RU2828748C2 - Heterocyclic compounds, methods for production and use thereof - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to heterocyclic compounds, specifically to a compound or a pharmaceutically acceptable salt thereof, where the compound is

Invention also relates to a pharmaceutical composition, a method of inhibiting the mutant KRAS G12C protein in a cell and a method of treating cancer associated with the G12C mutation in KRAS, based on said compounds.

EFFECT: obtaining alternative compounds for treating cancer associated with G12C mutation in KRAS.

9 cl, 6 dwg, 4 tbl, 23 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims priority to International Application Nos. PCT/CN2019/123,223, filed on December 5, 2019, PCT/CN2019/087772, filed on May 21, 2019, and PCT/CN2019/095947, filed on July 15, 2019, the contents of each of which are incorporated herein by reference in their entirety.

LEVEL OF TECHNOLOGY

Field of technology

[2] In various embodiments, the present invention generally relates to novel heterocyclic compounds, compositions thereof, methods of preparation, and methods of using them, such as for inhibiting RAS and/or for treating a variety of diseases or disorders, such as pancreatic cancer, colorectal cancer, and lung cancer.

State of the art

[3] RAS proteins regulate a key cellular pathway that transmits signals from cell membrane receptors to downstream molecules such as Raf, MEK, ERK, and PI3K, which are critical for cell proliferation and survival. RAS cycles between an inactive GDP-bound form and an active GTP-bound form. RAS proteins have three gene isoforms: KRAS, NRAS, and HRAS, and share extensive homology (>90%) in the N-terminal domain (amino acid 1-165). RAS is a commonly mutated cancer, with KRAS accounting for ~80% of all RAS mutations. KRAS mutations occur in approximately 60% of pancreatic cancers, 40% of colorectal cancers, 30% of lung cancers, and 20% of endometrial cancers (F. McCormick, 2017, Clin Cancer Res 21: 1797-1801). RAS hotspot mutations occur at codons 12, 13, and 61, with 75% of KRAS mutations occurring at codon 12 (Glycine) (D.K. Simanshu, D.V. Nissley and F. McCormick, 2017, Cell, 170: 17-33).

[4] There is a medical need for a therapeutic treatment for cancer patients with RAS mutations such as the KRAS G12C mutation.

SUMMARY OF THE INVENTION

[5] In various embodiments, the disclosure provides novel compounds, pharmaceutical compositions, methods for preparing and using them.

Typically, the compounds herein are RAS inhibitors, such as KRAS G12C inhibitors. The compounds and compositions provided herein are useful for treating various diseases or disorders, such as cancer, associated with a KRAS G12C mutation.

[6] In various embodiments, the present disclosure provides a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof:

wherein the variables are defined herein. In some embodiments, a compound of Formula I may have a subformula of Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8, as defined herein. In some embodiments, the present disclosure provides a compound selected from Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof. In some embodiments, where applicable, the compound may exist as a mixture of atropisomers in any ratio. In some embodiments, where applicable, the compound may exist as an isolated individual atropisomer, substantially free (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or an undetectable amount) of the other atropisomer(s).

[7] Some embodiments of the invention relate to a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or 1-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. The pharmaceutical composition described herein can be formulated for various modes of administration, such as oral administration, parenteral administration, or inhalation, etc.

[8] Some embodiments of the invention relate to a method of treating a disease or disorder associated with RAS, such as KRAS G12C. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, a method of treating cancer is provided. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the present disclosure or a therapeutically effective amount of a pharmaceutical composition described herein. In various embodiments, the cancer can be pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer is a hematological cancer (e.g., as described herein). In some embodiments, the cancer is MYH-associated polyposis. In some embodiments, the cancer can be gallbladder cancer, thyroid cancer, or bile duct cancer. Administration is not limited to any particular route of administration. For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalational, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. The compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments, combination therapy includes treating a subject with a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy.

[9] It should be understood that both the foregoing summary and the following detailed description are illustrative and explanatory only and are not limiting of the invention as claimed.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS/FIGURES

[10] FIG. 1 is a graph illustrating the tumor volume growth profile as a function of study days in the SW837 colorectal adenocarcinoma xenograft model following treatment with vehicle, AMG510 (60 mg/kg), Compound #44 (60 mg/kg), or Compound #126 (30 mg/kg).

[11] FIG. 2 is a graph illustrating the tumor volume growth profile as a function of study days in the H358 NSCLC xenograft model following treatment with vehicle, AMG510 (30 mg/kg), Compound #44 (30 mg/kg), or Compound #126 (30 mg/kg).

[12] FIG. 3 is a graph illustrating the tumor volume growth profile as a function of study days in the NSCLC xenograft model _H2122 following treatment with vehicle, AMG510 (60 mg/kg), or Compound #126 (60 mg/kg).

[13] FIG. 4 is a graph illustrating the tumor volume growth profile as a function of study days in the H358 NSCLC xenograft model following treatment with vehicle, carboplatin (30 mg/kg), Compound #145 (5 mg/kg), or carboplatin (30 mg/kg) or Compound #145 (5 mg/kg).

[14] FIG. 5 is a graph illustrating the tumor volume growth profile as a function of study days in the H358 NSCLC xenograft model following treatment with vehicle, cisplatin (2 mg/kg), RMC-4550 (10 mg/kg), Compound #126 (5 mg/kg), cisplatin (2 mg/kg) and Compound #126 (5 mg/kg), or RMC-4550 (10 mg/kg) and Compound #126 (5 mg/kg).

[15] FIG. 6 is a graph illustrating the tumor volume growth profile as a function of study days in the SW837 colorectal adenocarcinoma xenograft model following treatment with vehicle, trametinib (1 mg/kg), Compound #44 (30 mg/kg), or trametinib (1 mg/kg) and Compound #44 (30 mg/kg).

DETAILED DESCRIPTION OF THE INVENTION

[16] In various embodiments, provided herein are novel compounds, pharmaceutical compositions, methods of preparation, and methods of use.

Connections

[17] Some embodiments of the present disclosure relate to novel compounds. The compounds of this document may generally be an inhibitor of a KRAS protein, in particular a mutant KRAS G12C protein.

[18] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof:

Where:

X is O, NR ¹⁰ , S, SO ₂ or an optionally substituted heterocyclic ring (e.g., a 4-7 membered heterocyclic ring);

R ¹ is hydrogen, optionally substituted alkyl (eg C _1-4 alkyl) or -LR ²⁰ ,

wherein L is absent or is an optionally substituted alkylene (e.g., C _1-4 alkylene), an optionally substituted heteroalkylene (e.g., C _1-4 heteroalkylene), an optionally substituted carbocyclic ring (e.g., C _3-6 carbocyclic ring), or an optionally substituted heterocyclic ring (e.g., a 4-7 membered heterocyclic ring),

where R ²⁰ is hydrogen, optionally substituted alkyl, alkenyl or alkynyl, such as optionally substituted C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl, -NR ²¹ R ²² , -OR ²³ , optionally substituted heterocyclyl (eg 4-7 membered heterocyclyl),

or XR ¹ is COOH, -COOR ²³ , -CONR ²¹ R ²² , -CN, optionally substituted alkyl, alkenyl, alkynyl or a carbocyclic ring (e.g. cycloalkyl), such as C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or C _3-6 cycloalkyl is optionally substituted with, for example, 13 groups each independently selected from F, OH, protected OH and C _1-4 alkoxy;

wherein each of R ¹⁰ , R ²¹ and R ²² at each occurrence is independently hydrogen, optionally substituted alkyl, alkenyl or alkynyl, such as optionally substituted C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl, optionally substituted heteroalkyl (e.g. C _1-4 heteroalkyl), optionally substituted carbocyclic ring (e.g. C _3-6 carbocyclic ring), optionally substituted heterocyclic ring (e.g. 4-7 membered heterocyclic ring) or a nitrogen protecting group; R ²³ is independently hydrogen at each occurrence, optionally substituted alkyl, alkenyl or alkynyl, such as optionally substituted C _1-4 alkyl, C _2-4 alkenyl or C _2-4 alkynyl, optionally substituted heteroalkyl (e.g. C _1-4 heteroalkyl), optionally substituted carbocyclic ring (e.g. C _3-6 carbocyclic ring), optionally substituted heterocyclic ring (e.g. 4-7 membered heterocyclic ring) or an oxygen protecting group;

each of ^A1 , ^A2 , ^A3 , ^A4 and ^A5 is independently ^CR30 or N, wherein ^R30 in each occurrence is independently hydrogen, halogen (e.g. F, Cl), optionally substituted _C1-4 alkyl or optionally substituted alkoxy (e.g. _C1-4 alkoxy);

or R ¹ , X, and A ¹ may join together to form an optionally substituted ring structure, such as an optionally substituted heterocyclic or heteroaryl ring;

^R2 and ^R3 are each independently hydrogen, halogen, -OH, -CN, optionally substituted alkyl, alkenyl or alkynyl, such as optionally substituted _C1-4 alkyl, _C2-4 alkenyl or _C2-4 alkynyl, an optionally substituted carbocyclic ring (e.g. a _C3-6 carbocyclic ring), an optionally substituted heterocyclic ring (e.g. a 4-7 membered heterocyclic ring) or optionally substituted alkoxy (e.g. _C1-4 alkoxy);

(hereinafter simplified as "Het") is a heterocyclic ring (e.g., a 4 to 10-membered heterocyclic ring) that is optionally substituted, for example, by an independently selected group(s) ^R4 , ( ^R4 ) _n , where n is 0, 1, 2, or 3, and ^R4 at each occurrence is independently optionally substituted alkyl, alkenyl, or alkynyl, or a 3- or 4-membered ring, for example, ^R4 at each occurrence can be _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, a 3- or 4-membered ring (e.g., cyclopropyl), fluoro-substituted _C1-4 alkyl, hydroxyl-substituted _C1-4 alkyl, or cyano-substituted _C1-4 alkyl; or two R ⁴ groups may join together to form a ring structure, such as a 3-6 membered ring structure;

U is an electrophilic moiety capable of forming a covalent bond with a cysteine residue of a KRAS protein, such as the KRAS G12C mutant protein;

R ⁷ is hydrogen, halogen, -CN, a 3-4 membered ring (e.g. cyclopropyl), optionally substituted alkyl, alkenyl, alkynyl, or alkoxy, e.g. optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, or optionally substituted C _1-4 alkoxyl; and

R ⁸ is optionally substituted aryl or optionally substituted heteroaryl.

[19] In some embodiments, X in Formula I may be or include a heteroatom. For example, in some embodiments, X may be O. In some embodiments, X may be NR ¹⁰ . In some embodiments, X may be S or SO ₂ . In some embodiments, X may also be a heterocyclic ring, such as an optionally substituted 4-7 membered heterocyclic ring. In some embodiments, the 4-7 membered heterocyclic ring has 1 or 2 heteroatoms, such as 1 or 2 nitrogen atoms. A variety of heterocyclic rings are suitable. Non-limiting suitable examples include:

, each of which may be optionally substituted with, for example, 1-3 substituents each independently selected from halogen, -OH, oxo, C _1-4 alkyl and C _1-4 alkoxy, wherein the C _1-4 alkyl or C _1-4 alkoxy is optionally substituted with 1-3 fluorine, wherein the heterocyclic rings may be attached to the residue of formula I through any two available positions. For example, when X in formula I is an optionally substituted piperazine, wherein the piperazine ring may be attached to the residue of formula I through two nitrogen atoms, two carbon atoms, one carbon atom, or one nitrogen atom and one carbon atom, for example:

(optional substituent(s) not illustrated). Other heterocyclic rings should be understood similarly.

[20] Various R ¹ groups can be attached to X in formula I. In some embodiments, R ¹ can be hydrogen. In some embodiments, R ¹ can be optionally substituted C _1-4 alkyl, such as methyl, ethyl, isopropyl, CHF ₂ , CF ₃ , etc.

[21] In some embodiments, R ¹ may be -LR ²⁰ . In some embodiments, L may be absent. In some embodiments, L may be a linker, such as an optionally substituted C _1-4 alkylene, an optionally substituted C _1-4 heteroalkylene, an optionally substituted C _3-6 carbocyclic ring, or an optionally substituted 4-7 membered heterocyclic ring. In some embodiments, L may be C _1-4 alkylene, such as -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-CH ₂ -, etc. In some embodiments, L may be an optionally substituted C _1-4 alkylene, such as substituted with 1 or 2 substituents each of which is independently F, OH, or methyl. In the context of this document, optionally substituted C _1-4 alkylene also includes C _1-4 alkylene wherein two substituents, including two gem substituents, form a cyclic structure, such as .

In some embodiments, L can also be C _1-4 heteroalkylene, such as -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-, -CH ₂ -CH ₂ -N(H)-CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -O-, etc. Typically, when L is C _1-4 heteroalkylene, the heteroalkylene has one or two heteroatoms, such as one oxygen, one nitrogen, or two oxygen atoms, etc. Typically, -XLR ²⁰ does not contain two consecutive heteroatoms. In some embodiments, L can be optionally substituted C _1-4 heteroalkylene, such as substituted with 1 or 2 substituents each of which is independently F, -OH, or methyl. Similarly, in the context of this document, optionally substituted C _1-4 heteroalkylene also includes C _1-4 heteroalkylene wherein two substituents, including two gem substituents, form a cyclic structure, such as

In some embodiments, L can also be an optionally substituted C _3-6 carbocyclic ring. For example, in some embodiments, L can be cyclopropylene, cyclobutylene, cyclopentylene, etc. Heterocyclic rings are also suitable for some embodiments of the invention. For example, L can be a 4-7 membered heterocyclic ring having one or two heteroatoms independently selected from O, N, and S, wherein any two available positions of the heterocyclic ring can be used to link X to R ²⁰ . Non-limiting suitable heterocyclic rings include those described herein, such as azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, morpholinyl, etc. The heterocyclic ring may be optionally substituted, for example, with 1-3 substituents each independently selected from halogen, -OH, oxo, C _1-4 alkyl and C _1-4 alkoxy, wherein C _1-4 alkyl or C _1-4 alkoxy is optionally substituted with 1-3 fluorine atoms.

[22] R ²⁰ can typically be hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _1-4 alkynyl, -NR ²¹ R ²² , -OR ²³ or an optionally substituted 4-7 membered heterocyclyl. For example, in some embodiments, R ²⁰ can be hydrogen. In some embodiments, R ²⁰ can be C _1-4 alkyl such as methyl, ethyl, isopropyl, etc. In some embodiments, R ²⁰ can be C _1-4 alkyl substituted with 1-3 substituents each independently selected from F, -OH, -NH ₂ , -NH(C _1-4 alkyl), such as -NHMe, and -N(C _1-4 alkyl)(C _1-4 alkyl), such as -NMe ₂ or -N(Me)(Et). For example, in some embodiments, R ²⁰ can be -CH ₂ -OH, -CH ₂ -NMe ₂ , etc. In some embodiments, R ²⁰ can be -OR ²³ . For example, in some embodiments, R ²⁰ can be -OH or -O-C _1-4 alkyl, etc. In some embodiments, R ²⁰ can be protected OH, such as -O-C(O)-C _1-4 alkyl, or silyl-protected hydroxyl, such as -O-TMS. Compounds with protected OH such as R ²⁰ can be used during synthesis to prepare compounds with R ²⁰ being OH, in some embodiments. In some embodiments, R ²⁰ can be -NR ²¹ R ²² . For example, in some embodiments, R ²⁰ can be -NH ₂ , -NH(C _1-4 alkyl), such as -NHMe, or -N(C _1-4 alkyl)(C _1-4 alkyl), such as -NMe ₂ or -N(Me)(Et). In some embodiments, one or both of R ²¹ and R ²² can be a nitrogen protecting group. When both R ²¹ and R ²² are nitrogen protecting groups, this also includes situations where R ²¹ and R ²² join to form a ring structure, such as Compounds with such protected NH(R) or _NH2 as ^R20 in some embodiments can be used during synthesis to prepare compounds with ^R20 being NH(R) or _NH2 . In some embodiments, ^R20 can also be a 4-7 membered heterocyclyl, typically having one or two heteroatoms independently selected from O, N and S. Non-limiting suitable heterocyclyls include those described herein such as azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, morpholinyl, etc. Heterocyclyl may be optionally substituted, for example, with 1-3 substituents each independently selected from halogen, -OH, oxo, C _1-4 alkyl and C _1-4 alkoxy, wherein C _1-4 alkyl or C _1-4 alkoxy is optionally substituted with 1-3 fluorine atoms.

[23] In some embodiments, X, R ¹ , and A ¹ of Formula I may be joined together to form an optionally substituted ring structure, typically an optionally substituted heterocyclic or heteroaryl ring. For example, X, R ^{1 ,} and A ¹ may be joined together to form a 4-, 5-, or 6-membered heterocyclic ring structure, or a 5- or 6-membered heteroaryl ring structure. Those skilled in the art will appreciate that when X, R ^{1 ,} and A ¹ are joined together to form a ring structure, a fused bicyclic ring of Formula I is formed, with the overall Non-limiting suitable ring structures include the following, for purposes of illustration, the fused ring structure is illustrated in place of simply the ring structure formed from X, R ¹ , and A ¹ in Formula I, and optional substituents are not illustrated:

In some embodiments, A ² is CH. In some embodiments, A is N.

[24] In some embodiments, -XR ¹ in Formula I can be a carbon-bonded moiety, wherein X is not a heteroatom. For example, in some embodiments, -XR ¹ in Formula I can be -COOH, -COOR ²³ , -CONR ²¹ R ²² , -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl is optionally substituted, such as with 1-3 groups each independently selected from F, -OH, protected OH, and C _1-4 alkoxy. In some embodiments, -XR ¹ in Formula I can be hydroxyl-substituted C _2-6 alkyl, such as -C(CH ₃ ) ₂ -OH.

[25] In some embodiments, A ¹ and A ² in formula I can both be N. In some embodiments, one of A ¹ and A ² in formula I can be N and the other of A ¹ and A ² can be CH.

[26] R ² and R ³ in formula I may be the same or different. Typically, R ² and R ³ may independently be hydrogen, C _1-4 alkyl optionally substituted with 1-3 fluoro atoms, C _3-6 cycloalkyl, or halogen. For example, in some embodiments, R ² and R ³ may be independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, F, and Cl. In some specific embodiments, both R ² and R ³ are isopropyl. In some embodiments, both R ² and R ³ are cyclopropyl. In some embodiments, R ² and R ³ are the same. In some embodiments, R ² and R ³ are different. In some embodiments, one of R ² and R ³ is hydrogen or methyl.

[27] Various heterocyclic rings are suitable as Het in formula I.

It should be clarified that although the formulas in this document are shown as Het should not be interpreted as encompassing only a 6-membered monocyclic heterocyclic ring. Typically, Het may be a 4-9-membered heterocyclic ring, which may be monocyclic or polycyclic (e.g., bicyclic, fused, or spirobicyclic). Het typically includes one or two ring heteroatoms, such as one or two ring nitrogen atoms. Non-limiting examples of suitable heterocyclic rings include the following:

wherein the attachment point can be in any of the available positions. Typically, if applicable, two ring nitrogen atoms are attached to the 6,6-bicyclic structure in Formula I and the electrophilic moiety U. For example, in some embodiments, Het is piperazine, which can be attached to the residue of Formula I via two nitrogen atoms: (optional substituent(s) not illustrated).

[28] The compounds herein include an electrophilic moiety U that can react with a cysteine residue of the KRAS protein to form a covalent bond. In some embodiments, U can be an electrophilic moiety that contains a Michael acceptor. For example, in some embodiments, U can be an α,β-unsaturated carbonyl moiety, such as or , where R ⁵ and R ⁶ are as defined herein.

In some embodiments, U is linked to a nitrogen atom Het, such as having the structural fragment: or , wherein R ⁵ and R ⁶ are as defined herein. In some embodiments, U may be an electrophilic moiety, such as , wherein R ⁵ and R ⁶ are as defined herein. In some particular embodiments, U may be , wherein R ⁵ and R ⁶ are as defined herein. In some embodiments, U may be , where R ⁵ and R ⁶ are as defined herein.

[29] Various R ⁵ and R ⁶ are suitable. For example, in some embodiments, R ⁵ and R ⁶ can each independently be hydrogen, halogen, -CN, -COOR ²³ A, -CONR ²¹ AR ²² A, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4-7-membered heterocyclic ring, or R ⁵ and R ⁶ can join together to form an optionally substituted C _3-6 carbocyclic ring or an optionally substituted 4-7-membered heterocyclic ring, wherein each of R ^21A and R ^22A at each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring or a nitrogen protecting group; and R ^23A in each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring or an oxygen protecting group.

[30] In some specific embodiments, R ⁵ may be hydrogen. In some embodiments, R ⁵ may be a halogen, such as F or Cl. In some embodiments, R ⁵ may be -CN. In some embodiments, R ⁶ may be hydrogen. In some embodiments, R ⁶ can be C _1-4 alkyl optionally substituted with 1-3 substituents each independently selected from F, -OH, -NH ₂ , -NH(C _1-4 alkyl) such as -NHMe, -N(C _1-4 alkyl)(C _1-4 alkyl) such as -NMe ₂ or -N(Me)(Et), optionally substituted 4-7 membered heterocyclyl with 1 or 2 ring heteroatoms independently selected from O, N and S. For example, in some embodiments, R ⁶ can be -CH2-OMe, -( _CH2 ) _n -OH, -( _CH2 ) _n - _NMe2 , and so on, where n is equal to the integer 14.

