selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocycle, -CH2-(C 3-10 Carbocyclic ring), 3- to 10-membered heterocyclic ring, and -CH2- (3- to 10-membered heterocyclic ring) are not substituted with halogen, oxo, ═NH, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 21 , -SR 21 , -N(R 22 )(R 23 ), -C(O)OR 22 , -C(O)N(R 22 )(R 23 ), -C(O)C(O)N(R 22 )(R 23 ), -OC(O)N(R 22 )(R 23 ), -N(R 24 )C(O)N(R 22 )(R 23 ), -N(R 24 )C(O)OR 25 , -N(R 24 )C(O)R 25, -N(R 24 )S(O)2R 25 , -C(O)R 25 , -S(O)2R 25 , -S(O)2N(R 22 )(R 23 ), and -OC(O)R 25 and optionally substituted with 1, 2, or 3 groups independently selected from R 21 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 22 independently in each occurrence, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not halogenated and C 1-6 optionally substituted with 1, 2, or 3 groups independently selected from alkyl; R 23 independently in each occurrence, H and C 1-6 alkyl, R 24 independently in each occurrence, H and C 1-6 alkyl, R 25 independently in each occurrence, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, 1-6 Alkyl, C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are not substituted with halogen, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 optionally substituted with 1, 2, or 3 groups independently selected from carbocycle, and 3- to 10-membered heterocycle; [ka] indicates a single or double bond such that all valences are satisfied.

[0203] In some embodiments, the additional agent is an inhibitor of one or more targets selected from MEK, epidermal growth factor receptor (EGFR), A-Raf, B-Raf, C-Raf, ErbB2 (Her2), SHP2, wild-type KRas, KRas mutants, and CDK4 / 6. In some embodiments, the additional agent is a chemotherapeutic agent, a radioactive agent, or an immunomodulator.

[0204] In certain aspects, the present disclosure provides an SOS1 protein bound by a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the interaction between the SOS1 protein and a Ras protein is reduced compared to an SOS1 protein not bound to the compound.

[0205] In certain aspects, the disclosure provides methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (IA), (IB), (I-B1), (I-B2), (IC), (I-C1), (I-C2), (I-C3), (ID), (I-D1), (I-D2), (IE), (I-E1), (II-B), (II-C), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor or a hematological cancer, e.g., a solid tumor. In some embodiments, the cancer is prostate cancer, brain cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, lung cancer, non-small cell lung cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancer, cancer of the thyroid gland, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, cancer of the urethra, cancer of the penis, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, cancer of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, combinations of the above cancers, and metastatic lesions of the above cancers. In some embodiments, the cancer is a hematological cancer such as chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma or large cell follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, or preleukemia.In some embodiments, the cancer is one or more cancers selected from chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and acute lymphoblastic leukemia (ALL).

[0206] Any of the therapies disclosed herein can be administered alone or in combination or concomitantly with another therapy or other drug. "Combination" is meant to include (a) formulating a subject composition containing a subject compound together with another drug, and (b) using a subject composition separately from the other drug as part of an overall treatment regimen. "In combination" means that another therapy or drug is administered simultaneously, concurrently, or sequentially with a subject compound, including a compound disclosed herein, without specific time restrictions, and such combined administration results in a therapeutic effect.

[0207] In some embodiments, the subject treatment methods are combined with surgery, cell therapy, chemotherapy, radiation, and / or immunosuppressants. Additionally, the compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergy agents, anti-nausea (or anti-emetic) agents, analgesics, cytoprotective agents, immunostimulants, and combinations thereof. In some embodiments, the subject treatment methods are combined with chemotherapeutic agents.

