Methods of modulating cell proliferation

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof. The present disclosure further provides methods of using the compounds and pharmaceutically acceptable salts thereof, for example in combinations of two or more compounds. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic proteins.

Description

METHODS OF MODULATING CELL PROLIFERATION CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 593,212, filed October 25, 2023,and U.S. Provisional Application No.63 / 572,126, filed March 29, 2024, each incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML formatand is hereby incorporated by reference in its entirety. Said XML copy, created on October 21, 2024, is named 56690_781_601_SL.xml and is 4,097 bytes in size. BACKGROUND

[0003] Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to beresponsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PDAC).

[0004] Ras proteins have long been considered “undruggable,” due to, in part, high affinity to their substrateguanosine-5'-triphosphate (GTP) and / or their smooth surfaces without any obvious targeting region. The specific G12C Ras gene mutation has been identified as a druggable target to which a number of G12C specific inhibitors have been developed. However, such therapeutics are still of limited application, as the G12C mutation in Ras exhibits a much lower prevalence rate as compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of durability impose further limitations to such therapeutics.

[0005] Son of Sevenless 1 (SOS1), a homolog of SOS2 in mammalian cells, acts as a guanine nucleotide exchangefactor (GEF) that promotes release of inactive GDP from RAS-family proteins to enable GTP binding. SOS1 has been implicated in cancer via its ability to activate RAS-family protein signaling. SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1 / Grb2 complex binds to activated / phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4,TrkA, TrkB, TrkC, RET, c-MET, VEGFR1 / 2 / 3). SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor. This localization of SOS1 to the plasma membrane, proximal to RAS-family proteins, enables SOS1 to promote RAS-family protein activation. SUMMARY

[0006] There exists a considerable need for identifying combination therapies to address the long-felt need toovercome various challenges or limitations associated with a single agent therapy, such as, potential resistance mechanism to the single agent, and / or undesired side effects associated with a therapeutically required effective amount of the single agent. In particular, there remains a considerable need for compositions and methods to reduce Ras pathway signaling and hence Ras-driven neoplasm or malignancy by combining Ras inhibitors with another therapeutic agent. Such compositions and methods can be particularly useful for treating a variety of diseases including, but notlimited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and treatment for a wide diversity of diseases.

[0007] In an aspect is provided a method of reducing proliferation of cancer cells comprising a KRAS mutant proteinor KRAS protein overexpression, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0008] In an aspect is provided a method of downregulating KRAS signaling output in a plurality of cancer cells,comprising: (i) assessing KRAS mutation status in a biological sample comprising nucleic acid from a subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) a KRAS inhibitor of Formula (I), (I- 1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, if a KRAS mutation is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0009] In embodiments, the cancer cells can be any cancerous cells of hematological or solid tumor origin, includingbut are not limited to non-small cell lung cancer cells, colorectal cancer cells, or pancreatic cancer cells.

[0010] In embodiments, cancer cells of the subject comprise a KRAS G12C mutant protein. In embodiments, cancercells of the subject comprise a KRAS G12S mutant protein. In embodiments, cancer cells of the subject comprise overexpression of KRAS protein. In embodiments, cancer cells of the subject are refractory to at least one KRAS G12C inhibitor.

[0011] In embodiments, the method further comprises administering (c) an additional agent or additional therapy. Inembodiments, the additional agent is a checkpoint immune blockade agent, a SHP2 inhibitor, a PI3K inhibitor, a CDK4 / 6 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, or an AKT inhibitor. In embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0012] In embodiments, the administration of (a) and (b) synergistically reduces proliferation of the cancer cells witha synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

[0013] In an aspect is provided a method of treating cancer in a subject, comprising administering to the subject (a) aSOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0014] In embodiments, the cancer is a mutant KRAS-mediated cancer. In embodiments, the KRAS inhibitor is acompound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), or (II- 3) or any embodiment of the preceding formulae.

[0015] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject (a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b), and wherein the administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

[0016] In embodiments, the synergistic value is ascertained by Bliss independence criterion in accordance with theformula: YAB,O – YAB,Pwherein: YAB,Ois observed percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B; YAB,P is predicted percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B, wherein YAB,P= YA+ YB– YAYB; YAis observed percent growth inhibition of the cancer cells by (a) alone at dose A; YBis observed percent growth inhibition of the cancer cells by (b) alone at dose B; and YAYB is the product of YA and YB.

[0017] In embodiments, the synergistic value is at least 0.1. In embodiments, the synergistic value is at least 0.4. Inembodiments, the synergistic value is at least 1. In embodiments, the synergistic value is at least 5.

[0018] In embodiments, the administration of (a) and (b) exhibits a synergistic effect. In embodiments, the synergisticeffect is characterized by a synergistic value of at least 0.05 as ascertained by Bliss independence criterion. In embodiments, one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount. In embodiments, KRAS inhibitor is administered at a dose less than about 25% the standard monotherapy dose.

[0019] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI), (SI-A), (SI- B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, and (iii) a pharmaceutically acceptable excipient.

[0020] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0021] In embodiments, the cancer is lung cancer. In embodiments, the cancer is a non-small cell lung cancer. Inembodiments, the cancer is colorectal cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is a solid cancer.

[0022] In embodiments, cancer cells of the subject comprise a KRAS G12C mutant protein. In embodiments, cancercells of the subject comprise a KRAS G12S mutant protein. In embodiments, cancer cells of the subject comprise overexpression of KRAS protein. In embodiments, cancer cells of the subject are refractory to at least one KRAS G12C inhibitor.

[0023] In embodiments, the subject exhibits relapse of the cancer. In embodiments, the subject has previously beentreated with a KRAS G12C inhibitor. In embodiments, the subject is a naïve subject that has not been treated with a KRAS inhibitor prior to administering (a) and (b).

[0024] In embodiments, the method further comprises administering (c) an additional agent or additional therapy. Inembodiments, the additional agent is selected from an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, a chemotherapeutic agent, a SHP2 inhibitor, a PI3K inhibitor, a CDK4 / 6 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, and an AKT inhibitor. In embodiments, the additional agent is selected from an immunomodulatory agent, a cytokine blockade agent, and a checkpoint immune blockade agent. Inembodiments, the additional agent is selected from an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof. In embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0025] In embodiments, the administration of (a) and (b) reduces incidence of one or more adverse events associatedwith the SOS1 inhibitor or the KRAS inhibitor. In embodiments, the adverse event is selected from diarrhea, rash, nausea, vomiting, decreased appetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury. In embodiments, the adverse event is selected from diarrhea, rash, and nausea.

[0026] In embodiments, (a) and (b) are administered in the same formulation. In embodiments, (a) and (b) areadministered in separate formulations.

[0027] In embodiments of the methods described herein, (a) is administered prior to administering (b). Inembodiments of the methods described herein, (a) is administered concurrently with administering (b). In embodiments of the methods described herein, (a) is administered subsequent to administering (b).

[0028] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a small molecule SOS1 inhibitor of Formula (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI- E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae; (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae; and (3) instructions for using the composition(s) of (1) and (2).

[0029] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a small molecule SOS1 inhibitor of Formula (SI-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae; and (3) instructions for using the composition(s) of (1) and (2).

[0030] In embodiments of the kit, the SOS1 inhibitor and the KRAS inhibitor are formulated in the same unit dosageform. In embodiments of the kit, the SOS1 inhibitor and the KRAS inhibitor are formulated in different unit dosage forms.

[0031] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI), (SI-A),(SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, and (iii) a pharmaceutically acceptable excipient.

[0032] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or apharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, and (iii) a pharmaceutically acceptable excipient.

[0033] In embodiments of the methods described herein, the SOS1 inhibitor is a compound of Formula (SI-1):or a pharmaceutically acceptable salt or solvate thereof, wherein:is selected from C5-7carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more Rs11;is absent or selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more Rs11a; Ls1is selected from a bond, C1-6alkylene, and C1-6haloalkylene; Ls2is selected from C5-25alkylene, C5-25alkenylene, C5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rs11b, wherein Ls2is covalently bound to one of Ws3, Ws4, Ws5, Ws6, or Ws7; Ws3is selected from N(Rs3b), N, C(Rs3), and C(O); Ws4is selected from N(Rs4b), N, C(Rs4), and C(O); Ws5is selected from N(Rs5b), N, and C(Rs5); Ws6is selected from C(Rs6) and C(O); Ws7is C(Rs7); Rs1is C1-3alkyl optionally substituted with one or more Rs11c; Rs8is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10- membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, -OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), - N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), - N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), -S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), - CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three Rs20; Rs3, Rs4, Rs5, Rs6, and Rs7are each independently selected from a bond to Ls2, hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), - C(O)ORs12, -OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, - S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle isindependently optionally substituted with one, two, or three Rs20; Rs3b, Rs4b, and Rs5bare each independently selected from a bond to Ls2, hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -C(O)ORs12, -OC(O)N(Rs12)(Rs13), - C(O)Rs15, -S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three Rs20; Rs11and Rs11aare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, - OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, - OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, -CH2S(O)2N(Rs12)(Rs13), - CH2N(Rs12)S(O)2(Rs13), and -P(O)(Rs17)(Rs17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, - OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, - OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, -CH2S(O)2N(Rs12)(Rs13), - CH2N(Rs12)S(O)2(Rs13), and -P(O)(Rs17)(Rs17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs11cis independently selected at each occurrence from halogen, -ORs12, and -N(Rs12)(Rs13); Rs12is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or Rs12and Rs13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three Rs20; Rs14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; Rs15is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one, two, or three Rs20; Rs17and Rs17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two or three Rs20; or Rs17and Rs17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; Rs20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, -C(O)N(Rs22)(Rs23), -C(O)C(O)N(Rs22)(Rs23), - OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, -N(Rs24)C(O)Rs25, -N(Rs24)S(O)2Rs25, -C(O)Rs25, - S(O)2Rs25, -S(O)2N(Rs22)(Rs23), -OCH2C(O)ORs22, and -OC(O)Rs25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) areoptionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, -C(O)N(Rs22)(Rs23), - C(O)C(O)N(Rs22)(Rs23), -OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, -N(Rs24)C(O)Rs25, - N(Rs24)S(O)2Rs25, -C(O)Rs25, -S(O)2Rs25, -S(O)2N(Rs22)(Rs23), and -OC(O)Rs25; Rs21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs23is independently selected at each occurrence from H and C1-6alkyl; Rs24is independently selected at each occurrence from H and C1-6alkyl; Rs25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0034] In embodiments, the SOS1 inhibitor is selected from BI-3406, MRTX0902, BAY 293, RMC-5845, and BI-1701963.

[0035] In embodiments, the SOS1 inhibitoris .

[0036] In embodiments, the SOS1 inhibitor

[0037] In embodiments of the methods described herein, the SOS1 inhibitor is a compound of Formula (SIV-1):or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Ls1is a bond;Rs1is 6- to 10-membered aryl, wherein the 6- to 10-membered aryl is optionally substituted with one or more independently selected Rs10substituents; Rs2is halogen or ORs2a; Rs2ais C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl, wherein the C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl is optionally substituted with one, two, or three independently selected Rs20asubstituents; Rs3is halogen, C1-6alkyl, C3-14cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein the C1-6alkyl, C3-14 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl is optionally substituted with one, two, or three independently selected Rs20bsubstituents; Rs4is H, C1-6alkyl, or C1-6haloalkyl; Rs5is H, C1-6alkyl, or C1-6haloalkyl; Rs6is H, halogen, CN, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one, two, or three independently selected Rs20csubstituents; each Rs10is independently halogen, CN, C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three independently selected Rs20dsubstituents; each Rs20ais independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20bis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; andwherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20cis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20dis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs21is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C1-6alkyl;each Rs22is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C1-6alkyl; each Rs23is independently H or C1-6alkyl; each Rs24is independently H or C1-6alkyl; and each Rs25is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl, wherein each C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

[038] In embodiments, Rs3 is C2-9 heterocycloalkyl, wherein the C2-9 heterocycloalkyl is optionally substituted withone, two, or three independently selected Rs20bsubstituents. In embodiments, Rs3is C3-10cycloalkyl, wherein the C3-10cycloalkyl is optionally substituted with one, two, or three independently selected Rs20bsubstituents. In embodiments,, or . In embodiments, the SOS1 inhibitor is a compound selected from the group consisting o: , , ,

[039] In embodiments of the methods described herein, the KRAS inhibitor is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof: Formula (I); wherein W is a N, C(R18), N(R18b), C(R18)(R18a), C(O), S(O), or S(O)2; Z is N, C(R8), N(R8b), C(R8)(R8a), C(O), S(O), or S(O)2; wherein W and Z are not both selected from C(O), S(O), and S(O)2; V and J are each independently selected from C(R17), C(R17)(R16a), C(R16), C(R16)(R16a), N, N(R17b), and N(R16b); wherein exactly one of V and J is C(R17), C(R17)(R16a), or N(R17b); Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), or S(O)2; U is N, C(R2c), C(R2c)(R2c), N(R2b), S(O), S(O)2, or C(O); R10is -L7-R7; L7is a bond, -O-, -N(R14)-, -C(O)-, -S-, -S(O)2-, -S(O)-, C1-4alkyl, or 2-4 membered heteroalkyl linker, wherein the C1-4alkyl and 2-4 membered heteroalkyl linker are each optionally substituted with one, two or three R20a; R7W1and W3are independently selected from N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W2is independently selected from a N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W4is selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), S(O), and S(O)2;W5is selected from N, C(R1), and C(R4); s1 is 1 and s2 is 0, 2, or 3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5 and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3; s3 is an integer from 1 to 3; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, - CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, - (C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R6is -L2-R5, wherein R6is optionally capable of forming a covalent bond with a RAS amino acid; L2is a bond, -O-, -N(R4d)-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R4d-, CR4cR4c, -OCR4cR4c-, -N(R4d)CR4cR4c-, - C(O)CR4cR4c-, -SCR4cR4c-, -S(O)2CR4cR4c-, -S(O)CR4cR4c-, -P(O)R4dCR4cR4c-, -CR4cR4cCR4cR4c, -CR4cR4cO-, - CR4cR4cN(R4d)-, -CR4cR4cC(O)-, -CR4cR4cS-, -CR4cR4cS(O)2-, -CR4cR4cS(O)-, -CR4cR4cP(O)R4d-, -N(R4d)C(O)-, -N(R4d)S(O)2-, -N(R4d)S(O)-, -N(R4d)P(O)R4d-, -C(O)N(R4d)-, -S(O)2N(R4d)-, -S(O)N(R4d)-, -P(O)R4dN(R4d)-, - OC(O)-, -OS(O)2-, -OS(O)-, -OP(O)R4d-, -C(O)O-, -S(O)2O-, -S(O)O-, -P(O)R4dO-, -CR4cR4cCR4cR4cCR4cR4c-, -OCR4cR4cCR4cR4c-, -N(R4d)CR4cR4cCR4cR4c-, -C(O)CR4cR4cCR4cR4c-, -SCR4cR4cCR4cR4c-, - S(O)2CR4cR4cCR4cR4c-, -S(O)CR4cR4cCR4cR4c-, -P(O)R4dCR4cR4cCR4cR4c-, -CR4cR4cCR4cR4cO-, - CR4cR4cCR4cR4cN(R4d)-, -CR4cR4cCR4cR4cC(O)-, -CR4cR4cCR4cR4cS-, -CR4cR4cCR4cR4cS(O)2-, - CR4cR4cCR4cR4cS(O)-, or -CR4cR4cCR4cR4cP(O)R4d-; each R4cis independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2- C2- 9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, -OC(O)R14a, -N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14a, and -N(R14)S(O)2R14, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; each R4dis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, and -OC(O)R14a, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; R5is a 5 or 6 membered partially unsaturated heterocycloalkyl or a 5 or 6 membered heteroaryl, each optionally substituted with one, two or three R20k, wherein the partially unsaturated 5 or 6 membered heterocycloalkyl or 5 or 6 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and the 5 or 6 membered partially unsaturated heterocycloalkyl or 5 or 6 membered heteroaryl is each bonded to L2through a ring nitrogen; R8and R8aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R8bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R17is -L1-R19; R17bis -L1b-R19; L1is selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, - C(O)N(R14)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, -OCON(R14)-, - N(R14)C(O)O-, N(R1e), C(O)N(R1c), S(O)2N(R1c), S(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; L1bis selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -C(O)-, -C(O)N(R14)-, C(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; R1e, R1f, and R1gare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, - S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, - S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1fand R1gare joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 memberedheterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20i; R1cis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16and R16aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R16bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R2is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C4- 9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2cis independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2bis independently hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -C(O)OR12’, -OC(O)N(R12’)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –( C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or – (C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R12bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; X is C(R3), C(R3)(R3), N(R3), or N; each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’’is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12cis independently selected from hydrogen and R20m; each R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with thenitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20e; each R14is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R14ais independently selected from C1-6alkyl and C1-6haloalkyl; each R15is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; R18and R18aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; R18bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R20h, R20i, R20k, and R20mis independently selected from halogen, oxo, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), =C(R21b)2, -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), - N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R21, -N(R24)S(O)2R25, -C(O)R21, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25; wherein two R20kbonded to the same or adjacent atoms may optionally be joined to form a C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2- C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; R21bis independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkenyl , C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, or two R21bare taken together with the carbon atom to which they are attached to form C3-10cycloalkyl or C2-9heterocycloalkyl; each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH; each R22is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23is independently selected from H and C1-6alkyl; each R24is independently selected from H and C1-6alkyl; each R25is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and indicates a single or double bond such that all valences are satisfied.