In some embodiments, R ⁶ can be a halogen, such as F or O. In some embodiments, R ⁶ can be -CN. In some embodiments, R ⁶ can be -COOR ²³ A, such as -COO(C _1-4 alkyl). In some embodiments, R ⁶ can be -CONR ²¹ AR ²² A, such as -CON(C _1-4 alkyl)(C _1-4 alkyl), -CONH(C _1-4 alkyl), or -CONH ₂ . In some embodiments, R ⁶ can be optionally substituted phenyl or 5 or 6 membered heteroaryl, such as

[31] In some specific embodiments, both R ⁵ and R ⁶ are hydrogen. In some specific embodiments, R ⁵ is F or OMe, and R ⁶ is hydrogen. In some specific embodiments, R ⁵ is hydrogen, and R ⁶ is -CH ₂ -OMe or

[32] As illustrated in Formula I, Het is substituted with an electrophilic moiety U and may optionally be further substituted with independently selected R ⁴ , (R ⁴ ) _n groups, wherein n is typically 0, 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[33] Typically, when present, R ⁴ at each occurrence can independently be C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), a fluoro-substituted C _1-4 alkyl, a hydroxyl-substituted C _1-4 alkyl, or a cyano-substituted C _1-4 alkyl; or two R ⁴ groups can join to form a 3-6 membered ring structure. For example, in some embodiments, R ⁴ at each occurrence can be methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN. In some embodiments, n can be 1 and R ⁴ can be methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN. In some embodiments, n may be 2 and one R ⁴ may be methyl and the other R ⁴ may be methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN.

[34] In some embodiments, Het in Formula I, together with (R ⁴ ) _n and U, is represented by:

where R 6 and R ⁶ are defined herein, for example, both R ⁵ and R ⁶ may be hydrogen.

[35] A in formula I is typically N. Although in some embodiments, A ³ may also be CR ³⁰ . For example, in some embodiments, A may be CH.

[36] A ⁴ in formula I is typically CH. Although in some embodiments of the invention, A ⁴ may also be N.

[37] A ⁵ in formula I is typically N. Although in some embodiments, A ⁵ may also be CR ³⁰ . For example, in some embodiments, A ⁵ may be CH.

[38] In some embodiments, R in Formula I can be hydrogen, halogen, -CN, a 3-4 membered ring (e.g., cyclopropyl), optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, or optionally substituted C _1-4 alkoxyl. For example, in some embodiments, R ⁷ can be hydrogen, F, Cl, methyl, -CN, or -CF ₃ . In some embodiments, R ⁷ can be F. In some embodiments, R can be Cl.

[39] R ⁸ in formula I is typically optionally substituted phenyl or naphthyl, or optionally substituted 5-10 membered heteroaryl. In some embodiments, R ⁸ can be phenyl optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, ^R8 may be phenyl substituted with F and optionally further substituted with -OH, _-NH2 , a protected hydroxyl group, or a protected amino group. In some embodiments, the phenyl substituent(s) may be located at the ortho position to the 6,6-bicyclic structure in Formula I.

[40] In some embodiments, R ⁸ may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, NH ₂ , a protected hydroxyl group, a protected amino group, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy.

[41] In some specific embodiments, R ⁸ may be .

[42] In some embodiments, the present disclosure provides illustrative examples of compounds of Formula I having Formula I-1 or I-2, or a pharmaceutically acceptable salt thereof:

Where:

X is O, S, N or NR ¹⁰ , each of J ¹ and J ² is independently selected from O, S, N, CR ⁴⁰ and NR ⁴¹ ,

wherein each of R ⁴⁰ and R ⁴¹ at each occurrence independently represents hydrogen, -OH, -CN, halogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 alkoxy, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring or optionally substituted 4-7 membered heterocyclic ring,

where the dotted line indicates that the corresponding compound is a single or double bond, provided that the bicyclic ring as a whole is aromatic, where ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , Het, n, ^A3 , ^A4 and ^A5 may represent any of the values defined herein for the corresponding variable.

In some embodiments, each of R ⁴⁰ and R ⁴¹ at each occurrence is independently hydrogen or C _1-4 alkyl, such as methyl.

[43] In some specific embodiments, the present disclosure also provides illustrative examples of compounds of Formula I having the formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C, or a pharmaceutically acceptable salt thereof:

Where:

A is CH or N,

wherein ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , ^R10 , ^R40 , ^R41 , Het, n, ^A3 , ^A4 , and ^A5 can be any of the values defined herein for the respective variable. In some embodiments, each of ^R10 , ^R40 , and ^R41 at each occurrence is independently hydrogen or _C1-4 alkyl (e.g., methyl). In some embodiments, ^A2 is CH. In some embodiments, ^A2 is N. In some embodiments, ^A3 is N, ^A4 is CH, and ^A5 is N.

[44] In some specific embodiments, the present disclosure also provides illustrative examples of compounds of Formula I having Formula 1-5 or 1-6, or a pharmaceutically acceptable salt thereof:

wherein ^R2 , ^R3 , R4, ^R5 , ^R6 , ^R7 , ^R8 , L, ^R20 , Het, ⁿ , ^A3 , ^A4 , and ^A5 may be any of the values defined herein for the respective variable. In some embodiments, L is absent, substituted _C1-4 alkylene, or an optionally substituted 4-7 membered heterocyclic ring containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms). In some embodiments, R ²⁰ is hydrogen, optionally substituted C _1-4 alkyl, -NR ²¹ R ²² , -OR ²³ , optionally substituted 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein R ²¹ , R ²² and R ²³ can be any of the values defined herein for the respective variable. In some embodiments, each of R ²¹ , R ²² and R ²³ at each occurrence is independently hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, the OLR ²⁰ moiety in Formula 1-5 or 1-6 can be:

[45] In some specific embodiments, the present disclosure also provides illustrative examples of compounds of Formula I having Formula I-7 or I-8, or a pharmaceutically acceptable salt thereof:

Where:

ring B is a 4-7 membered heterocyclic ring containing 1 or 2 ring heteroatoms, such as 1 or 2 ring nitrogen atoms, optionally substituted with group(s) R ⁴² , (R ⁴² ) _m , wherein R ⁴² at each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, -NR ²¹ R ²² or -OR ²³ , and m is 0, 1 or 2; and

^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 , L, ^R10 , ^R20 , ^R21 , ^{R22, R23 ,} Het, n, ^A1 , ^A2 , ^A3 , ^A4 , and ^A5 can be any of the values defined herein for the corresponding variable. In some embodiments, L is absent, substituted _C1-4 alkylene, or an optionally substituted 4-7 membered heterocyclic ring containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms). In some embodiments, R ²⁰ is hydrogen, optionally substituted C _1-4 alkyl, -NR ²¹ R ²² , -OR ²³ , optionally substituted 4-7 membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), wherein R ²¹ , R ²² and R ²³ can be any of the values defined herein for the corresponding variable.

In some embodiments, each of R ¹⁰ , R ^{21 ,} and R ²³ , if applicable, is independently, at each occurrence, hydrogen, optionally substituted C _1-4 alkyl, or a nitrogen protecting group. In some embodiments, R ²³ , as appropriate, at each occurrence is hydrogen or optionally substituted C _1-4 alkyl. In some embodiments, the moiety in formula 1-7 is selected from -NH ₂ , -NHCH ₃ , -NHC(O)CH ₃ , -N(CH ₃ )SO ₂ CH ₃ , -N(CH ₃ ) ₂ and

In some embodiments, in Formula 1-8, Ring B together with the optional substituent(s) R ⁴² is

[46] As described above, the variables in the subformulas of formula I, for example formulas I-1, I-2,1-3A, I-3B, I-3C, I-4A, I-4C, I-5,1-6, I-7 or I-8, may have any of the applicable corresponding definitions defined for formula I. For example, in some embodiments, R ² and R ³ in formula I and any of its subformulas may be independently selected from hydrogen, C _1-4 alkyl optionally substituted with 1-3 fluoro atoms, C _3-6 cycloalkyl and halogen. In some embodiments, R ² and R ³ in formula I and any of its subformulas may be independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F and Cl. In some embodiments, R ² and R ³ in formula I and any of its subformulas can both be isopropyl or cyclopropyl. In some embodiments, R and R ³ in formula I and any of its subformulas can be different, wherein one of R ² and R ³ is hydrogen or methyl. In some embodiments, in formula I and any of its subformulas, Het, together with (R ⁴ ) _n and U, can be represented by where n is 0, 1, or 2, wherein when n is 1 or 2, R ⁴ is independently methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN at each occurrence. In some embodiments of Formula I and any of its subformulas, Het, together with (R ⁴ ) _n and U, may be represented by

In some embodiments, in Formula I and any of its subformulas, Het, together with (R ⁴ ) _n and U, may be represented

In some embodiments, both R ⁵ and R ⁶ can be hydrogen. In some specific embodiments, R ⁵ is F or OMe, and R ⁶ is hydrogen. In some specific embodiments, R ⁵ is hydrogen, and R ⁶ is -CH ₂ -OMe or

In some embodiments, A ¹ and A ² of formula I and any of its subformulas, if applicable, can be N. In some embodiments, A ¹ and A ² of formula I and any of its subformulas, if applicable, can be different, for example, one of A ¹ and A ² is N and the other of A ¹ and A ² is CH. In some embodiments, A in formula I and any of its subformulas can be N. In some embodiments, A ⁴ of formula I and any of its subformulas can be CH. In some embodiments, A ⁵ of formula I and any of its subformulas can be N. In some embodiments, R ⁷ of formula I and any of its subformulas can be hydrogen, F, Cl, methyl, or -CF ₃ . In some embodiments, R ⁷ can be F. In some embodiments, R ⁸ can be Cl. In some embodiments, R ⁸ in Formula I and any of its subformulas can be phenyl optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R ⁸ in Formula I and any of its subformulas can be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R ⁸ in Formula I and any of its subformulas can be selected from:

[47] To further illustrate, using the subformula of formula I-3A as an example, some specific embodiments of the present disclosure include illustrative examples of a compound of formula I having formula I-3A-C or formula I-3A-N, or a pharmaceutically acceptable salt thereof:

where R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁰ , R ⁴⁰ , Het and n can be any of the values defined herein for the respective variable. For example, typically, R ² and R ³ in Formula I-3A-C or Formula I-3A-N can independently be selected from hydrogen, C alkyl optionally substituted with 1-3 fluoro atoms, C _3-6 cycloalkyl, and halogen. In some embodiments, R hR in Formula I-3A-C or Formula I-3A-N can be independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, F and Cl. In some embodiments, R ² and R ³ in Formula I-3A-C or Formula I-3A-N can both be isopropyl and cyclopropyl. In some embodiments, R ² and R ³ in formula I-3A-C or formula I-3A-N may be different, such as one of R ² and R ³ is hydrogen, F, or methyl, and the other of R ² and R ³ is isopropyl or cyclopropyl. In some embodiments, in formula I-3A-C or formula I-3A-N, one of R ² and R ³ may be F, and the other of R ² and R ³ is isopropyl or cyclopropyl, such as R ² is F and R ³ is isopropyl or cyclopropyl; or R ³ is F and R ² is isopropyl or cyclopropyl. In some embodiments of formula I-3A-C or formula I-3A-N, one of R ² and R ³ can be methyl, wherein the other of R ² and R ³ is isopropyl or cyclopropyl, for example, R ² is methyl and R ³ is isopropyl or cyclopropyl; or R ² is methyl and R ³ is isopropyl or cyclopropyl. As will be appreciated by those skilled in the art, when R ² and R ³ are different, the compounds of formula I-3A-C or formula I-3A-N can exist as a mixture of atropisomers, for example, in any ratio. In some embodiments, when applicable, compounds of formula I-3A-C or formula I-3A-N may exist as an isolated individual atropisomer that is substantially free (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or an undetectable amount) of the other atropisomer. Illustrative examples of methods for isolating atropisomers are described herein, see, e.g., the Examples section.

Typically, R ¹⁰ and R ⁴⁰ in formula I-3A-C or formula I-3A-N can independently be selected from hydrogen and C _1-4 alkyl. In some embodiments, R ⁴⁰ in formula I-3A-C or formula I-3A-N can be hydrogen. In some embodiments, R ¹⁰ in formula I-3A-C or formula I-3A-N can be C _1-4 alkyl, preferably methyl.

Typically in formula I-3A-C or formula I-3A-N, Het, together with (R ⁴ ) _n and can be presented where n is 0, 1, or 2, wherein when n is 1 or 2, R ⁴ is independently methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN at each occurrence. In some embodiments, in Formula I-3A-C or Formula I-3A-N, Het, together with (R ⁴ ) _n and can be presented

In some embodiments, in Formula I-3A-C or Formula I-3A-N, Het, together with (R ⁴ ) _n and can be presented

In some embodiments, both R ⁵ and R ⁶ can be hydrogen. In some specific embodiments, R ⁵ is F or OMe, and R ⁶ is hydrogen. In some specific embodiments, R ⁵ is hydrogen, and R ⁶ is -CH ₂ -OMe or

In some preferred embodiments of the invention, in formula I-3A-C or formula I-3A-N, Het, together with (R ⁴ ) _n and can be presented

R in formula I-3A-C or formula I-3A-N can generally be hydrogen, F, Cl, methyl, or _-CF3 . In some embodiments, ^R7 can be F. In some embodiments, ^R7 can be Cl.

R in formula I-3A-C or formula I-3A-N can typically be phenyl optionally substituted with 1 to 3 groups, each independently selected from F, CI, -OH, _NH2 , protected hydroxyl, protected amino, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), _C1-4 alkoxy, fluorine-substituted _C1-4 alkyl, and fluorine-substituted _C1-4 alkoxy. In some embodiments, R ⁸ of Formula 1-3A-C or Formula I-3A-N may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , a protected hydroxyl group, a protected amino group, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R of Formula I-3A-C or Formula I-3A-N may be selected from:

In some embodiments, R ⁸ in formula I (e.g., any of subformulas I-1, I-2, I-3A, I-3A-1,1-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1,1-4B-1, I4C-1, I-5, I-6, I-7, or I-8) is

[48] Some embodiments of the present disclosure also relate to a compound of formula II or a pharmaceutically acceptable salt thereof:

Where:

G ¹ is hydrogen, -COOH, -COOR ²³ , -CONR ²¹ R ²² , -CN, optionally substituted alkyl, alkenyl, alkynyl, or a carbocyclic ring (e.g., cycloalkyl), such as C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl, wherein the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl is optionally substituted with 1 to 3 groups each independently selected from F, OH, protected OH, and C _1-4 alkoxy; or G ¹ is -XR ¹ ;

where X is O, NR ¹⁰ , S, SO ₂ , or an optionally substituted 4-7 membered heterocyclic ring;

R ¹ is hydrogen, optionally substituted alkyl (eg C _1-4 alkyl) or -LR ²⁰ ,

wherein L is absent or is an optionally substituted alkylene (e.g., C _1-4 alkylene), an optionally substituted heteroalkylene (e.g., C _1-4 heteroalkylene), an optionally substituted carbocyclic ring (e.g., C _3-6 carbocyclic ring), or an optionally substituted heterocyclic ring (e.g., a 4-7 membered heterocyclic ring),

wherein R ²⁰ is hydrogen, optionally substituted alkyl, alkenyl or alkynyl, for example optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, -NR ²¹ R ²² , -OR ²³ , optionally substituted 4-7 membered heterocyclyl, wherein R ¹⁰ , R ²¹ and R ²² are each independently hydrogen, optionally substituted alkyl, alkenyl or alkynyl, for example optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, an optionally substituted C _3-6 carbocyclic ring, an optionally substituted 4-7 membered heterocyclic ring or a nitrogen protecting group; R ²³ is independently hydrogen in each occurrence, optionally substituted alkyl, alkenyl or alkynyl, for example optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring or an oxygen protecting group;

each of A ¹ , A ² , A ³ , A ⁴ and A ⁵ independently represents CR ³⁰ or N,

wherein R ³⁰ in each occurrence independently represents hydrogen, halogen (e.g. F, Cl), optionally substituted C _1-4 alkyl, optionally substituted alkoxy (e.g. C _1-4 alkoxy);

or, where applicable, R ¹ , X, and A ¹ together form an optionally substituted ring structure, such as an optionally substituted heterocyclic or heteroaryl ring;

Het is a 4- to 10-membered heterocyclic ring optionally substituted by group(s) R ⁴ , (R ⁴ ) _n ,

wherein R ⁴ at each occurrence, independently, is optionally substituted alkyl, alkenyl or alkynyl, or a 3 or 4 membered ring, for example, R ⁴ at each occurrence can be C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), fluoro-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl or cyano-substituted C _1-4 alkyl; or two R ⁴ groups can join together to form a ring structure, for example, a 3-6 membered ring structure;

U is an electrophilic moiety capable of forming a covalent bond with a cysteine residue of a KRAS protein, such as the KRAS G12C mutant protein;

R ⁷ is hydrogen, halogen, -CN, a 3-4 membered ring (e.g., cyclopropyl), optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, or optionally substituted C _1-4 alkoxyl; and

R ⁸ is optionally substituted aryl or optionally substituted heteroaryl.

[49] A variety of groups may be suitable for G ¹ in Formula II. In some embodiments, G ¹ may be hydrogen. In some embodiments, G ¹ may be -COOH, -COOR ²³ , -CONR ²¹ R ²² , -CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl, wherein the C _1-4 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, or C _3-6 cycloalkyl is optionally substituted with, for example, 13 groups each independently selected from F, -OH, protected OH, and C _1-4 alkoxy. In some embodiments, G ¹ in formula II can be a hydroxyl-substituted C _1-4 alkyl, for example a hydroxyl-substituted C _1-4 alkyl such as -C(CH ₃ ) ₂ -OH. In some embodiments, G ¹ in formula II can be a hydroxyl-substituted C _3-6 cycloalkyl, for example a hydroxyl-substituted C _3-5 cycloalkyl. In some embodiments, G ¹ in formula II can also be -XR ¹ , which can have any of the definitions defined in the context of formula I and its subformulas. In some embodiments, G ¹ in formula II can be hydrogen, methyl, -COOH, OCF ₂ H, -OCF ₃ , cyclopropyl, -C(CH ₃ ) ₂ OH, CF ₃ or CN. In some preferred embodiments, G ¹ in formula II is hydrogen.

[50] In some embodiments, the variables in Formula II R ⁴ , R ⁷ , R ⁸ , Het, n, U, A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be any of those defined herein in the context of Formula I and its subformulas.

For example, in some embodiments, U in Formula II may be represented by where R ⁵ and R ⁶ are defined herein. For example, in some embodiments, R ⁵ and R ⁶ are each independently hydrogen, halogen, -CN, -COOR ²³ A, -CONR ²¹ AR ²² A, optionally substituted Cl _-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4-7-membered heterocyclic ring, or R ⁵ and R ⁶ can join together to form an optionally substituted C _3-6 carbocyclic ring or an optionally substituted 4-7-membered heterocyclic ring, wherein each occurrence of R ²¹ A and R ²² A is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7 membered heterocyclic ring, or a nitrogen protecting group; and R ²³ A at each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7 membered heterocyclic ring, or an oxygen protecting group. In some embodiments, in Formula II, Het, together with (R ⁴ ) _n and U, may be represented by where n is 0, 1, or 2, wherein when n is 1 or 2, R ⁴ is independently methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN at each occurrence. In some embodiments, in Formula II, Het, together with (R ⁴ ) _n and U, may be represented by .

In some embodiments, in Formula II, Het, together with (R ⁴ ) _n and U, may be represented

In some embodiments, both R ⁵ and R ⁶ can be hydrogen. In some specific embodiments, R ⁵ is F or OMe, and R ⁶ is hydrogen. In some specific embodiments, R ⁵ is hydrogen, and R ⁶ is -CH ₂ -OMe or In some embodiments, A ¹ and A ² of formula II may be N. In some embodiments, A ¹ and A ² of formula II, if applicable, may be different, such as one of A ¹ and A ² is N and the other of A ¹ and A ² is CH. In some embodiments, A in formula II may be N. In some embodiments, A ⁴ of formula II may be CH. In some embodiments, A ⁵ of formula II may be N. In some embodiments, R in formula II may be hydrogen, F, Cl, methyl, or CF ₃ . In some preferred embodiments, R ⁷ is F or Q. In some embodiments, R ⁷ may be F. In some embodiments, R ⁸ may be Cl. In some embodiments, R ⁸ in Formula II may be phenyl optionally substituted with 1-3 groups, each independently selected from F, O, -OH, -NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R in formula II may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R ⁸ in formula II may be selected from: In some preferred embodiments of the invention, R ⁸ in formula II is

[51] The introduction of dicyclopropyl groups in Formula II provides various advantages. As illustrated in the Examples section and in Figs. 1-3, some compounds of Formula II, such as compounds 44 and 126, have superior anticancer effects in several animal models compared to the current clinical compound AMG-510. The introduction of the 4,6-dicyclopropylpyrimidin-5-yl group can also result in improved RAS protein inhibition in vitro (e.g., KRAS G12C). As discussed herein, there is data showing that changing the isopropylpyrimidin-5-yl group to the corresponding cyclopropylpyrimidin-5-yl group will result in a 2- to 6-fold decrease in activity. However, this trend is reversed when the R group in Formula II is a 2-amino-6-fluorophenyl group. For example, compounds 44 and 126 were found to be more potent in inhibiting ERAS G12C than their corresponding isopropyl analogs. Moreover, the introduction of the 4,6-dicyclopropylpyrimidin-5-yl group may also result in improved in vivo profiles, such as increased cancer treatment efficacy and/or safety profile. As discussed herein, compared to the control compounds, compounds 44 and 126 have a better overall pharmacokinetic (“PK”) profile, such as a better human hepatocyte clearance profile and a better overall rat PK profile with significantly improved oral bioavailability. These data are expected to provide a superior m vivo profile, such as an efficacy and/or safety profile.