[0208] Exemplary chemotherapeutic agents include anthracyclines (e.g., doxorubicin (e.g., liposomal doxorubicin)), vinca alkaloids (e.g., vinblastine, vincristine, vindesine, vinorelbine), alkylating agents (e.g., cyclophosphamide, decylcarbazine, melphalan, ifosfamide, temozolomide), immune cell antibodies (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), and chemotherapeutic agents (e.g., cefotaxime ... These include agonists (including, for example, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors (e.g., fludarabine)), TNFR glucocorticoid-inducible TNFR-related protein (GITR) agonists, proteasome inhibitors (e.g., aclacinomycin A, gliotoxin, or bortezomib), and immunomodulators such as thalidomide or thalidomide derivatives (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), idarubicin (Idamycin®), mitoxantrone (Novantrone®), gemtuzumab ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®),Capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, gemcitabine (difluorodeoxycytidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantro®), ne®), Mylotarg, paclitaxel (Taxol®), Phoenix (Yttrium 90 / MX-DTPA), pentostatin, polipheprosan 20 and carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), injectable topotecan hydrochloride (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0209] Anti-cancer agents of particular interest for combination with the compounds of the present disclosure include anthracyclines; alkylating agents; antimetabolites; drugs that inhibit either the calcium-dependent phosphatase calcineurin or the p70S6 kinase FK506 or that inhibit p70S6 kinase; mTOR inhibitors; immunomodulatory agents; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; CDK4 kinase inhibitors; BTK inhibitors; MKN kinase inhibitors; DGK kinase inhibitors; or oncolytic viruses.

[0210] Exemplary antimetabolites include, but are not limited to, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors: methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine, and gemcitabine (Gemzar®). Preferred antimetabolites include cytarabine, clofarabine, and fludarabine.

[0211] Exemplary alkylating agents include, but are not limited to, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes: uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard, etc.) Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), pipou These include broman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Further exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (also known as CCNU, CeeNU®); cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); chlorambucil (Leukeran®) cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (DTIC, also known as DIC and imidazole carboxamide, DTIC-Dome®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prednummustine; procarbazine (Matulane®); mechlorethamine (nitrogen mustard, mustine and These include mechloroethamine hydrochloride, Mustargen®; streptozocin (Zanosar®); thiotepa (also known as thiophosphamide, TESPA and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).

[0212] In some embodiments, the compositions provided herein can be administered in combination with radiation therapy, such as radiation. Total body irradiation can be administered at 12 Gy. The radiation dose can include a cumulative dose of 12 Gy to the whole body, including healthy tissue. The radiation dose can include 5 Gy to 20 Gy. The radiation dose can be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12 Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. The irradiation can be total body irradiation or partial body irradiation. If the irradiation is total body irradiation, the irradiation can be uniform or non-uniform. For example, if the radiation is non-uniform, a smaller area of ​​the body, such as the neck, may receive a higher dose than a larger area, such as the lower back.

[0213] If desired, immunosuppressants can be used in combination with the subject treatment methods. Exemplary immunosuppressants include, but are not limited to, cyclosporine, azathioprine, methotrexate, mycophenolate esters, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and radiation, peptide vaccines, and any combination thereof. In accordance with the subject matter of the present disclosure, the various methods described above may include administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of an immunostimulatory agent, a checkpoint immune blockade agent (e.g., a blocker or inhibitor of immune checkpoint genes such as PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs, and CD39), a radiotherapy agent, a chemotherapeutic agent, and combinations thereof. In some embodiments, the immunostimulatory agent is selected from the group consisting of IL-12, an agonistic costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonistic costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, taborixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In some embodiments, the agonistic costimulatory monoclonal antibody is an anti-4-l BB antibody.In some embodiments, the checkpoint immune blockade is selected from the group consisting of anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade is an anti-PD-L1 antibody. In some cases, the compounds of the present disclosure can be administered to a subject in combination with (e.g., before, concurrently with, or after) T-cell ablative therapy using bone marrow transplantation, chemotherapy such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, the expanded cells can be administered before or after surgery. Alternatively, compositions containing the compounds described herein can be administered with an immunostimulant. The immunostimulant can be a vaccine, colony-stimulating agent, interferon, interleukin, virus, antigen, costimulatory agent, immunogenic agent, immunomodulatory agent, or immunotherapeutic agent. The immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced using the modified cells provided herein. Cytokines can be used to enhance the function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) and allow them to proliferate within the tumor microenvironment. In some cases, IL-2 can be used to promote the proliferation of the modified cells described herein. Cytokines such as IL-15 can also be used. Other cytokines relevant in the field of immunotherapy, such as IL-2, IL-7, IL-12, IL-15, IL-21, or combinations thereof, can also be used. The interleukin can be IL-2 or aldesleukin. Aldesleukin can be administered at low or high doses.A high-dose aldesleukin regimen can include intravenously administering aldesleukin at a dose of about 0.037 mg / kg (600,000 IU / kg) every 8 hours for up to about 14 doses, depending on tolerability. The immunostimulant (e.g., aldesleukin) can be administered within 24 hours after cell administration. The immunostimulant (e.g., aldesleukin) can be administered as an infusion over about 15 minutes about every 8 hours for up to about 4 days after cell infusion. The immunostimulant (e.g., aldesleukin) can be administered at a dose of about 100,000 IU / kg, 200,000 IU / kg, 300,000 IU / kg, 400,000 IU / kg, 500,000 IU / kg, 600,000 IU / kg, 700,000 IU / kg, 800,000 IU / kg, 900,000 IU / kg, or up to about 1,000,000 IU / kg. In some cases, aldesleukin may be administered at a dose of about 100,000 IU / kg to 300,000 IU / kg, 300,000 IU / kg to 500,000 IU / kg, 500,000 IU / kg to 700,000 IU / kg, or 700,000 IU / kg to about 1,000,000 IU / kg.