[040] In embodiments, R5 is a 5 membered heteroaryl optionally substituted with one, two or three R20k, wherein the5 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and the 5 membered heteroaryl is bonded to L2through a ring nitrogen. In embodiments, L2is -C(O)-; and R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and L2is directly bonded to an N ring atom of R5.

[041] In embodiments, L7 is a bond.

[0042] In embodiments, s1 is 2 and s2 is 0, 1, or 3.

[0043] In embodiments, R7 is selected from, , ,, and ; wherein R1and R4substituents may be bonded to either spirocyclic ring.

[044] In embodiments, R17 is -L1-R19 or -L1b-R19; L1 is a bond, and L1b is a bond.

[0045] In embodiments, R19 is:,o ; Q1, Q3, and Q5are independently selected from N and C(R1d); Q4and Q6are independently selected from O, S, C(R1a)(R1b), and N(R1c); X4, X5, X6, X9, X10are independently selected from C(R1a) and N; X13is selected from a bond, C(R1a), N, C(O), C(R1a)(R1b), C(O)C(R1a)(R1b), C(R1a)(R1b)C(R1a)(R1b), C(R1a)(R1b)N(R1c), and N(R1c); X14, X15, X17, X18are independently selected from a C(O), C(R1a), N, C(R1a)(R1b), and N(R1c); X16are independently selected from C, N, and C(R1a); each R1a, R1b, R1d, and R1hare each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1aand R1bbonded to the same carbon are joined to form a 3- 10 membered heterocycloalkyl ring or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or two R1abonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-10aryl ring, 5-12 membered heteroaryl ring, or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or R1hand one of R1a, R1b, R1c, and R1dbonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, and C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; and each R1cis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i.

[046] In embodiments, R19 is selected from

[047] In embodiments, R2 is -OR12’. In embodiments, R2 is selected fromF, , , ,

[0048] In embodiments of the methods described herein, wherein the KRAS inhibitor is a compound of Formula (I) asrecited above, or a pharmaceutically acceptable salt or solvate thereof; W is a C(R18) or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L1is a bond; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R2is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12’, -SR12’, and - N(R12’’)(R13), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20d; R8is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R8bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R16is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20g; R18is hydrogen; and all other variables are as described for a compound of Formula (I) as recited in the method above.

[0049] In embodiments of the methods described herein, wherein the KRAS inhibitor is a compound of Formula (I) asrecited above, or a pharmaceutically acceptable salt or solvate thereof; W1, W2, and W3are independently selected from CH2and O; W4is CH2; W5is selected from N and CH; R2is -OR12’; R8is independently selected halogen and C1-6haloalkyl; R8bis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R16is halogen; and all other variables are as described for a compound of Formula (I), as recited in the method or embodiment thereof, of the two paragraphs immediately above.

[0050] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (SI-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV- 1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) instructions for using the composition(s) of (1) and (2).

[0051] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or apharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0052] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0053] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (SIV-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV- 1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) instructions for using the composition(s) of (1) and (2).

[0054] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SIV-1), ora pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0055] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SIV-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0056] In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the SOS1inhibitor is a compound of Table 2a, or a pharmaceutically acceptable salt or solvate thereof. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the SOS1 inhibitor is a compound of Table 2b, or a pharmaceutically acceptable salt or solvate thereof. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the KRAS inhibitor is a compound of Table 1a, or a pharmaceutically acceptable salt or solvate thereof. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the KRAS inhibitor is a compound of Table 1b, or a pharmaceutically acceptable salt or solvate thereof. INCORPORATION BY REFERENCE

[0057] All publications, patents, and patent applications mentioned in this specification are herein incorporated byreference to the same extent as if each individual publication, patent, or patent application was specifically andindividually indicated to be incorporated by reference. BRIEF DESCRIPTION OF DRAWINGS

[0058] The novel features of the invention are set forth with particularity in the appended claims. A betterunderstanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0059] FIG. 1A shows a degree of growth inhibition of H358 cells (KRAS-G12C mutant) cells upon treatment with(i) a SOS1 inhibitor of the present disclosure (e.g., Compound A, at various concentrations) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii) at various concentrations.

[0060] FIG. 1B shows a degree of synergy across the drug combinations in FIG. 1A, as calculated using the BLISSindependence model.

[0061] FIG. 2A shows a degree of growth inhibition of H2122 (KRAS-G12C mutant) cells upon treatment with (i) aSOS1 inhibitor of the present disclosure (e.g., Compound A, at various concentrations) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii) at various concentrations.

[0062] FIG. 2B shows a degree of synergy across the combinations in FIG. 2A, as calculated using the BLISSindependence model.

[0063] FIG. 3A shows a degree of growth inhibition of LU99 (KRAS-G12C mutant) cells upon treatment with (i) aSOS1 inhibitor of the present disclosure (e.g., Compound A, at various concentrations) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii) at various concentrations.

[0064] FIG. 3B shows a degree of synergy across the combinations in FIG. 3A, as calculated using the BLISSindependence model.

[0065] FIG. 4 shows results of a study in which mice bearing CR9528 PDX tumors (colorectal cancer exhibiting aKRAS G12C mutation) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with a KRAS inhibitor in the tumor model.

[0066] FIG. 5 shows results of a study in which mice bearing SW837 xenograft tumors (colorectal cancer exhibiting aKRAS G12C mutation) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with a KRAS inhibitor in the tumor model.

[0067] FIG. 6 shows results of a study in which mice bearing LU1147 PDX tumors (NSCLC exhibiting a KRASG12C mutation) were treated with (i) a SOS1 inhibitor of the present disclosure (e.g., Compound A) alone, (ii) a subject KRAS inhibitor (e.g., Compound K) alone, or (iii) a combination of (i) and (ii). The results demonstrate that the SOS1 inhibitor disclosed herein synergistically reduces tumor volume in combination with a KRAS inhibitor in the tumor model. DETAILED DESCRIPTION

[0068] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventionaltechniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: ALaboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al. eds.); the series Methods In Enzymology (Academic Press, Inc.); PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)); Antibodies, A Laboratory Manual (Harlow and Lane, eds. (1988)); and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)).

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonlyunderstood to which the claimed subject matter belongs. In the event that there are a plurality of 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) referred to herein are incorporated by reference. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0070] It is to be understood that the foregoing general description and the following detailed description areexemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0071] The section headings used herein are for organizational purposes only and are not to be construed as limitingthe subject matter described.

[0072] Definition of standard chemistry terms may be found in reference works, including but not limited to, Careyand Sundberg “Advanced Organic Chemistry 4thEd.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology.

[0073] It is to be understood that the methods and compositions described herein are not limited to the particularmethodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein.

[0074] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, oralkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-y alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, that contain from x to y carbons in the chain.

[0075] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branchedalkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-8alkyl) or one to six carbon atoms (C1-6alkyl). Exemplary alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0076] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein.

[0077] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groupsinclude trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0078] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenylgroups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6alkenyl). 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 specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0079] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynylgroups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12alkynyl), such as two to eight carbon atoms (C2-8alkynyl) or two to six carbon atoms (C2-6alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0080] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups,including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C1-12alkylene), such as one to eight carbon atoms (C1-8 alkylene) or one to six carbon atoms (C1-6alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points 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 specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0081] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl andalkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0082] “Heteroalkylene”, “heteroalkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene,alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkylene group has a chain length of 3 to 8 atoms. The points 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 by one or more substituents such as thosesubstituents described herein.

[0083] “Carboxy” refers to -CO2H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acidbioisostere”, which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to, ,.

[0084] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbonatom. Carbocycle may include C3-10monocyclic rings, C6-12bicyclic rings, C6-12spirocyclic rings, and C6-12bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the carbocycle is a C6-12aryl group, such as C6-10aryl. In some embodiments, the carbocycle is a C6-12cycloalkyl group. In some embodiments, the carbocycle is a C6-12cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocycle. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0085] The term “cycloalkyl” refers to a monocyclic i) carbocyclic saturated or partially unsaturated non-aromaticring or a ii) polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spirocyclic) to a heterocycloalkyl ring in the polycyclic ring system. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In embodiments, a cycloalkyl is a monocyclic ring. In embodiments, a cycloalkyl is a fused ring polycyclic system. In embodiments, a cycloalkyl is a bridged ring polycyclic system. In embodiments, a cycloalkyl is a spirocyclic polycyclic ring system. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group).

[0086] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, forexample 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 of a bicyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6- membered heteroaryl. In some embodiments, the 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 stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0087] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least oneskeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocycloalkyl refers to a monocyclic saturated or partially unsaturated non- aromatic ring including one or more heteroatoms or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is saturated or partially unsaturated, non-aromatic, and includes one or more heteroatoms and 2) a bond to the remainder of the compound is directly bonded to a ring of the ring system that is a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms or a non-aromatic ring directly bonded (e.g., fused) to a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms of the ring system. Heterocycloalkyls may be saturated or partially unsaturated. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In embodiments, a heterocycloalkyl is a monocyclic ring. In embodiments, a heterocycloalkyl is a fused ring polycyclic system. In embodiments, a heterocycloalkyl is a bridged ring polycyclic system. In embodiments, a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise noted, heterocycloalkyls have from 2 to 13 carbons in the ring or ring system. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group).

[0088] “Heteroaryl” refers to a 5- to 12-membered aromatic ring that comprises at least one heteroatom, such as 1, 2or 3 heteroatoms, selected from O, S and N. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic—including fused, spirocyclic and bridged ring systems—wherein at least one of the rings in the ring system is aromatic. The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. 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 stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0089] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy thevalence requirement.

[0090] The term “oxo” refers to the =O radical.

[0091] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when theatoms joined by the bond are considered to be part of larger substructure.

[0092] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are oftenrecognized chemical entities embedded in or appended to a molecule.

[0093] The suffix “-di-yl” will be understood to mean the substituent or linker is a divalent substituent or linker.

[0094] A waved line “ ” drawn across a bond or a dashed bond “ ” are used interchangeably herein to denotewhere a bond disconnection or attachment occurs. For example, in the structure, if R7is 1-cyclopropyl-1-carbonitrile as in , then R7 may be depicted a

[0095] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituentselected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0096] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons orheteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated 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 non-aromatic 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 may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0097] In embodiments, a compound disclosed herein, is optionally substituted by one or more, such as 1, 2 or 3substituents selected from: halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and - CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), - C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6alkyl; andR25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle.

[0098] In some embodiments, a compound disclosed herein, is optionally substituted by one or more, such as 1, 2 or 3substituents selected from: halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and - CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, and -N(R22)(R23); R21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; R23is independently selected at each occurrence from H and C1-6alkyl; R24is independently selected at each occurrence from H and C1-6alkyl; and R25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle.

[0099] In embodiments, a compound disclosed herein, is optionally substituted by one or more, such as 1, 2 or 3substituents selected from: halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, - C(O)N(Rs22)(Rs23), -C(O)C(O)N(Rs22)(Rs23), -OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, - N(Rs24)C(O)Rs25, -N(Rs24)S(O)2Rs25, -C(O)Rs25, -S(O)2Rs25, -S(O)2N(Rs22)(Rs23), -OCH2C(O)ORs22, and -OC(O)Rs25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -ORs21, -SRs21, - N(Rs22)(Rs23), -C(O)ORs22, -C(O)N(Rs22)(Rs23), -C(O)C(O)N(Rs22)(Rs23), -OC(O)N(Rs22)(Rs23), - N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, -N(Rs24)C(O)Rs25, -N(Rs24)S(O)2Rs25, -C(O)Rs25, -S(O)2Rs25, - S(O)2N(Rs22)(Rs23), and -OC(O)Rs25; Rs21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl,C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs23is independently selected at each occurrence from H and C1-6alkyl; Rs24is independently selected at each occurrence from H and C1-6alkyl; and Rs25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6 alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle.

[0100] In some embodiments, a compound disclosed herein, is optionally substituted by one or more, such as 1, 2 or 3substituents selected from: halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, - C(O)N(Rs22)(Rs23), -C(O)C(O)N(Rs22)(Rs23), -OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, - N(Rs24)C(O)Rs25, -N(Rs24)S(O)2Rs25, -C(O)Rs25, -S(O)2Rs25, -S(O)2N(Rs22)(Rs23), -OCH2C(O)ORs22, and -OC(O)Rs25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -ORs21, -SRs21, and - N(Rs22)(Rs23); Rs21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs23is independently selected at each occurrence from H and C1-6alkyl; Rs24is independently selected at each occurrence from H and C1-6alkyl; and Rs25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle.

[0101] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), (H), (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), is optionally substituted by one or more, such as 1, 2 or 3 substituents selected from halogen, oxo, =NH, -CN, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, - CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and - NHCH2CH3.

[0102] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo.

[0103] The abbreviations “Fmoc”, “Ac”, “Bn”, “PMB”, “Tr”, “Ts”, “Boc”, and “Cbz” are used in accordance withtheir well understood common meanings in Chemistry and mean the monovalent chemical substituents fluorenylmethyloxycarbonyl, acetyl, benzyl, p-methoxybenzyl, trityl or triphenylmethyl, tosyl, tert-butyloxycarbonyl, and carbobenzyloxy, respectively.

[0104] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens maythe same or they may be different. Non-limiting examples of haloalkyls include -CH2Cl, -CF3, -CHF2, -CH2CF3, - CF2CF3, and the like.

[0105] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substitutedwith one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF3, -CHF2, -CH2F, -CH2CF3, - CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups, include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.

[0106] indicates the location of attachment (e.g., location of a bond to another atom) of the depicted chemicalformula or atom to a substituent, a further component of a molecule, or an atom. may equivalently be located at the end of a bond or overlapping a bond. A waved line drawn across a bond or at the end of a bond and adashed bond “ “ are used interchangeably herein to denote where a bond disconnection or attachment occurs.

[0107] “About” as used herein when referring to a measurable value such as an amount, a duration, and the like, ismeant to encompass variations of ± 10% of a stated number or value.

[0108] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0109] Where bivalent substituent groups are specified herein by their conventional chemical formulae, written fromleft to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0110] “Optional” or “optionally” means that the subsequently described event or circumstances may or may notoccur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0111] 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, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0112] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atomsmay be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number 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 has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,13C,14C,15N,18O,17O,35S,36Cl, and18F. Of particular interest are compounds of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C),(D), (E), (F), (G), (H), (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or embodiments of any of the precedingformulae, enriched in tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds ofthe disclosure enriched in deuterium—especially at a site of metabolism—resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), (H), (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or embodiments of any ofthe preceding formulae, enriched in a positron emitting isotope, such as 11C, 18F, 15O and 13N, which can be used, forexample, in Positron Emission Topography (PET) studies. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0113] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended tobe limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0114] Certain compounds described herein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0115] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms andtopoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0116] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptablewhen used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material—such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier—that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0117] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid.Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, 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.

[0118] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectivenessand properties of the free bases, which are not biologically or otherwise undesirable, and which are 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. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, 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. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. 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 forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0119] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectivenessand properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an 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, for example, 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 and the like. See Berge et al., supra.

[0120] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results withrespect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease ormedical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.

[0121] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylacticbenefit as 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. In embodiments, a “therapeutic effect” does not include a prophylactic benefit. In embodiments, a “therapeutic effect” includes slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. In embodiments, a “therapeutic effect” includes reducing or eliminating one or more symptoms of a disease or condition. In embodiments, a “therapeutic effect” includes reducing or eliminating a disease or condition.

[0122] The terms “administer”, “administering”, “administration”, and derivatives thereof refer to the methods thatmay be used to enable delivery of a composition to the desired site of biological action. These methods include, but are not limited to parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, intrathecal, intranasal, intravitreal, infusion and local injection), transmucosal injection, oral administration, administration as a suppository, and topical administration. Administration is by any route, including parenteral. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transplantation, etc. One skilled in the art will know of additional methods for administering a therapeutically effective amount of a composition of the present disclosure for preventing or relieving one or more symptoms associated with a disease.