[52] In some embodiments, the present disclosure also provides a compound of formula III, or a pharmaceutically acceptable salt thereof:

where G ¹ , R ² , R ³ , R ⁴ , R ⁷ , Het, n, U, A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be any of those defined herein for the corresponding variable, for example in the context of formula I and its subformulas or formula II.

[53] For example, in some embodiments, G ¹ in formula III can be hydrogen, methyl, cyclopropyl, -C(CH ₃ ) ₂ OH, CF _3, or CN. In some embodiments, U in formula III can be wherein R ⁵ and R ⁶ are as defined herein. In some embodiments, in Formula III, Het, together with (R ⁴ ) _n and U, may be represented by where n is 0, 1, or 2, wherein when n is 1 or 2, R ⁴ is independently methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN at each occurrence. In some embodiments, in Formula III, Het, together with (R ⁴ ) _n and U,

can be presented

In some embodiments, in Formula III, Het, together with (R ⁴ ) _n and U, may be represented

In some embodiments, both R ⁵ and R ⁶ can be hydrogen. In some specific embodiments, R ⁵ is F or OMe, and R ⁶ is hydrogen. In some specific embodiments, R ⁵ is hydrogen, and R ⁶ is -CH ₂ -OMe or

In some embodiments, R ² and R ³ can be independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl a, F, and Cl. In some specific embodiments, both R ² and R ³ are isopropyl. In some embodiments, both R ² and R ³ are cyclopropyl. In some embodiments, R ² and R ³ are the same. In some embodiments, R ² and R ³ are different. In some embodiments, one of R ² and R ³ is hydrogen or methyl. In some embodiments, A ¹ and A ² of formula III can be N. In some embodiments, A ¹ and A ² of formula III can be different, such as one of A ¹ and A ² is N and the other of A ¹ and A ² is CH. In some embodiments, A in formula III can be N. In some embodiments, A ⁴ of formula III can be CH. In some embodiments, A ⁵ in formula III may be N. In some embodiments, R ⁷ in formula III may be hydrogen, F, Cl, methyl, or CF _3. In some embodiments, R ⁸ may be F. In some embodiments, R ⁸ may be Q.

[54] In some embodiments, the present disclosure also provides a compound of formula IV, or a pharmaceutically acceptable salt thereof:

123781234 5

where G ¹ , R ² , R ³ , R ⁷ , R ⁸ , A ¹ , A ² , A ³ , A ⁴ and A ⁵ may be any of those defined herein for the corresponding variable, for example in the context of formula I and its subformulas or formula II.

[55] For example, in some embodiments, G ¹ in Formula IV can be hydrogen, methyl, cyclopropyl, -C(CH ₃ ) ₂ OH, -CF ₃ or -CN. In some embodiments, R ² and R ³ can be independently selected from hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclopropyl, F and Cl. In some specific embodiments, both R ² and R ³ are isopropyl. In some embodiments, both R ² and R ³ are cyclopropyl. In some embodiments, R ² and R ³ are the same. In some embodiments, R ^{2 and R 3 are different. In some embodiments, one of R 2 and R 3 is hydrogen} or methyl. In some embodiments, A ¹ and A ² of formula IV may be N. In some embodiments, A ¹ and A ² of formula IV may be different, such as one of A ¹ and A ² is N and the other of A ¹ and A ² is CH. In some embodiments, A ³ of formula IV may be N. In some embodiments, A ⁴ of formula IV may be CH. In some embodiments, A ⁵ of formula IV may be N. In some embodiments, R ⁷ of formula IV may be hydrogen, F, Cl, methyl, or CF ₃ . In some embodiments, R ⁷ may be F. In some embodiments, R may be Cl. In some embodiments, R ⁸ in formula IV may be phenyl optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , protected hydroxy, protected amino, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluoro-substituted C _1-4 alkyl, and fluoro-substituted C _1-4 alkoxy. In some embodiments, R in formula IV can be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from B, O, -OH, _NH2 , protected hydroxy, protected amino, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), _C1-4 alkoxy, fluoro-substituted C1-4 alkyl, and fluoro-substituted _C1-4 alkoxy. In some embodiments, R in formula IV can be selected from: In some embodiments, R ⁸ in formula IV is

[56] In some embodiments, the present disclosure also provides a compound selected from any one of Compounds Nos. 1-186, or a pharmaceutically acceptable salt thereof:

[57] In some embodiments, the present disclosure also provides a compound selected from any of Compounds Nos. 1, 6, 8, 13, 20, 26, 33, 42, 44, 65, 68, 69, 70, 71, 72, 117, 124, 126, 127, 145, 146, 151, 152, 157, 158, 179, and 180, or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, unless otherwise indicated or contradicted by context, a compound of the present disclosure may be Compound No. 44, 126, or 145, or a pharmaceutically acceptable salt thereof.

[58] In some embodiments, to the extent applicable, the genus of compounds in the present disclosure also excludes any of the compounds specifically prepared and disclosed in WO 2019/213516.

Additional illustrative embodiments

[59] In some embodiments, the present disclosure provides the following additional illustrative examples of embodiments of the invention.

Embodiment of the invention 1. A compound of formula I-3A-1, I-3B-1, I-3C-1,1-4A-1, I-4B-1 or I-4C-1, or a pharmaceutically acceptable salt thereof:

where in each formula, if applicable:

A represents CH or N;

R ² and R ³ each independently represent hydrogen, halogen, -OH, -CN, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring, or optionally substituted C _1-4 alkoxy;

Het is a 4- to 10-membered heterocyclic ring optionally substituted with group(s) independently selected from ^R4 , ( ^R4 ) _n , where n is 0, 1, 2, or 3, and ^R4 at each occurrence is independently _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), a fluoro-substituted _C1-4 alkyl, a hydroxyl-substituted _C1-4 alkyl, or a cyano-substituted _C1-4 alkyl; or two ^R4 groups may join together to form a 3- to 6-membered ring structure;

R ² and R ³ are each independently hydrogen, halogen, -CN, -COOR, -CONR ²¹ AR ²² A, optionally substituted C _2-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 4-7-membered heterocyclic ring, or R ⁵ and R ⁶ may join together to form an optionally substituted C _3-6 carbocyclic ring or an optionally substituted 4-7-membered heterocyclic ring, wherein each of R ^21A and R ^22A at each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring, or a nitrogen protecting group; and R ²³ A at each occurrence is independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring, or an oxygen protecting group;

R ⁷ is hydrogen, halogen, CN, a 3-4 membered ring (e.g. cyclopropyl), optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, or optionally substituted C _1-4 alkoxyl;

R ⁸ is optionally substituted aryl or optionally substituted heteroaryl;

R ¹⁰ is hydrogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring, optionally substituted 4-7-membered heterocyclic ring or a nitrogen protecting group; and

each of R ⁴⁰ and R ⁴¹ at each occurrence independently represents hydrogen, OH, CN, halogen, optionally substituted C _1-4 alkyl, optionally substituted C _2-4 alkenyl, optionally substituted C _2-4 alkynyl, optionally substituted C _1-4 alkoxy, optionally substituted C _1-4 heteroalkyl, optionally substituted C _3-6 carbocyclic ring or optionally substituted 4-7-membered heterocyclic ring.

Embodiment 2. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein in each formula A is CH.

Embodiment 3. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein in each formula A ² are N.

Embodiment 4. A compound according to any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein in each formula, R ² and R ³ are independently selected from hydrogen, C _1-4 alkyl optionally substituted with 1-3 fluorine atoms, C _3-6 cycloalkyl and halogen.

Embodiment 5. A compound according to any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein in each formula, R ² and R ³ are independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F and Cl.

Embodiment 6. A compound according to any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein in each formula, R ² and R ³ are both isopropyl or both are cyclopropyl.

Embodiment 7. A compound according to any one of embodiments 1-3 or a pharmaceutically acceptable salt thereof, wherein in each formula, one of R ² and R ³ is hydrogen, F or methyl, and the other of R ² and R ³ is isopropyl or cyclopropyl.

Embodiment 8. A compound according to any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein in each formula one of R ² and R ³ is F and the other of R ² and R ³ is isopropyl or cyclopropyl, for example, R ² is F and R ³ is isopropyl or cyclopropyl; or R ³ is F and R ² is isopropyl or cyclopropyl.

Embodiment 9. A compound according to any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein in each formula one of R ² and R ³ is methyl and the other of R ² and R ³ is isopropyl or cyclopropyl, for example, R ² is methyl and R ³ is isopropyl or cyclopropyl; or R ³ is methyl and R ² is isopropyl or cyclopropyl.

Embodiment 10. A compound according to any one of embodiments 19, or a pharmaceutically acceptable salt thereof, wherein in each formula, if applicable, the compound exists as an isolated individual atropisomer that is substantially free (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or in an undetectable amount) of the other atropisomer.

Embodiment 11. A compound according to any one of embodiments 1-10 or a pharmaceutically acceptable salt thereof, wherein in each formula, if applicable, R ¹⁰ , R ⁴⁰ and R ⁴¹ are independently selected from hydrogen and C _1-4 alkyl.

Embodiment 12. A compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁴⁰ is hydrogen.

Embodiment 13. A compound according to any one of embodiments 1-12 or a pharmaceutically acceptable salt thereof, wherein in each formula, if applicable, R ¹⁰ is C _1-4 alkyl, preferably methyl.

Embodiment 14. A compound according to any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein in each formula, Het, together with (R ⁴ ) _n and presented where n is 0, 1, or 2, and wherein when n is 1 or 2, R ⁴ is independently methyl, ethyl, -CF ₃ , -CF ₂ H, -CH ₂ OH, or -CH ₂ CN in each occurrence.

Embodiment 15. A compound according to any one of embodiments 1-13 or a pharmaceutically acceptable salt thereof, wherein in each formula, Het, together with (R ⁴ ) _n and presented

Embodiment 16. A compound according to any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein in each formula, Het, together with (R ⁴ ) _n and presented

Embodiment 17. A compound according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein in each formula, both R ⁵ and R ⁶ are hydrogen.

Embodiment 18. A compound according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein in each formula, R ⁵ is F or OMe, and R ⁶ is hydrogen.

Embodiment 19. A compound according to any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁵ is hydrogen and R ⁶ is -CH ₂ -OMe or

Embodiment 20. A compound according to any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein in each formula, Het, together with (R ⁴ ) _n and presented

Embodiment 21. A compound according to any one of embodiments 1-20 or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁷ is hydrogen, F, Cl, methyl or -CF ₃ .

Embodiment 22. A compound according to any one of embodiments 1-20 or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁷ is F.

Embodiment 23. A compound according to any one of embodiments 1-20 or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁸ is Cl.

Embodiment 24. A compound according to any one of Embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein in each formula, R ⁸ is phenyl optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, NH ₂ , a protected hydroxyl group, a protected amino group, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluorine-substituted C _1-4 alkyl, and fluorine-substituted C _1-4 alkoxy.

Embodiment 24. A compound according to any one of Embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein R is a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1-3 groups, each independently selected from F, Cl, -OH, -NH ₂ , a protected hydroxyl group, a protected amino group, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, a 3 or 4 membered ring (e.g., cyclopropyl), C _1-4 alkoxy, fluorine-substituted C _1-4 alkyl, and fluorine-substituted C _1-4 alkoxy.

Embodiment 25. A compound according to any one of embodiments 1-23 or a pharmaceutically acceptable salt thereof, wherein in each formula R ⁸ is selected from: preferably,

Embodiment 26. A pharmaceutical composition comprising a compound according to any one of embodiments 1-25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Embodiment 27. A method for inhibiting a mutant KRAS G12C protein in a cell, comprising contacting the cell with a compound according to any one of embodiments 1-25 or a pharmaceutically acceptable salt thereof.

Embodiment 28. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 26.

Embodiment 29. The method according to embodiment 28, wherein the cancer is a hematological malignancy, lung cancer (e.g., non-small cell lung cancer), pancreatic cancer, endometrial cancer, gallbladder cancer, thyroid cancer, bile duct cancer, and/or colon cancer.

Embodiment 30. The method of embodiment 28 or 29, further comprising treating the subject with an additional therapy.

Embodiment 31. The method according to embodiment 30, wherein the additional therapy is a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy.

Embodiment 32. The method according to any one of embodiments 28-31, wherein the subject has a G12C mutation in KRAS, HRAS and/or NRAS.

Method of synthesis

[60] The compounds of the present disclosure can be readily synthesized by those skilled in the art given the present disclosure. Synthetic examples are also illustrated in the Examples section.

[61] The following synthetic process of Formula I is illustrative, which can be applied similarly by those skilled in the art to synthesize compounds of Formula II, by replacing a starting material or intermediate with a group -XR ¹ with the corresponding starting material or intermediate with a group G ¹ . Compounds of Formula III or IV can be prepared in a similar manner. In some embodiments, the present disclosure also provides synthetic methods and synthetic intermediates for preparing compounds of Formula I, II, III, or IV, as represented by the schemes herein.

[62] As illustrated in Scheme 1, in some embodiments, compounds of Formula I can be prepared by reacting intermediate S-2 with heterocyclic compound S-1 under suitable conditions, wherein Lg ¹ is a leaving group such as a halide or a sulfonate leaving group such as triflate (CF ₃ SO3-) or tosylate, etc. In some embodiments, S-1 can react S-2 with a base such as an amine base (e.g., diisopropylethylamine) or an inorganic base such as a carbonate base in a suitable solvent. In some embodiments, R ^8A is the same as R ⁸ . In some embodiments, however, R ^8A can also be different from R ⁸ , and the synthetic method can comprise converting R ^8A into R ⁸ . For example, in some embodiments, R ^8A can be a leaving group, such as a halide or a sulfonate leaving group, and the reaction product of S-1 and S-2 can be coupled with a suitable partner to introduce the desired R ⁸ group in either a single step or a plurality of steps. Typically, when applicable, the introduction of the R ⁸ group can be mediated by a metal-catalyzed cross-coupling reaction, such as a palladium-catalyzed cross-coupling reaction as illustrated herein. Suitable reagents and reaction conditions for palladium-catalyzed cross-coupling reactions are generally known, see examples of WO 2019/051291, WO 2018/119183, and WO 2018/217651. In some embodiments, a suitable partner can be a boronic acid or ester compound, such as R ⁸ -B(OH) ₂ . In some embodiments, R ^8A can be converted to a boronic acid or ester and then coupled to R ⁸ -Lg ² when Lg ² is a leaving group such as a halide or sulfonate leaving group. Other suitable cross-coupling reactions, such as the Stille or Negishi cross-coupling, are known in the art and can be adapted to synthesize the compounds described herein given this disclosure. Example 4 illustrates an example of reaction S-1 and S-2, wherein A ³ is N and Lg ¹ is Cl. Other compounds of formula I can be prepared in a similar manner. The variables X, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , Het, n, U, A ¹ , A ² , A ³ , A ⁴ and A ⁵ in Scheme 1 can be any of those defined herein.

[63] In some cases, the introduction of R ⁸ and/or the U group may occur after the inclusion of a heterocyclic ring lacking the U group. For example, as illustrated in Scheme 2, heterocycle S-3 may react with S-2 to form intermediate S-4. Pg1 in S-3 is typically hydrogen or a nitrogen protecting group such as Boe. Typically, S-4 may be deprotected under suitable conditions to introduce the U group. This deprotection step may then form an NH moiety, which may react with a suitable U group donor to yield formula I. Typically, such a U group donor may have the formula U-Lg ³ , where Lg is OH, O, or another suitable leaving group, an illustrative example of a U group donor may be represented by the molecule or an activated form such as an acyl chloride, where R ⁵ and R ⁶ may be any of those defined herein. As in Scheme 1, R ^8A may be the same as or different from R ⁸ . In cases where R ^8A is different from R ⁸ , the synthetic method also includes converting R ^8A and R ⁸ . As discussed above, R ^8A may be a leaving group, such as a halide or sulfonate leaving group, and may be coupled with a suitable partner to introduce the desired Rs group, either in a single step or in multiple steps. If possible, the conversion of RSA to R ⁸ may occur before or after the introduction of the S-3 heterocyclic ring and/or the U group. The variables X, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , RS, Het, n, U, A ¹ , A ² , A ³ , A ⁴ and A ⁵ in Scheme 2 may be any of those defined herein.

[64] In some embodiments, the -XR ¹ group of Formula I can be derived from other compounds of Formula L For example, in some embodiments, the -XR ¹ group in some compounds of Formula I can be -SO ₂ Me, and such compounds can be derived from the corresponding compounds of Formula L wherein the -XR ¹ group is -S-Me via an oxidative process. Compounds of Formula I wherein the -XR ¹ group is -SO ₂ Me can also serve as starting materials for the synthesis of other compounds of Formula I. As will be apparent to those skilled in the art, such a transformation can be carried out in any of the suitable intermediates described herein. Other derivatives of the -XR ¹ group of Formula I are also possible and can be used in some cases to prepare the compounds of the present disclosure.

[65] Intermediates S-2 can generally be prepared by processes involving formation of a 6,6-bicyclic ring. For example, Scheme 3 illustrates a typical process for preparing compounds S-2 with A ³ and A ⁵ representing N. Thus, compound S-5 can be coupled with S-6 via a carbonyl donor such as oxalyl chloride to form intermediate S-7, wherein Lg ⁴ is a leaving group such as a halide (e.g., Cl) or a sulfonate leaving group. S-7 can then be cyclized to form compound S-8, typically base-mediated. S-8 can then be converted to compound S-9, for example, by reaction with POCl ₃ or other suitable reagents. An illustrative example of the synthesis of various S-5 compounds is shown in the Examples section. Other S-5 compounds can be synthesized in a similar manner in light of this disclosure. Compounds S-6 may sometimes be commercially available or may be otherwise prepared by those skilled in the art. The variables X, ^R1 , ^R2 , ^R3 , ^R7 , ^R8A , ^A1 , ^A2 , and ^A4 in Scheme 3 may be any of those defined herein.

[66] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent undesirable reactions of certain functional groups. Suitable protecting groups for a variety of functional groups, as well as suitable conditions for the protection and deprotection of certain functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis", ^4th ed. PGM Wilts; TW Greene, John Wiley, 2007, and references cited therein. The reagents for the reactions described herein are well known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, WI, USA), Sigma (St. Louis, MO, USA). Others may be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7th Edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any updates available at the time of filing this application.

Pharmaceutical compositions

[67] Certain embodiments of the invention relate to a pharmaceutical composition comprising one or more compounds of the present disclosure.

[68] The pharmaceutical composition may optionally comprise a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or 1-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof) and optionally a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrating agents, emulsifiers, fillers, bulking agents, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, anti-adherents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which describes various excipients useful in formulating pharmaceutical compositions and known methods for their preparation.

[69] The pharmaceutical composition may include any one or more compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., Formulas 1-1,1-2,1-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1,1-3C-1, I-4A-1,1-4B-1,1-4C-1, I-5, I-6, I-7, or 1-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof), e.g., in a therapeutically effective amount. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof.

[70] The pharmaceutical composition may also be prepared for delivery by any of the known delivery routes, which include, but are not limited to, oral, parenteral, inhalation, etc.

[71] In some embodiments, the pharmaceutical composition may be formulated for oral administration. Formulations for oral use may be presented as discrete units such as capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethylcellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water and mixtures thereof.

[72] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (such as intravenous injection or infusion, subcutaneous or intramuscular injection). Formulations for parenteral administration can be, for example, an aqueous solution, a suspension or an emulsion. Excipients for preparing formulations for parenteral administration are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water and mixtures thereof.

[73] In some embodiments, the pharmaceutical composition is formulated for inhalation. Compositions for inhalation can be, for example, prepared as a nasal spray, a dry powder, or an aerosol administered through a metered dose inhaler. Excipients for preparing formulations for inhalation are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, as well as mixtures of these substances. Aerosols can further contain propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[74] The pharmaceutical composition may comprise varying amounts of the compounds of the present disclosure depending on various factors such as the intended use, potency, and selectivity of the compounds. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas 1-1,1-2, I-3A, I-3A-1,1-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or 1-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disease or disorder as described herein, which may depend on the recipient of the treatment, the disease or disorder being treated and its severity, the formulation containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound (e.g., for inhibiting KRAS G12C), its rate of clearance, and whether another drug is co-administered.

[75] For veterinary use, the compound of the present disclosure can be administered in a suitable composition in accordance with normal veterinary practice. A veterinarian can readily determine the dosage regimen and route of administration that are most appropriate for a particular animal.

[76] In some embodiments, all of the necessary components for treating a KRAS-associated disorder using a compound of the present disclosure, either alone or in combination with another agent or intervention conventionally used to treat such a disorder, can be packaged in a kit. In particular, in some embodiments, the present invention provides a kit for use in a therapeutic intervention for a disease, comprising a packaged kit of drugs that comprises a compound described herein, as well as buffers and other components for preparing deliverable forms of said drugs, and/or devices for delivering such drugs, and/or any agents that are used in combination therapy with a compound of the present disclosure, and/or instructions for treating the disease packaged with the drugs. The instructions can be recorded on any tangible medium, such as printed paper, or a computer-readable magnetic or optical medium, or instructions for linking to a remote computer data source, such as a world wide web page accessible via the Internet. Method of Treatment

[77] The compounds of the present disclosure are useful as therapeutically active agents for the treatment and/or prevention of diseases or disorders that are associated with RAS, such as KRAS G12C.