[0214] In some embodiments, the compounds disclosed herein capable of modulating SOS proteins (e.g., SOS1) to reduce Ras signaling output may be administered in combination with or in conjunction with one or more pharmacologically active agents, including, but not limited to: (1) inhibitors of MEK (e.g., MEK1, MEK2) or mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) inhibitors of epidermal growth factor receptor (EGFR) and / or mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, (3) immunotherapeutics (e.g., checkpoint immune blockers as disclosed herein); (4) taxanes (e.g., paclitaxel, docetaxel); (5) antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (arabinose), C), fludarabine); (6) inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or variants thereof (e.g., nintedanib); (7) mitotic kinase inhibitors (e.g., CDK4 / 6 inhibitors, such as palbociclib, ribociclib, abemaciclib, etc.); (8) antiangiogenic agents (e.g., anti-VEGF antibodies, such as bevacizumab, etc.); (9) topoisomerase inhibitors (e.g., epipoids such as etoposide and etoposide, etc. phyllotoxin, teniposide, amsacrine, topotecan, irinotecan, mitoxantrone; (10) platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin); (11) inhibitors of ALK and / or their variants (e.g., crizotinib, alectinib, entrectinib, brigatinib); (12) inhibitors of c-MET and / or their variants (e.g., K252a, SU11274, PHA665752, PF2341066);(13) BCR-ABL inhibitors and / or mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) ErbB2 (Her2) inhibitors and / or mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) AXL inhibitors and / or mutants thereof (e.g., R428, amuvatinib, XL-880); (16) NTRK1 inhibitors and / or mutants thereof (e.g., merestinib); (17) RET inhibitors and and / or mutants thereof (e.g., BLU-667, lenvatinib); (18) inhibitors of A-Raf, B-Raf (e.g., sorafenib, vemurafenib, debrafenib, encorafenib) and / or inhibitors of C-Raf and / or mutants thereof (RAF-709, LY-3009120); (19) inhibitors of ERK and / or mutants thereof (e.g., ulixertinib); (20) MDM2 inhibitors (e.g., HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115; (21) mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) BET inhibitors (e.g., I-BET 151, I-BET 762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645; (23) inhibitors of IGF1 / 2 and / or IGF1-R (e.g., zentuzumab, MEDI-573); (24) inhibitors of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B) B), AT7519, dinaciclib, SNS-032; (25) farnesyltransferase inhibitors (e.g., tipifarnib); (26) SHIP pathway inhibitors, including SHIP2 inhibitors (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine) and SHIP1 inhibitors; (27) SRC inhibitors (e.g., dasatinib); (28) JAK inhibitors (e.g., tofacitinib);(29) PARP inhibitors (e.g., olaparib, rucaparib, niraparib, talazoparib); (30) BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib); (31) ROS1 inhibitors (e.g., entrectinib); (32) inhibitors of FLT3 HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, or AKT; (33) inhibitors of Kras12C mutants (e.g., including, but not limited to, AMG510, MRTX849, and any covalent inhibitors that bind to cysteine ​​residue 12 of Kras. The structures of these compounds are known) (e.g., US2018 / 0334454, US2019 / 0144444, US2015 / 0239900, US10246424, US201 8 / 0086753, WO2018 / 143315, WO2018 / 206539, WO2019 / 1107519, WO2019 / 141250, WO2019 / 150305, US9862701, US2017 / 01979 45, US2018 / 0086753, US10144724, US2019 / 0055211, US2019 / 0092767, US2018 / 0127396, US2018 / 0273523, US10280172, US2 018 / 0319775, US2018 / 0273515, US2018 / 0282307, US2018 / 0282308, WO2019 / 051291, WO2019 / 213526, WO2019 / 213516, WO20 19 / 217691, WO2019 / 241157, WO2019 / 217307, WO2020 / 047192, WO2017 / 087528, WO2018 / 218070, WO2018 / 218069, WO2018 / 21 8071, WO2020 / 027083, WO2020 / 027084, WO2019 / 215203, WO2019 / 155399, WO2020 / 035031, WO2014 / 160200, WO2018 / 195349, WO2018 / 112240, WO2019 / 204442, WO2019 / 204449, WO2019 / 104505, WO2016 / 179558, WO2016 / 176338, or related patents and applications, each of which is incorporated by reference in its entirety;(34) SHC inhibitors (e.g., PP2, AID371185); (35) GAB inhibitors (e.g., GAB-0001); (36) GRB inhibitors; (37) PI-3 kinase inhibitors (e.g., idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-AN); (38) MARPK inhibitors; (39) CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib); (40) MAPK inhibitors (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); (41) inhibitors of the SHP pathway, SHP2 inhibitors (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601); [ka] and SHP1 inhibitors; or (42) inhibitors of wild-type KRas or Kras mutants (e.g., Kras G12D, KRas G12C, KRas G12D, KRas G12S, KRas G12V, KRas G13D, KRas G13C, or KRas G13V, including compounds described in WO2021 / 041671), such as LY3537982, JAB-21822, BBO-8520, D-1553, BI-1823911, RMC-9805, [ka] In some embodiments, the KRAS or mutant KRAS inhibitor is a compound disclosed in WO2021 / 041671, WO2023 / 004102, WO2022 / 223037, WO2023 / 041059, WO2021 / 118877, WO2020 / 233592, WO2021 / 091967, WO2021 / 091982, WO2021 / 091956, WO2022 / 060836, or related patents and applications, each of which is incorporated by reference in its entirety. Inhibitors of any of the exemplary targets are applicable to corresponding mutant targets having one or more mutations therein. In some embodiments, compounds disclosed herein that can inhibit SOS proteins (e.g., SOS1) and reduce Ras signaling output can be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies).