[0123] The term “effective amount” or “therapeutically effective amount” or “therapeutically effective dose” refers tothe amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0124] The terms “sub-therapeutic amount”, “sub-effective amount”, and “sub-therapeutic dose” are usedinterchangeably and refer to the amount of an agent that is less than the effective amount for that agent, but when combined with an effective or sub-therapeutic amount of a different agent can produce a desired result, due to, for example, synergy in the resulting efficacious effects and / or reduced side effects by the combination of (i) the sub- therapeutic amount of the agent and (ii) the different agent (e.g., one or more different agents). For example, an agentcan be approved for clinical use for a specified indication at a defined dose or range thereof (e.g., 150 milligrams per day (mg / d)) over the course of one or more administrations, and a sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at least about 0.1-fold, 0.2-fold, 0.5-fold, 1-fold, 2-fold, 5-fold, 10-fold, 20- fold, 50-fold, 100-fold, 200-fold, 500-fold, 1,000-fold, 2,000-fold, 5,000-fold, 10,000-fold, 20,000-fold, 50,000-fold, 100,000-fold, or more. The sub-therapeutic amount of such agent can be lower than the approved dose or range thereof by at most about 100,000-fold, 50,000-fold, 20,000-fold, 10,000-fold, 5,000-fold, 2,000-fold, 1,000-fold, 500-fold, 200- fold, 100-fold, 50-fold, 20-fold, 10-fold, 5-fold, 2-fold, 1-fold, 0.5-fold, 0.2-fold, 0.1-fold or less. A sub-therapeutic amount of an agent can be achieved by reducing the amount of the agent per dosage and / or by reducing the number of administrations (or cycles) of the agent to the subject.

[0125] The term “synergistic” or “synergizing” effect refers to when a desired effect (e.g., one or more differenteffects) of a combination (or combination treatment) comprising two or more different therapeutic components (e.g., two or more different therapies, two or more therapeutic agents, etc.) is greater than (i) the effect of each therapeutic component alone and / or (ii) the sum of the effect of each therapeutic component alone when administered individually (e.g., the sum of individual effects). The synergistic effect can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 5,000%, or more than (i) the effect of each therapeutic component alone and / or (ii) the sum of individual effects. The effect can be any measurable effect including but not limited to an enhancement of a therapeutic effect of an individual component within the combination or a reduction in a side effect of an individual component within the combination. In some embodiments, the effect is a pharmacodynamic effect, such as phosphorylated ERK (p-ERK) and / or DUSP6 inhibition, optionally assessed in whole blood. To yield the synergistic effect, the two or more different therapeutic components of the combination treatment as disclosed herein can be administered concurrently or sequentially, as separate components or as a unit dosage. For example, a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., in treating cancer) that is comparable (e.g., substantially the same) or better than (i) the therapeutic outcome of each therapeutic component alone at the therapeutically effective amount and / or (ii) the sum of individual effects, where either or both of the first and the second agent are administered in a respective sub-therapeutic amount. In another example, a synergistic effect of a combination comprising a first agent and a second agent can yield a desired therapeutic outcome (e.g., reducing side effect of either one of the agent) that is comparable (e.g., substantially the same) or better than the therapeutic outcome of each therapeutic component alone.

[0126] The term “IC50” refers to the half maximal inhibitory amount (e.g., concentration) of an inhibitor in inhibitinga biological or biochemical effect. IC50 can be a quantitative measure that indicates how much of a particular inhibitor is needed to inhibit a given biological or biochemical effect (e.g., expression and / or activity level of a gene / protein of interest, growth, or growth rate of a cell, etc.) by substantially half (e.g., about 50%). For example, determination of IC50 can be made by determining and constructing a dose-response curve and examining the effect of different concentrations of an inhibitor on reducing cell growth (e.g., inhibiting proliferation of cancer cells), and determining the concentration of the inhibitor at which 50% inhibition of cell growth is observed.

[0127] The term “combination”, as applied to agents including inhibitors disclosed herein, refers to the use of two ormore agents (e.g., a SOS1 inhibitor and at least another inhibitor against a different signaling molecule (e.g., a RAS orKRAS inhibitor)) in vitro, in vivo, or ex-vivo. The two or more agents in combination can be formulated in one singleformulation, or in separate formulation(s). A combination treatment or therapy with two or more agents can be carried out conjunctively in any temporal order, administered simultaneously or separately.

[0128] The term “conjunction” refers to a temporal aspect of the use of two or more agents (e.g., a SOS1 inhibitor andat least another inhibitor against a different signaling molecule (e.g., a RAS or KRAS inhibitor)) in vitro, in vivo, or ex- vivo. For example, one agent of a set of agents of interest can be administered prior to, subsequent to, or concurrently with the administration of a second agent of the set. Simultaneous administration can be effectuated by simultaneously administering multiple agents as separate agents, or as a unit dosage comprising the multiple agents.

[0129] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having theability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., SOS1, RAS, or KRAS). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0130] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent topreferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0131] The terms “subject”, “individual”, and “patient” are used interchangeably herein to refer to an animal, such asa mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed.

[0132] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably andrefer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0133] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers ofamino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0134] The terms “polynucleotide”, “nucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” areused interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid(PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 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. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0135] The term “nucleic acid agent” refers to an inhibitory agent capable of downregulating (e.g., reducing orinhibiting) expression and / or activity of a target moiety (e.g., a protein or a gene encoding thereof). In some embodiments, a nucleic acid agent may consist of a nucleic acid molecule. In some embodiments, a nucleic acid agent may comprise a nucleic acid molecule. In some embodiments, a nucleic acid agent may comprise a nucleic acid molecule and a non-nucleic acid molecule. The nucleic acid molecule and the non-nucleic acid molecule may be operatively coupled to each other to yield the inhibitory effect on the target moiety. The nucleic acid molecule and the non-nucleic acid molecule may be coupled (e.g., covalently and / or non-covalently) to each other. In some cases, the nucleic acid molecule and the non-nucleic acid molecule can be linked to each other via a linker. In some cases, the nucleic acid molecule can be configured to bind to the non-nucleic acid molecule. In some cases, the non-nucleic acid molecule can be configured to bind to the nucleic acid molecule. Non-limiting examples of the non-nucleic acid molecule include a small molecule, a polypeptide (e.g., an enzyme), etc. In some cases, the non-nucleic acid molecule is a nuclease, e.g., an endonuclease.

[0136] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNAtemplate (such as into and mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0137] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to anantibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full- length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG“ (or half antibody). Examples of modified fragments of antibodies may 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).

[0138] The term “antibody” and “antibodies” encompass any antigen binding units, including without limitation:monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0139] The term “diseased cell” refers to the state of a cell, tissue, or organism that diverges from the normal orhealthy state. A diseased cell may result from the influence of a pathogen, a toxic substance, irradiation, or cell internal deregulation (e.g., genetic mutation). In an example, a diseased cell is a cell that has been infected with a pathogenic virus. In an example, a diseased cell is a malignant cell or neoplastic cell that may constitute or give rise to cancer in a subject (e.g., a mammal such as a human subject).

[0140] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or bysolvolysis to a biologically active compound described herein (e.g., a compound of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), (H), (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI- C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or embodiments of any of the preceding formulae). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. 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 in full by reference herein). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.

[0141] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an eventthat first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0142] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Suchproducts may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the 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 radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0143] The term “Ras” or “RAS” refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such asin the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (K-Ras or 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 from KRAS, HRAS,NRAS, RALA, RALB, and any combination thereof. Methods

[0144] In an aspect is provided a method of reducing proliferation of cancer cells comprising a KRAS mutant proteinor KRAS protein overexpression, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0145] In an aspect is provided a method of downregulating KRAS signaling output in a plurality of cancer cells,comprising: (i) assessing KRAS mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, if a KRAS mutation is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b). In embodiments of the method, the KRAS mutation is a G12C mutation. In embodiments of the method, the KRAS mutation is a G12S mutation. In embodiments of the method, the KRAS mutation is a G12D mutation. In embodiments of the method, the KRAS mutation is a G12V mutation.

[0146] In embodiments, the cancer cells are non-small cell lung cancer cells, colorectal cancer cells, or pancreaticcancer cells.

[0147] In embodiments, cancer cells of the subject comprise a KRAS G12C mutant protein. In embodiments, cancercells of the subject comprise a KRAS G12S mutant protein. In embodiments, cancer cells of the subject comprise overexpression of KRAS protein. In embodiments, cancer cells of the subject are refractory to at least one KRAS G12C inhibitor.

[0148] In embodiments, the method further comprises administering (c) an additional agent or additional therapy.Suitable agents that can be administered in combination with (a) the SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, include other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof. In embodiments, the additional agent is a checkpoint immune blockade, a SHP2 inhibitor, a PI3K inhibitor, a CDK4 / 6 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, or an AKT inhibitor. In embodiments, the additional agent is an EGFR inhibitor. In embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0149] In embodiments, the administration of (a) and (b) synergistically reduces proliferation of the cancer cells witha synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

[0150] In an aspect is provided a method of treating cancer in a subject, comprising administering to the subject (a) aSOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

[0151] In embodiments, the cancer is a mutant KRAS-mediated cancer. In embodiments, the KRAS inhibitor is acompound, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), or (II- 3) or any embodiment of the preceding formulae.

[0152] A KRAS-mediated disease or condition may be any disease or condition in which the KRAS signalingpathway contributes to the progression of the disease or condition. In some embodiments, the disease or condition ischaracterized by aberrant activity of KRAS, optionally due to KRAS amplification, KRAS overexpression, and / or occurrence of one or more KRAS mutations (a mutant KRAS-mediated disease or condition).

[0153] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject (a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b), and wherein the administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

[0154] In embodiments, the synergistic value is ascertained by Bliss independence criterion in accordance with theformula: YAB,O– YAB,Pwherein: YAB,Ois observed percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B; YAB,Pis predicted percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B, wherein YAB,P = YA + YB – YAYB; YAis observed percent growth inhibition of the cancer cells by (a) alone at dose A; YBis observed percent growth inhibition of the cancer cells by (b) alone at dose B; and YAYBis the product of YAand YB.

[0155] In embodiments, the synergistic value is at least 0.1. In embodiments, the synergistic value is at least 0.4. Inembodiments, the synergistic value is at least 1. In embodiments, the synergistic value is at least 5.

[0156] In embodiments, the administration of (a) and (b) exhibits a synergistic effect. In embodiments, the synergisticeffect is characterized by a synergistic value of at least 0.05 as ascertained by Bliss independence criterion. In embodiments, one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount. In embodiments, KRAS inhibitor is administered at a dose less than about 25% the standard monotherapy dose.

[0157] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI), (SI-A), (SI- B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, and (iii) a pharmaceutically acceptable excipient.

[0158] In an aspect is provided a method of treating a mutant KRAS-mediated cancer in a subject, comprisingadministering to the subject a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

[0159] In embodiments, the cancer is lung cancer. In embodiments, the cancer is a non-small cell lung cancer. Inembodiments, the cancer is colorectal cancer. In embodiments, the cancer is pancreatic cancer. In embodiments, the cancer is a solid cancer.

[0160] In embodiments, cancer cells of the subject comprise a KRAS G12C mutant protein. In embodiments, cancercells of the subject comprise a KRAS G12S mutant protein. In embodiments, cancer cells of the subject comprise overexpression of KRAS protein. In embodiments, cancer cells of the subject are refractory to at least one KRAS G12C inhibitor.

[0161] In embodiments, the subject exhibits relapse of the cancer. In embodiments, the subject has previously beentreated with a KRAS G12C inhibitor. In embodiments, the subject is a naïve subject that has not been treated with a KRAS inhibitor prior to administering (a) and (b).

[0162] In embodiments, the method further comprises administering (c) an additional agent or additional therapy.Suitable agents that can be administered in combination with (a) the SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, include other anti- cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agents, steroids, chemotherapeutic agents, and combinations thereof. In embodiments, the additional agent is selected from an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, a chemotherapeutic agent, a SHP2 inhibitor, a PI3K inhibitor, a CDK4 / 6 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, and an AKT inhibitor. In embodiments, the additional agent is an EGFR inhibitor. In embodiments, the additional agent is selected from an immunomodulatory agent, a cytokine blockade agent, and a checkpoint immune blockade agent. In embodiments, the additional agent is selected from an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof. In embodiments, the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

[0163] In embodiments, the administration of (a) and (b) reduces incidence of one or more adverse events associatedwith the SOS1 inhibitor or the KRAS inhibitor. In embodiments, the adverse event is selected from diarrhea, rash, nausea, vomiting, decreased appetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury. In embodiments, the adverse event is selected from diarrhea, rash, and nausea.

[0164] In embodiments, (a) and (b) are administered in the same formulation. In embodiments, (a) and (b) areadministered in separate formulations.

[0165] In embodiments of the methods described herein, (a) is administered prior to administering (b). Inembodiments of the methods described herein, (a) is administered concurrently with administering (b). In embodiments of the methods described herein, (a) is administered subsequent to administering (b).

[0166] In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the canceris a solid tumor. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the cancer is a hematological cancer. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the cancer can be, without limitation, prostate cancer, brain cancer, colon cancer, rectal cancer, renal- cell carcinoma, liver cancer, various lung cancers including non-small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, non-Hodgkin’s lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS),primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi’s sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, or metastatic lesions of said cancers. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T-cell acute lymphoid leukemia (T-ALL), chronic myelogenous 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- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia. In embodiments of any one of the methods, kits, or pharmaceutical compositions described herein, the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), and / or acute lymphoblastic leukemia (ALL).

[0167] The presence of genetic aberration in a Ras gene (e.g., KRAS, NRAS, or HRAS) can be determined by a widevariety of nucleic acid assays. Exemplary nucleic acid assays include but are not limited to genotyping assays and sequencing methods. Sequencing methods can include next-generation sequencing, targeted sequencing, exome sequencing, whole genome sequencing, massively parallel sequencing, and the like. Several platforms for next generation sequencing are commercially available, including those marketed by Illumina and Pacific Biosciences. Additional nucleic acid assays include but not limited to in situ hybridization (e.g., FISH), polymerase chain reaction (PCR), quantitative PCR (qPCR), quantitative real-time PCR (qRT-PCR), and ligase chain reaction (LCR), all of which are applicable for detecting a genetic aberration in a Ras gene (e.g., KRAS, NRAS, or HRAS). Where desired, one or more nucleic acids can be employed to detect a genetic aberration in a Ras gene (e.g., KRAS, NRAS, or HRAS), including but not limited to translation, as well as genetic mutations within a Ras gene (e.g., KRAS, NRAS, or HRAS) via point mutation, insertion, deletion, or frameshift.

[0168] In some embodiments, the step of assessing for presence of a genetic aberration associated with resistance to aKRAS inhibitor detects overexpression of a Ras gene (e.g., KRAS, NRAS, or HRAS). In some embodiments, the step of assessing detects a mutation in a Ras gene (e.g., KRAS, NRAS, or HRAS).

[0169] In some embodiments, the step of assessing detects a mutation a Ras gene (e.g., KRAS, NRAS, or HRAS),including but not limited point mutations selected from the group consisting of G12D, G12R, G12S, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, and Y96C. In some embodiments, the step of assessing detects amplification of a Ras gene (e.g., KRAS, NRAS, or HRAS).

[0170] A variety of techniques for protein analysis can also be applied for assessing the presence and / oroverexpression of a Ras protein (e.g., KRAS, NRAS, HRAS, or mutants thereof such as G12C, G12D, G12R, G12S, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, or Y96C). Suitable protein assays include, without limitation, immunohistochemistry (IHC), ELISA (enzyme linked immunosorbent assays), “sandwich” immunoassays, immunoradiometric assays, in situ immunoassays, western blot analysis, immunoprecipitation assays, immunofluorescent assays, flow cytometry, confocal microscopy, enzymatic assays, surface plasmon resonance, and PAGE-SDS. One or more of these protein assays utilize antibodies or fragments thereof that exhibit specific binding to a Ras protein (e.g., KRAS, NRAS, HRAS, or mutants thereof such as G12C, G12D, G12R, G12S, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, or Y96C).

[0171] In practicing a subject method, the presence of a Ras mutant protein (e.g., mutants or KRAS, NRAS, or HRAS,such as G12C, G12D, G12R, G12S, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, or Y96C) or overexpression of a Ras protein can be determined using any biological sample comprising the target cells (e.g., cancer cells from a subject under investigation) or constituents thereof (e.g., constituents such as cfDNA from the tumor tissue or cancer cells). The biological sample may be a liquid biological sample or a solid biological sample (in case of metastasis to other tissues) from the subject under investigation or treatment. The biological sample may be a biopsy sample that is fixed, paraffin-embedded, fresh, or frozen. The biological sample may be obtained by any suitable means, including but not limited to blood draw, needle aspiration, fine needle aspiration, core needle biopsy, vacuum assisted biopsy, large core biopsy, incisional biopsy, excisional biopsy, punch biopsy, shave biopsy, skin biopsy, surgical specimen, and venipuncture.