[78] In some embodiments, the present disclosure provides a method of inhibiting RAS-mediated signaling comprising contacting a cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formulas 1-1, 1-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, 1-5, 1-6, 1-7, or 1-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof). Inhibition of RAS-mediated signaling can be assessed and demonstrated by a wide variety of methods known in the art. Non-limiting examples include demonstration of (a) a decrease in RAS GTPase activity; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in the K _0ff of GTP or a decrease in the K _0ff of GDP; (d) a decrease in the levels of signal transduction molecules downstream of the RAS pathway, such as a decrease in the levels of pMEK, pERK, or pAKT; and/or (e) a decrease in the binding of the RAS complex to downstream signaling molecules, including, but not limited to, Raf. Kits and commercially available assays can be used to determine one or more of the foregoing.

[79] In some embodiments, provided herein is a method of inhibiting KRAS, HRAS, and/or NRAS G12C in a cell, the method comprising contacting the cell with an effective amount of one or more compounds of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof).

[80] In some embodiments, the present disclosure provides a method of treating a disease or disorder, such as cancer associated with a G12C mutation in KRAS, HRAS and/or NRAS, such as KRAS G12C-associated cancer, in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[81] In some embodiments, a method of treating cancer comprising administering to a subject in need thereof an effective amount of any compound of this disclosure (e.g., a compound of Formula I (e.g., Formulas I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound of this disclosure. In some embodiments, the cancer comprises a G12C, KRAS, HRAS and/or NRAS mutation, such as a KRAS G12 mutation. Determining whether a tumor or cancer is a G12C KRAS, HRAS and/or NRAS mutation is known in the art, such as described in US2018/0334454. In various embodiments, the cancer may be pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer is a hematological cancer (e.g., as described herein). In some embodiments, the cancer is MYH-associated polyposis. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, or bile duct cancer. Non-limiting examples of cancer also include acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic Ductal carcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrial cancer ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, oral and lip cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma of the neck with occult primary, midline tract carcinoma, oral cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasms, mycosis fungoides, myelodysplasia syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, cancer of the nasal cavity and paranasal sinuses, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, cancer of the lip and oral cavity, oropharynx cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, cancer of the paranasal sinuses and nasal cavity, parathyroid cancer, penile cancer, cancer pharynx, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymus carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, unusual childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or cancer caused by a virus.

[82] In some embodiments, the present disclosure provides a method of treating a disease or disorder (e.g., a cancer as described herein) in a subject in need thereof, the method comprising determining whether the subject has a G12C mutation in KRAS, HRAS, and/or NRAS, e.g., a KRAS G12C mutation, and if the subject is determined to have a KRAS, HRAS, and/or NRAS G12C mutation, e.g., a KRAS G12C mutation, then administering to the subject a therapeutically effective dose of at least one compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), formula II, formula III, formula IV, any of compounds Nos. 1-186, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition containing at least one compound of the present disclosure.

[83] The G12C mutation in KRAS, HRAS, and/or NRAS has also been found in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and/or lymph nodes). Accordingly, certain embodiments relate to a method of treating a hematological malignancy in a subject in need thereof, the method typically comprising administering to the subject a compound of the present disclosure (e.g., in the form of a pharmaceutical composition). Such malignancies include, but are not limited to, leukemias and lymphomas such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphomas (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and/or other leukemias. In some embodiments, hematological malignancies may also include lymphomas such as Hodgkin's lymphoma or non-Hodgkin's lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.

[84] The compounds of the present disclosure can be used as a monotherapy or in combination therapy. In some embodiments, the combination therapy comprises treating a subject with a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy, or immunotherapy. In some embodiments, the compounds of the present disclosure can also be co-administered with an additional pharmaceutically active compound, simultaneously or sequentially in any order, to a subject in need thereof (e.g., a subject having a cancer associated with a KRAS G12C mutation as described herein). In some embodiments, the additional pharmaceutically active compound can be a chemotherapeutic agent, a therapeutic antibody, etc. Any of the known chemotherapeutic agents can be used in combination with the compounds of the present disclosure. In some embodiments, the compounds of the present invention can also be used in combination with radiation therapy, hormonal therapy, cell therapy, surgery, and immunotherapy, therapies for which are well known to those of skill in the art.

[85] Many chemotherapeutic agents are currently known in the art and can be used in combination with the compounds of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), venetoclax, and adriamycin, as well as a variety of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXANTM); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbochone, meturedopa, and uredopa; ethyleneimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomycin, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, streptozocin, streptococcin, streptorubicin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); Folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; Androgens such as calusterone, dromostanolone propionate, epithiostanol, mepitiostonane; Adrenal suppressants such as aminoglutethimide, mitotane, trilostane, Folic acid replenisher such as frolinic acid; Aceglatone; Aldophosphamide glycoside; Aminolevulinic acid; Amsacrine; bestrabucil; bisantrene; edatrazate; defofamine; demecolcine; diaziquone; elfomitin; elliptinium acetate; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamole; nitracrine; pentostatin; fenamet; pirarubicin; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosin; arabinoside ("Ara-S"); cyclophosphamide; thiotepa; taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

[86] Also included as suitable chemotherapeutic cell conditioners are antihormonal agents that regulate or inhibit the action of hormones on tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex TM), raloxifene, 4(5)-imidazoles, 4-hydroxytamoxifen, aromatase inhibitors, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navel; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO).

[87] If desired, the compounds or pharmaceutical composition of the present disclosure can be used in combination with commonly prescribed anticancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, avicin abagovomab, acridinecarboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22, antineoplastic drugs, antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricodar, brostalicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, enterocolytic agents, non-specific cell cycle antineoplastic agents, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexone, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanton, lurtotecan, mafosfamide, mitozolomide, naoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swainsonine, talaporfin, tariquidar, tegafururacil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[88] The compounds of the present disclosure may also be used in combination with an additional pharmaceutically active compound that disrupts or inhibits the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways. In other such combinations, the additional pharmaceutically active compound is a PD-1 and PD-L1 antagonist. The compounds or pharmaceutical compositions of the present disclosure can also be used in combination with one or more agents selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, McI-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies including monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTE.

[89] Representative antibodies against PD-1 or PDL-1 and methods for their use are described in Goldberg et al., Blood 110(1): 186–192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757–1761 (2007), and Korman et al., International Application No. PCT/JP2006/309606 (Publication No. WO 2006/121168 A1), the contents of each of which are expressly incorporated herein by reference, include: pembrolizumab (Keytruda®), nivolumab (Opdivo®), Yervoy™ (ipilimumab) or tremelimumab (to CTLA-4), galiximab (to B7D), M7824 (a bifunctional anti-PD-L1/TGF-β fusion protein), AMP224 (for B7DC), BMS-936559 (for B7-HI), MPDL3280A (for B7-H1), MEDI-570 (for ICOS), AMG 404, AMG557 (for B7H2), MGA271 (for B7H3), IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Health Services), huMAbOX40L (for OX40L), Atacicept (for TACI), CP-870893 (for CD40), lucatumumab (for CD40), dacetuzumab (for CD40), muromonab-CD3 (for CD3), ipilumumab (for CTLA-4). Immunotherapy also includes genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE). Non-limiting suitable additional agents also include anti-EGFR antibody and small molecule EGFR inhibitors such as cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib (Tarceva), lapatinib (TykerB), etc. Non-limiting suitable additional agents also include CDK inhibitors such as CDK4/6 inhibitors such as seliciclib, UCN-01, P1446A-05, palbociclib (PD-0332991), abemaciclib, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965, etc. Non-limiting suitable additional agents also include MEK inhibitors such as trametinib (Mekinist®), CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901. WO 2019/213516 describes a list of additional agents that can be used in combination with KRAS G12C inhibitors. These additional agents can also be used in combination with the compounds of the present disclosure.

[90] As illustrated in the Examples section, the combination of compounds #44, 126 and 145 with various agents including platinum-based agents (cisplatin or carboplatin), SHP2 inhibitor (RMC-4550, (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4,5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), MEK inhibitor (trametinib) has been shown to have a synergistic tumor volume reducing effect in several animal models. Thus, in some embodiments, the compounds of the present disclosure (e.g., compound 44, 126, or 145) can be used in combination with a platinum-based drug (e.g., cisplatin or carboplatin), a SHP2 inhibitor (e.g., RMC-4550, RMC-4630, TN0155), and/or a MEK inhibitor (e.g., trametinib).

[91] Administration herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhalational, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral. In some embodiments, administration is oral.

[92] The dosage regimen, including doses, may vary and be adjusted, which may depend on the recipient of the treatment, the disease or disorder being treated and its severity, the formulation containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its rate of elimination, and whether another drug is being administered concomitantly.

Definitions

[93] It is understood that the proper valences are maintained for all fragments and their combinations.

[94] It should also be understood that a particular embodiment of a variable fragment of the present document may be the same or different from another particular embodiment having the same identifier.

[95] Suitable atoms or groups for variables in this document are selected independently. The definitions of variables may be combined. Using Formula I as an example, any of the definitions of one of X, ^R1 , ^R2 , ^R3 , ^R4 , ^R7 , ^R8 , Het, n, U, ^A1 , ^A2 , ^A3 , ^A4 , and ^A5 in Formula I may be combined with any of the definitions of the other X, R1, R2, R3, R4, R7, R8, Het, n, U, ^A1 , ^A2 , ^A3 , ^A4 , and ^A5 in Formula I. Such a combination is contemplated and is within the scope of the present invention.

[96] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th ed., inner cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March Advanced Organic Chemistry, 5th ed., John Wiley and Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge University Press, Cambridge, 1987. This description is not intended to limit in any way the illustrative example of the list of substituents described herein.

[97] The compounds of the present disclosure may contain one or more centers of asymmetry and/or axial chirality and thus may exist in different isomeric forms, such as enantiomers and/or diastereomers.

For example, the compounds described herein may exist in the form of a single enantiomer, diastereomer, atropisomer, or geometric isomer, or may exist in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers can be separated from the mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and, alternatively, as mixtures of various isomers, including racemic mixtures. When stereochemistry is specifically drawn, it is to be understood that, relative to that particular chiral center or axial chirality, the compound exists predominantly as the stereoisomer as illustrated in the drawing, e.g., with less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or with an undetectable amount of the other stereoisomer(s). The presence and/or amounts of stereoisomers can be determined by those skilled in the art given the present disclosure, including through the use of chiral HPLC.

[98] The compounds of the present disclosure may have atropisomers. In any of the embodiments described herein, where applicable, a compound of the present disclosure may exist as a mixture of atropisomers in any ratio. In some embodiments, where applicable, the compound may exist as an isolated individual atropisomer that is substantially free (e.g., less than 20%, less than 10%, less than 5%, less than 1% by weight, by HPLC area, or both, or an undetectable amount) of the other atropisomer(s). The Examples section illustrates some illustrative isolated atropisomers of the compounds of the present disclosure. As will be appreciated by those skilled in the art, when rotation is restricted about a single bond, such as a single biaryl bond, the compound may exist as a mixture of atropisomers with each individual atropisomer being isolable.

[99] When a range of values is specified, it must encompass every value and subrange within the range. For example, "C _1-6 " is intended to encompass C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1-6 , C _1-5 , C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-5 , C _2-4 , C _2-3 , C _3-6 , C _3-5 , C _3-4 , C _4-6 , C _4-5 and C _5-6 .

[100] As used herein, the term “compound(s) of the present disclosure” or “compound(s) of the present invention” refers to any of the compounds described herein according to Formula I (e.g., Formula I-1, I-2, I-3A, I-3A-1, I-3A-C, I-3A-N, I-3B, I-3C, I-4A, I-4B, I-4C, I-3B-1, I-3C-1, I-4A-1, I-4B-1, I-4C-1, I-5, I-6, I-7, or I-8), Formula II, Formula III, Formula IV, any of Compound Nos. 1-186, isotopically labeled compound(s) thereof (e.g., a deuterated analog in which one of the hydrogen atoms is replaced by a deuterium atom in excess of its natural abundance), possible stereoisomers thereof (including diastereoisomers, enantiomers and racemic mixtures), geometric isomers, their atropisomers, their tautomers, their conformational isomers and/or their pharmaceutically acceptable salts (e.g., an acid addition salt, such as an HCl salt, or a base addition salt, such as a sodium salt). For the avoidance of doubt, Compound Nos. 1-186 or Compounds 1-186 refer to the compounds described herein designated by the integers 1, 2, 3, ..., 186, see, for example, the title compounds of Examples 1-23 and Table 1. Hydrates and solvates of the compounds of the present disclosure are considered to be compositions of the present disclosure in which the compound(s) is in association with water or a solvent, respectively.

[101] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, and ¹²⁵ I. Compounds that contain other isotopes of these and/or other atoms are within the scope of the present invention.

[102] As used herein, the phrase “administering” a compound, “administered” a compound, or other variations thereof means providing the compound or a prodrug of the compound to a person in need of treatment.

[103] As used herein, the term "alkyl" by itself or as part of another group refers to a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, alkyl may contain from one to twelve carbon atoms (i.e., C _1-12 alkyl) or the number of designated carbon atoms (i.e., C ₁ alkyl such as methyl, C ₂ alkyl such as ethyl, C ₃ alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is a straight chain C _1-10 alkyl group. In another embodiment, the alkyl group is a branched chain C _3-10 alkyl group. In another embodiment, the alkyl group is a straight chain C _1-6 alkyl group. In another embodiment, the alkyl group is a branched chain C _3-6 alkyl group. In another embodiment, the alkyl group is a C _1-4 straight chain alkyl group. For example, a C _1-4 alkyl group as used herein refers to a group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. An optionally substituted C _1-4 alkyl group refers to a C _1-4 alkyl group as defined, optionally substituted with one or more permissible substituents as described herein. As used herein, the term "alkylene," used alone or as part of another group, refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -, and the like.

[104] As used herein, the term "heteroalkyl" refers to an alkyl group, as defined above, with one or more carbon atoms substituted with a heteroatom such as O or N. Heteroalkyl may be designated by the number of carbon atoms. For example, C _1-4 heteroalkyl refers to a heteroalkyl group containing 1-4 carbon atoms. When optionally substituted, either the heteroatom or the carbon atom of the heteroalkyl group may be substituted with a permissible substituent. As used herein, the term "heteroalkylene", used alone or as part of another group, refers to a divalent radical derived from a heteroalkyl group.

[105] As used herein, the term "alkenyl" used alone or as part of another group refers to an alkyl group, as defined above, containing one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is a C _2-6 alkenyl group. In another embodiment, the alkenyl group is a C _2-4 alkenyl group. Non-limiting examples of alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[106] As used herein, the term "alkynyl," used alone or as part of another group, refers to an alkyl group, as defined above, containing one to three carbon-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is a C _2-6 alkynyl group. In another embodiment, the alkynyl group is a C _2-4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[107] As used herein, the term “alkoxy,” whether used alone or as part of another group, refers to a radical of the formula OR ^al , where R ^al is alkyl.

[108] As used herein, the term "haloalkyl" used alone or as part of another group refers to an alkyl substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl group substituted with one, two or three fluorine atoms. In one embodiment, the haloalkyl group is a C _1-10 haloalkyl group. In one embodiment, the haloalkyl group is a C _1-6 haloalkyl group. In one embodiment, the haloalkyl group is a C _1-4 haloalkyl group.

[109] The term "carbocyclyl" or "carbocyclic", whether used alone or as part of another group, refers to a radical of a non-aromatic cyclic hydrocarbon group having 3-10 ring carbon atoms ("C _3-10 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. The carbocyclic group may be either monocyclic ("monocyclic carbocyclyl") or contain a fused, bridged, or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclic ring, in which cases, the number of carbon atoms still indicates the number of carbon atoms in the carbocyclic ring system. Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl.

[110] In some embodiments, "carbocyclyl" is a monocyclic saturated carbocyclic group having from 3 to 10 ring carbon atoms ("C _3-10 cycloalkyl"). In some embodiments, the cycloalkyl group has from 3 to 8 carbon atoms ("C _3-8 cycloalkyl"). In some embodiments, the cycloalkyl group has from 3 to 6 carbon atoms ("C _3-6 cycloalkyl"). In some embodiments, the cycloalkyl group has from 5 to 6 carbon atoms ("C _5-6 cycloalkyl"). In some embodiments, the cycloalkyl group has from 5 to 10 carbon atoms ("C _5-10 cycloalkyl").

[111] "Heterocyclyl" or "heterocyclic" whether used alone or as part of another group, refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and from 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. The heterocyclyl group may be either monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl") and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclic ring as defined above is fused to one or more carbocyclyl groups wherein the point of attachment is on either the carbocyclyl or heterocyclic ring, or ring systems in which a heterocyclic ring as defined above is fused to one or more aryl or heteroaryl groups wherein the point of attachment is on the heterocyclic ring, and in such cases the number of ring members continues to denote the number of ring members in the heterocyclic ring system.

[112] Illustrative examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, thiiranyl. Illustrative examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.

Illustrative examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Illustrative examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Illustrative examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Illustrative examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Illustrative examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Illustrative examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Illustrative examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Illustrative examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Illustrative examples of 5-membered heterocyclyl groups fused to a C$ aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Typical 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[113] "Aryl" as used alone or as part of another group, refers to a radical monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., that has 6, 10, or 14 pi electrons shared within the ring system) having 6 to 14 ring carbon atoms and zero heteroatoms within the aromatic ring system ("C _6-14 aryl"). In some embodiments, an aryl group has six ring carbon atoms ("C ₆ aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C ₁₀ aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms ("C ₁₄ aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups in which the radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to denote the number of carbon atoms in the aryl ring system.

[114] "Aralkyl" used alone or as part of another group refers to alkyl substituted with one or more aryl groups, preferably substituted with one aryl group. Examples of aralkyl include benzyl, phenethyl, etc. When aralkyl is considered optionally substituted, either the alkyl portion or the aryl portion of the aralkyl may be optionally substituted.

[115] "Heteroaryl" as used alone or as part of another group, refers to a radical of a 5 to 10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared within the ring system) having ring carbon atoms and 1 to 4 ring heteroatoms present within the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom if valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to denote the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on either the aryl or heteroaryl ring, and in such cases, the number of ring members denotes the number of ring members in the fused (aryl/heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment may be on either ring, i.e., on the ring with the heteroatom (e.g., 2-indolyl) or the ring that does not contain the heteroatom (e.g., 5-indolyl).

[116] Illustrative examples of 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl.

Illustrative examples of 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Illustrative examples of 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Illustrative examples of 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Illustrative example of 6-membered heteroaryl groups containing one heteroatom includes, but are not limited to, pyridinyl. Illustrative example of 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Illustrative examples of 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Illustrative examples of 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Illustrative examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Illustrative examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[117] "Heteroaralkyl," used alone or as part of another group, refers to alkyl substituted by one or more heteroaryl groups, preferably substituted by one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl may be optionally substituted.

[118] As generally understood by those skilled in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene and heteroarylene refer to the corresponding divalent radicals of the group: alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, respectively.

[119] An "optionally substituted" group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl group, refers to the corresponding group being unsubstituted or substituted. In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, e.g., a substituent that, upon substitution, results in the formation of a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituent may be either the same or different at each position. Generally, when substituted, optionally substituted groups herein may be substituted with 1-5 substituents. The substituents may be a substituent on a carbon atom, a substituent on a nitrogen atom, a substituent on an oxygen atom, or a substituent on a sulfur atom, as applicable.

[120] Unless otherwise expressly stated, combinations of substituents and/or variables are permissible only if such combinations are chemically permissible and result in a stable compound. A “stable” compound is one that can be prepared and isolated and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to the subject matter).

[121] In some embodiments, an “optionally substituted” non-aromatic group in this disclosure may be unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, -OH, oxo (if applicable), C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, a 5- or 6-membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, a 4-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy-phenyl, heteroaryl, and heterocyclyl is optionally substituted 1, 2 or 3 substituents independently selected from F, -OH, oxo (if applicable), C _1-4 alkyl, fluoro-substituted C _1-4 alkyl (e.g. CF3), C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy. In some embodiments, an "optionally substituted" aromatic group (including aryl and heteroaryl groups) may be unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, -OH, -CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, phenyl, a 5- or 6-membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, a 4-7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted 1, 2 or 3 substituents independently selected from F, -OH, oxo (if applicable), C _1-4 alkyl, fluoro-substituted C _1-4 alkyl, C _1-4 alkoxy and fluoro-substituted C _1-4 alkoxy.