[0215] In combination therapy, the compounds provided herein and other anticancer drugs can be administered simultaneously, in parallel, or sequentially, without specific time restrictions, providing therapeutically effective levels of the two compounds in the patient's body. In some embodiments, the compounds disclosed herein and other anticancer drugs are generally administered sequentially in any order via infusion or orally. The administration regimen may vary depending on the stage of the disease, the patient's physical condition, the safety profile of each drug, the tolerance of each drug, and other criteria known to the attending physician and doctor administering the combination. The compounds of the present invention and other anticancer drugs can be administered within minutes, hours, days, or weeks of each other, depending on the specific cycle used in treatment. In addition, the cycle may include administering one drug more frequently than the other during the treatment cycle, or administering different doses for each drug administration.

[0216] Antibiotics can be administered to a subject as part of a treatment regimen. Antibiotics can be administered at therapeutically effective doses. Antibiotics can kill or inhibit the growth of bacteria. Antibiotics can be broad-spectrum antibiotics that can target a wide range of bacteria. Third- or fourth-generation broad-spectrum antibiotics can be cephalosporins or quinolones. Antibiotics can also be narrow-spectrum antibiotics that can target specific types of bacteria. Antibiotics such as penicillins and cephalosporins can target bacterial cell walls. Antibiotics such as polymyxins can target cell membranes. Antibiotics such as rifamycins, lipiarmycins, quinolones, and sulfonamides can inhibit essential bacterial enzymes. Antibiotics can also be protein synthesis inhibitors such as macrolides, lincosamides, and tetracyclines. Antibiotics can also be cyclic lipopeptides such as daptomycin, glycylcyclines such as tigecycline, oxazolidinones such as linezolid, or lipiarmycins such as fidaxomicin. In some cases, the antibiotic may be a first-generation, second-generation, third-generation, fourth-generation, or fifth-generation antibiotic. A first-generation antibiotic may have a narrow spectrum. Examples of first-generation antibiotics include penicillins (penicillin G or penicillin V), cephalosporins (cefazolin, cephalothin, cephapirin, cepharetin, cephradine, or cefadroxine). In some cases, the antibiotic may be a second-generation antibiotic. A second-generation antibiotic may be a penicillin (amoxicillin or ampicillin), a cephalosporin (cefuroxime, cefamandole, cefoxitin, cefaclor, cefrodil, or loracarbef). In some cases, the antibiotic may be a third-generation antibiotic. A third-generation antibiotic may be a penicillin (carbenicillin and ticarcillin) or a cephalosporin (cefixime, ceftriaxone, cefotaxime, ceftizoxime, and ceftazidime). The antibiotic may also be a fourth generation antibiotic. The fourth generation antibiotic may be Cefipime. The antibiotic may also be a fifth generation antibiotic. The fifth generation antibiotic may be Ceftaroline or Septobiprole. ...