[0172] Depending on the tumor tissue or cancer cells to be treated, the biological sample can be obtained from,without limitation, blood or plasma, skin, heart, lung, kidney, bone marrow, breast, pancreas, liver, muscle, smooth muscle, bladder, gall bladder, colon, intestine, brain, prostate, esophagus, thyroid, serum, saliva, urine, gastric and digestive fluid, tears, stool, semen, vaginal fluid, interstitial fluids derived from tumorous tissue, ocular fluids, sweat, mucus, earwax, oil, glandular secretions, spinal fluid, hair, fingernails, plasma, nasal swab or nasopharyngeal wash, spinal fluid, cerebral spinal fluid, tissue, throat swab, biopsy, placental fluid, amniotic fluid, cord blood, emphatic fluids, cavity fluids, sputum, pus, microbiota, meconium, breast milk, and / or other excretions or body tissues of the subject.

[0173] In some embodiments, a biological sample comprises cell-free DNA (cfDNA) derived from a whole blood orplasma of the subject. A sample may be analyzed directly for its contents, or may be processed to purify one or more of its contents for analysis. In some embodiments, one or more components are purified from the sample for detecting the presence of a Ras mutant protein (e.g., mutants or KRAS, NRAS, or HRAS, such as G12C, G12D, G12R, G12S, G12V, G12W, G13D, Q61H, R68S, H95D, H95Q, H95R, or Y96C) or overexpression of a Ras protein. In some embodiments, the purified component of the biological sample is protein (e.g. total protein, cytoplasmic protein, or membrane protein). In some embodiments, the purified component of the sample is a nucleic acid, such as DNA (e.g. genomic DNA, cDNA, ctDNA, or cfDNA) or RNA (e.g. total RNA, mRNA, or microRNA).

[0174] In practicing a subject method disclosed herein, administrating a SOS1 inhibitor or a pharmaceuticalcomposition comprising an effective amount of a SOS1 inhibitor typically involves contacting a cell with a SOS1inhibitor disclosed herein. The contacting, as disclosed herein, can occur in vitro, ex vivo, or in vivo.

[0175] In some embodiments, the cell is contacted with (i) a SOS1 inhibitor disclosed herein and (ii) a KRASinhibitor disclosed herein. Contacting with (i) and (ii) can take place conjunctively. For example, a SOS1 inhibitor can be administered prior to, subsequent to, or concurrently with the administration of a KRAS inhibitor disclosed herein. For simultaneous contacting, the SOS1 inhibitor and the KRAS inhibitor disclosed herein can be in the same composition (e.g., as a formulation or as a unit dosage) or in different compositions (e.g., subjecting the cell to two different compositions at the same time). For sequential contacting, SOS1 inhibitor and the KRAS inhibitor disclosed herein can be in the same composition (e.g., a single composition exhibiting different release profiles or in different compositions). For sequential contacting, a first contacting of the cell (e.g., with the SOS1 inhibitor or the KRAS inhibitor disclosed herein) and a second contacting of the cell (e.g., with the KRAS inhibitor disclosed herein or the SOS1 inhibitor) can be separated by at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 16 hours, 24 hours, 1 day, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or longer. The first contacting and the second contacting can beseparated by at most about 1 month, 1 week, 24 hours, 20 hours, 16 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, 60 minutes, or less.

[0176] Suitable agents that can be administered in combination with a subject SOS1 inhibitor and KRAS inhibitordisclosed herein include but are not limited to TKIs, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunomodulatory agent, chemotherapeutic agent, and combinations thereof.

[0177] Exemplary immunomodulatory agents include but are not limited to immunostimulatory agents, checkpointimmune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-1BB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4- 1BB antibody. In some embodiments, the checkpoint immune blockade agents are 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 agent is an anti-PD-L1 antibody.

[0178] In embodiments, an additional agent (e.g., in addition to a KRAS inhibitor and SOS1 inhibitor) may beincluded in a method, kit, or pharmaceutical composition described herein. In embodiments, an additional agent may be selected from other anti-cancer agents, chemotherapeutic agents, anti-allergic agents, anti-nausea agents (or anti- emetics), pain relievers, cytoprotective agents, immunostimulants, and combinations thereof. In one embodiment, a subject treatment method includes a chemotherapeutic agent.

[0179] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)),a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody, an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor, an immunomodulator such as thalidomide or a thalidomide derivative. 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 (difluorodeoxycitidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase(ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), pemetrexed (Alimta®), phoenix (Yttrium90 / MX-DTPA), pentostatin, platinum-based chemotherapy, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0180] In some embodiments, a method described herein that comprises administering (a) a SOS1 inhibitor and (b) aKRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, further comprises administering (c) an additional agent selected from (1) a SHP2 inhibitor (e.g., 6-(4-amino-4- methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, RMC-4630, ERAS-601, TNO155, JAB-3068, IACS- 13909 / BBP-398, SHP099, RMC-4550), (2) an inhibitor of wildtype or mutant RAS, such as wildtype KRAS, wildtype HRAS, wildtype NRAS, mutant KRAS, mutant HRAS, mutant NRAS, KRAS G12C, KRAS G12D, KRAS G12S, KRAS G12V, KRAS G13D, KRAS G13C, KRAS G13V, or KRAS Q61H (e.g., LY3537982, JAB-21822, BBO-8520, D-1553, BI-1823911, RMC-9805, MRTX1133, MRTX849, AMG510, GDC-6036, AZD4625, JDQ443, RMC-6291, RMC-6236, BI-2493, MK-1084, RMC-8839, SHR1127, JAB-21822, GFH925, IBI351, BPI-421286, JMKX1899, HBI- 2438, D3S-001, GFH375, VS-7375, RMC-7977, RMC-5127, FMC-376), and (3) a MET inhibitor (e.g., foretinib, AMG-458, tivantinib, crizotinib, cabozantinib, tepotinib, capmatinib, savolitinib, glesatinib).

[0181] Anti-cancer agents of particular interest for use in the methods of the present disclosure include:anthracyclines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit the p70S6 kinase; mTOR inhibitors; immunomodulators; anthracyclines; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus.

[0182] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosinedeaminase 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.

[0183] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkylsulfonates, nitrosoureas and triazenes: uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, 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 (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HCl (Treanda®).

[0184] In certain aspects, compositions provided herein can be administered in combination with radiotherapy, suchas radiation. Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may 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. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips.

[0185] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method.Exemplary immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. In accordance with the presently disclosed subject matter, the above-described various methods can comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody, an anti- OX40 antibody, an anti-ICOS antibody, and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-l BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-L1 antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TIM3 antibodies, and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Ll antibody. In some embodiments, the method includes bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, subject methods may include immunostimulants. Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co- stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL-15 can also be employed. Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or anycombination thereof. An interleukin can be IL-2, or aldesleukin. Aldesleukin can be administered in low dose or high dose. A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg / kg (600,000 IU / kg). An immunostimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immunostimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immunostimulant (e.g., aldesleukin) can be administered at a dose from 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 can be administered at a dose from about 100,000 IU / kg to 300,000 IU / kg, from 300,000 IU / kg to 500,000 IU / kg, from 500,000 IU / kg to 700,000 IU / kg, from 700,000 IU / kg to about 1,000,000 IU / kg.

[0186] In embodiments, an additional agent (e.g., in addition to a KRAS inhibitor and SOS1 inhibitor) may beincluded in a method, kit, or pharmaceutical composition described herein. In some embodiments, an additional agent (e.g., in addition to a KRAS inhibitor and SOS1 inhibitor) included in a method, kit, or pharmaceutical composition described herein is selected from (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof; (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or of mutants thereof; (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or of mutants thereof; (7) a mitotic kinase inhibitor (e.g., a CDK4 / 6 inhibitor); (8) an anti-angiogenic drug (e.g., an anti-VEGF antibody); (9) a topoisomerase inhibitor; (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and / or of mutants thereof; (12) an inhibitor of c-MET and / or of mutants thereof; (13) an inhibitor of BCR-ABL and / or of mutants thereof; (14) an inhibitor of ErbB2 (Her2) and / or of mutants thereof; (15) an inhibitor of AXL and / or of mutants thereof; (16) an inhibitor of NTRK1 and / or of mutants thereof; (17) an inhibitor of RET and / or of mutants thereof; (18) an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or of mutants thereof; (19) an inhibitor of ERK and / or of mutants thereof; (20) an MDM2 inhibitor; (21) an inhibitor of mTOR; (22) an inhibitor of BET; (23) an inhibitor of IGF1 / 2 and / or of IGF1-R; (24) an inhibitor of CDK9; (25) an inhibitor of farnesyl transferase; (26) an inhibitor of SHIP pathway including SHIP2 inhibitor, as well as SHIP1 inhibitors; (27) an inhibitor of SRC; (28) an inhibitor of JAK; (29) a PARP inhibitor, (30) a BTK inhibitor, (31) a ROS1 inhibitor, (32) an inhibitor of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT, (33) an inhibitor of KRAS G12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of KRAS, the structures of which are publicly known) (e.g., an inhibitor of Ras G12C as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or related patents and applications, each of which is incorporated by reference in its entirety), (34) an SHC inhibitor, (35) a GABinhibitor, (36) a GRB inhibitor, (37) a PI-3 kinase inhibitor, (38) a MARPK inhibitor, (39) a CDK4 / 6 inhibitor, (40) a MAPK inhibitor, or (41) a SHP pathway inhibitor, such as a SHP2 inhibitor (e.g., RMC-4630, ERAS-601,and ) or a SHP1 inhibitor. In some embodiments, an additional agent is a checkpoint immune blockade agent (e.g., anti-PD-1 and / or anti-PD-L1 antibody, anti-CLTA-4 antibody). In some embodiments, an additional agent comprises an inhibitor against one or more targets selected from: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinase, topoisomerase, ALK, ALK5, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1 / 2, IGF1-R, CDK9, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KRAS G12C mutant, and ROS1.

[187] In some embodiments, the agents of the method are administered either simultaneously, concurrently orsequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two or more compounds in the body of the patient.

[188] In some embodiments, the agents of the method are administered sequentially in any order by a suitable route,such as infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria known to the attending physician and medical practitioner(s) administering the combination. In embodiments, the agents of the method are administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.

[189] In some cases, a treatment regime may be dosed according to a body weight of a subject. In subjects who aredetermined obese (BMI > 35) a practical weight may need to be utilized. BMI is calculated by: BMI = weight (kg) / [height (m)]2. Body weight may be calculated for men as 50 kg + 2.3*(number of inches over 60 inches) or for women 45.5 kg + 2.3*(number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight + (0.4*(Actual body weight – ideal body weight)). In some cases, a body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2) = √Height (cm) ∗Weight (kg) / 3600.

[190] A reduction in Ras signaling can be evidenced by one or more of the following: (i) an increase in steady statelevel of GDP-bound modified protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202 / y204, (v) a reduction of phosphorylated S6S235 / 236, (vi) a reduction of cell growth of a tumor cell expressing a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) protein, (vii) a reduction in Ras interaction with a Ras-pathway signaling protein, and (viii) a reduction in expression level of Ras protein. Non-limiting examples of Ras-pathway signaling proteins include SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, andGNAQ. In some embodiments, the reduction in Ras signaling output can be evidenced by two, three, four, five, six, seven, or all of (i)-(viii) above. In some embodiments, the reduction of any one or more of (i)-(viii) can be 0.1-fold, 0.2- fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7- fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000- fold, or more as compared to a control not treated with a method or composition described herein. A reduction in cell growth can be demonstrated with the use of tumor cells or cell lines. A tumor cell line can be derived from a tumor in one or more tissues, e.g., pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine, colon), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of tumor cell lines comprising a K- Ras mutation include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K- Ras G12A), NCI-H1944 (e.g., K-Ras G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras G12V), NCI- H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), Panc-10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K-Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K- Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K- Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SU.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K- Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)).

[0191] A reduction of signaling output can be ascertained by a wide variety of methods known in the art. For example,phosphorylation of a substrate or a specific amino acid residue thereof can be detected and / or quantified using one or more techniques, such as kinase activity assays, phospho-specific antibodies, Western blot, enzyme-linked immunosorbent assays (ELISA), cell-based ELISA, intracellular flow cytometry, mass spectrometry, and multi-analyte profiling. A host of readout can evidence a reduction of Ras signaling output, including without limitation: (i) an increase in steady state level of GDP-bound modified protein; (ii) a reduction in steady state level of GTP-bound Ras protein; (iii) a reduction of phosphorylated AKTs473, (iv) a reduction of phosphorylated ERKT202 / y204, (v) a reduction of phosphorylated S6S235 / 236, (vi) a reduction of cell growth of a tumor cell expressing a Ras mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) protein, (vii) a reduction in Ras interaction with a Ras-pathway signaling protein, and (viii) a reduction in expression level of Ras protein. In some embodiments, a reduction is evidenced by 2, 3, 4 or more of items (i)-(viii). In some embodiments, the reduction in Ras signaling output can be evidenced by any one of (i)-(viii) as compared to control corresponding Ras protein in the absence of a compound disclosed herein. For example, a control Ras protein, as described herein, can be a Ras protein (e.g., wildtype ormutated) that is not bound to any subject compound of the present disclosure. The increase in item (i) or reduction in items (ii) through (vi) can be at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900- fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more as compared to the control Ras protein. In some embodiments, a reduction in Ras interaction with a Ras-pathway signaling protein is established by a reduced interaction with SOS (including SOS1 and SOS2), RAF, SHC, SHP (including SHP1 and SHP2), MEK, MAPK, ERK, GRB, RASA1, or GNAQ.

[0192] In some embodiments, additional therapies, can be administered to the subject for other purposes. For example,anti-inflammatory agents or other agents that treat symptoms associated with cancer, but not the underlying cancer itself, including, e.g., inflammation, pain, nausea, weight loss, and general malaise can be administered to a subject with cancer during the period of monotherapy treatment. A subject being treated by the present methods can have completed any prior treatment (e.g., surgery, chemotherapy, bone marrow transplant, or being treated with some other anti-cancer agents) before the monotherapy treatment or receive additional therapies after the monotherapy treatment.

[0193] A synergistic effect of a combination treatment comprising a plurality of agents, as disclosed herein, can becharacterized by a synergistic value as ascertained by an “excess over Bliss independence” or “BLISS” independence criterion. The BLISS independence criterion can be used to screen for candidate drug combinations. The criterion can compare the observed combination response with the predicted combination response, which predicted combination response is obtained based on the assumption that there is no effect from drug-drug interactions. The combination effect can be determined to be synergistic when the observed combination response is greater than the predicted combination response (e.g., greater by a threshold value). To determine a synergistic value of a combination treatment comprising inhibitor (a) (e.g., a SOS1 inhibitor) and inhibitor (b) (e.g., a KRAS inhibitor disclosed or exemplified herein) for inducing growth inhibition of target cells (e.g., cells including a KRAS mutant or cells overexpressing KRAS), the BLISS independence criterion can utilize the following equation: YAB,O-YAB,P(1) wherein: YAB,Ois observed percentage growth inhibition of the target cells by the combination comprising (a) at dose A and (b) at dose B; and YAB,P is predicted percentage growth inhibition of the target cells by the combination comprising (a) at the dose A, and (b) at the dose B, wherein: YAB,P =YA+ YB– YAYB(2) wherein further: YA is observed percentage growth inhibition of the target cells by (a) alone at the dose A; YBis observed percentage growth inhibition of the target cells by (b) alone at the dose B; and YAYBis product of YAand YB. The observed combined percentage inhibition YAB,O is compared with the predicted percentage growth inhibition YAB,P in accordance with equation (1). The comparison can determine whether the combination treatment promotes a synergistic effect, an additive effect, or an antagonistic effect, as summarized in equation (3). When YAB,O> YAB,P, the combination treatment can be determined to be more efficacious than expected (e.g., a synergistic effect). When YAB,O< YAB,P, the combination treatment can be determined to be worse than expected (e.g., an antagonistic effect). When YAB,O = YAB,P, the combination treatment can be determined to be substantially the same as a simple addition oftwo separate drugs (e.g., independent effects, or an additive effect). >YAB,PSynergy YAB,P{= YAB,PIndependent (3) <YAB,PAntagonism

[0194] When using the BLISS independence criterion, the percentage growth inhibition of the target cells can beprovided based on a percentage scale (e.g., between about 0% to about 100%) or a fractional scale (e.g., between about 0 to 1). For example, a 75% growth inhibition of the target cells can be expressed as 0.75 for purposes of analysis in accordance with the BLISS independence criterion. For example, with the fractional scale is used, the difference between the observed combined percentage inhibition YAB,Oand the predicted percentage growth inhibition YAB,P, in accordance with equation (1) (e.g., based on one or more in vitro experiments), can be determined to be additive (or antagonistic) when the difference is less than or equal to zero. Such difference can be determined to be synergistic when the difference is greater than zero. Here, the synergistic effect can be divided into a plurality of sub-ranges, e.g., a first synergistic sub-range having the difference between about 0.05 and about 0.1 (e.g., mild synergy), a second synergistic sub-range having the difference between about 0.1 and about 0.2 (e.g., moderate synergy), and a third synergistic sub- range having the difference greater than or equal to 0.2 (e.g., robust synergy).