[122] Examples of substituents on a carbon atom include, but are not limited to, halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^aa , -ON(R ^bb ) ₂ , -N(R ^bb ) ₂ , -N(R ^bb ) ₃ ⁺ X ^- , -N(OR ^cc )R ^bb , -SH, -SR ^aa , -SSR ^cc , -C(=O)R ^aa , -CO ₂ H, -CHO, -C(OR ^cc ) ₂ , -CO ₂ R ^aa , OC(=O)R ^aa , OCO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , OC(=O)N(R ^bb ) ₂ , NR ^bb C(=O)R ^aa , -NR ^bb CO ₂ R ^aa , -NR ^bb C(=O)N(R ^bb )2, -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -OC(=NR ^bb )R ^aa , -OC(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -OC(=NR ^bb )N(R ^bb ) ₂ , NR ^bb C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -NR ^bb SO ₂ R ^aa , -SO ₂ N(R ^bb ) ₂ , -SO2R ^aa , -SO ₂ OR ^aa , -OSO ₂ R ^aa , -S(=O)R ^aa , OS(=O)R ^aa , -Si(R ^aa ) ₃ , -OSi(R ^aa ) ₃ -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa , -C(=S)SR ^aa , -SC(=S)SR ^aa , -SC(=O)SR ^aa , -OC(=O)SR ^aa , -SC(=O)OR ^aa , -SC(=O)R ^aa -P(=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -OP(=O)(R ^aa ) ₂ , -OP(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^bb ) ₂ ) ₂ , -OP(=O)(N(R ^bb ) ₂ ) ₂ , -NR ^bb P(=O)(R ^aa ) ₂ , -NR ^bb P(=O)(OR ^cc ) ₂ , -NR ^bb P(=O)(N(R ^bb ) ₂ ) ₂ , -P(R ^cc ) ₂ , -P(OR ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ XP(OR ^cc ) ₃ ⁺ X, -P(R ^cc ) ₄ , -P(OR ^cc ) ₄ , -OP(R ^cc ) ₂ , OP(R ^cc ) ₃ ⁺ X -OP(OR ^cc ) ₂ , -OP(OR ^cc ) ₃ ⁺ X- -OP(R ^cc ) ₄ , -OP(OR ^cc ) ₄ , -B(R ^aa ) ₂ , -B(OR ^cc ) ₂ , -BR ^aa (OR ^cc ), C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, _C2-10 alkynyl, _C3-10 carbocyclyl, 3-14 membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 ^Rdd groups; wherein X is a counterion;

or two geminal hydrogen atoms on a carbon atom are replaced by the group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa ,=NNR ^bb S(=O) ₂ R ^aa ,=NR ^bb or =NOR ^cc ;

each occurrence of R ^aa is independently selected from C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^aa groups are joined to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups;

each occurrence of R ^bb is independently selected from hydrogen, -OH, -OR ^aa , -N(R ^cc ) ₂ , -CN, -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , - CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R ^cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O)(R ^aa ) ₂ , -P(=O)(OR ^cc ) ₂ , -P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl or two R ^bb groups are joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups; where ^X is a counterion;

each occurrence ^{of Rcc} is independently selected from hydrogen, _C1-10 alkyl, _C1-10 haloalkyl, _C2-10 alkenyl, _C2-10 alkynyl, C3-10 carbocyclyl, _3-14 membered heterocyclyl, ^C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 ^Rdd groups;

each occurrence of R ^dd is independently selected from halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OR ^ee , -ON(R ^ff ) ₂ , -N(R ^ff ) ₂ , -N(R ^ff ) ₃ ⁺ X ^- , -N(OR ^ee )R ^ff , -SH, -SR ^ee , -SSR ^ee , -C(=O)Re ^e , -CO ₂ H, -CO ₂ R ^ee , -OC(=O)R ^ee , -OCO ₂ R ^ee , -C(=O)N(R ^ff ) ₂ , -OC(=O)N(R ^ff ) ₂ , -NR ^ff C( =O)R ^ee , -NR ^ff CO ₂ R ^ee , -NR ^ff C(=O)N(R ^ff ) ₂ , -C(=NR ^ff )OR ^ee , -OC(=NR ^ff )R ^ee , -OC(=NR ^ff )OR ^ee , -C(=NR ^ff )N(R ^ff ) ₂ , -OC(=NR ^ff )N(R ^ff ) ₂ , -NR ^ff C(=NR ^ff )N(R ^ff ) ₂ ,-NR ^ff SO ₂ R ^ee , -SO ₂ N(R ^ff ) ₂ , -SO ₂ R ^ee , SO ₂ OR ^ee , OSO ₂ R ^ee , S(=O)R ^ee , -Si(R ^ee ) ₃ , -OSi(R ^ee ) ₃ , C(=S)N(R ^ff ) ₂ , C(=O)SR ^ee , C(=S)SR ^ee , -SC(=S)SR ^ee , -P(=P)(OR ^ee ) ₂ , -P(=O)(R ^ee ) ₂ , -OP(=O)(R ^ee ) ₂ , -OP(=O)(OR ^ee )2, C _{1 -6} alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R ^gg groups, or two geminal R ^dd substituents may be joined to form =O or =S; where X is counterion;

each occurrence of R ^ee is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups;

each occurrence of R ^ff is independently selected from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; and

each occurrence of R ^gg independently represents halogen, -CN, -NO ₂ , -N ₃ , -SO ₂ H, -SO ₃ H, -OH, -OC _1-6 alkyl, -ON(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₂ , -N(C _1-6 alkyl) ₃ ⁺ X ^- , -NH(C _1-6 alkyl) ₂ ⁺ X ^- -NH ₂ (C _1-6 alkyl) ⁺ X ^- -NH ₃ ⁺ X ^- , -N(OC _1-6 alkyl)(C _1-6 alkyl), -N(OH)(C _1-6 alkyl), -NH(OH), -SH, -SC _1-6 alkyl, -SS(C _1-6 alkyl), -C(=O)(C _1-6 alkyl), -CO ₂ H, -CO ₂ (C _1-6 alkyl), -OC(=O)(C _1-6 alkyl), -OCO ₂ (C _1-6 alkyl), -C(=O)NH ₂ , -C(=O)N(C _1-6 alkyl) ₂ , -OC(=O)NH(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C _1-6 alkyl)C(=O)(C _1-6 alkyl) , -NHCO ₂ (C _1-6 alkyl), -NHC(=O)N(C _1-6 alkyl) ₂ , NHC(=O)NH(C _1-6 alkyl), NHC(=O)NH ₂ , -C(=NH)O(C _1-6 alkyl), -OC(=MH)(C _1-6 alkyl), -OC(=NH)OC _1-6 alkyl, -C(=NH)N(C _1-6 alkyl) ₂ , -C(=NH)NH(C _1-6 alkyl), -C(=NH)NH ₂ , -OC(=NH)N(C _1-6 alkyl) ₂ , -OC(NH)NH(C _{1- 6} alkyl), -OC(NH)NH ₂ , -NHC(NH)N(C _1-6 alkyl) ₂ , -NHC(=NH)NH ₂ , -NHSO ₂ (C _1-6 alkyl), -SO ₂ N(C _1-6 alkyl) ₂ , -SO ₂ NH(C _1-6 alkyl), -SO ₂ NH ₂ , -SO ₂ C _1-6 alkyl, SO ₂ OC _1-6 alkyl, -OSO ₂ C _{1 -6} alkyl, -SOC _1-6 alkyl, -Si(C _1-6 alkyl) ₃ , -OSi(C _1-6 alkyl) ₃ -C(=S)N(C _1-6 alkyl) ₂ , C(=S)NH(C _1-6 alkyl), C(=S)NH ₂ , -C(=O)S(C _1-6 alkyl), -C(=S)SC _1-6 alkyl, -SC(=S)SC _1-6 alkyl, -P(=O)(OC _1-6 alkyl) ₂ , -P(=O)(C _1-6 alkyl) ₂ , -OP(=O)(C _1-6 alkyl) ₂ , -OP(=O)(OC _1-6 alkyl) ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl; or two geminal substituents R ^gg may be joined to form =O or =S; where X is a counterion.

[123] A "counterion" or "anionic counterion" is a negatively charged group bonded to a positively charged group to maintain electron neutrality. An anionic counterion may be monovalent (i.e., include one formal negative charge). An anionic counterion may also be multivalent (i.e., include more than one formal negative charge), such as divalent or trivalent. Illustrative examples of counterions include ions (e.g., F, Cl ^- , Br ^- , I ^- ), NO ^- , ClO ₄ ^- , OH ^- , H ₂ PO ₄ ^- , HSO ₄ ^- , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate and the like), BF ₄ ^- , PF ₄ ^- , PF ^- , AsF ^- , SbF ₆ ^- . B[ _3,5- ( _CP3 ) _2C6H3 ] ₄ ] ^- , _BPh4- ^, Al( _OC ( _CP3 ) ₃ ) _4- ^, _{and a} carborane anion (e.g., _CB11H12- or ( _HCB11Me5Br6 ) ^- ₎ . Illustrative examples of counterions that may _be polyvalent include _CO32- , ^{HPO42- ,} _PO43- ^{, B4O72-} _, ^SO42- _, ^S2O32- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, _suberate , azelate, sebacate, salicylate, phthalates, aspartate, glutamate, ^etc. ₎ , and carboranes _.

[124] The term "halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br), or iodine (iodine, -I).

[125] “Acyl” refers to a moiety selected from the group consisting of C(=O)R ^aa , -CHO, -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C(=NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -C(=O)NR ^bb SO ₂ R ^aa , -C(=S)N(R ^bb ) ₂ , -C(=O)SR ^aa or -C(=S)SRm, wherein R ^aa and R ^bb are as defined herein.

[126] Nitrogen atoms may be substituted or unsubstituted, as valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Examples of substituents on the nitrogen atom include, but are not limited to, hydrogen, -OH, -OR ^aa , -N(r ^cc ) ₂ , -CN, C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^bb )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc )2, -SO ₂ N(RCO) ₂ , -SO ₂ RCO, -SO ₂ ORCO, -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SR ^cc , -C(=S)SR ^cc , -P(=O)(OR ^cc ) ₂ , -P(=O)(R ^aa ) ₂ ,-P(=O)(N(R ^cc ) ₂ ) ₂ , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, or two R ^cc groups attached to a nitrogen atom are joined to form a 3-14 membered heterocyclyl or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined above.

[127] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Protecting groups for nitrogen include, but are not limited to, -OH, -ORm, -N(R ^cc ) ₂ , -C(=O)R ^aa , -C(=O)N(R ^cc ) ₂ , -CO ₂ R ^aa , -SO ₂ R ^aa , -C(=NR ^cc )R ^aa , -C(=NR ^cc )OR ^aa , -C(=NR ^cc )N(R ^cc ) ₂ , -SO ₂ N(R _cc ) ₂ , -SO ₂ R ^cc , -SO ₂ OR ^cc , -SOR ^aa , -C(=S)N(R ^cc ) ₂ , -C(=O)SRCO, -C(=S)SR ^cc , C _1-10 alkyl, ap-C _1-10 alkyl, heteroar-C _1-10 alkyl, C _1-10 alkenyl, C _1-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

[128] Examples of substituents on an oxygen atom include, but are not limited to, -R ^aa ,

-C(=O)SR ^aa , -C(=O)R ^aa , -CO ₂ R ^aa , -C(=O)N(R ^bb ) ₂ , -C(=NR ^bb )R ^aa , -C( =NR ^bb )OR ^aa , -C(=NR ^bb )N(R ^bb ) ₂ , -S(=O)R ^aa , -SO ₂ R ^aa , -Si(R ^aa ) ₃ , -P(R ^cc ) ₂ , -P(R ^cc ) ₃ ⁺ X ^- , -P(OR ^cc ) ₂ , -P(OR ^cc ) ₃ ⁺ X ^- , -P(=O)(R ^aa ) ₂ ,-P(=O) (OR ^cc ) ₂ and -P(=O)(N(R ^bb ) ₂ ) ₂ , where X ^- , R ^aa , R ^bb and R ^cc are as defined herein. In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a "hydroxy protecting group"). Oxygen protecting groups are well known in the art and include groups described in detail in Protective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Illustrative examples of oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc., acetals or ketals such as tetrahydropyranyl ( THP), esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, etc., carbonates, sulfonates such as methanesulfonate (mesylate), benzylsulfonate (Ts), etc.

[129] The term "leaving group" has its usual meaning in the field of synthetic organic chemistry, for example, it can refer to an atom or group that can be displaced by a nucleophile. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pyxyl, and haloformates.

[130] The term "pharmaceutically acceptable salt" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like and are proportionate to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

[131] The term "tautomers" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction to form a tautomeric pair) can be acid-catalyzed or base-catalyzed. Examples of tautomerization include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(another enamine) tautomerization.

[132] As used herein, the term "subject" (alternatively referred to herein as "subject") refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation, or experiment.

[133] As used herein, the terms "treat," "treating," "treatment," and the like refer to the elimination, reduction, or alleviation of a disease or condition and/or symptoms associated therewith. Although not excluded, treatment of a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. As used herein, the terms "treat," "treating," "treatment," and the like may include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or condition or relapse of a previously controlled disease or condition in a subject who is not ill but is at risk or predisposed to recurrence of the disease or condition or relapse of the disease or condition. The term "treat" and synonyms include the administration of a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

Examples

[134] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be accomplished using conventional techniques such as melting point determination, mass spectra, nuclear magnetic resonance, and various other spectroscopic analyses. Illustrative embodiments of steps for performing the synthesis of the products described herein are described in more detail below.

Example 1. Synthesis of compound 1

[135] Stage 1:

[136] A mixture of 4,6-dichloropyrimidin-5-amine (8.15 g, 50 mmol), cyclopropylboronic acid (21.5 g, 250 mmol), K ₃ PO ₄ (31.8 g, 150 mmol), Pd ₂ (dba) ₃ (4.6 g, 5 mmol), and Sphos (4.1 g, 10 mmol) in toluene (180 mL) and water (20 mL) was stirred at 95 °C under nitrogen atmosphere for 30 min. The reaction mixture was cooled to room temperature and then washed with water. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate=4/1) to give 1-1.

[137] Step 2: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol) in dichloromethane (100 mL) at room temperature were added oxalyl chloride (11 g, 88 mmol) and 15 drops of dry DMF. After 30 min, the resulting solution was concentrated to give a residue, which was dissolved in dioxane (40 mL). 100 mL of ammonia (28% NH ₃ in water) was added dropwise at 0 °C, and the reaction mixture was allowed to stir for an additional 10 min, filtered, and washed with water. The filter cake was collected and freeze-dried to give 1-2.

[138] Step 3: A solution of 1-2 (550 mg, 2.44 mmol) in DCE (5 mL) was treated with oxalyl chloride (464.5 mg, 3.66 mmol). The mixture was stirred for 45 min at 80 °C and then concentrated. The residue was dissolved in acetonitrile (5 mL) and cooled to -10 °C, and a solution of 1-1 (1 g, 5.86 mmol) in acetonitrile (5 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1/9 to 1/3) to give 1-3.

[139] Step 4: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL) at -20 °C was added KHMDS (5 mL, 1 M in THF, 5.0 mmol). The resulting mixture was then stirred at room temperature for 2 h. The reaction was quenched with sat. NH ₄ Cl (aq.) and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1/9 to 2/1) to afford 1-4.

[140] Step 5: A mixture of 1-4 (250 mg, 0.64 mmol), DIEA (107.6 mg, 0.83 mmol), and _POCl3 (117.9 mg, 0.77 mmol) in MeCN (3 mL) was stirred at 80 °C for 30 min. The reaction mixture was cooled to -10 °C and DIEA (248.4 mg, 1.92 mmol) was added followed by the dropwise addition of a solution of tert-butyl (3S)-3-methylpiperazine-1-carboxylate (384.9 mg, 1.92 mmol) in MeCN (1 mL). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with ice and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=1/4 to 1/1) to give 1-5.

[141] Step 6: A mixture of 1-5 (100 mg, 0.18 mmol), 2-fluorophenylboronic acid (48.9 mg, 0.35 mmol), KOAc (85.7 mg, 0.87 mmol), and Pd(dppf)Cl2 (12.8 mg, 0.017 mmol) in 1,4-dioxane (2 mL) and _H2O (3 drops) was stirred at 90 °C for 1.5 h under N2. The mixture was cooled and extracted with EtoAc. The combined organic layers were dried over anhydrous _Na2SO4 and concentrated. The residue was purified by preparative TLC (CH2Cl2/ _MeOH =15/1) to afford 1-6.

[142] Step 7: A solution of 1-6 (70 mg, 0.11 mmol) and HCl in 1,4-dioxane (4 M, 1 mL, 4 mmol) in DCM (2 mL) was stirred at 0 °C for 2 h. The mixture was then concentrated to give a residue, which was dissolved in DCM (3 mL). DIEA (171.7 mg, 1.33 mmol) was added at 0 °C followed by the dropwise addition of acryloyl chloride (10.2 mg, 0.11 mmol) in DCM (1 mL). The mixture was stirred at 0°C for 10 min and then concentrated to give a residue which was purified _by preparative HPLC (aqueous _NH4HCO3 (10 mM) with acetonitrile (30%-54%)) to give compound 1 (30 mg). LCMS (PER, m/z): [M+H] ⁺ = 586.3; NMR (300 MHz, DMSO-d ₆ , ppm): δ 8.73 (s, 1H), 8.47 (s, 1H), 7.55 (m, 1H), 7.40-7.28 (m, 3H), 6.87 (m, 1H), 6.24-6.18 (m, 1H), 5.78 (dd, J= 10.4, 2.4 Hz, 1H), 4.98 (br. s, 1H), 4.43-4.03 (m, 3H), 3.90-3.70 (m, 1H), 3.66-3.44 (m, 1H), 3.27-3.08 (m, 1H), 1.85-1.68 (m, 2H), 1.35 (d, J=6.7 Hz, 3H), 0.97-0.81 (m, 8H). FNMR (282 MHz, DMSO- _d6 , ppm): δ-113.10 (1F).

Example 2. Synthesis of compound 42

[143] Step 1: To a stirred solution of tert-butyl (2S,5R)-2,5-dimethylpiperazine-1-carboxylate (2.14 g, 10 mmol) and acryloyl chloride (990 mg, 11 mmol) in THF (30 mL) was added a solution of triethylamine (3.03 g, 30 mmol) in THF (10 mL) at -10 °C under N ₂ atmosphere. The mixture was allowed to gradually warm to room temperature and stirred for 0.5 h. Then the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1/10) to give 42-1.

[144] Step 2: To a solution of 42-1 (804 mg, 3 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1.5 h and then concentrated to give 42-2.

[145] Step 3: To a solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol) in acetonitrile (20 mL) was added POCl3 (367 mg, 2.4 mmol) dropwise at room temperature. The mixture was stirred at 80 °C for 2 h. The mixture was then cooled to -10 °C and treated with DIEA (3.87 g, 30 mmol), followed by the addition of a solution of 42-2 (1.58 g, 4 mmol) in acetonitrile (10 mL). The mixture was stirred at room temperature for 1 h, then diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (DCM to DCM/MeOH=10/1) to give 42-4.

[146] Step 4: A mixture of 42-4 (104 mg, 0.2 mmol), (2-fluorophenyl)boronic acid (42 mg, 0.3 mmol), potassium acetate (157 mg, 1.6 mmol), and [1,1''-bis(diphenylphosphino)ferroceno]dichloropalladium(II) (15 mg, 0.02 mmol) in 1,4-diocean (3 mL) and water (3 drops) was stirred at 90 °C for 3 h under nitrogen. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (acetonitrile, 0.05% TFA in water: 25% to 95%) to give compound 42 (58 mg). LCMS (ESI, m/z): [M+H] ⁺ = 584.1; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.73 (s, 1H), 8.33-29 (m, 1H), 7.58-7.51 (m, 1H), 7.40-7.29 (m, 3H), 6.87-6.74 (m, 1H), 6.17-6.13 (m, 1H), 5.74-5.69 (m, 1H), 4.91-4.72 (m, 1.5H), 4.51-4.43 (m, 0.5H), 4.20-4.12 (m, 1.5H), 3.82-3.77 (m, 2H), 3.49-3.45 (m, 0.5H), 1.73-1.66 (m, 2H), 1.30-1.15 (m, 6H), 0.99-0.72 (m, 8H). FNMR (376 MHz, DMSO-4, ppm): 5 -113.32 (1F), -128.68 (1F).

Example 3. Synthesis of compound 13

[147] Step 1: To a sealed 250 mL tube were added 2,6-dimethylheptane-3,5-dione (10 g, 64.0 mmol), urea (7.69 g, 128.0 mmol), EtOH (120 mL), and conc. HCl (50 mL) at room temperature. The resulting mixture was stirred at 100 °C for 18 h. The mixture was cooled to room temperature and concentrated. Water and ethyl acetate were added, and the organic layer was separated, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 13-1.

[148] Step 2: To a stirred solution of 13-1 (8.40 g, 46.6 mmol) in conc. H ₂ SO ₄ (100 mL) was added fuming HNO ₃ (11.75 g, 186.4 mmol) dropwise at room temperature. The resulting mixture was stirred at 65 °C for 6 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 13-2.

[149] Step 3: To a stirred solution of 13-2 (4 g, 17.8 mmol) and K ₂ CO ₃ (4.9 g, 35.5 mmol) in acetone (80 mL) was added 2-bromo-N,N-dimethylethane-1-amine hydrobromide (4.96 g, 21.3 mmol) in portions at room temperature. The resulting mixture was stirred at 60 °C for 16 h under nitrogen, cooled to room temperature, and concentrated. The residue was diluted with water and extracted with DCM/MeOH (10/1). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to give 13-3.

[150] Step 4: A mixture of 13-3 (300 mg, 1.0 mmol), 10% Pd/C (38.1 mg), and MeOH (10 mL) was stirred at room temperature under H ₂ overnight. The resulting mixture was filtered, and the filtrate was concentrated to give 13-4.

[151] Following similar steps in Example 1 for the synthesis of 13. LCMS (ESI, m/z): [M+H] ⁺ =677.4; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.48 (s, 1H), 7.60-7.44 (m, 1H), 7.32 (m, 2H), 7.20 (t, J=6.7 Hz, 1H), 6.98-6.79 (m, 1H), 6.22 (d, J=15.6 G tz, 1H), 5.78 (d, J=10.2 Hz, 1H), 4.98 (br. s, 1H), 4.50-4.28 (m, 4H), 4.21-4.03 (m, 1H), 3.90-3.60 (m, 2H), 3.30-3.20 (m, 1H), 2.71-2.59 (m, 4 N), 2.21 (s, 6H), 1.35 (d, J=6.6 Hz, 3H), 1.06 (d, J=6.5 Hz, 6H), 0.91 (d, J=6.4 Hz, 6H). FNMR (282 MHz, DMSO-d ₆ , ppm): 5 -114.70 (1F).

Example 4. Synthesis of compound 8

[152] Step 1: A mixture of 8-3 (350 mg, 0.82 mmol), (2-fluorophenyl)boronic acid (172 mg, 1.23 mmol), potassium acetate (640 mg, 6.56 mmol), and [1,1'-bis(diphenylphosphino)ferroceno]dichloropalladium(II) (58 mg, 0.08 mmol) in 1,4-dioxane (7 mL) and water (0.2 mL) was stirred at 90 °C for 2 h under nitrogen. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 2/1) to give 8-4.