Claims

1. Compound of formula (I): 【Chemical 401】 or a pharmaceutically acceptable salt or solvate thereof, in the formula, 【Chemical 402】 C ５－７ Selected from carbon rings and 5- to 7-membered heterocycles, each of which contains one or more R １１ It is optionally replaced by, 【Chemical 403】 is absent, or C ３－８ Selected from carbon rings and 3- to 8-membered heterocycles, each of which contains one or more R １１ａ It is optionally replaced by, L １ C １－６ Alkylene and C １－６ Selected from haloalkylenes, L ２ is selected from C ５－２５ alkylene, C ５－２５ alkenylene, C ５－２５ alkynylene, 5- to 25-member heteroalkylene, and 5- to 25-member heteroalkenylene, each of which is optionally substituted with one or more R １１ｂ and L ２ is covalently bonded to one of W ３ , W ４ , W ５ , W ６ , or W ７ ​ W ２ N is, W ３ N(R) ３ｂ ), N, C (R ３ Selected from C(O), W ４ N(R) ４ｂ ), N, C (R ４ Selected from C(O), W ５ N(R) ５ｂ ), N, and C (R ５ ) are selected from, W ６ is C(R ６ Selected from C(O), W ７ is C(R ７ ) and W ８ is C(R ８ ) and W ９ C is, W １０ C is, R １ is one or more R １１ｃ C is optionally replaced by １－３ It is alkyl, R8 is hydrogen, halogen, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ carbocyclic ring, 3- to 10-membered heterocyclic ring, -OR １２ , -SR １２ , -N(R １２ )(R １３ ), -C(O)OR １２ , -OC(O)N(R １２ )(R １３ ), -N(R １４ )(O)N(R １２ )(R １３ ), -N(R １４ )(O)OR １５ , -N(R １４ )(O)R ２ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １５ )(R １２ ), -C(O)C(O)N(R １３ )(R １２ ), -N(R １３ )(O)R １４ ), -S(O)R １５ , -S(O)R ２ , -S(O)N(R １５ )(R ２ ), -S(=O)(=NH)N(R １２ )(R １３ ), -CH １２ C(O)N(R １３ )(R ２ ), -CH １２ N(R １３ )(O)R<0OO0078>), -CH １４ S(O)R １５ , and -CH ２ S(O)N(R ２ )(R １５ ), and is selected from -CH ２ S(O)N(R ２ )(R １２ )(R １３ ), and each C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C [[ID=1o3]] ３－１０ The carbon ring and the 3- to 10-membered heterocycle independently have 1, 2, or 3 R groups. ２０ It is optionally replaced by, R ３ 、R ４ 、R ５ 、R ６ 、and R ７ are each independently, a bond with L ２ , hydrogen, halogen, -CN, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ carbocycle, 3- to 10-membered heterocycle, -OR １２ , -SR １２ , -N(R １２ )(R １３ ), -C(O)OR １２ , -OC(O)N(R １２ )(R １３ ), -N(R １４ )(O)N(R １２ )(R １３ ), -N(R １４ )(O)OR １５ , -N(R １４ )(O)S ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ )(R １３ ), -C(O)C(O)N(R １２ )(R １３ ), -N(R １４ )(O)R １５ , -S(O) ２ R １５ , -S(O) ２ , -S(O)N(R １２ )(R １３ ), -S(=O)(=NH)N(R １２ )(R １３ ), -CH ２ C(O)N(R １２ )(R １３ ), -CH ２ N(R １４ )(O)R １５ , -CH ２ , -S(O) ２ R １５ , and -CH ２ , -S(O)<​​​ １３ ) are selected from each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The carbon ring and the 3- to 10-membered heterocycle independently have 1, 2, or 3 R groups. ２０ It is optionally replaced by, R ３ｂ , R ４ｂ , and R5b are each independent of L ２ Bonding with hydrogen, -CN, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings, 3- to 10-membered heterocycles, -OR １２ ,-SR １２ , -C(O)OR １２ , -OC(O)N(R １２ ) (Caution １３ ), -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (Caution １３ ), -C(O)C(O)N(R １２ ) (Caution １３ ), -S(O) ２ R １５ , -S(O) ２ N(R) １２ ) (Caution １３ ), -S(=O)(=NH)N(R １２ ) (Caution １３ ), -CH ２ C(O)N(R) １２ ) (Caution １３ ), -CH ２ N(R) １４ ) C(O)R １５ ien-CH ２ S(O) ２ R １５ , and -CH ２ S(O) ２ N(R) １２ ) (Caution １３ ) are selected from each C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ The carbon rings and 3- to 10-membered heterocycles independently contain 1, 2, or 3 R groups. ２０ It is optionally replaced by, R １１ And R11a independently represents halogen, -CN, and C in each appearance. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings, 3- to 10-membered heterocycles, -OR １２ ,-SR １２ , -N(R １２ ) (Caution １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)OR １５ , -N(R １４ ) S(O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (Caution １３ ), -C(O)C(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N(R) １２ ) (Caution １３ ), -S(=O)(=NH)N(R １２ ) (Caution １３ ), -CH ２ C(O)N(R) １２ ) (Caution １３ ), -CH ２ N(R) １４ ) C(O)R １５ ien-CH ２ S(O) ２ R １５ ien-CH ２ S(O) ２ N(R) １２ ) (Caution １３ ), -CH ２ N(R) １２ ) S(O) ２ (R １３ ), and -P(O)(R １７ ) (Caution １７ａ ) is selected from C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles have 1, 2, or 3 R atoms. ２０ It is optionally replaced by, R １１ｂ In each occurrence, halogen, oxo, -CN, and C appear independently. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings, 3- to 10-membered heterocycles, -OR １２ ,-SR １２ , -N(R １２ ) (Caution １３ ), -C(O)OR １２ , -OC(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)OR １５ , -N(R １４ ) S(O) ２ R １５ , -C(O)R １５ , -S(O)R １５ , -OC(O)R １５ , -C(O)N(R １２ ) (Caution １３ ), -C(O)C(O)N(R １２ ) (Caution １３ ), -N(R １４ ) C(O)R １５ , -S(O) ２ R １５ , -S(O) ２ N(R) １２ ) (Caution １３ ), -S(=O)(=NH)N(R １２ ) (Caution １３ ), -CH ２ C(O)N(R) １２ ) (Caution １３ ), -CH ２ N(R) １４ ) C(O)R １５ ien-CH ２ S(O) ２ R １５ ien-CH ２ S(O) ２ N(R) １２ ) (Caution １３ ), -CH ２ N(R) １２ ) S(O) ２ (R １３ ), and -P(O)(R １７ ) (Caution １７ａ ) is selected from C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles have 1, 2, or 3 R atoms. ２０ It is optionally replaced by, R １１ｃ Each occurrence is independent of halogen, -OR １２ , and -N(R １２ ) (Caution １３ ) are selected from, R １２ In each appearance, hydrogen and C appear independently. １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Selected from carbon rings and 3- to 10-membered heterocycles, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles have 1, 2, or 3 R atoms. ２０ It is optionally replaced by, R １３ In each appearance, hydrogen and C appear independently. １－６ Alkyl and C １－６ Selected from haloalkyls, or R １２ and R １３ These, together with the nitrogen atom to which they bond, form one, two, or three R atoms. ２０ They form 3- to 10-membered heterocycles that are optionally substituted, R １４ In each appearance, hydrogen and C appear independently. １－６ Alkyl and C １－６ Selected from haloalkyl groups, R １５ In each occurrence, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Selected from carbon rings and 3- to 10-membered heterocycles, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles have 1, 2, or 3 R atoms. ２０ It is optionally replaced by, R １７ and R １７ａ Each occurrence is independent of C １－６ Alkyl and C ３－６ Selected from cycloalkyl, C １－６ Alkyl and C ３－６ Cycloalkyl groups have 1, 2, or 3 R groups. ２０ It is either optionally replaced by R １７ and R １７ａ These, together with the phosphorus atoms to which they are bonded, form a 3- to 10-membered heterocycle. R ２０ In each occurrence, halogen, oxo, =NH, -CN, and C are independent. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbocycle, -CH ２ - (C ３－１０ Carbon rings), 3- to 10-membered heterocycles, -CH ２ - (3- to 10-membered complex ring), - OR ２１ ,-SR ２１ , -N(R ２２ ) (Caution ２３ ), -C(O)OR ２２ , -C(O)N(R ２２ ) (Caution ２３ ), -C(O)C(O)N(R ２２ ) (Caution ２３ ), -OC(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)OR ２５ , -N(R ２４ ) C(O)R ２５ , -N(R ２４ ) S(O) ２ R ２５ , -C(O)R ２５ , -S(O) ２ R ２５ , -S(O) ２ N(R) ２２ ) (Caution ２３ ), -OCH ２ C(O)OR ２２ , and -OC(O)R ２５ Selected from, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Carbocycle, -CH ２ - (C ３－１０ Carbon rings), 3- to 10-membered heterocycles, and -CH ２ - (3- to 10-membered heterocycles) are halogens, oxo, =NH, -CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ２１ ,-SR ２１ , -N(R ２２ ) (Caution ２３ ), -C(O)OR ２２ , -C(O)N(R ２２ ) (Caution ２３ ), -C(O)C(O)N(R ２２ ) (Caution ２３ ), -OC(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)N(R ２２ ) (Caution ２３ ), -N(R ２４ ) C(O)OR ２５ , -N(R ２４ ) C(O)R ２５ , -N(R ２４ ) S(O) ２ R ２５ , -C(O)R ２５ , -S(O) ２ R ２５ , -S(O) ２ N(R) ２２ ) (Caution ２３ ), and -OC(O)R ２５ It is optionally substituted with one, two, or three elements independently selected from the above, R ２１ In each occurrence, H and C appear independently. １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Selected from carbon rings and 3- to 10-membered heterocycles, C ３－１０ Carbon rings and 3- to 10-membered heterocycles contain halogens and C １－６ Optionally substituted with one, two, or three groups independently selected from the alkyl group, R ２２ In each occurrence, H and C appear independently. １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Selected from carbon rings and 3- to 10-membered heterocycles, C ３－１０ Carbon rings and 3- to 10-membered heterocycles contain halogens and C １－６ Optionally substituted with one, two, or three groups independently selected from the alkyl group, R ２３ In each appearance, H and C are independent. １－６ Selected from alkyl groups, R ２４ In each appearance, H and C are independent. １－６ Selected from alkyl groups, R ２５ In each occurrence, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Selected from carbon rings and 3- to 10-membered heterocycles, C １－６ Alkyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles are halogens, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ３－１０ They are optionally substituted with one, two, or three groups independently selected from carbon rings and 3- to 10-membered heterocycles. 【Chemical 404】 This refers to a compound exhibiting single or double bonds such that all valencies are satisfied, or a pharmaceutically acceptable salt or solvate thereof.