[0195] In some embodiments, the combination treatment comprising a plurality of agents (e.g., a SOS1 inhibitor and aKRAS inhibitor disclosed herein), can be utilized to reduce growth or proliferation of target cells, in vitro or in vivo. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of above 0.1 as ascertained by the Bliss independence criterion. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of at least about 0.1, 0.2, 0.3, 0.4, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, or above as ascertained by the Bliss independence criterion. The therapeutic efficacy of the combination treatment can be characterized by a synergistic value of about 0.1 to about 1, about 1.0-5, about 5 to about 10, or about 10-15.

[0196] The subject combination therapy comprising a plurality of different therapeutic agents (e.g. a SOS1 inhibitorand a KRAS inhibitor disclosed herein) can synergistically achieve one or more desired therapeutic actions or outcomes. In some embodiments, the reduced progression of a cancer is evidenced by an improvement of a response such as a molecular response or cytogenetic response in a subject being treated. A subject treated according to a method of the present disclosure may exhibit one or more desired therapeutic outcomes described herein, any of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer. For example, a subject treated according to a method of the present disclosure may exhibit one or more of (i) disease stabilization, (ii) disease regression, and (iii) improvement of one or more symptoms of the cancer, any one or more of which may persist for at least 1 month, such as at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or longer.

[0197] The subject combination treatment disclosed herein can achieve such desired actions or outcomes, whilesynergistically providing one or more superior advantages including, but not limited to, (i) decreased amount (e.g., dosage regimen, number of doses, etc.) of one, more, or all of the therapeutic agents utilized in the combination therapy; (ii) avoiding, limiting, or reducing one or more undesirable side-effects associated with the use of any one of the plurality of different therapeutic agents when used in the therapeutically effective amount or clinically approved amount; (iii) allowing for the use of a KRAS inhibitor disclosed herein that would otherwise be intolerable to thesubject.

[0198] Through the administration of a combination therapy disclosed herein, a range of undesirable side-effectsassociated may be reduced, including diarrhea, rash, nausea, vomiting, decreased appetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury. In some embodiments, other side effects of a KRAS inhibitor disclosed herein including diarrhea, rash, nausea, vomiting, decreased appetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury can be reduced. The combination treatment with a SOS1 inhibitor disclosed herein may allow administration of a KRAS inhibitor disclosed herein that is otherwise not tolerable to the subject. The combination treatment with a subject SOS1 inhibitor may allow a more frequent dosage regimen of KRAS inhibitor disclosed herein that is otherwise too toxic or not tolerable to a subject in need of such treatment.

[0199] The combination treatment as disclosed herein can utilize a KRAS inhibitor disclosed herein that can betherapeutically sub-optimal when used alone, but in combination with a SOS1 inhibitor disclosed herein yields an overall therapeutic efficacy (e.g., promoting one or more desired therapeutic outcomes and / or reducing undesirable side-effects). In some embodiments, the combination therapy utilizes a sub-therapeutic dose of a KRAS inhibitor disclosed herein approved for treating a human subject for a given indication. In some embodiments, the sub- therapeutic dose is less than 95% of the approved dose of the KRAS inhibitor, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the approved dose of the KRAS inhibitor.

[0200] In practicing any of the subject methods, the SOS1 inhibitor may be administered at a dose of at least 5 mgdaily, such as 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg daily in combination with a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof,. In some embodiments, the SOS1 inhibitor is administered at a dose of 5 to 1000 mg, such as about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 160 mg, about 180 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1000 mg in combination with a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV- 1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof.

[0201] In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof. Themethod comprises administering a pharmaceutical composition that comprises an effective amount of a small molecule SOS1 inhibitor to the subject, wherein said SOS1 inhibitor inhibits growth of a cancer cell line with an IC50 less than about 100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, 0.1 nM or even less, as ascertained in a growth inhibition assay utilizing the cancer cell line. In some embodiments, the SOS1 inhibitor inhibits growth of a cancer cell line with an IC50 at least 100 times less than that of BI3406 or that of MRTX0902. In some embodiments, the SOS1 inhibitor synergistically inhibits growth of a cancer cell line in combination with a KRAS inhibitor disclosed herein. In some embodiments, the SOS1 inhibitor is characterized in that it synergistically increases percent of cell growth inhibition from about 10% to at least about 50%, when less than about100 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM of the SOS1 inhibitor is applied in combination with the KRAS inhibitor disclosed herein applied at its IC10 molarity, as ascertained in an in vitro growth inhibition assay using cancer cells.

[0202] In yet another aspect, the present disclosure provides a method of reducing proliferation of a cancer cell. Themethod comprises administering to the cell (a) a small molecule SOS1 inhibitor disclosed herein, and (b) a KRAS inhibitor disclosed herein, wherein the administration of (a) and (b) synergistically inhibits growth of cancer cells as evidenced by achieving a comparable or higher degree of growth inhibition when either (1) less than 90% of the SOS1 inhibitor is administered as compared to the amount required for the SOS1 inhibitor when administered alone; or (2) less than 90% of the KRAS inhibitor disclosed herein is administered as compared to the amount required for the KRAS inhibitor disclosed herein when administered alone. In some embodiments, the KRAS inhibitor disclosed herein administered is less than about 80%, 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, or 10% of the amount required to achieve a comparable or higher degree of growth inhibition.

[0203] In some embodiments, the subject is a naïve subject that has not been treated for the cancer. In someembodiments, the naïve subject has not been treated with a KRAS inhibitor prior to administering (a) and (b). In some embodiments, the subject has been treated with chemotherapy. In some embodiments, the subject has received surgery to treat the cancer. In some embodiments, the subject has not been treated with chemotherapy. In some embodiments, the subject has not received surgery. In some embodiments, the subject has been treated with a KRAS inhibitor prior to administering (a) and (b). In some embodiments, the subject has not been treated with a KRAS inhibitor prior to administering (a) and (b).

[0204] In some embodiments, a subject suitable for a treatment method of the present disclosure has previously beentreated with one or more KRAS inhibitors prior to administering (a) and (b). In some embodiments, a subject suitable for a treatment method of the present disclosure has previously been treated with platinum-based chemotherapy prior to administering (a) and (b). In some embodiments, the disease of the subject has progressed on or after platinum-based chemotherapy. In some embodiments, the subject has undergone tumor resection. In some embodiments, the disease of the subject has progressed on or after platinum-based chemotherapy in the locally advanced metastatic setting or recurred in the adjuvant setting. In some embodiments, the disease of the subject has progressed on or after KRAS inhibitor treatment. In some embodiments, the disease of the subject has progressed on or after KRAS inhibitor treatment in the locally advanced metastatic setting or recurred in the adjuvant setting.

[0205] Drug resistance and / or intolerance to the certain KRAS inhibitors may severely limit treatment options forsubjects who exhibit resistance or intolerance to one or more KRAS inhibitors, or relapse following treatment with one or more KRAS inhibitors. Resistance to a KRAS inhibitor may be characterized by one or more changes selected from (1) progression of the cancer, (2) mutation of KRAS that was not present prior to the earlier treatment, including point mutation, (3) KRAS gene amplification, (4) RAS-MAPK pathway activation, (5) histologic transformation, and (6) phenotypic transformation. In some embodiments, resistance to a KRAS inhibitor is characterized by a new mutation at the amino acid corresponding to the 12 position of KRAS.

[0206] In some embodiments, a subject suitable for a treatment method of the present disclosure exhibits intoleranceto a KRAS inhibitor. In some embodiments, the subject suffers from one or more side effects selected from fluid retention, headache, diarrhea, fatigue, cough, dyspnea, musculoskeletal pain, nausea, skin rash, myalgia, arthralgia, infection, abdominal pain, hemorrhage, pruritis, pain, constipation, myelosuppression, bleeding-related events, cardiovascular toxicity, pulmonary arterial hypertension, QT prolongation, dermatologic reactions, Stevens-Johnson syndrome, erythema multiforme, tumor lysis syndrome, musculoskeletal disorder, decreased appetite, hepatic enzyme increase (e.g., AST, ALK, alkaline phosphatase), and hepatotoxicity.

[0207] A subject resistant to treatment with a KRAS inhibitor may exhibit progression of the disease or condition,such as cancer (e.g., NSCLC, lung cancer, colorectal cancer, pancreatic cancer), despite treatment with the KRAS inhibitor.

[0208] Progression may be established by a lack of reduction in any or some of the symptoms disclosed herein orknown in the art that are associated with a KRAS-mediated cancer, such as NSCLC, lung cancer, colorectal cancer, or pancreatic cancer. In some embodiments, progression is established for a lack of reduction in one or more symptoms after, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more months from the initial treatment of KRAS inhibitor.

[0209] In some embodiments, a subject suitable for a treatment method of the present disclosure suffers from a relapseof a KRAS-mediated cancer, such as NSCLC, lung cancer, colorectal cancer, or pancreatic cancer. A relapse can be established by a renewed onset of any of the symptoms associated with the cancer with which the subject has previously been diagnosed, or by the detection of the cancer via a suitable method, such as a CT scan, a PET scan, an MRI, a bronchoscopy, or a lung biopsy. A relapse may occur, e.g., 3, 5, 7, 8, 9, 10, 11, 12, 15, 18, 24, 25, 26, 27, 28, 29, 30, 36, or more months after the initial treatment with KRAS inhibitor. Kits

[0210] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a small molecule SOS1 inhibitor of Formula (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI- E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae; (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae; and (3) instructions for using the composition(s) of (1) and (2).

[0211] In an aspect is provided a kit for use in reducing proliferation of cancer cells comprising a KRAS mutantprotein or KRAS overexpression, the kit comprising: (1) a composition comprising a small molecule SOS1 inhibitor of Formula (SI-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae; and (3) instructions for using the composition(s) of (1) and (2).

[0212] In embodiments of the kit, the SOS1 inhibitor and the KRAS inhibitor are formulated in the same unit dosageform. In embodiments of the kit, the SOS1 inhibitor and the KRAS inhibitor are formulated in different unit dosage forms.

[0213] In embodiments, the small molecule SOS1 inhibitor is a small molecule SOS1 inhibitor of Formula (SI), (SI-A), (SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1). In some embodiments, instructions for contacting the cells in vitro, ex vivo, or in vivo are provided. In some embodiments, the kit can comprise a multi-day supply, including instructions directing the multi-day administration. Pharmaceutical Compositions

[0214] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI), (SI-A),(SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2),(II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, and (iii) a pharmaceutically acceptable excipient.

[0215] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI), (SI-A),(SI-B), (SI-1), (SI-B1), (SI-B2), (SI-C), (SI-C1), (SI-C2), (SI-C3), (SI-D), (SI-D1), (SI-D2), (SI-E), (SI-E1), (SI-1), (SII-B), (SII-C), (SIII), (SIV), (SIV-1), or (SIVa-1), or any embodiment of the preceding formulae, or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, and (iii) a pharmaceutically acceptable excipient.

[0216] In an aspect is provided a pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or apharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or any embodiment of the preceding formulae, and (iii) a pharmaceutically acceptable excipient.

[0217] Compounds described herein, or pharmaceutically acceptable salts or solvates thereof, may be administered toa subject in biologically compatible forms suitable for administration to treat or prevent a disease, disorder or condition. Compounds described herein may be administered in any pharmacological form including a therapeutically effective amount administered separately or in combination. Compounds described herein may be administered in any pharmacological form including therapeutically effective amounts of the compounds alone or in combination with pharmaceutically acceptable carriers. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and compounds described herein, or pharmaceutically acceptable salts or solvates thereof.

[0218] In some embodiments, a compound described herein is administered as a pure chemical. In someembodiments, a compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0219] Accordingly, provided herein is a pharmaceutical composition comprising compounds described herein, orpharmaceutically acceptable salts, together with one or more pharmaceutically acceptable excipients. The excipient(s) (or carrier(s)) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient of the composition.

[0220] In practicing any of the subject methods, the compounds described herein may be administered either alone orin combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient. By way of example only, a compound described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ. In some embodiments, a compound described herein is administered orally.

[0221] In practicing any of the subject methods, a pharmaceutical composition suitable for oral administration may bepresented as a discrete unit such as a capsule, cachet or tablet, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0222] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, aswell as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0223] In some embodiments, a pharmaceutical composition is formulated for parenteral administration by injection,e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0224] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterileinjection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0225] Pharmaceutical compositions may also be formulated as a depot preparation. Such long-acting formulationsmay be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. Compounds

[0226] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:wherein W is a N, C(R18), N(R18b), C(R18)(R18a), C(O), S(O), or S(O)2; Z is N, C(R8), N(R8b), C(R8)(R8a), C(O), S(O), or S(O)2; wherein W and Z are not both selected from C(O), S(O), and S(O)2; V and J are each independently selected from C(R17), C(R17)(R16a), C(R16), C(R16)(R16a), N, N(R17b), and N(R16b); wherein exactly one of V and J is C(R17), C(R17)(R16a), or N(R17b); Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), or S(O)2; U is N, C(R2c), C(R2c)(R2c), N(R2b), S(O), S(O)2, or C(O); R10is -L7-R7; L7is a bond, -O-, -N(R14)-, -C(O)-, -S-, -S(O)2-, -S(O)-, C1-4alkyl, or 2-4 membered heteroalkyl linker, wherein the C1-4alkyl and 2-4 membered heteroalkyl linker are each optionally substituted with one, two or three R20a;W1and W3are independently selected from N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W2is independently selected from a N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W4is selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), S(O), and S(O)2; W5is selected from N, C(R1), and C(R4); a) s1 is 1 and s2 is 0, 2, or 3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3; or b) s1 is an integer from 1 to 6; s2 is an integer from 0 to 3; s1 and s2 are not both 1; and s1 and s2 are notboth 2; s3 is an integer from 1 to 3; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, - (C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R6is -L2-R5, wherein R6is optionally capable of forming a covalent bond with a RAS amino acid; L2is a bond, -O-, -N(R4d)-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R4d-, CR4cR4c, -OCR4cR4c-, -N(R4d)CR4cR4c-, - C(O)CR4cR4c-, -SCR4cR4c-, -S(O)2CR4cR4c-, -S(O)CR4cR4c-, -P(O)R4dCR4cR4c-, -CR4cR4cCR4cR4c, -CR4cR4cO-, - CR4cR4cN(R4d)-, -CR4cR4cC(O)-, -CR4cR4cS-, -CR4cR4cS(O)2-, -CR4cR4cS(O)-, -CR4cR4cP(O)R4d-, -N(R4d)C(O)-, -N(R4d)S(O)2-, -N(R4d)S(O)-, -N(R4d)P(O)R4d-, -C(O)N(R4d)-, -S(O)2N(R4d)-, -S(O)N(R4d)-, -P(O)R4dN(R4d)-, - OC(O)-, -OS(O)2-, -OS(O)-, -OP(O)R4d-, -C(O)O-, -S(O)2O-, -S(O)O-, -P(O)R4dO-, -CR4cR4cCR4cR4cCR4cR4c-, -OCR4cR4cCR4cR4c-, -N(R4d)CR4cR4cCR4cR4c-, -C(O)CR4cR4cCR4cR4c-, -SCR4cR4cCR4cR4c-, - S(O)2CR4cR4cCR4cR4c-, -S(O)CR4cR4cCR4cR4c-, -P(O)R4dCR4cR4cCR4cR4c-, -CR4cR4cCR4cR4cO-, - CR4cR4cCR4cR4cN(R4d)-, -CR4cR4cCR4cR4cC(O)-, -CR4cR4cCR4cR4cS-, -CR4cR4cCR4cR4cS(O)2-, - CR4cR4cCR4cR4cS(O)-, or -CR4cR4cCR4cR4cP(O)R4d-; each R4cis independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, -OC(O)R14a, -N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14a, and -N(R14)S(O)2R14, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; each R4dis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, and -OC(O)R14a, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; R5is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12cycloalkyl, -CH2- C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2- C6-12aryl, -CH2-C1-11eteroaryl, C1-11heteroaryl,-OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, - N(R14)S(O)2R15, -C(O)R12, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, - S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)- N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, -(C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, C1-11heteroaryl are optionally substituted with one, two, or three R20k; R8and R8aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R8bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R17is -L1-R19; R17bis -L1b-R19; L1is selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, - C(O)N(R14)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, -OCON(R14)-, - N(R14)C(O)O-, N(R1e), C(O)N(R1c), S(O)2N(R1c), S(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; L1bis selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -C(O)-, -C(O)N(R14)-, C(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; R1e, R1f, and R1gare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, - S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, - S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1fand R1gare joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20i; R1cis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl,and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16and R16aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R16bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R2is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C4-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2cis independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), – (C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one,two, or three R20d; R2bis independently hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -C(O)OR12’, -OC(O)N(R12’)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or – (C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R12bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; X is C(R3), C(R3)(R3), N(R3), or N; each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl,C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’’is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12cis independently selected from hydrogen and R20m; each R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20e; each R14is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl;each R14ais independently selected from C1-6alkyl and C1-6haloalkyl; each R15is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; R18and R18aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; R18bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R20h, R20i, R20k, and R20mis independently selected from halogen, oxo, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), =C(R21b)2, -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), - N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R21, -N(R24)S(O)2R25, -C(O)R21, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25; wherein two R20kbonded to the same or adjacent atoms may optionally be joined to form a C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; R21bis independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, or two R21bare taken together with the carbon atom to which they are attached to form C3-10cycloalkyl or C2-9heterocycloalkyl; each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH; each R22is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23is independently selected from H and C1-6alkyl; each R24is independently selected from H and C1-6alkyl;each R25is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; indicates the location of attachment of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom; and indicates a single or double bond such that all valences are satisfied.