[153] Step 2: To a solution of 8-4 (82 mg, 0.17 mmol) and DIEA (360 mg, 2.8 mmol) in acetonitrile (3 mL) was added _POCl3 (135 mg, 0.88 mmol) dropwise at room temperature. The reaction mixture was heated at 80 °C for 30 min, cooled to -10 °C and DIEA (129 mg, 1 mmol) was added, followed by the addition of a solution of 8-1 (118 mg, 0.26 mmol) in acetonitrile (2 mL). The mixture was stirred at room temperature for 1 h, diluted with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative HPLC (acetonitrile, 0.05% TFA in water: 5% to 65%) to give compound S (26.2 mg). LCMS (ESI, m/z): [M+H] ⁺ = 620.1; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.44-8.42 (m, 1H), 7.52-7.46 (m, 1H), 7.31-7.25 (m, 2H), 7.18-7.14 (m, 1H), 6.85-6.81 (m, 1H), 6.20-6, 16 (m, 1H), 5.73 (dd, J=10.4, 2.4 Hz, 1H), 4.94 (br. s, 1H), 4.34-4.24 (m, 2H), 4.12-3.99 (m, 1H), 3.84 (s, 3H), 3.55-3.43 (m, 2H), 3.24-3.08 (m, 1H), 2.60-2.58 (m, 2H), 1.31 (d, J=6.4 Hz, 3H), 1.02 (d, J=6.8 Hz, 6H), 0.87 (d, J=6.4 Hz, 6H). FNMR (376 MHz, DMSO-d ₆ , ppm): 5 -114.78 (1F).

Example 5. Synthesis of compound 6

[154] Step 1: To a solution of 13-2 (7 g, 31 mmol) in trichlorophosphate (40 mL) was added DMF (0.4 g, 5.6 mmol). The mixture was stirred at 105 °C for 0.5 h, cooled and concentrated. The crude residue was diluted with ethyl acetate and ice water. The organic layer was separated and dried over sodium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford 6-1.

[155] Step 2: A mixture of 6-1 (0.95 g, 3.7 mmol) and ammonia (8 mL) in tetrahydrofuran (40 mL) was stirred at room temperature for 20 h. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 6-2.

[156] Step 3: A mixture of 6-2 (1.1 g, 4.9 mmol), di-tert-butyl dicarbonate (3.2 g, 14.7 mmol), and 4-dimethylaminopyridine (0.6 g, 4.9 mmol) in tetrahydrofuran (30 mL) was heated under reflux for 0.5 h. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford 6-3.

[157] Step 4: A mixture of 6-3 (1.7 g, 4 mmol), ammonia (0.05 mL), and 10% Pa/C (400 mg) in methanol (40 mL) was stirred at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to give 6-4.

[158] Step 5: To a solution of 6-6 (50 mg, 0.062 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The mixture was stirred for 1 h, concentrated and purified by preparative HPLC (acetonitrile, 0.05% TFA in water: 25% to 95%) to give compound 6 (17.8 mg). LCMS (ESI, m/z): [M+H] ⁺ = 605.1; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.41-8.39 (m, 1H), 7.53-7.47 (m, 1H), 7.32-7.26 (m, 2H), 7.21-7.17 (m, 1H), 6.85-6.81 (m, 1H), 6.20-6.15 (m, 1H), 5.73 (dd, J=10.4, 2.4 Hz, 1H), 4.92 (br s, 1H), 4.34-4.23 (m, 2H), 4.13-3.98 (m, 1H), 3.58-3.43 (m, 2H), 3.24-3.08 (m, 1H), 2.50-2.48 (m, 2H), 1.29 (d, J=6.8 Hz, 3H), 0.98 (d, J=6.4 Hz, 6H), 0.83 (d, J=6.8 Hz, 6H). FNMR (376 MHz, DMSO- _d6 , ppm): δ -114.67 (1F).

Example 6. Synthesis of compound 20

[159] Step 1: To a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (2.4 g, 12.5 mmol) in ethanol (50 mL) was added tin dichloride (8.3 g, 43.7 mmol), and the reaction mixture was heated at 80 °C for 4 h. The reaction mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 5/1) to afford 20-1.

[160] Step 2: To a mixture of 20-1 (1.8 g, 8.6 mmol), cyclopropylboronic acid (3.7 g, 42.8 mmol), potassium phosphate (6.5 g, 30.2 mmol), and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (705 mg, 1.72 mmol) in toluene (60 mL) and _H2O (20 mL) was added tris(dibenzylideneacetone)dipalladium (789 mg, 0.86 mmol) under _N2 . The reaction mixture was stirred at 95 °C for 3 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate=5/1) to give 20-2.

[161] Step 3: To a solution of 20-2 (1.4 g, 6.3 mmol) in dichloromethane (70 mL) was added 3-chloroperoxybenzoic acid (3.3 g, 19.0 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 2/1) to give 20-3.

[162] Step 4: To a solution of 2-(dimethylamino)ethanol (1.5 g, 18 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (1.4 g, 36 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min, and 20-3 (1.4 g, 5.5 mmol) was added. After stirring for 3 h at room temperature, the mixture was quenched with water and concentrated. The residue was purified by preparative HPLC (acetonitrile, 0.05% TFA in water: 5% to 25%) to afford 20-4 as the TFA salt.

[163] Following similar steps in Example 1 and Example 4 for the synthesis of 20, LCMS (ESI, m/z): [M+H] ⁺ =673.1; NMR (400 MHz, DMSO-d ₆ , ppm): δ 9.46 (br s, 1H), 8.42 (s, 1H), 7.54-7.52 (m, 1H), 7.34-7.29 (m, 3H), 6.85-6.78 (m, 1H), 6.17 (d, J=16.8 Hz . J=4.4 Hz, 6H), 1.71-1.67 (m, 2H), 1.31 (d, J=6.8 Hz, 3H), 1.08-0.80 (m, 8H). FNMR(376 MHz, DMSO-d ₆ , ppm): δ -113.43 (1F).

Example 7. Synthesis of compound 33

[164] Step 1: To a mixture of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (2.4 g, 10 mmol), cyclopropylboronic acid (3.7 g, 42.8 mmol), sodium carbonate (3.2 g, 30.2 mmol) in toluene (60 mL) and H ₂ O (20 mL) was added Pd(PPh ₃ ) ₄ (1.1 g, 1.0 mmol) under N ₂ . The reaction mixture was stirred at 95 °C for 3 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 6/1) to give 33-1.

[165] Step 2: To a solution of 33-1 (2.0 g, 8.0 mmol) in dichloromethane (80 mL) was added 3-chloroperoxybenzoic acid (3.5 g, 20.0 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 4/1) to give 33-2.

[166] Step 3: To a solution of 33-2 (940 mg, 5.0 mmol) and DIEA (1.29 g, 10.0 mmol) in tetrahydrofuran (12 mL) was added N,N-dimethylethylenediamine (510 mg, 5.8 mmol), and the mixture was stirred at room temperature for 2 hours. Then, the reaction solution was concentrated, and the residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 2/1) to give 33-3.

[167] Step 4: A mixture of 33-3 (700 mg, 3.6 mmol) and Zn powder (1.3 g, 20.0 mmol) in ethanol (20 mL) and saturated NH ₄ Cl solution (3.0 mL) was stirred at 85 °C for 4 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 1/1) to give 33-4.

[168] Following similar steps in Example 1 and Example 4 for the synthesis of 33, LCMS (ESI, m/z): [M+H] ⁺ = 656.2; HNMR (400 MHz, methanol-d ₆ ppm): δ 8.25-8.20 (m, 1H), 7.53 - 7.51 (m, 1H), 7.48-7.44 (m, 1H), 7.27-7.19 (m, 2H), 6.83-6.81 (m, 1H), 6.26 (dd, J=16.8, 3.2 Hz, 1H), 5.79 (dd, J=10.8, 1.6 Hz, 1H), 5.10-5.00 (m, 1H), 4.49-4.43 (m, 2H), 4.20-4.04 (m, 1H), 3.82-3.80 (m, 1H), 3.73-3.65 (m, 2H), 3.64-3.52 (m, 1H), 3.41-3.31 (m, 3H), 2.89 (s, 6H), 1.62-1.50 (m, 2H), 1.45 (d, J=6.0 Hz, 3H), 1.05-1.01 (m, 4H), 0.88-0.73 (m, 4H ). FNMR (376 MHz, methanol, d.): δ -115.0 (1F), -129.2 (1F).

Example 8. Synthesis of compound 26

[169] Following similar steps in Example 1 to synthesize 26-1.

[170] Step 1: To a solution of 26-1 (500 mg, 0.75 mmol) in dichloromethane (8 mL) was added 3-chloroperoxybenzoic acid (260 mg, 1.5 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/dichloromethane = 1/1 to ethyl acetate) to give 26-2.

[171] Step 2: To a solution of 26-2 (300 mg, 0.43 mmol) in DMSO (4 mL) was added NaCN (106 mg, 2.2 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 18 h. After that, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to give 26-3.

[172] Following a similar step in Example 1 for the synthesis of 26. LCMS (PER, m/z): [M+H] ⁺ = 595.3; NMR (300 MHz, DMSO-d ₆ , ppm): δ 8.43-8.35 (m, 1H), 7.62-7.57 (m, 1H), 7.44-7.27 (m, 3H), 6.95-6.81 (m, 1H), 6.21 (d, J=17.0 Hz, 1H), 5.7 8 (dd, J=10.4, 2.4 Hz, 1H), 4.98 (lat s, 1H), 4.39-4.32 (m, 2H), 4.19-4.03 (m, 1H), 3.85-3.78 (m, 1H), 3.70-3.42 (m, 1H), 3.25-3.11 (m, 1H), 1.98-1.85 (m, 2H), 1.35 (d, J=6.7 Hz, 3H), 1.15-0.90 (m, 8H). FNMR (282 MHz, DMSO- _d6 , ppm): δ -113.63 (1F), -128.34 (1F).

Example 9. Synthesis of compound 71

[173] Step 1: To a solution of 5-nitro-1,3-benzothiazole (8.0 g, 44.4 mmol) in tetrahydrofuran (50 mL) was added a solution of isopropyl magnesium bromide in tetrahydrofuran (2 M, 24.4 mL, 48.8 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then, DDQ (12.1 g, 53.2 mmol) in tetrahydrofuran (10 mL) was added thereto. The resulting mixture was stirred at 0 °C for 1 h and at room temperature for additional 2 h. The mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give 71-1.

[174] HNMR (300 MHz, DMSO-d ₆ , ppm): δ 9.62 (s, 1H), δ 27 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 3.56-3.47 (m, 1H), 1.54 (d, J = 6.9 Hz, 6H).

[175] Step 2: A mixture of 71-1 (79 mg, 0.35 mmol), NH ₄ Cl (189 mg, 3.5 mmol), Zn (231 mg, 3.5 mmol) in MeOH (100 mL) and H ₂ O (10 mL) was stirred at 55 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The combined organic layers were concentrated to give a residue which was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give 71-2.

[176] Following similar steps in Example 1 for the synthesis of 71. LCMS (ESI, m/z): [M+H] ⁺ = 603.3; NMR (300 MHz, DMSO-d ₆ , ppm): δ 9.42 (s, 1H), 8.46-8.42 (m, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.52-7.42 (m, 1H), 7.32-7.12 (m, 4H), 6.97-6.81 (m, 1H), 6.25-6.19 (d, J=17.4 Hz, 1H), 5.79 (dd, J=10.2, 2.4 Hz, 1H), 5.05-4.85 (m, 1H), 4.45-4.00 (m, 3H), 3.90-3.40 (m, 2H), 3.00-3.30 (m , 1H), 2.99-2.85 (m, 1H), 1.44-1.26 (m, 9H). FNMR (282 MHz, DMSO- _d6 , ppm): δ -114.01 (1F).

Example 10. Synthesis of compound 68

[177] Step 1: A solution of 71-2 (2.0 g, 10.6 mmol) in HOAc (40 mL) was added _Br2 (1.7 g, 10.6 mmol) at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The mixture was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 99/1) to give 68-1.

[178] Step 2: To a solution of 71-2 (2.4 g, 8.8 mmol) in 20 mL of 1,4-dioxane/H ₂ O (5/1) were added trimethyl 1,3,5,2,4,6-trioxatriborinane (2.2 g, 17.6 mmol), Na ₂ CO ₃ (2.35 g, 22.1 mmol), and Pd(PPh ₃ ) ₄ (1.0 g, 0.89 mmol). The resulting mixture was stirred at 100 °C for 5 h under N2. After cooling to room temperature, the mixture was washed with water and then extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO ₄ . concentrated and purified by preparative TLC (petroleum ether/ethyl acetate = 5/1) to give 68.

[179] Following similar steps in Example 1 for the synthesis of 68. LCMS (ESI, m/z): [M+H] ⁺ = 617.1; NMR (300 MHz, DMSO-d ₆ , ppm): δ 9.33 (s, 1H), 8.49 (s, 1H), 7.95 (d, J=0.9 Hz, 1H), 7.51-7.44 (m, 1H), 7.31-7.16 (m, 3H), 6.98-6.81 (m, 1 H), 6.22 (d, J=16.7 Hz, 1H), 5.78 (dd, J=10.2, 2.4 Hz, 1H), 4.97 (lat s, 1H), 4.49-4.28 (m, 2H), 4.25-4.02 (m, 1H), 3.87 - 3.45 (m, 2H), 3.22-3, 05 (m, 1H), 3.02-2.88 (m, 1H), 2.05-1.98 (m, 1H), 1.42-1.32 (m, 6H), 1.27 (dd, J=6.9, 1.8 Hz, 3H). FNMR (282 MHz, DMSO- _d6 , ppm): δ -114.35 (1F).

Example 11. Synthesis of compound 70

[180] Step 1: To a stirred mixture of 2,6-dibromo-3-nitropyridine (50 g, 177 mmol) and _Na2CO3 (37.6 g, 355 mmol) in EtOH (500 mL) was added a solution of _CH3NH2 in THF (107 _mL , 214 mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. _The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a solid, which was recrystallized from ethyl acetate/petroleum ether (10/1) to give 70-1.

[181] Step 2: To a solution of 70-1 (10 g, 43 mmol) and XantPhos Pd G3 (408 mg, 0.43 mmol) in THF (100 mL) was added a solution of chapropyloyl zinc bromide in THF (0.5 M, 33 mL, 66 mmol) dropwise at room temperature. The resulting mixture was stirred at 30 °C for 3 h under argon atmosphere. The reaction was quenched with saturated aqueous NH ₄ Cl solution at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1) to give 70-2.

[182] Step 3: To a solution of 70-2 (1.5 g, 7.7 mmol) in DMF (15 mL) was added NBS (1.64 g, 9.2 mmol) in DMF (15 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 2 h, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated to give a residue which was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 70-3.

[183] Step 4: A mixture of 70-3 (1.5 g, 5.5 mmol), NH4Cl (2.34 g, 43.7 mmol), and Zn (1.8 g, 27.4 mmol) in methanol (15 mL)/ _H2O (8 mL) was stirred at 60 °C for 2 h. The mixture was filtered, concentrated to remove methanol, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered, and concentrated to give 70-4.

[184] Step 5: A solution of 70-4 (1.2 g, 4.9 mmol) in formic acid (10 mL) was stirred at 100 °C overnight. It was then cooled, diluted with water, and neutralized to pH 7 with NaOH. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to give 70-5.

[185] Step 6: A mixture of 70-5 (2.9 g, 11.4 mmol) and Cu (362 mg, 5.7 mmol) in ammonia (40 mL) was stirred at room temperature for 0.5 h and then stirred at 100 °C overnight. The resulting mixture was extracted with ethyl acetate, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 3/1) to give 70-6.

[186] Following similar steps in Example 1 for the synthesis of 70. LCMS (ESI, m/z): [M+H] ⁺ = 601.4; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.51-8.39 (m, 2H), 7.92-7.88 (m, 1H), 7.53-7.45 (m, 1H), 7.35-7.12 (m, 3H), 6.94-6.81 (m, 1H), 6.23 (d, J=16.4 Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 5.10-4.85 (m, 1H), 4.45-4.00 (m, 3H), 3.83 (s, 3H), 3.73-3.60 (m, 1H), 3.55-3.40 (m, 1H), 3.15-3.05 (m, 1H), 2.85-2.75 (m, 1H), 1.35 (dd, J=13.1, 6.6 Hz, 3H), 1.16 (d, J=6.7 Hz, 3H), 1.06 (dd, J=6.7, 2.3 Hz, 3H). FNMR (376 MHz, DMSO-d ₆ , ppm): δ-114.16 (1F).

Example 12. Synthesis of compound 65

[187] Step 1: To a solution of 70-6 (30 mg, 1.57 mmol) in HOAc (15 mL) and CHCl ₃ (6 mL) was added Br ₂ (252 mg, 1.57 mmol) in HOAc (1 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 0.5 h and then quenched with saturated NaHCO 3 solution. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated and purified by flash column chromatography on silica gel (ether/ethyl acetate = 1/9) to give 65-1.

[188] Step 2: A mixture of 65-1 (200 mg, 0.74 mmol), trimethyl 1,3,5,2,4,6-trioxatriborinane (559 mg, 4.45 mmol), Pd(PPh ₃ ) ₄ (85 mg, 0.074 mmol), Na ₂ CO ₃ (196 mg, 1.85 mmol) and dioxane/H ₂ O (5/1, 2 mL) was stirred at 110 °C for 3 h under nitrogen atmosphere. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 1/1) to give 65-2.

[189] Following similar steps in Example 1 for the synthesis of 65. LCMS (ESI, m/z): [M+H] ⁺ = 615.3, HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.48-8.47 (m, 1H), 8.33 (s, 1H), 7.49-7.46 (m, 1H), 7.30-7.17 (m, 3H), 6.94-6.83 (m, 1H), 6.24-6.19 (m, 1H), 5.79-5.76 (m, 1H), 4.97 (br s, 1H), 4.44-4.32 (m, 2H), 4.19-4.04 (m, 1H), 3.90-3.46 (m, 5H), 3.16-3.10 (m, 1H), 2.78-2.76 (m, 1H), 2.21-2.15 (m, 3H), 1.35 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.02 (dd, J=6.4, 1.8 Hz, 3). FNMR (376 MHz, DMSO-d ₆ , ppm): δ -114.52 (1F).

Example 13. Synthesis of compound 72

[190] Step 1: To a solution of N ¹ -methyl-4-nitrobenzene-1,2-diamine (25 g, 149 mmol) and trimethyl orthoformate (200 mL) in DMF (300 mL) was added conc. HCl (16 mL) dropwise at room temperature. After stirring at room temperature overnight, the mixture was concentrated. The residue was dissolved in ethyl acetate. The mixture was basified with Et ₃ N. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue which was purified by flash column chromatography on silica gel (dichloromethane/methanol = 12/1) to give 72-1.

[191] Step 2: To a solution of 72-1 (32 g, 180 mmol) in tetrahydrofuran (80 mL) was added i-PrMgCl.LiCl (210 mL, 1.3 M in THF, 271 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then DDQ (49.2 g, 216 mmol) in tetrahydrofuran (40 mL) was added. The mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched with water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography to give 72-2.

[192] Step 3: A mixture of 72-2 (7.0 (petroleum ether/ethyl acetate = 4/1) g, 31.9 mmol) and 10% Pd/C (3.4 g) in methanol (30 mL) was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated to give 72-3.

[193] Following similar steps in Example 1 for the synthesis of 72. LCMS (ESI, m/z): [M+H] ⁺ = 600.4; HNMR (300 MHz, DMSO-d ₆ , ppm): δ 8.44-8.36 (m, 1H), 8.15 (s, 1H), 7.48 - 7.43 (m, 1H), 7.41-7.38 (d, J = 8.4 Hz, 1H), 7.27-7.14 (m, 3H), 7.02-6.98 (dd, J = 10.5, 2.1 Hz, 1H), 6.91-6.85 (m, 1H), 6.24-6.19 (d, J = 16.2 Hz, 1H), 5.79-5.75 (dd, J = 12.9, 2.4 Hz, 1H), 4.95-4.85 (m, 1H), 4.36-4.05 (m, 3H), 3.81 (s, 3H), 3.67-3.40 (m, 2H), 3.20-2.90 (m, 1H), 2.75-2.70 (m, 1H), 1.39-1.29 (m, 9H). FNMR (282 MHz, DMSO-d ₆ ppm): δ-114.19 (1F).

Example 14. Synthesis of compound 69

[194] Step 1: To a solution of 4-isopropyl-1-methyl-1,3-benzodiazol-5-amine (6.0 g, 31.7 mmol) in HOAc (20 mL) was added Br ₂ (5.1 g, 31.7 mmol) in HOAc (2 mL) dropwise at 0 °C. After stirring for 1 h, the mixture was concentrated. The residue was partitioned between ethyl acetate and 2 M NaOH. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give 69-1.

[195] Step 2: A mixture of 69-1 (3.8 g, 14.2 mmol), trimethyl 1,3,5,2,4,6-trioxatriborinane (3.6 g, 28.4 mmol), Na ₂ CO ₃ (3.0 g, 28.4 mmol) and Pd(PPh _ρ ) ₄ (1.64 g, 1, 42 mmol) in 30 mL of dioxane/H ₂ O (5/1) was stirred at 100 °C for 5 h under N ₂ atmosphere. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1) to give 69-2.