2. Structure of formula (I-B1) or (I-B2): 【Chemical 411】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

3. Structure of formula (I-C1), (I-C2), or (I-C3): 【Chemical 412】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

4. R １ However, -CH ３ The compound, salt, or solvate according to claim 1.

5. R ３ However, hydrogen, halogen, -CN, -OR １２ , and 1, 2, or 3 R ２０ C is optionally replaced by １－６ A compound, salt, or solvate according to claim 1, selected from alkyl groups.

6. R ６ However, hydrogen, -OR １２ , and 1, 2, or 3 R ２０ C is optionally replaced by １－６ Selected from alkyl groups, R １２ However, C １－６ A compound, salt, or solvate according to claim 1, selected from alkyl groups.

7. R ７ However, C １－６ Alkyl, C ３－１０ Cycloalkyl, 3-10 member heterocycloalkyl, and -N(R １２ ) (Caution １３ ) is selected from C １－６ Alkyl, C ３－１０ Cycloalkyl and 3- to 10-membered heterocycloalkyl groups, with 1, 2, or 3 R groups. ２０ The compound, salt, or solvate according to claim 1, which is optionally substituted with.

8. R ７ but, 【Chemical Engineering 417-1】 【Chemical Engineering 417-2】 A compound, salt, or solvate according to claim 1, selected from the above.