[0227] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein s1 is an integer from 1 to 6 and s2 is an integer from 1 to 3; and all other variables are as described for the aspect immediately above.

[0228] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, s1 is 1 and s2 is 0, 2, or3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5 and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3. In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, s1 is an integer from 1 to 6; s2 is an integer from 0 to 3; s1 and s2 are not both 1; and s1 and s2 are not both 2.

[0229] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein W is a N, C(R18), N(R18b), C(R18)(R18a), C(O), S(O), or S(O)2; Z is N, C(R8), N(R8b), C(R8)(R8a), C(O), S(O), or S(O)2; wherein W and Z are not both selected from C(O), S(O), and S(O)2; V and J are each independently selected from C(R17), C(R17)(R16a), C(R16), C(R16)(R16a), N, N(R17b), and N(R16b); wherein exactly one of V and J is C(R17), C(R17)(R16a), or N(R17b); Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), or S(O)2; U is N, C(R2c), C(R2c)(R2c), N(R2b), S(O), S(O)2, or C(O); R10is -L7-R7; L7is a bond, -O-, -N(R14)-, -C(O)-, -S-, -S(O)2-, -S(O)-, C1-4alkyl, or 2-4 membered heteroalkyl linker, wherein the C1-4alkyl and 2-4 membered heteroalkyl linker are each optionally substituted with one, two or three R20a; R7is; W1and W3are independently selected from N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W2is independently selected from a N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2;W4is selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), S(O), and S(O)2; W5is selected from N, C(R1), and C(R4); s1 is 1 and s2 is 0, 2, or 3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5 and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3; s3 is an integer from 1 to 3; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, - CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, - (C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R6is -L2-R5, wherein R6is optionally capable of forming a covalent bond with a RAS amino acid; L2is a bond, -O-, -N(R4d)-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R4d-, CR4cR4c, -OCR4cR4c-, -N(R4d)CR4cR4c-, - C(O)CR4cR4c-, -SCR4cR4c-, -S(O)2CR4cR4c-, -S(O)CR4cR4c-, -P(O)R4dCR4cR4c-, -CR4cR4cCR4cR4c, -CR4cR4cO-, - CR4cR4cN(R4d)-, -CR4cR4cC(O)-, -CR4cR4cS-, -CR4cR4cS(O)2-, -CR4cR4cS(O)-, -CR4cR4cP(O)R4d-, -N(R4d)C(O)-, -N(R4d)S(O)2-, -N(R4d)S(O)-, -N(R4d)P(O)R4d-, -C(O)N(R4d)-, -S(O)2N(R4d)-, -S(O)N(R4d)-, -P(O)R4dN(R4d)-, - OC(O)-, -OS(O)2-, -OS(O)-, -OP(O)R4d-, -C(O)O-, -S(O)2O-, -S(O)O-, -P(O)R4dO-, -CR4cR4cCR4cR4cCR4cR4c-, -OCR4cR4cCR4cR4c-, -N(R4d)CR4cR4cCR4cR4c-, -C(O)CR4cR4cCR4cR4c-, -SCR4cR4cCR4cR4c-, - S(O)2CR4cR4cCR4cR4c-, -S(O)CR4cR4cCR4cR4c-, -P(O)R4dCR4cR4cCR4cR4c-, -CR4cR4cCR4cR4cO-, - CR4cR4cCR4cR4cN(R4d)-, -CR4cR4cCR4cR4cC(O)-, -CR4cR4cCR4cR4cS-, -CR4cR4cCR4cR4cS(O)2-, - CR4cR4cCR4cR4cS(O)-, or -CR4cR4cCR4cR4cP(O)R4d-; each R4cis independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, -OC(O)R14a, -N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14a, and -N(R14)S(O)2R14, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; each R4dis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, and -OC(O)R14a, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; R5is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, C1-11heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, - N(R14)S(O)2R15, -C(O)R12, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, - S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)- N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, -(C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, C1-11heteroaryl are optionally substituted with one, two, or three R20k; R8and R8aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R8bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R17is -L1-R19; R17bis -L1b-R19; L1is selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, - C(O)N(R14)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, -OCON(R14)-, - N(R14)C(O)O-, N(R1e), C(O)N(R1c), S(O)2N(R1c), S(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; L1bis selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -C(O)-, -C(O)N(R14)-, C(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; R1e, R1f, and R1gare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, - S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1fand R1gare joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20i; R1cis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16and R16aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R16bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R2is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6- 10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C4-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d;R2cis independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), – (C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2bis independently hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -C(O)OR12’, -OC(O)N(R12’)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or – (C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R12bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; X is C(R3), C(R3)(R3), N(R3), or N; each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’’is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12cis independently selected from hydrogen and R20m; each R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20e; each R14is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R14ais independently selected from C1-6alkyl and C1-6haloalkyl; each R15is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; R18and R18aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; R18bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R20h, R20i, R20k, and R20mis independently selected from halogen, oxo, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), =C(R21b)2, -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), - N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R21, -N(R24)S(O)2R25, -C(O)R21, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25; wherein two R20kbonded to the same or adjacent atoms may optionally be joined to form a C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; R21bis independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, or two R21bare taken together with the carbon atom to which they are attached to form C3-10cycloalkyl or C2-9heterocycloalkyl; each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH; each R22is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23is independently selected from H and C1-6alkyl; each R24is independently selected from H and C1-6alkyl; each R25is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; indicates the location of attachment of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom; and indicates a single or double bond such that all valences are satisfied.

[0230] In embodiments of the methods described herein, the KRAS inhibitor is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:wherein W is a N, C(R18), N(R18b), C(R18)(R18a), C(O), S(O), or S(O)2; Z is N, C(R8), N(R8b), C(R8)(R8a), C(O), S(O), or S(O)2; wherein W and Z are not both selected from C(O), S(O), and S(O)2; V and J are each independently selected from C(R17), C(R17)(R16a), C(R16), C(R16)(R16a), N, N(R17b), and N(R16b); wherein exactly one of V and J is C(R17), C(R17)(R16a), or N(R17b); Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), or S(O)2; U is N, C(R2c), C(R2c)(R2c), N(R2b), S(O), S(O)2, or C(O); R10is -L7-R7; L7is a bond, -O-, -N(R14)-, -C(O)-, -S-, -S(O)2-, -S(O)-, C1-4alkyl, or 2-4 membered heteroalkyl linker, wherein the C1-4alkyl and 2-4 membered heteroalkyl linker are each optionally substituted with one, two or three R20a;W1and W3are independently selected from N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W2is independently selected from a N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W4is selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), S(O), and S(O)2; W5is selected from N, C(R1), and C(R4);s1 is 1 and s2 is 0, 2, or 3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5 and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3; s3 is an integer from 1 to 3; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, - CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, - (C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R6is -L2-R5, wherein R6is optionally capable of forming a covalent bond with a Ras amino acid; L2is a bond, -O-, -N(R4d)-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R4d-, CR4cR4c, -OCR4cR4c-, -N(R4d)CR4cR4c-, - C(O)CR4cR4c-, -SCR4cR4c-, -S(O)2CR4cR4c-, -S(O)CR4cR4c-, -P(O)R4dCR4cR4c-, -CR4cR4cCR4cR4c, -CR4cR4cO-, - CR4cR4cN(R4d)-, -CR4cR4cC(O)-, -CR4cR4cS-, -CR4cR4cS(O)2-, -CR4cR4cS(O)-, -CR4cR4cP(O)R4d-, -N(R4d)C(O)-, -N(R4d)S(O)2-, -N(R4d)S(O)-, -N(R4d)P(O)R4d-, -C(O)N(R4d)-, -S(O)2N(R4d)-, -S(O)N(R4d)-, -P(O)R4dN(R4d)-, - OC(O)-, -OS(O)2-, -OS(O)-, -OP(O)R4d-, -C(O)O-, -S(O)2O-, -S(O)O-, -P(O)R4dO-, -CR4cR4cCR4cR4cCR4cR4c-, -OCR4cR4cCR4cR4c-, -N(R4d)CR4cR4cCR4cR4c-, -C(O)CR4cR4cCR4cR4c-, -SCR4cR4cCR4cR4c-, - S(O)2CR4cR4cCR4cR4c-, -S(O)CR4cR4cCR4cR4c-, -P(O)R4dCR4cR4cCR4cR4c-, -CR4cR4cCR4cR4cO-, - CR4cR4cCR4cR4cN(R4d)-, -CR4cR4cCR4cR4cC(O)-, -CR4cR4cCR4cR4cS-, -CR4cR4cCR4cR4cS(O)2-, - CR4cR4cCR4cR4cS(O)-, or -CR4cR4cCR4cR4cP(O)R4d-; each R4cis independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, -OC(O)R14a, -N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14a, and -N(R14)S(O)2R14, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; each R4dis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, and -OC(O)R14a, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, areoptionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, -SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), - C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, - N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; R5is a 5 or 6 membered partially unsaturated heterocycloalkyl or a 5 or 6 membered heteroaryl, each optionally substituted with one, two or three R20k, wherein the partially unsaturated 5 or 6 membered heterocycloalkyl or 5 or 6 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and the 5 or 6 membered partially unsaturated heterocycloalkyl or 5 or 6 membered heteroaryl is each bonded to L2through a ring nitrogen; R8and R8aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R8bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R17is -L1-R19; R17bis -L1b-R19; L1is selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, - C(O)N(R14)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, -OCON(R14)-, - N(R14)C(O)O-, N(R1e), C(O)N(R1c), S(O)2N(R1c), S(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; L1bis selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -C(O)-, -C(O)N(R14)-, C(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; R1e, R1f, and R1gare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, - S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, - S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1fand R1gare joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20i;R1cis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3- 12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16and R16aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R16bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R2is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C4- 9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2cis independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), – (C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, –(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2bis independently hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -C(O)OR12’, -OC(O)N(R12’)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or – (C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R12bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; X is C(R3), C(R3)(R3), N(R3), or N; each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’’is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12cis independently selected from hydrogen and R20m; each R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, orthree R20e; each R14is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R14ais independently selected from C1-6alkyl and C1-6haloalkyl; each R15is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; R18and R18aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6- 10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; R18bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R20h, R20i, R20k, and R20mis independently selected from halogen, oxo, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), =C(R21b)2, -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), - N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R21, -N(R24)S(O)2R25, -C(O)R21, -S(O)2R25, - S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25; wherein two R20kbonded to the same or adjacent atoms may optionally be joined to form a C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, - S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; R21bis independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, or two R21bare taken together with the carbon atom to which they are attached to form C3-10cycloalkyl or C2-9heterocycloalkyl; each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH; each R22is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;each R23is independently selected from H and C1-6alkyl; each R24is independently selected from H and C1-6alkyl; each R25is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; and indicates a single or double bond such that all valences are satisfied.

[0231] In embodiments of the methods described herein, wherein the KRAS inhibitor is a compound of Formula (I) asrecited above, or a pharmaceutically acceptable salt or solvate thereof; W is a C(R18) or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L1is a bond; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R2is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12’, -SR12’, and - N(R12’’)(R13), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20d; R8is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R8bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R16is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20g; R18is hydrogen; and all other variables are as described for a compound of Formula (I) as recited in the method above.

[0232] In embodiments of the methods described herein, wherein the KRAS inhibitor is a compound of Formula (I) asrecited above, or a pharmaceutically acceptable salt or solvate thereof; W1, W2, and W3are independently selected from CH2and O; W4is CH2; W5is selected from N and CH; R2is -OR12’; R8is independently selected halogen and C1-6haloalkyl; R8bis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R16is halogen; and all other variables are as described for a compound of Formula (I), as recited in the method or embodiment thereof, of the two paragraphs immediately above.

[0233] In an aspect is provided a compound of Formula (I-1), or a pharmaceutically acceptable salt or solvate thereof:Formula (I-1); wherein Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), S(O)2, or C(O); W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); R2is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, - OC(O)N(R12’)(R13), -N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R19is selected from C2-11heterocycloalkyl and C2-12heteroaryl, wherein the C2-11heterocycloalkyl and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0234] In an aspect is provided a compound of Formula (I-2), or a pharmaceutically acceptable salt or solvate thereof:Formula (I-2); wherein Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), S(O)2, or C(O); R2is hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), -CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, –(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d;Q1, Q3, and Q5are independently selected from N and C(R1d); Q4and Q6are independently selected from O, S, C(R1a)(R1b), and N(R1c); X4, X5, X6, X9, X10are independently selected from C(R1a) and N; X13is selected from a bond, C(R1a), N, C(O), C(R1a)(R1b), C(O)C(R1a)(R1b), C(R1a)(R1b)C(R1a)(R1b), C(R1a)(R1b)N(R1c), and N(R1c); X14, X15, X17, X18are independently selected from a C(O), C(R1a), N, C(R1a)(R1b), and N(R1c); X16are independently selected from C, N, and C(R1a); each R1a, R1b, R1d, and R1hare each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, - C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, - S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and - CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1aand R1bbonded to the same carbon are joined to form a 3-10 membered heterocycloalkyl ring or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or two R1abonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-10aryl ring, 5-12 membered heteroaryl ring, or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or R1hand one of R1a, R1b, R1c, and R1dbonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, and C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; each R1cis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0235] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof, W is a C(R18) or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond;W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is selected from -C(O)-; R5is a 5-6 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5-6 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R8is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R8bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; L1is a bond; R16is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20g; R2is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12’, -SR12’, and - N(R12’’)(R13), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20d; R18is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20h; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0236] In further embodiments of the embodiment immediately above, or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof, R8bis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c.

[0237] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH; Z is N or C(R8); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from s selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R8is independently selected from hydrogen and halogen; L1is a bond; R19is selected from a C6-12aryl and C2-12heteroaryl, wherein the C6-12aryl and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1i is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R20i; R16is independently selected from hydrogen and halogen; R2is -OR12’; each R12’is independently selected from - C(R12c)2-C2-9heterocycloalkyl, wherein -C(R12c)2-C2-9heterocycloalkyl is optionally substituted with one, two, or three R20d; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0238] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH; Z is N or C(R8); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R8is independently selected from hydrogen and halogen; L1is a bond; R19is selected from a C6-12aryl and C2-12heteroaryl, wherein the C6-12aryl and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1i is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R20i; R16is independently selected from hydrogen and halogen; R2is -OR12’; each R12’is independently selected from - C(R12c)2-C2-9heterocycloalkyl, wherein -C(R12c)2-C2-9heterocycloalkyl is optionally substituted with one, two, or three R20d; each R20kis independently selected from halogen, -CN, -CH2-CN, C1-6alkyl, and C3-10cycloalkyl, wherein C1-6alkyl and C3-10cycloalkyl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, - N(R24)C(O)R25, -N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0239] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH; Z is N or C(R8); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R8is independently selected from hydrogen and halogen;L1is a bond; R19is selected from a C6-12aryl and C2-12heteroaryl, wherein the C6-12aryl and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1i is independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -OR12, -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one, two, or three R20i; R16is independently selected from hydrogen and halogen; R2is -OR12’; each R12’is independently selected from - C(R12c)2-C2-9heterocycloalkyl, wherein -C(R12c)2-C2-9heterocycloalkyl is optionally substituted with one, two, or three R20d; each R20kis independently selected from halogen, -CN, -CH2-CN, C1-3alkyl, and C3-4cycloalkyl, wherein C1-3alkyl and C3-4cycloalkyl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, - CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[0240] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH; Z is N or C(R8); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-;R5 is selected fromR8is independently selected from hydrogen and halogen; R17is selected from, , and ; R16is independently selected from hydrogen and halogen; R2is selected from, , a d ;all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[241] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH; Z is N or C(R8); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5 is selected from, , , , , , , ,R8is independently selected from hydrogen and halogen; R17is selected from, , and ; R16is independently selected from hydrogen and halogen; R2is selected froall other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[242] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond;,, , and ; wherein R1and R4substituents may be bonded to either spirocyclic ring; L2 is -C(O)-; R5 is a selected from, , , , , , ,R8is independently selected from hydrogen or halogen; R8bis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R17is selected fromindependently selected from hydrogen and halogen; R2is selected from, , andall other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied. In embodiments, [(R1)0-6 and (R4)0-6] is equal to R4, and R4is selected from halogen, methyl, and -CH2CN. In embodiments, [(R1)0-6 and (R4)0-6] is equal to [(R1)0and (R4)0] (i.e., no R1or R4substituent). In embodiments, [(R1)0-6and (R4)0-6] is equal to two R4, and each R4is independently selected from halogen, methyl, and -CH2CN.