Method B

[196] Step 1: To a solution of 2-fluoro-4-methylaniline (10.0 g, 79.9 mmol) in H ₂ SO ₄ (100 mL) was added a solution of conc. HNO3 (5.66 g, 87.9 mmol) in H ₂ SO ₄ (11.2 mL) dropwise at 0 °C. After stirring for 3 h at 0 °C, the reaction mixture was poured into ice water (600 mL), and the resulting mixture was made basic by slowly adding NaOH solution (180 g dissolved in 240 mL water). It was then filtered and dried to give 69-3.

[197] Step 2: To a solution of 69-3 (5 g, 29.4 mmol) in DMSO (35 mL) were added CS2CO3 (47.88 g, 146.9 mmol) and methylamine hydrochloride (5.95 g, 88.2 mmol). The mixture was stirred at 120 °C overnight. The mixture was poured into water and the solution was extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 1/4) to give 69-4.

[198] Step 3: To a solution of 69-4 (3.2 g, 15.9 mmol) in toluene (12 mL) were added trimethoxymethane (3.54 g, 33.4 mmol) and 4-methylbenzenesulfonic acid (60.5 mg, 0.35 mmol). The solution was stirred at 100 °C for 2 h under N ₂ . The solvent was removed to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to give 69-5.

[199] Step 4: A mixture of 69-5 (3.2 g, 16.7 mmol) and Pd/C (10%, 300 mg) in MeOH (10 mL) and THF (30 mL) was stirred at room temperature under hydrogen atmosphere for 6 h. It was then filtered and the filtrate was concentrated to give 69-6.

[200] Step 5: To a solution of 69-6 (2.51 g, 15.5 mmol) in HOAc (25 mL) was added bromine (2.5 g, 15.5 mmol). After stirring at room temperature for 1 h, the solution was diluted with H ₂ O and basified to pH 8 with saturated sodium hydrogen carbonate solution. The solution was extracted with ethyl acetate. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a residue which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 to 1/4) to give 69-7.

[201] Step 6: To a mixture of 69-7 (1.6 g, 6.6 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.67 g, 10.0 mmol) and Cs2CO3 (5.41 g, 16.6 mmol) in dioxane (16 mL) and water (3 mL) was added Pd(dppf) _Cl2 (243 mg, 0.33 mmol) under _N2 . The mixture was stirred at 80 °C for 2.5 h under nitrogen. The solution was diluted with ethyl acetate and H ₂ O. The organic layer was dried with Na ₂ SO ₄ and concentrated to give a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1 to 1/3) to give 69-8.

[202] Step 7: A mixture of 69-8 (1.1 g, 5.4 mmol) and Pd/C (10%, 100 mg) in ethyl acetate (10 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. It was then filtered and the filtrate was concentrated to give 69-2.

[203] Following similar steps in Example 1 for the synthesis of 69. LCMS (ESI, m/z): [M+H] ⁺ = 614.1; NMR (300 MHz DMSO-d ₆ , ppm): δ 8.49-8.42 (m, 1H), 8.08 (s, 1H), 7.54-7.41 (m, 1H), 7.33-7.13 (m, 4H), 6.94-6.80 (m, 1H), 6.22 (d, J=16.4 Hz, 1H), 5.78 (dd, J=10.4, 2.4 Hz 1H), 4.92 (br. s, 1H), 4.46-4.04 (m, 3H), 3.78 (s, 3H), 3.70-3.05 (m, 3H), 2.78 (d, J=7.1 Hz, 1H), 1.98 (s, 3H ), 1.43-1.20 (m, 9H). FNMR (282 MHz, DMSO-de, ppm): 5 -114.52 (IF).

Example 15. Synthesis of compound 117

[204] Step 1: To a mixture of 6-bromo-4-methylpyridin-2-amine (10 g, 53.5 mmol), K ₂ CO ₃ (18.5 g, 133.7 mmol), and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (11.7 g, 69.5 mmol) in dioxane (100 mL) and H ₂ O (20 mL) was added Pd(dppf)Cl ₂ (3.91 g, 5.35 mmol) at room temperature under argon. The resulting mixture was stirred at 90 °C for 2 h under argon. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/ ₁ ) to give 117-1.

[205] Step 2: A mixture of 117-1 (6.0 g, 40.5 mmol) and 10% Pd/C (1.2 g) in methanol (60 mL) was stirred at room temperature overnight under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to give 117-2.

[206] Step 3: To a solution of 117-2 (3.0 g, 20 mmol) in H ₂ SO ₄ (35 mL) was added fuming HNO ₃ (4.5 mL, 71 mmol) dropwise at 0 °C. The mixture was stirred at 50 °C for 2 h. The reaction mixture was quenched with ice at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ H, and concentrated to give 117-3.

[207] Step 4: A mixture of 117-3 (3.8 g, 15.75 mmol), 10% Pd/C (1.0 g), and hydrazine hydrate (80%, 3.8 mL) in ethyl alcohol (80 mL) was stirred at 80 °C for 1.5 h under argon. The mixture was filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated to give 117-4.

[208] Step 5: A mixture of 117-4 (2.0 g, 9.47 mmol), HCl in MeOH (1 mL, 4.0 mmol), and triethyl orthoformate (20 mL) was stirred at 120 °C for 2 days under argon. The mixture was concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give 117-5.

[209] Step 6: A mixture of 117-5 (1.1 g, 4.97 mmol) and 10% Pd/C (354 mg) in MeOH (10 mL) and THF (10 mL) was stirred at room temperature overnight under hydrogen atmosphere. The mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to give 117-6.

[210] Following similar steps in Example 1 for the synthesis of 117. LCMS (ESI, m/z): [M+H] ⁺ = 602.4; NMR (300 MHz, DMSO-d ₆ , ppm): δ 8.83 (s, 1H), 8.55-8.45 (m, 1H), 7.54-7.41 (m, 1H), 7.36-7.13 (m, 3H), 6.96-6.80 (m, H), 6.25 (d, J=16.8 G tz, 1H), 5.78 (dd, J=10.4, 2.4 Hz, 1H), 4.99 (br. s, 1H), 4.43-4.33 (m, 2H), 4.25-4.00 (m, 1H), 3.83-3.79 (m, 1H), 3.69-3.44 (m, 1H), 3.27-3.1 2 (m, 1H), 2.84-2.78 (m, 1H), 2.20 (d, J=2.4 Hz, 3H), 1.34 (d, J=6.6 Hz, 3H), 1.10 (d, J=6.6 Hz, 3H), 1.00-0.98 (m, 3H). FNMR (282 MHz, DMSO-d ₆ ppm): δ -114.30 (1F).

Example 16. Synthesis of compound 44

[211] Step 1: To a mixture of 2,6-dichloro-5-fluoronicotinic acid (23 g, 0.11 mol) in dichloromethane (300 mL) was added dimethylformamide (0.2 mL). Oxalyl chloride (33 g, 0.26 mol) was then added slowly over 30 min at room temperature. The mixture was stirred at room temperature for 1 h and then concentrated to give an oil, which was dissolved in dioxane (50 mL). The solution was added to ammonium hydroxide solution (150 mL) at 0 °C over 30 min. The resulting mixture was stirred at 0 °C for 30 min and then filtered. The filter cake was washed with cold water (50 mL) and dried to give 42-5.

[212] Step 2: A solution of 42-5 (11 g, 52.6 mmol) in 1,2-dichloroethane (80 mL) was treated with oxalyl chloride (8.68 g, 68.4 mmol). The mixture was stirred at 80 °C for 45 min, and the reaction mixture was concentrated. The residue was dissolved in acetonitrile (100 mL), cooled to -10 °C, and then a solution of 1-1 (9.6 g, 55.2 mmol) in THF (30 mL) was added. The resulting mixture was stirred at room temperature for 2 h. The solution was diluted with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 4/1) to give 42-6.

[213] Step 3: To a stirred solution of 42-6 (7.9 g, 19.3 mmol) in THF (100 mL) at -20 °C was added KHMDS (38.6 mL, 1 M in THF, 38.6 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 2/1) to afford 42-3.

[214] Step 4: To a solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol) in MeCN (20 mL) was added POl ₃ (367 mg, 2.4 mmol) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 45 min, followed by the addition of DIEA (3.87 g, 30 mmol) and a solution of 42-2 (1.58 g, 4 mmol) in MeCN (10 mL) dropwise at -10 °C. After stirring at room temperature for 1 h, the reaction mixture was quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (dichloromethane to dichloromethane/methanol=10/1) to give 42-4.

[215] Step 5: A mixture of 42-4 (8 mg, 0.15 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (42 mg, 0.18 mmol), Pd(dppf)Cl2 (13 mg, 0.018 mmol) and KOAc (40 mg, 0.41 mmol) in dioxane (3 mL)/ _H2O (1 drop) was stirred at 80 °C for 2 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. _The combined organic layers were dried over anhydrous _Na2SO4 and concentrated. The residue was purified by preparative HPLC (acetonitrile, 0.05% TFA in water (30% to 65%) to give 44. LCMS (PER, m/z): [M+H] ⁺ = 599.1; HNMR (400 MHz, methanol-d ₆ , ppm): δ 8.73 (s, 1H), 8.26-8.22 (m, 1H), 7.15-7.09 (m, 1H), 6.84-6.74 (m, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.42-6.38 (m, 1H), 6.30-6.24 (m, 1H), 5.83-5.78 (m, 1H), 5.01 (br s, 1H), 4.91-4.83 (m, 1H), 4.53-4.29 (m, 2H), 3.96-3.89 (m, 1.5H), 3.54-3.50 (m, 0.5H), 1.82-1.75 (m, 1H), 1.73-1.66 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.37-1.27 (m, 3H), 1.16-1.05 (m, 4H), 1.03-0.97 (m, 2H), 0.88-0.83 (m, 2H). FNMR (376 MHz, methanol-s^, ppm): 5 -114.9 (1F), -125.6 (1F).

Example 17. Synthesis of compound 126

[216] Step 1: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol) in dichloromethane (100 mL) at room temperature were added oxalyl chloride (11 g, 88 mmol) and 15 drops of dry DMF. After 30 min, the resulting solution was concentrated to give a residue, which was dissolved in dioxane (40 mL). 100 mL of ammonia (28% NH ₃ in water) was added dropwise at 0 °C, and the reaction mixture was allowed to stir for an additional 10 min, filtered, and washed with water. The filter cake was collected and freeze-dried to give 1-2.

[217] Step 2: A solution of 1-2 (550 mg, 2.44 mmol) in DCE (5 mL) was treated with oxalyl chloride (464.5 mg, 3.66 mmol). The mixture was stirred at 80 °C for 45 min and then concentrated. The residue was dissolved in acetonitrile (5 mL), cooled to -10 °C, and a solution of 1-1 (1 g, 5.86 mmol) in acetonitrile (5 mL) was added. The resulting mixture was stirred at room temperature overnight and then concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1/9 to 1/3) to give 1-3.

[218] Step 3: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL) at -20 °C was added KHMDS (5 mL, 1 M in THF, 5.0 mmol). The resulting mixture was then stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1/9 to 2/1) to afford 1-4.

[219] Step 4: To a solution of 1-4 (1.0 g, 2.56 mmol) and DIEA (1.32 g, 10.25 mmol) in MeCN (20 mL) was added _POCl3 (790 mg, 5.12 mmol) dropwise at room temperature. The resulting solution was stirred at 80 °C for 45 min, followed by the addition of DIEA (6.62 g, 51.25 mmol) and a solution of 42-2 (1.45 g, 5.12 mmol) in MeCN (5 mL) dropwise at -10 °C. After stirring at room temperature for 1 h, the reaction mixture was then quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 0/1 to 3/1) to give 126-1.

[220] Step 5: A mixture of 126-1 (120 mg, 0.22 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (104 mg, 0.44 mmol), Pd(dppf)Cl ₂ (16 mg, 0.022 mmol) and KOAc (108 mg, 1.11 mmol) in dioxane (3 mL)/H ₂ O (1 drop) was stirred at 80 °C for 2 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative LC-PELC (acetonitrile, 0.05% TFA in water (34% to 45%) to give 126. LCMS (ESI, m/z): [M+H] ⁺ = 615.3; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.74 (s, SH), 8.52-8.35 (m, 1H), 7.16-7.07 (m, 1H), 6.94-6.76 (m, 1H), 6.51 (d, J=6.0 Hz, SH), 6.38 (t, J=6.6 Hz, 1H), 6.20 (dd, J=12.6, 1.8 Hz, 1H), 5.76 (dd, J=12.6, 1.6 Hz, 1H), 4.91-4.80 (m, 2H), 4.51-3.50 (m, 6H), 1.91-1.65 (m, W), 1.45-1.15 (m, 6H), 1.10-0.70 (m, 8H). FNMR. (376 MHz, DMSO-d ₆ , ppm): δ -114.30 (1F).

Example 18. Synthesis of compound 127

[221] Step 1: A mixture of 126-1 (200 mg, 0.37 mmol), 2-fluoro-6-hydroxyphenylboronic acid (115 mg, 0.74 mmol), Pd(dppf)Cl ₂ (27 mg, 0.037 mmol), and KOAc (181 mg, 1.85 mmol) in dioxane (3 mL)/H ₂ O (1 drop) was stirred at 80 °C for 2 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC (acetonitrile 0.05%) TFA in water: 25% to 48%) to give 127. LCMS (ESI, m/z): [M+H] ⁺ = 616.2; НЯМР (300 МГц, ДМСО-d ₆ , м. д.): δ 10,16 (с, 1H), 8,71 (с, 1H), 8,50-8,40 (м, 1Н), 7,31-7,23 (м, 1H), 6,86-6,67 (м, 3Н), 6,20 (д, J=16,5 Гц, 1H), 5,79-5,74 (м, 1H), 4,99-4,78 (м, 1,5Н), 4,55-4,45 (м, 0,5Н), 4,40-4,05 (м, 1,5Н), 3,95-3,68 (м, 2Н), 3,55-3,45 (м, 0,5Н), 1,80-1,60 (m, 2H), 1.34 (s, 3H), 1.30-1.23 (m, 3H), 0.95 (d, J=5.7 Hz, 2H), 0.90 (s, 4H), 0.82 (s, 2H). FNMR (282 MHz, DMSO- _d6 , ppm): δ -115.33 (1F).

Example 19. Synthesis of compound 124

[222] Step 1: To a solution of 8-1 (900 mg, 2.3 mmol) and DIEA (1.2 g, 9.3 mmol) in MeCN (3 mL) was added _POCl3 (707 mg, 4.6 mmol) dropwise at room temperature. The resulting solution was stirred at 80 °C for 45 min, followed by the addition of DIEA (6.62 g, 51.25 mmol) and a solution of 8-1 (889 mg, 5.8 mmol) in MeCN (2 mL) dropwise at -10 °C. After stirring at room temperature for 1 h, the reaction mixture was quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=0/1 to 3/1) to give 124-1.

[223] Step 2: A mixture of 124-1 (170 mg, 0.32 mmol), 3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (153 mg, 0.64 mmol), Pd(dppf)Cl ₂ (36 mg, 0.048 mmol) and KOAc (158 mg, 1.61 mmol) in dioxane (3 mL)/H ₂ O (1 drop) was stirred at 80 °C for 2 h under nitrogen. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC (10 mM aqueous _NH4HCO3 with _acetonitrile (26% to 42%)) to give 124. LCMS (ESI, m/z): [M+H ^]+ = 601.4; HNMR (300 MHz, DMSO-d ₆ , ppm): δ 8.74 (s, 1H), 8.52-8.35 (m, 1H), 7.19-7.07 (m, 1H), 6.86-6.80 (m, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.38 (t, J - 9.0 Hz, 1H), 6.22 (d, J=16.8 Hz, 1H), 5.78 (dd, J=10.5, 2.4 Hz, 1H), 5.22 (br s, 2H), 5.12-4.96 (m, 1H), 4.49-4.29 (m, 1H), 4.20-4.03 (m, 1H), 3.71-3.64 (m, 1H), 3.25-3.17 (m, 1H), 1.90-1.75 (m, 2H), 1.35 (dd, J=23.7, 6.4 Hz, 3H), 1.15-0.75 (m, 8H). FNMR (282 MHz, DMSO- _d6 , ppm): δ -114.17 (1F).

Example 20. Synthesis of Compound 151 and Compound 152

[224] Following similar steps in Example 1 for the synthesis of 151-1, 151-1 (1.7 g) was purified by SFC (Dr. Maisch MIC, 250 × 25 mm, 10 μm, 55% MeOH/CO ₂ , 70 mL/min, 100 bar) to give two peaks: 151-1-P1 (peak 1, 623 mg, 98.1% ee) and 151-1-P2 (peak 2, 756 mg, >99% ee).

[225] Following similar steps in Example 1 for the synthesis of 151. LCMS (ESI, m/z): [M+H] ⁺ = 629.3; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.45-8.40 (m, 1H), 8.07 (s, 1H), 7.27 (s, 1H), 7.01 (dd, J=15.2, 8.0 Hz, 1H), 6.90-6.86 (m, 1H), 6.40 (d, J =8.0 Hz, 1H), 6.34-6.18 (m, 2H), 5.77 (dd, J=10.4, 2.4 Hz, 1H), 5.07-5.02 (m, 2H), 4.92 (s, 1H), 4.44-4.41 (m, 0.5H), 4.32-4.15 (m, 2H), 4.08-4.04 (m, 0.5H), 3.84-3.61 (m, 4.5H), 3.50-3.47 (m, 0.5H), 3.18-3.01 (m, 1H), 2.92-2.86 (m, 0.5H), 2.74-2.70 (m, 0.5H), 2.01 (s, 2H), 1.88 (s, 1H), 1.35-1.18 (m, 9H).

[226] Following similar steps in Example 1 for the synthesis of 152. LCMS (ESI, m/z): [M+H] ⁺ = 629.1; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.40 (s, 1H), 8.06 (s, 1H), 7.27 (s, 1H), 7.01 (dd, J=15.2, 7.9 Hz, 1H), 6.95-6.80 (m, 1H), 6.40 (d, J=8.2 Hz, 1H), 6.29 (t, J=8.8 Hz, 1H), 6.21 (d, J=16.4 Hz, 1H), 5.77 (dd, J=10.4, 2.3 Hz, 1H), 5.04 (s, 2H), 4.89 (s, 1H), 4.47-3.99 (m, 3H), 3.85-3.39 (m, 5H), 3.21-3.01 (m, 1H), 2.91-2.63 (m, 1H), 2.05-1.86 (m, 3H), 1.39-1.14 (m, 9H).

Example 21. Synthesis of compound 157 and compound 158

[227] Step 1: To a mixture of 2-chloro-6-methyl-3-nitropyridine (25 g, 144.5 mmol) and K ₂ CO ₃ (59.8 g, 433.5 mmol) in DMSO (200 mL) was added dropwise methylamine hydrochloride (11.8 g, 173.4 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated to give 157-1.

[228] Step 2: A solution of 157-1 (23.3 g, 139.5 mmol) and N-bromosuccinimide (26 g, 146.5 mmol) in DMF (250 mL) was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to give 157-2.

[229] Step 3: A mixture of 157-2 (32 g, 131 mmol), Zn powder (85 g, 1310 mmol), a solution of NH ₄ Cl (34.7 g, 655 mmol) in water (30 mL) and dichloromethane/methanol (1/1, 150 mL) was stirred at room temperature for 2 h under N ₂ atmosphere.

The mixture was filtered and the filter cake was washed with dichloromethane. The combined filtrates were diluted with water and extracted with _{dichloromethane} . The combined organic layers were washed with brine, dried over anhydrous _Na2SO4 and concentrated to give 157-3.

[230] Step 4: A solution of 157-3 (19.3 g, 89.8 mmol) and p-toluenesulfonic acid monohydrate (1.7 g, 8.97 mmol) in triethyl orthoformate (150 mL) was stirred at 100 °C for 2 h under N ₂ . The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated to give a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/1) to give 157-4.

[231] Step 5: A mixture of 157-4 (11 g, 48.9 mmol), diphenylmethanimine (13.3 g, 73.3 mmol), cesium carbonate (31.9 g, 97.8 mmol), Pd ₂ (dba) ₃ (2.23 g, 2.44 mmol), and Xantphos (2.83 g, 4.88 mmol) in DMF (100 mL) was stirred at 120 °C overnight under N ₂ . The resulting mixture was cooled, diluted with water, and extracted with ethyl acetate. _The combined organic layers were washed with brine, dried over _Na2SO4 and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/5) to give 157-5.

[232] Step 6: To a solution of 157-5 (12.80 g, 39.26 mmol) in dichloromethane (60 mL) was added dropwise a solution of HCl in dioxane (4 M, 30 mL). The mixture was stirred at room temperature for 1 h. Acetonitrile (30 mL) was added to the solution, and it was filtered to give 157-6.

[233] Step 7: To a solution of 157-6 (8.8 g, 54.3 mmol) in acetic acid (150 mL) was added Br ₂ (8.7 g, 54.3 mmol) dropwise. The mixture was stirred at room temperature for 2 h under N ₂ . The resulting solution was adjusted to pH 7-8 with saturated sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 1/5) to give 157-7.

[234] Step 8: A mixture of 157-7 (6.3 g, 26.25 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.93 g, 47.25 mmol), potassium carbonate (9.1 g, 65.6 mmol), and Pd(dppf)Cl ₂ (1.54 g, 2.1 mmol) in 1,4-dioxane (60 mL) and H ₂ O (12 mL) was stirred at 80 °C overnight under N ₂ . The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over _Na2SO4 and concentrated to give _a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give 157-8.

[235] Step 9: A mixture of 157-8 (4.5 g, 22.28 mmol) and 10% Pd/C (0.45 g) in tetrahydrofuran (50 mL) was stirred at room temperature overnight under hydrogen atmosphere. The mixture was filtered and the solid was washed with tetrahydrofuran. The filtrate was concentrated to give 157-9.