9. R ７ but, 【Chemical 418】 A compound, salt, or solvate according to claim 8, selected from the above.

10. R ８ The compound, salt, or solvate according to claim 1, wherein the compound is hydrogen. 【Request Item 11】 【Chemistry 419】 However, these are selected from phenyl and 5- to 7-membered heteroaryls, each of which contains one or more R １１ The compound, salt, or solvate according to claim 1, which is optionally substituted with. 【Request Item 12】 【Chemistry 421】 A compound, salt, or solvate according to claim 1, selected from the above.

13. R １１ However, if present, fluorine and -CH exist independently in each occurrence. ３ A compound, salt, or solvate according to claim 12, selected from the above.

14. L １ However, C １－３ A compound, salt, or solvate according to claim 1, which is a haloalkylene.

15. L １ However, -CF ２ -, -CF ２ CH ２ -, and -CF ２ CH ２ CH ２ A compound, salt, or solvate according to claim 14, selected from the following. 【Request Item 16】 【Chemistry 422】 However, R is selected from absent, phenyl, and 4- to 8-membered heterocycles, and the phenyl and 4- to 8-membered heterocycles contain one or more R １１ａ The compound, salt, or solvate according to claim 1, which is optionally substituted with. 【Request Item 17】 【Chemistry 424】 However, it is selected from azetidine, pyrrolidine, and piperidine, each of which contains one or more -CH groups. ３ The compound, salt, or solvate according to claim 16, which is optionally substituted with.

18. L ２ However, C ６－１５ Alkylene, C ６－１５ Alkenylene, C ６－１５ Selected from alkylylene, 6-15 member heteroalkylene, and 6-15 member heteroalkene, each of which contains one or more R １１ｂ The compound, salt, or solvate according to claim 1, which is optionally substituted with.

19. L ２ However, C ５－１０ Alkylene, C ５－１０ Selected from alkenylenes, 5-10 membered heteroalkylenes, and 5-10 membered heteroalkenylenes, each of which contains one or more R １１ｂ The compound, salt, or solvate according to claim 1, which is optionally substituted with.

20. The compound, salt, or solvate according to claim 18, wherein the alkenylene and heteroalkenylene contain one carbon-carbon double bond.

21. The compound, salt, or solvate according to claim 18, wherein the heteroalkylene and heteroalkenylene each contain at least one oxygen atom or nitrogen atom.

22. R ５ However, it is hydrogen, R ５ｂ However, -CH ３ And, R ６ However, hydrogen and -OCH ３ Selected from, R ７ However, C １－６ Alkyl, C ３－１０ Carbon ring, 3-10 membered heterocycle, -N(R) １２ ) (Caution １３ ), -C(O)R １５ , -C(O)N(R １２ ) (Caution １３ ), -S(O) ２ R １５ , and -SO ２ N(R) １２ ) (Caution １３ ) is selected from C １－６ Alkyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles, with 1, 2, or 3 R groups ２０ It is optionally replaced by, R ８ The compound, salt, or solvate according to claim 2, wherein the compound is hydrogen.

23. R ３ However, hydrogen or -CH ３ And, R ３ｂ However, -CH ３ And, R ６ However, hydrogen and -OCH ３ Selected from, R ７ However, C １－６ Alkyl, C ３－１０ Carbon ring, 3-10 membered heterocycle, -N(R) １２ ) (Caution １３ ), -C(O)R １５ , -C(O)N(R １２ ) (Caution １３ ), -S(O) ２ R １５ , and -SO ２ N(R) １２ ) (Caution １３ ) is selected from C １－６ Alkyl, C ３－１０ Carbon rings and 3- to 10-membered heterocycles, with 1, 2, or 3 R groups ２０ It is optionally replaced by, R ８ The compound, salt, or solvate according to claim 3, wherein the compound is hydrogen. 【Request Item 24】 【Chemistry 442-1】 【Chemistry 442-2】 【Chemistry 442-3】 【Chemistry 442-4】 【Chemistry 442-5】 【Chemistry 442-6】 【Chemistry 442-7】 【Chemistry 442-8】 【Chemistry 442-9】 【Chemistry 442-10】 【Chemistry 442-11】 A compound selected from the above, or a pharmaceutically acceptable salt or solvate thereof.

25. Structure 【Chemistry 443】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

26. Structure 【Chemistry 444】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the above.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

28. A composition for providing cancer treatment to a patient requiring such treatment, comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof.

29. The composition according to claim 28, wherein the treatment further comprises an additional agent or therapy.

30. A composition for inhibiting cell proliferation in cells expressing SOS1, comprising a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof.

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