[0243] In embodiments of a compound of Formula (I), (I-1), or (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L7is a bond;R7is selected from , , , ,, , and ; wherein R1and R4substituents may be bonded to either spirocyclic ring; L2is -C(O)-; R5is a selected from R8is independently selected from hydrogen or halogen; R8bis selected from C1-2alkyl and C3-4cycloalkyl, wherein C1-2alkyl and C3-4cycloalkyl are optionally substituted with one, two, or three R20cselected from halogen and CN; R17is selected frR16is independently selected from hydrogen and halogen; R2is selected from andall other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied.

[244] In embodiments of a compounds of Formula (I), (I-1), (I-2), or embodiments thereof, or a pharmaceuticallyacceptable salt or solvate thereof: W is a CH or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; R10is -L7-R7; L7is a bond;s ; L2is -C(O)-; R5is a selected fromR8is independently -Cl; R8bis cyclopropyl; R17is ; R16 is -F; R2 is selected fromand ;all other variables are as described for compounds of Formula (I), or embodiments thereof; and indicates a single or double bond such that all valences are satisfied. In embodiments, R2is . In embodiments, R2is. In embodiments, R5is. In embodiments, R5is. In embodiments, W is a CH. In embodiments, W is C(O) and Z is N(R8b). In embodiments, Z is N. In embodiments, Z is C(R8).

[245] In an aspect is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:Formula (I); wherein W is a C(R18) or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; R10is -L7-R7; L7is a bond;W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; s1 is an integer from 1 to 6; s2 is an integer from 1 to 3; s3 is an integer from 1 to 3; R6is -L2-R5and wherein R6is optionally capable of forming a covalent bond with a Ras amino acid; L2is selected from -C(O)-; R5is a 5-6 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5-6 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N atom of R5; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, - CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2- C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -(C1-6alkyl)- C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, -(C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)- S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R8is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R8bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R17is -L1-R19; L1is a bond; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15,-C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20g; R2is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12’, -SR12’, and - N(R12’’)(R13), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20d; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3- 10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alk...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of reducing proliferation of cancer cells comprising a KRAS mutant protein or KRAS proteinoverexpression, the method comprising administering to the cells (a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

2. The method of claim 1, wherein the cancer cells are non-small cell lung cancer cells, colorectal cancer cells, orpancreatic cancer cells.

3. A method of downregulating KRAS signaling output in a plurality of cancer cells, comprising:(i) assessing KRAS mutation status in a biological sample comprising nucleic acid from the subject; and (ii) administering an effective dose of (a) a SOS1 inhibitor and an effective dose of (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), if a KRAS mutation is detected in the sample, wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

4. A method of treating cancer in a subject, comprising administering to the subject (a) a SOS1 inhibitor and (b) aKRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), wherein (a) is administered prior to, concurrently with, or subsequent to administering (b).

5. The method of claim 4, wherein the cancer is a mutant KRAS-mediated cancer.

6. The method of any one of claims 1 to 5, wherein the KRAS inhibitor is a compound, or a pharmaceuticallyacceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), or (II-3).

7. The method of any one of the preceding claims, wherein the administration of (a) and (b) synergisticallyreduces proliferation of the cancer cells with a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

8. A method of treating an mutant KRAS-mediated cancer in a subject, comprising administering to the subject(a) a SOS1 inhibitor and (b) a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), wherein (a) is administered prior to, concurrently with, or subsequent to administering (b), and wherein the administration of (a) and (b) synergistically reduces proliferation of the cancer cells with a synergistic value of at least 0.05 as ascertained by Bliss independence criterion.

9. The method of claim 7 or 8, wherein the synergistic value is ascertained by Bliss independence criterion inaccordance with the formula: YAB,O– YAB,Pwherein: YAB,O is observed percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B; YAB,Pis predicted percent growth inhibition of the cancer cells by the application of (a) and (b) comprising (a) at dose A and (b) at dose B, wherein YAB,P = YA + YB – YAYB;YAis observed percent growth inhibition of the cancer cells by (a) alone at dose A; YBis observed percent growth inhibition of the cancer cells by (b) alone at dose B; and YAYBis the product of YAand YB.

10. The method of any one of claims 7 to 9, wherein the synergistic value is at least 0.1.

11. The method of any one of claims 7 to 9, wherein the synergistic value is at least 0.4.

12. The method of any one of claims 7 to 9, wherein the synergistic value is at least 1.

13. The method of any one of claims 7 to 9, wherein the synergistic value is at least 5.

14. The method of any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound of Formula (SI-1):or a pharmaceutically acceptable salt or solvate thereof, wherein:is selected from C5-7 carbocycle and 5- to 7-membered heterocycle, each of which is optionally substituted with one or more Rs11;is absent or selected from C3-8carbocycle and 3- to 8-membered heterocycle, each of which is optionally substituted with one or more Rs11a; Ls1is selected from a bond, C1-6alkylene, and C1-6haloalkylene; Ls2is selected from C5-25alkylene, C5-25alkenylene, C5-25alkynylene, 5- to 25-membered heteroalkylene, and 5- to 25-membered heteroalkenylene, each of which is optionally substituted with one or more Rs11b, wherein Ls2is covalently bound to one of Ws3, Ws4, Ws5, Ws6, or Ws7; Ws3is selected from N(Rs3b), N, C(Rs3), and C(O); Ws4is selected from N(Rs4b), N, C(Rs4), and C(O); Ws5is selected from N(Rs5b), N, and C(Rs5); Ws6is selected from C(Rs6) and C(O); Ws7is C(Rs7); Rs1is C1-3alkyl optionally substituted with one or more Rs11c; Rs8is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10- membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, -OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), - N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), -S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), - CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three Rs20; Rs3, Rs4, Rs5, Rs6, and Rs7are each independently selected from a bond to Ls2, hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), - C(O)ORs12, -OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, - S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three Rs20; Rs3b, Rs4b, and Rs5bare each independently selected from a bond to Ls2, hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -C(O)ORs12, -OC(O)N(Rs12)(Rs13), - C(O)Rs15, -S(O)Rs15, -OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, and -CH2S(O)2N(Rs12)(Rs13), wherein each C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle and 3- to 10-membered heterocycle is independently optionally substituted with one, two, or three Rs20; Rs11and Rs11aare each independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, - OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, - OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, -CH2S(O)2N(Rs12)(Rs13), - CH2N(Rs12)S(O)2(Rs13), and -P(O)(Rs17)(Rs17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs11bis independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, 3- to 10-membered heterocycle, -ORs12, -SRs12, -N(Rs12)(Rs13), -C(O)ORs12, - OC(O)N(Rs12)(Rs13), -N(Rs14)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)ORs15, -N(Rs14)S(O)2Rs15, -C(O)Rs15, -S(O)Rs15, - OC(O)Rs15, -C(O)N(Rs12)(Rs13), -C(O)C(O)N(Rs12)(Rs13), -N(Rs14)C(O)Rs15, -S(O)2Rs15, -S(O)2N(Rs12)(Rs13), - S(=O)(=NH)N(Rs12)(Rs13), -CH2C(O)N(Rs12)(Rs13), -CH2N(Rs14)C(O)Rs15, -CH2S(O)2Rs15, -CH2S(O)2N(Rs12)(Rs13), - CH2N(Rs12)S(O)2(Rs13), and -P(O)(Rs17)(Rs17a), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs11cis independently selected at each occurrence from halogen, -ORs12, and -N(Rs12)(Rs13); Rs12is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three Rs20; Rs13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or Rs12and Rs13, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocycle optionally substituted with one, two, or three Rs20; Rs14is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; Rs15is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle,and 3- to 10-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one, two, or three Rs20; Rs17and Rs17aare each independently selected at each occurrence from C1-6alkyl and C3-6cycloalkyl, wherein C1-6alkyl and C3-6cycloalkyl are optionally substituted with one, two or three Rs20; or Rs17and Rs17a, together with the phosphorous atom to which they are attached, form a 3- to 10-membered heterocycle; Rs20is independently selected at each occurrence from halogen, oxo, =NH, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, -C(O)N(Rs22)(Rs23), -C(O)C(O)N(Rs22)(Rs23), - OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, -N(Rs24)C(O)Rs25, -N(Rs24)S(O)2Rs25, -C(O)Rs25, - S(O)2Rs25, -S(O)2N(Rs22)(Rs23), -OCH2C(O)ORs22, and -OC(O)Rs25, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-10carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -ORs21, -SRs21, -N(Rs22)(Rs23), -C(O)ORs22, -C(O)N(Rs22)(Rs23), - C(O)C(O)N(Rs22)(Rs23), -OC(O)N(Rs22)(Rs23), -N(Rs24)C(O)N(Rs22)(Rs23), -N(Rs24)C(O)ORs25, -N(Rs24)C(O)Rs25, - N(Rs24)S(O)2Rs25, -C(O)Rs25, -S(O)2Rs25, -S(O)2N(Rs22)(Rs23), and -OC(O)Rs25; Rs21is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs22is independently selected at each occurrence from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C3-10carbocycle and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; Rs23is independently selected at each occurrence from H and C1-6alkyl; Rs24is independently selected at each occurrence from H and C1-6alkyl; Rs25is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, and 3- to 10-membered heterocycle, wherein C1-6alkyl, C3-10carbocycle, and 3- to 10-membered heterocycle are optionally substituted with one, two, or three groups independently selected from halogen, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C3-10carbocycle, and 3- to 10-membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

15. The method of any one of claims 1 to 14, wherein the SOS1 inhibitor is selected from BI-3406, MRTX0902,BAY 293, RMC-5845, and BI-1701963.

16. The method of any one of claims 1 to 14, wherein the SOS1 inhibitor17. The method of any one of claims 1 to 14, wherein the SOS1 inhibitor i.

18. The method of any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound of Formula (SIV-1):or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: Ls1is a bond; Rs1is 6- to 10-membered aryl, wherein the 6- to 10-membered aryl is optionally substituted with one or more independently selected Rs10substituents; Rs2is halogen or ORs2a; Rs2ais C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl, wherein the C1-6alkyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl is optionally substituted with one, two, or three independently selected Rs20asubstituents; Rs3is halogen, C1-6alkyl, C3-14cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein the C1-6alkyl, C3-14 cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl is optionally substituted with one, two, or three independently selected Rs20bsubstituents; Rs4is H, C1-6alkyl, or C1-6haloalkyl; Rs5is H, C1-6alkyl, or C1-6haloalkyl; Rs6is H, halogen, CN, or C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one, two, or three independently selected Rs20csubstituents; each Rs10is independently halogen, CN, C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three independently selected Rs20dsubstituents; each Rs20ais independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23,NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9 heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20bis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9 heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20cis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs20dis independently halogen, CN, C1-6alkyl, CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C2-6alkenyl, C2-6alkynyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25,NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OCH2C(O)ORs22, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, S(O)2NRs22Rs23, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein each C1-6alkyl, C2-6alkenyl, and C2-6alkynyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; and wherein each CH2C3-10cycloalkyl, CH2C2-9heterocycloalkyl, CH2C6-10aryl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C1-6alkyl, C1-6haloalkyl, C(O)Rs25, C(O)C(O)NRs22Rs23, C(O)NRs22Rs23, C(O)ORs22, NRs22Rs23, NRs24C(O)Rs25, NRs24C(O)NRs22Rs23, NRs24C(O)ORs25, NRs24S(O)2Rs25, =NH, ORs21, OC(O)Rs25, OC(O)NRs22Rs23, =O, SRs21, S(O)2Rs25, and S(O)2NRs22Rs23; each Rs21is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C1-6alkyl; each Rs22is independently H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen and C1-6alkyl; each Rs23is independently H or C1-6alkyl; each Rs24is independently H or C1-6alkyl; and each Rs25is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl, wherein each C1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, C1-6alkyl, C1-6haloalkyl, OC1-6alkyl, C3-7cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl.

19. The method of claim 18, wherein Rs3 is C2-9 heterocycloalkyl, wherein the C2-9 heterocycloalkyl is optionallysubstituted with one, two, or three independently selected Rs20bsubstituents.

20. The method of claim 18, wherein Rs3 is C3-10 cycloalkyl, wherein the C3-10 cycloalkyl is optionally substitutedwith one, two, or three independently selected Rs20bsubstituents.

21. The method of any one of claims 18 to 20, wherein Rs1 is, or22. The method of any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound selected from the group23. The method of any one of claims 1 to 22, wherein the KRAS inhibitor is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:Formula (I); wherein W is a N, C(R18), N(R18b), C(R18)(R18a), C(O), S(O), or S(O)2; Z is N, C(R8), N(R8b), C(R8)(R8a), C(O), S(O), or S(O)2; wherein W and Z are not both selected from C(O), S(O), and S(O)2;V and J are each independently selected from C(R17), C(R17)(R16a), C(R16), C(R16)(R16a), N, N(R17b), and N(R16b); wherein exactly one of V and J is C(R17), C(R17)(R16a), or N(R17b); Y is N, C(R2), C(R2)(R2c), N(R2b), S(O), or S(O)2; U is N, C(R2c), C(R2c)(R2c), N(R2b), S(O), S(O)2, or C(O); R10is -L7-R7; L7is a bond, -O-, -N(R14)-, -C(O)-, -S-, -S(O)2-, -S(O)-, C1-4alkyl, or 2-4 membered heteroalkyl linker, wherein the C1-4alkyl and 2-4 membered heteroalkyl linker are each optionally substituted with one, two or three R20a; R7is; W1and W3are independently selected from N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W2is independently selected from a N(R1), N(R4), C(R1)(R1), C(R1)(R4), C(R4)(R4), C(O), S, O, S(O), and S(O)2; W4is selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), S(O), and S(O)2; W5is selected from N, C(R1), and C(R4); s1 is 1 and s2 is 0, 2, or 3; s1 is 2 and s2 is 0, 1, or 3; s1 is 3 and s2 is 0 to 3; s1 is 4 and s2 is 0 to 3; s1 is 5 and s2 is 0 to 3; or s1 is 6 and s2 is 0 to 3; or s3 is an integer from 1 to 3; each R1is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2- C1-11heteroaryl, and C1-11heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C3-12cycloalkyl, -CH2-C3-12cycloalkyl, C1-11heterocycloalkyl, -CH2-C1-11heterocycloalkyl, C6-12aryl, -CH2-C6-12aryl, -CH2-C1-11heteroaryl, and C1-11heteroaryl are optionally substituted with one, two, or three R20a; each R4is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), =C(R21b)2, -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R12, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R12, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - (C1-6alkyl)-C(O)N(R12)(R13), -(C1-6alkyl)-N(R14)C(O)R12, -(C1-6alkyl)-S(O)2R15, -(C1-6alkyl)-N(R12)(R13), and -(C1-6alkyl)-S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20a; R6is -L2-R5, wherein R6is optionally capable of forming a covalent bond with a Ras amino acid; L2is a bond, -O-, -N(R4d)-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R4d-, CR4cR4c, -OCR4cR4c-, -N(R4d)CR4cR4c-, - C(O)CR4cR4c-, -SCR4cR4c-, -S(O)2CR4cR4c-, -S(O)CR4cR4c-, -P(O)R4dCR4cR4c-, -CR4cR4cCR4cR4c, -CR4cR4cO-, - CR4cR4cN(R4d)-, -CR4cR4cC(O)-, -CR4cR4cS-, -CR4cR4cS(O)2-, -CR4cR4cS(O)-, -CR4cR4cP(O)R4d-, -N(R4d)C(O)-, - N(R4d)S(O)2-, -N(R4d)S(O)-, -N(R4d)P(O)R4d-, -C(O)N(R4d)-, -S(O)2N(R4d)-, -S(O)N(R4d)-, -P(O)R4dN(R4d)-, -OC(O)-, - OS(O)2-, -OS(O)-, -OP(O)R4d-, -C(O)O-, -S(O)2O-, -S(O)O-, -P(O)R4dO-, -CR4cR4cCR4cR4cCR4cR4c-, - OCR4cR4cCR4cR4c-, -N(R4d)CR4cR4cCR4cR4c-, -C(O)CR4cR4cCR4cR4c-, -SCR4cR4cCR4cR4c-, -S(O)2CR4cR4cCR4cR4c-, - S(O)CR4cR4cCR4cR4c-, -P(O)R4dCR4cR4cCR4cR4c-, -CR4cR4cCR4cR4cO-, -CR4cR4cCR4cR4cN(R4d)-, - CR4cR4cCR4cR4cC(O)-, -CR4cR4cCR4cR4cS-, -CR4cR4cCR4cR4cS(O)2-, -CR4cR4cCR4cR4cS(O)-, or -CR4cR4cCR4cR4cP(O)R4d-; each R4cis independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), -OCH2C(O)OR14, -OC(O)R14a, -N(R14)(R14), -N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14a, and -N(R14)S(O)2R14, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, - SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; each R4dis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, -OR14, -SR14, -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), -C(O)R14a, -S(O)2R14, - S(O)2N(R14)(R14), -OCH2C(O)OR14, and -OC(O)R14a, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2- C3-10cycloalkyl, C2-9heterocycloalkyl, and -CH2-C2-9heterocycloalkyl, are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR14, - SR14, -N(R14)(R14), -C(O)OR14, -C(O)N(R14)(R14), -C(O)C(O)N(R14)(R14), -OC(O)N(R14)(R14), - N(R14)C(O)N(R14)(R14), -N(R14)C(O)OR14, -N(R14)C(O)R14, -N(R14)S(O)2R14, -C(O)R14a, -S(O)2R14, -S(O)2N(R14)(R14), and -OC(O)R14a; R5is a 5 or 6 membered partially unsaturated heterocycloalkyl or a 5 or 6 membered heteroaryl, each optionally substituted with one, two or three R20k, wherein the partially unsaturated 5 or 6 membered heterocycloalkyl or 5 or 6 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and the 5 or 6 membered partially unsaturated heterocycloalkyl or 5 or 6 membered heteroaryl is each bonded to L2through a ring nitrogen; R8and R8aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R8bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20c; R17is -L1-R19; R17bis -L1b-R19; L1is selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -O-, -N(R14)-, -C(O)-, -N(R14)C(O)-, - C(O)N(R14)-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R14)-, -S(O)N(R14)-, -N(R14)S(O)-, -N(R14)S(O)2-, -OCON(R14)-, - N(R14)C(O)O-, N(R1e), C(O)N(R1c), S(O)2N(R1c), S(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g);wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; L1bis selected from a bond, C1-C4alkyl, C2-C4alkenyl, C2-C4alkynyl, -C(O)-, -C(O)N(R14)-, C(O)N(R1c), C(R1f)(R1g)O, C(R1f)(R1g)N(R1c), and C(R1f)(R1g); wherein the C1-C4alkyl, C2-C4alkenyl, and C2-C4alkynyl are optionally substituted with one, two, or three R20i; R1e, R1f, and R1gare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1fand R1gare joined to form a 4-7 membered heterocycloalkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocycloalkyl ring or 4-7 membered cycloalkyl ring are optionally substituted with one, two, or three R20i; R1cis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R19is selected from a C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl, wherein the C3-12cycloalkyl, C2-11heterocycloalkyl, C6-12aryl, and C2-12heteroaryl are optionally substituted with one, two, three, four, five, six, or seven R1i; each R1iis independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; R16and R16aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R16bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20g; R2is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -N(R12’’)(R13), -N=(R15), -C(O)OR12’, -OC(O)N(R12’)(R13), - N(R14)C(O)N(R12’)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C4-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, and –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2cis independently hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R2bis independently hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12’, -SR12’, -C(O)OR12’, -OC(O)N(R12’)(R13), -C(O)R15, -S(O)R15, -OC(O)R15, - C(O)N(R12’)(R13), -C(O)C(O)N(R12’)(R13), -S(O)2R15, -S(O)2N(R12’)(R13)-, S(=O)(=NH)N(R12’)(R13), - CH2C(O)N(R12’)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, -CH2S(O)2N(R12’)(R13), –(C1-C6alkyl)-R12b, –(C2-6alkenyl)-R12b, –(C2-6alkynyl)-R12b, -(C3-10cycloalkyl)-R12b, -(C2-9heterocycloalkyl)-R12b, -(C6-10aryl)-R12b, or –(C1-9heteroaryl)-R12b, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; R12bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; X is C(R3), C(R3)(R3), N(R3), or N; each R3is independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20b; each R12is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, - CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’is independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, - C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2- C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12’’is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -C(R12c)2-C3-10cycloalkyl, C2-9heterocycloalkyl, -C(R12c)2-C2-9heterocycloalkyl, C6-10aryl, -C(R12c)2-C6-10aryl, -C(R12c)2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20d; each R12cis independently selected from hydrogen and R20m; each R13is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13, together with the nitrogen to which they are attached, form a C2-9heterocycloalkyl ring optionally substituted with one, two, or three R20e; each R14is independently selected from hydrogen, C1-6alkyl, and C1-6haloalkyl; each R14ais independently selected from C1-6alkyl and C1-6haloalkyl; each R15is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20f; R18and R18aare independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; R18bis independently selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -C(O)OR12, -OC(O)N(R12)(R13), -C(O)R15, -S(O)R15, - OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), - CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20h; each R20a, R20b, R20c, R20d, R20e, R20f, R20g, R20h, R20i, R20k, and R20mis independently selected from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, C1-9heteroaryl, -OR21, -SR21, -N(R22)(R23), =C(R21b)2, - C(O)OR22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R21, -N(R24)S(O)2R25, -C(O)R21, -S(O)2R25, -S(O)2N(R22)(R23), -OCH2C(O)OR22, and -OC(O)R25; wherein two R20kbonded to the same or adjacent atoms may optionally be joined to form a C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, or C1-9heteroaryl; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, -CH2-C3-10cycloalkyl, C2-9heterocycloalkyl, -CH2-C2-9heterocycloalkyl, C6-10aryl, -CH2-C6-10aryl, -CH2-C1-9heteroaryl, and C1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR21, -SR21, -N(R22)(R23), -C(O)OR22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -OC(O)N(R22)(R23), -N(R24)C(O)N(R22)(R23), -N(R24)C(O)OR25, -N(R24)C(O)R25, - N(R24)S(O)2R25, -C(O)R25, -S(O)2R25, -S(O)2N(R22)(R23), and -OC(O)R25; each R21is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl;R21bis independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, or two R21bare taken together with the carbon atom to which they are attached to form C3-10cycloalkyl or C2-9heterocycloalkyl; each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH; each R22is independently selected from H, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; each R23is independently selected from H and C1-6alkyl; each R24is independently selected from H and C1-6alkyl; each R25is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl; indicates the location of attachment of the depicted chemical formula or atom to a substituent, a further component of a molecule, or an atom; and indicates a single or double bond such that all valences are satisfied.

24. The method of claim 23, wherein R5 is a 5 membered heteroaryl optionally substituted with one, two or threeR20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and the 5 membered heteroaryl is bonded to L2through a ring nitrogen.

25. The method of claim 23, wherein L2 is -C(O)-; and R5 is a 5 membered heteroaryl, optionally substituted withone, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms; and L2is directly bonded to an N ring atom of R5.

26. The method of any one of claims 23 to 25, wherein L7 is a bond.

27. The method of any one of claims 23 to 26, wherein s1 is 2 and s2 is 0, 1, or 3.

28. The method of any one of claims 23 to 26, wherein R7 is selected from,, , , , ,R4substituents may be bonded to either spirocyclic ring.

29. The method of any one of claims 23 to 28, wherein R17 is -L1-R19 or -L1b-R19; L1 is a bond, and L1b is a bond.

30. The method of any one of claims 23 to 29, wherein R19is:Q1, Q3, and Q5are independently selected from N and C(R1d); Q4and Q6are independently selected from O, S, C(R1a)(R1b), and N(R1c); X4, X5, X6, X9, X10are independently selected from C(R1a) and N; X13is selected from a bond, C(R1a), N, C(O), C(R1a)(R1b), C(O)C(R1a)(R1b), C(R1a)(R1b)C(R1a)(R1b), C(R1a)(R1b)N(R1c), and N(R1c); X14, X15, X17, X18are independently selected from a C(O), C(R1a), N, C(R1a)(R1b), and N(R1c); X16are independently selected from C, N, and C(R1a); each R1a, R1b, R1d, and R1hare each independently selected from hydrogen, halogen, -CN, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, C1-9heteroaryl, -OR12, -SR12, -N(R12)(R13), - C(O)OR12, -OC(O)N(R12)(R13), -N(R14)C(O)N(R12)(R13), -N(R14)C(O)OR15, -N(R14)S(O)2R15, -C(O)R15, -S(O)R15, -OC(O)R15, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R14)C(O)R15, -S(O)2R15, -S(O)2N(R12)(R13)-, S(=O)(=NH)N(R12)(R13), -CH2C(O)N(R12)(R13), -CH2N(R14)C(O)R15, -CH2S(O)2R15, and -CH2S(O)2N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i; or R1aand R1bbonded to the same carbon are joined to form a 3- 10 membered heterocycloalkyl ring or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or two R1abonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, C6-10aryl ring, 5-12 membered heteroaryl ring, or C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; or R1hand one of R1a, R1b, R1c, and R1dbonded to adjacent atoms are joined to form a 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, or a C3-10cycloalkyl ring, wherein the 3-10 membered heterocycloalkyl ring, a C6-10aryl ring, a 5-12 membered heteroaryl ring, and C3-10cycloalkyl ring are optionally substituted with one, two, or three R20i; and each R1cis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, C6-10aryl, and C1-9heteroaryl are optionally substituted with one, two, or three R20i.

31. The method of any one of claims 23 to 29, wherein R19 is selected from,32. The method of any one of claims 23 to 31, wherein R2 is -OR12’.

33. The method of any one of claims 23 to 31, wherein R2 is selected from, ,F34. The method of claim 23, whereinW is a C(R18) or C(O); Z is N, C(R8), or N(R8b); V is C(R17); J is C(R16); Y is C(R2); U is N; X is N; L1is a bond; L7is a bond; W1, W2, and W3are independently selected from C(R1)(R1), C(R1)(R4), C(R4)(R4), and O; W4is selected from C(R1)(R1), C(R1)(R4), and C(R4)(R4); W5is selected from N and CH; L2is -C(O)-; R5is a 5 membered heteroaryl, optionally substituted with one, two, or three R20k, wherein the 5 membered heteroaryl comprises one, two, or three ring nitrogen atoms and further wherein when R5is directly bonded to a C(O) of L2, L2is directly bonded to an N ring atom of R5; R2is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12’, -SR12’, and -N(R12’’)(R13), wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20d; R8is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R8bis selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20c; R16is independently selected from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C2-9heterocycloalkyl, -OR12, -SR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, or three R20g; and R18is hydrogen.

35. The method of claim 34, whereinW1, W2, and W3are independently selected from CH2and O; W4is CH2; W5is selected from N and CH; R2is -OR12’; R8is independently selected halogen and C1-6haloalkyl; R8bis selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and C2-9heterocycloalkyl are optionally substituted with one, two, orthree R20c; and R16is halogen.

36. The method of any one of claims 4 to 35, wherein the cancer is lung cancer.

37. The method of any one of claims 4 to 35, wherein the cancer is a non-small cell lung cancer.

38. The method of any one of claims 4 to 35, wherein the cancer is colorectal cancer.

39. The method of any one of claims 4 to 35, wherein the cancer is pancreatic cancer.

40. The method of any one of claims 4 to 35, wherein the cancer is a solid cancer.

41. The method of any one of claims 4 to 40, wherein cancer cells of the subject comprise a KRAS G12C mutantprotein.

42. The method of any one of claims 4 to 40, wherein cancer cells of the subject are refractory to at least oneKRAS G12C inhibitor.

43. The method of any one of claims 4 to 40, wherein cancer cells of the subject comprise a KRAS G12S mutantprotein.

44. The method of any one of claims 1 to 43, wherein cancer cells of the subject comprise overexpression ofKRAS.

45. The method of any one of the preceding claims, wherein the subject exhibits relapse of the cancer.

46. The method of any one of the preceding claims, wherein the subject has previously been treated with a KRASG12C inhibitor.

47. The method of any one of the preceding claims, further comprising administering (c) an additional agent oradditional therapy.

48. The method of claim 47, wherein the additional agent is selected from an immunomodulatory agent, an anti-nausea agent, an antiemetic, a pain reliever, a chemotherapeutic agent, a SHP2 inhibitor, a PI3K inhibitor, a CDK4 / 6 inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, an EGFR inhibitor, and an AKT inhibitor.

49. The method of claim 47, wherein the additional agent is selected from an immunomodulatory agent, a cytokineblockade agent, and a checkpoint immune blockade agent.

50. The method of claim 47, wherein the additional agent is selected from an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-LAG3 antibody, an anti-TIM3 antibody, and combinations thereof.

51. The method of claim 47, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy,and radiation.

52. The method of any one of the preceding claims, wherein the administration of (a) and (b) reduces incidence ofone or more adverse events associated with the SOS1 inhibitor or the KRAS inhibitor.

53. The method of claim 52, wherein the adverse event is selected from diarrhea, rash, nausea, vomiting, decreasedappetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury.

54. The method of claim 52, wherein the adverse event is selected from diarrhea, rash, and nausea.

55. The method of any one of the preceding claims, wherein the administration of (a) and (b) exhibits a synergisticeffect.

56. The method of claim 54, wherein the synergistic effect is characterized by a synergistic value of at least 0.05 asascertained by Bliss independence criterion.

57. The method of any one of the preceding claims, wherein one or both of (a) and (b) are administered at a sub-therapeutic dose but achieve a therapeutic effect at least comparable to administering (a) or (b) alone at its therapeutically effective amount.

58. The method of any one of the preceding claims, wherein KRAS inhibitor is administered at a dose less thanabout 25% the standard monotherapy dose.

59. The method of any one of the preceding claims, wherein (a) and (b) are administered in the same formulation.

60. The method of any one of the preceding claims, wherein (a) and (b) are administered in separate formulations.

61. A kit for use in reducing proliferation of cancer cells comprising a KRAS mutant protein or KRASoverexpression, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (SI-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV- 1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) instructions for using the composition(s) of (1) and (2).

62. A kit for use in reducing proliferation of cancer cells comprising a KRAS mutant protein or KRASoverexpression, the kit comprising: (1) a composition comprising a SOS1 inhibitor of Formula (SIV-1); (2) a composition comprising a KRAS inhibitor of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV- 1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) instructions for using the composition(s) of (1) and (2).

63. The kit of any one of claims 61 to 62, wherein the SOS1 inhibitor and the KRAS inhibitor are formulated inthe same unit dosage form.

64. The kit of any one of claims 61 to 62, wherein the SOS1 inhibitor and the KRAS inhibitor are formulated indifferent unit dosage forms.

65. A pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or a pharmaceuticallyacceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

66. A method of treating a mutant KRAS-mediated cancer in a subject, comprising administering to the subject apharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SI-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I- 2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

67. A pharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SIV-1), or a pharmaceuticallyacceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

68. A method of treating a mutant KRAS-mediated cancer in a subject, comprising administering to the subject apharmaceutical composition comprising (i) a SOS1 inhibitor of Formula (SIV-1), or a pharmaceutically acceptable salt or solvate thereof, (ii) a KRAS inhibitor, or a pharmaceutically acceptable salt or solvate thereof, of Formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), and (iii) a pharmaceutically acceptable excipient.

69. The method of claim 1, 3, 4, 8, 66, or 68, wherein the subject is a naïve subject that has not been treated with aKRAS inhibitor prior to administering (a) and (b).

70. The method, kit, or pharmaceutical composition of any one of claim 1-69, wherein the SOS1 inhibitor is acompound of Table 2a, or a pharmaceutically acceptable salt or solvate thereof.

71. The method, kit, or pharmaceutical composition of any one of claim 1-69, wherein the SOS1 inhibitor is acompound of Table 2b, or a pharmaceutically acceptable salt or solvate thereof.

72. The method, kit, or pharmaceutical composition of any one of claim 1-71, wherein the KRAS inhibitor is acompound of Table 1a, or a pharmaceutically acceptable salt or solvate thereof.

73. The method, kit, or pharmaceutical composition of any one of claim 1-71, wherein the KRAS inhibitor is acompound of Table 1b, or a pharmaceutically acceptable salt or solvate thereof.

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