[236] Following similar steps in Example 1 for the synthesis of 157-10, 157-10 (1.15 g) was purified by SFC (Dr. Maisch MIC, 250 × 25 mm, 10 cm, 40% EtOH/CO ₂ , 70 mL/min, 100 bar) to give two peaks: 157-10-P1 (peak 1, 523 mg, >99% ee) and 157-10-P2 (peak 2, 578 mg, >99% ee).

[237] Following similar steps in Example 1 for the synthesis of 157. LCMS (ESI, m/z): [M+H] ⁺ = 614.6; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.40-8.25 (m, 2H), 7.06 (dd, J=15.0, 8.1 Hz, 1H), 6.95-6.80 (m, 1H), 6.42 (d, J=8.2 Hz, 1H), 6.37-6.30 (m , 1H), 6.22 (d, J=16.8 Hz, 1H), 5.77 (dd, J=10.4, 2.2 Hz, 1H), 5.29 (s, 2H), 4.95 (s, 1H), 4.45-4.41 (m, 0.5H), 4.31-4.28 (m, 1.5H), 4.17 (d, J=11.6 Hz, 0.5H), 4.04 (d, J=13.0 Hz, 0.5H), 3.81 (s, 3H), 3.75-3.59 (m, 1H), 3.53-3.46 (m, 1H), 3.11 (t, J=11.3 Hz, 1H), 2.85-2.70 (m, 1H), 2.16 (s, 3H), 1.34 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.9 Hz, 3H).

[238] Following similar steps in Example 1 for the synthesis of 158. LCMS (ESI, m/z): [M+H]+=614.2; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.40-8.25 (m, 2H), 7.06 (dd, J=15.0, 8.2 Hz, 1H), 6.94-6.81 (m, 1H), 6.42 (d, J=8.2 Hz, 1H), 6.37-6.31 (m , 1H), 6.21 (dd, J=16.2, 4.6 Hz, 1H), 5.77 (dd, J=10.4, 2.2 Hz, 1H), 5.29 (s, 2H), 4.90 (s, 1H), 4.45-4.41 (m, 0.5H), 4.31-4.28 (m, 1.5H), 4. 17 (d, J=11.6 Hz, 0.5H), 4.04 (d, J=13.0 Hz, 0.5H), 3.81 (s, 3H), 3.72-3.68 (m, 1.5H), 3.49-3.33 (m, 0.5H), 3.12 (t, J=12.0 Hz, 1H), 2.82-2.72 ( m, 1H), 2.15 (s, 3H), 1.35 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.8 Hz, 3H).

Example 22. Synthesis of compound 145 and compound 146

[239] Step 1: To a solution of 1,5-difluoro-2,4-dinitrobenzene (50.0 g, 245 mmol) and DCM (500 mL) was added triethylamine (49.5 g, 490 mmol) at 0 °C followed by the addition of methylamine hydrochloride (16.5 g, 245 mmol) in portions. The resulting solution was stirred at 0 °C for 2 h. Water (1 L) and ethyl acetate (1 L) were added. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/1) to give 145-1.

[240] Step 2: To a solution of 145-1 (34.0 g, 158 mmol) in ethyl acetate (500 mL) was added 10% Pd(OH) ₂ /C (3.4 g). The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere. It was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give 145-2.

[241] Step 3: A mixture of 145-2 (19 g, 122 mmol), triethyl orthoformate (36.1 g, 244 mmol) and p-toluenesulfonic acid monohydrate (2.32 g, 12.2 mmol) in tetrahydrofuran (200 mL) was refluxed for 2 h. The mixture was cooled, diluted with water and extracted with ethyl acetate/tetrahydrofuran (1/1). The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/3) to give 145-3.

[242] Step 4: To a solution of 145-3 (9 g, 54.5 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (9.7 g, 54.5 mmol) portionwise at 0 °C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with water and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 1/2) to give 145-4.

[243] Step 5: A mixture of 145-4 (5.95 g, 23.4 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.14 g, 36.6 mmol), potassium carbonate (8.07 g, 58.5 mmol), and Pd(dppf)Cl2 (1.71 g, 2.34 mmol) in dioxane (60 mL) and _H2O (12 mL) was stirred at 90 °C overnight under argon. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over _Na2SO4 and concentrated to give a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate=1/1) to give 145-5.

[244] Step 6: A mixture of 145-5 (2.53 g, 12.3 mmol) and 10% Pd/C (0.25 g) in tetrahydrofuran (50 mL) was stirred at room temperature overnight under hydrogen atmosphere. The mixture was filtered and the solid was washed with tetrahydrofuran. The filtrate was concentrated to give 145-6.

[245] Following similar steps in Example 1 for the synthesis of 145-7, 145-7 (1.08 g) was purified by SFC (Dr. Maisch MIC, 250 × 25 mm, 10 μm, 50% MeOH/CO ₂ , 80 mL/min, 100 bar) to give two peaks: 145-7-P1 (peak 1, 600 mg, >99% ee) and 145-7-P2 (peak 2, 326 mg, >99% ee).

[246] Following similar steps in Example 1 for the synthesis of 145. LCMS (ESI, m/z): [M+H] ⁺ = 631.4; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.28-8.20 (m, 1H), 8.20 (s, 1H), 7.43 (d, J = 9.6 Hz, 1H), 7.08 (dd, J = 15.2, 8.0 Hz, 1H), 6.91-6.78 (m, 1H), 6.44 (d, J = 8.4 Hz, 1H), 6.37 (t, J = 8.0 Hz, 1H), 6.19 (d, J = 16.8 Hz, 1H), 5.77-5.74 (m, 1H), 5.35 (s, 2H), 4.85-4.72 (m, 1.5H), 4.50-4.47 (m, 0.5H), 4.25-4.15 (m, 1.5H), 3.91-3.70 (m, 5H), 3.50-3.42 (m, 0.5H), 2.94-2.89 (m, 1H), 1.47-1.08 (m, 12H).

[247] Following similar steps in Example 1 for the synthesis of 146. LCMS (ESI, m/z): [M+H] ⁺ =631.3; HNMR (400 MHz, DMSO-d ₆ , ppm): δ 8.33 (d, J = 9.6 Hz, 1H), 8.20 (s, 1H), 7.44 (d, J = 9.6 Hz, 1H), 7.09 (dd, J = 15.2, 8.0 Hz, 1H), 6.90-6.79 (m, 1H), 6.45 (d, J = 8.0 Hz, 1H), 6.37 (t, J = 8.0 Hz, 1H), 6.19 (dd, J = 16.8, 2.0 Hz, 1H), 5.76-5.74 (m, 1H), 5.37 (s, 2H), 4.90-4.82 (m, 1H), 4.79-4.74 (m, 0.5H), 4.49-4.45 (m, 0.5H), 4.18-4.02 (m, 1.5H), 3.99-3.66 (m, 5H), 3.58-3.54 (m, 1H), 3.04-2.99 (m, 1H), 1.50-0.95 (m, 12H).

Example 23. Synthesis of compound 179 and compound 180

[248] Step 1: A mixture of 145-4 (1 g, 4.1 mmol), cyclopropylboronic acid (2.8 g, 32.9 mmol), Pd(dtbpf)Cl ₂ (270 mg, 0.4 mmol), and K ₂ CO ₃ (1.4 g, 10.1 mmol) in dioxane (50 mL) and water (10 mL) was stirred at 90 °C overnight under nitrogen. The mixture was cooled and concentrated to give a residue, which was purified by reverse-phase HPLC (acetonitrile with 0.05% TFA in water: 18% to 20%) to give 179-1.

[249] Following similar steps in Example 1 for the synthesis of 179-2, 179-2 (1.34 g) was purified by SFC (Dr. Maisch MIC, 250 × 25 mm, 10 cm, 55% MeOH/CO ₂ , 100 mL/min, 100 bar) to give two peaks: 179-2-P1 (peak 1, 560 mg, >99% ee) and 179-2-P2 (peak 2, 730 mg, >99% ee).

[250] Following similar steps in Example 1 for the synthesis of 179. LCMS (ESI, m/z): [M+H] ⁺ = 629.3; NMR (400 MHz, DMSO-d ₆ , ppm): δ 8.30 (d, J=9.6 Hz, 1H), 8.12 (s, 1H), 7.34 (d, J=9.6 Hz, 1H), 7.10-7.04 (m, 1H), 6.86-6.75 (m, 1H), 6.43 (d, J=8 Hz, 1H), 6.38-6.32 (m, 1H), 6.18-6.13 (m, 1H), 5.74-5.70 (m, 1H), 5.43 (s, 2H), 4.91-4.70 (m, 2H), 4.50-4.40 (m, 0.5H), 4.12-4.06 (m, 1.5H), 3.86-3.82 (m, 2H), 3.77 (s, 3H), 1.70-1.66 (m, 1H), 1.49-1.46 (m, 2H), 1.29-1 D7 (m, 3H), 1.23-1.13 (m, 3H), 0.79-0.75 (m, 1H), 0.68-0.66 (m, 1H). FNMR (376 MHz, DMSO-d ₆ , ppm): δ -113.81 (1F), -126.99 (1F), -127.16 (1F).

[251] Following a similar step in Example 1 to synthesize 180 as a TFA salt. LCMS (ESI, m/z): [M+H] ⁺ =629.3; NMR (400 MHz, MeOD-d ₄ , ppm): δ 9.24 (s, 1H), 8.26-8.21 (m, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.10-7.05 (m, 1H), 6.90-6.70 (m, 1H), 6.42 (d, J=8 ,4 Hz, 1H), 6.37-6.25 (m, 2H), 5.84-5.79 (m, 1H), 5.03-4.90 (m, 2H), 4.61-4.56 (m, 1H), 4.50-4.32 (m, 1H), 4.06 (s, 3H), 3.91-3.86 (m, 2H), 1.95-1.85 (m, 1H), 1.53-1.50 (m, 3H), 1.39-1.30 (m, 3H), 0.94-0.81 (m, 3H), 0.55-0.53 (m, 1H). FNMR (376 MHz, DMSO- _d6 , ppm): δ -116.28 (1F), -123.46 (1F), -126.84 (1F).

[252] Compounds of formulas (I) and (II) can be prepared by following the synthetic methods described herein. Table 1 provides representative analytical data for some compounds prepared analogously to the processes described in Examples 1-23.

Biological example 1. Analysis of cell proliferation

[254] The lung cancer cell line NCI-H358 (ATCC CRL-5807) containing the KRas G12C mutation was grown in RPMI 1640 medium supplemented with 10% fetal bovine serum, penicillin/streptomycin. One hundred fifty microliters (150 μl) of medium containing 2000 cells per well were seeded into each well of a 96-well culture plate and allowed to attach overnight in a 37°C incubator with 5% CO ₂ . Compound dilutions (0.75 μl per well) were added with a liquid handler to a final concentration of 0.5% DMSO. Cells were treated in the incubator for 5 days. The Cell Titer Glo (CTG) kit (Promega) was used to assess cell proliferation. It should be noted that 120 μl of CTG reagent was added to each well and incubated at room temperature for 10 minutes. The luminescence signal was then collected on an Envision 2104 plate reader.

[256] The in vitro data presented above show that changing the position of R ⁸ (see, e.g., formula I-IV) from a 2-fluorophenyl group to a 2-amino-6-fluorophenyl group can result in an almost 20-fold increase in potency in some series of compounds, but not in others. Compounds #126 and 128 are identical except for the R ⁸ position, but compound #126 with a 2-amino-6-fluorophenyl group is about 15 times more potent than compound #128 with a 2-fluorophenyl group, IC ₅₀ 0.6 nM versus 8.7 nM. Similarly, compounds #44 and 42 are identical except for the ^R8 position, but compound #44 with a 2-amino-6-fluorophenyl group is about 19 times more potent than compound #42 with a 2-fluorophenyl group, _IC50 2.1 nM versus 39.5 nM. However, this does not mean that any compound with a 2-amino-6-fluorophenyl group at the ^R8 position has significantly improved potency compared to compounds having a 2-fluorophenyl group at the ^R8 position. For example, compounds #78 and 48 are also identical except for the ^R8 position, and compound #78 with a 2-amino-6-fluorophenyl group is only slightly more potent than compound #48 with a 2-fluorophenyl, _IC50 10.4 nM versus 25.8 nM. We also tested the IC ₅₀ using the same assay (NCI-H358 assay described above) for 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one and 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluorophenyl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)pyrido[2,3-d]pyrimidin-2(1H)-one; the compound having a 2-amino-6-fluorophenyl group was only slightly more potent than the compound with a 2-fluorophenyl group, IC ₅₀ of 1.6 nM versus 4.0 nM. Additionally, the IC _{50 of} 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-amino-6-fluorophenyl)-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one was tested as 5.3 nM using the same assay (NCI-H358 assay described above); and the corresponding compound with 2-fluorophenyl group, 4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-7-(2-fluorophenyl)-1-(4,6-diisopropylpyrimidin-5-yl)-6-fluoropyrido[2,3-d]pyrimidin-2(1H)-one were tested with IC ₅₀ of 19.0 nM using the same assay. These data indicate that compounds with 4,6-dicyclopropylpyrimidin-5-yl group and 2-amino-6-fluorophenyl at the R position are better suited for inhibition of the KRAS G12C enzyme. This contrasts with data showing that when the isopropyl group is replaced by a cyclopropyl group in the pyrimidine ring, a decrease in potency of about 2-6 times is expected, compare, for example, compounds No. 2 and 5, 49 and 50, etc. This trend is generally observed except for compounds containing 2-amino-6-fluoro-phenyl at the R ⁸ position; in these series of compounds the trend is reversed, with the cyclopropyl-pyrimidyl compounds being more potent than the corresponding isopropyl-pyrimidyl compounds.

Biological example 2. Study of human hepatocyte clearance

[257] The clearance of the compounds described herein from human hepatocytes in vitro was studied using pooled human hepatocytes purchased from BioreclamationlVT (Westbury, NY, catalog #X008001, lot #TQJ). The assay was performed according to the manufacturer's instructions. Briefly, 10 mM stock solutions of test compounds and positive control (verapamil) were prepared in 100% DMSO. The thawing medium (50 mL) used in the study consisted of 31 mL Williams E medium (GIBCO catalog #12551-032), 15 mL isotonic Percoll (GE Healthcare catalog #17-0891-09), 500 µL 100X GlutaMax (GIBCO catalog #35050), 750 µL HEPES (GIBCO catalog #15630-080), 2.5 mL FBS (Corning catalog #35-076-CVR), 50 µL human insulin (GIBCO catalog #12585-014), and 5 µL dexamethasone (NICPBP). Incubation medium consisted of Williams E medium supplemented with 1X GlutaMax. Both thawing medium and incubation medium (without serum) were placed in a 37°C water bath for at least 15 min before use. Compound stock solutions were diluted to 100 μM by combining 198 μL of 50% acetonitrile/50% water and 2 μL of 10 mM stock solution. Verapamil was used as a positive control in the assay. Vials containing cryopreserved hepatocytes were removed from storage and thawed in a 37°C water bath with gentle shaking. Vial contents were poured into a 50 mL conical tube containing thawing medium. Vials were centrifuged at 100 g for 10 min at room temperature. The thawed medium was aspirated and the hepatocytes were resuspended in serum-free incubation medium to yield ~1.5 x 10 ⁶ cells/mL. Hepatocyte viability and density were quantified using trypan blue exclusion and the cells were then diluted with serum-free incubation medium to a working cell density of 0.5 x 10 ⁶ viable cells/mL. A portion of the hepatocytes at 0.5 x 10 ⁶ viable cells/mL were then boiled for 5 min before being added to the plate as a negative control to eliminate enzymatic activity so that no or no substrate turnover would be observed. Boiled hepatocytes were used to generate negative samples. Aliquots of 198 μL of hepatocytes were dispensed into each well of an uncoated 96-well plate. The plate was incubated on an orbital shaker at 500 rpm for ~10 min. Aliquots of 2 μl of 100 μM test compound or positive control were added to appropriate wells of an uncoated 96-well plate to initiate the reaction. This assay was performed in duplicate. The plate was incubated in an orbital shaker at 500 rpm for the indicated time points. Twenty-five microliters of the contents were transferred and mixed with 6 volumes (150 μl) of cold acetonitrile with IS (200 nM imipramine, 200 nM labetalol, and 200 nM diclofenac) to stop the reaction at time points of 0, 15, 30, 60, 90, and 120 min. Samples were centrifuged at 3220 g for 25 min and 150 μl aliquots of the supernatants were used for LC-MS/MS analysis. For data analysis, all calculations were performed using Microsoft Excel. Peak areas were determined from extracted ion chromatograms. The in vitro half-life (t _1/2 ) of the parent compound was determined by regression analysis of the percentage disappearance of the parent compound versus time. The in vitro half-life (in vitro t _1/2 ) was determined from the slope: in vitro t _1/2 = 0.693/k. Conversion of in vitro t _1/2 (in minutes) to incremental unbound intrinsic clearance (incremental unbound CL _int , in mL/min/kg) was performed using the following equation (average of duplicate determinations): Incremental unbound CL _int = kV/N × scaling factor, where V = incubation volume (0.5 mL); N = number of hepatocytes per well (0.25 × 10 ⁶ cells). The scaling factors for predicting in vivo intrinsic clearance using human hepatocytes are listed as: liver weight (g liver/kg body weight): 25.7; hepatocyte concentration (10 ⁶ cells/g liver): 99; scaling factor: 2544.3.

Biological example 3. PK studies of rats

[259] The pharmacokinetic (PK) profile of the compounds was determined after a single intravenous administration to SD rats obtained from SIPPER B&K Laboratory Animal Co., LTD, Shanghai. Three female rats weighing approximately 220 g were used. The compounds were prepared at a concentration of 1 mg/mL with a composition of 10% DMSO+10% solutol HS15+80% (10% HPβCD in water). Blood samples (0.2 mL) were collected at 0 h (before dosing) and 0.25, 0.5, 1, 2, 4, 8, 24 h after dosing the compounds at a dose of 10 mg/kg.

[260] Collected blood samples were immediately centrifuged, plasma was separated and transferred to tubes before storage at -70°C prior to analysis. Aliquots of unknown plasma samples, blanks and calibration standards were placed in 1.5 mL tubes and mixed with acetonitrile/methanol (1/1, v/v) containing IS. After mixing for 5 min, each sample was centrifuged at 14,000 rpm at 4°C for 10 min. The supernatant was injected into the LC-MS/MS system.

[261] Samples were separated using a Simazhu LC-30D UPLC system equipped with a Shimadzu Shim-pack GIST C18 (2.1 x 50 mm 2 μm) at 45°C. Eluates were analyzed using an API4000 Q-Trap mass spectrometer with a TurboIonSpray interface. Chromatographic separation was performed using a mobile phase consisting of water with 0.1% formic acid (solution A) and acetonitrile with 0.1% formic acid (solution B). The mobile phase was fed at a flow rate of 0.6 ml/min using a step gradient elution program. To increase the sensitivity of test compound screening, MRM in positive electrospray ionization mode was used. Mass spectrometric data were acquired and analyzed using AB Sciex Analyst software version 1.6.2. Pharmacokinetic parameters were obtained using standard non-compartmental methods with Phoenix WinNonLin Professional Version 8.1. The following pharmacokinetic parameters were calculated: terminal half-life (T1/2), area under the concentration-time curve (AUC), T _max , C _max , clearance, apparent volume of distribution, mean residence time, and other parameters.

Biological Example 4: In vivo studies to evaluate KRAS G12C inhibitors alone or in combination with other agents

[263] All procedures related to animal handling, care, and treatment in this study were performed in accordance with the guidelines approved by the SIPPER B&K Institutional Animal Care and Use Committee (IACUC) as directed by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). During routine monitoring, animals were observed for any effects of tumor growth on normal behavior such as mobility, food and water intake (gazing only), weight gain/loss (body weight was measured twice weekly), eyes/hair matting, and any other abnormal effect. Deaths and observed clinical signs were recorded based on the number of animals in each subgroup. Animals that consistently deteriorated were euthanized prior to death or coma.

[264] NCI-H358, SW837, NCI-H2122 tumor cells were purchased from the American Type Culture Collection (ATCC). Cells were maintained in vitro as a monolayer cultured in RPMI-1640 or DMEM supplemented with 10% fetal bovine serum, 50 IU/ml penicillin/streptomycin (GIBCO) at 37°C in an atmosphere of 5% _CO2 in air. Tumor cells were routinely subcultured twice weekly by trypsin-EDTA treatment. Cells growing in the exponential growth phase were collected and counted for tumor inoculation.

[265] For tumor models, 6-8 week old female BALB/c athymic nude mice were used for human cancer cell lines. Tumor cells (10×10 ⁶ ) in 0.1 ml PBS were inoculated subcutaneously into the right flank of each mouse. Treatment was started when the average tumor size reached approximately 200-250 mm ³ . Carboplatin, cisplatin were administered twice weekly intraperitoneally. Vehicle and other test drugs were orally administered as a suspension via gavage once daily during the study or treatment period.

[266] Tumor volume was calculated by measuring two perpendicular diameters using the following formula: (L×W 2)/2, where L and W refer to the length and width of the tumor diameter, respectively. Results are expressed as the mean and standard deviation of the mean.

[267] The results of the various treatments are illustrated in FIGS. 1-6. FIGS. 1-3 compare the efficacy of certain representative compounds of the present disclosure with AMG510, which is currently in Phase I/II clinical trials for the treatment of KRAS G12C mutant non-small cell lung cancer, colorectal cancer, and appendiceal cancer. AMG510 is believed to be 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-(1]pyrimidin-2-one. FIG. 1 illustrates that Compound #44 at 60 mg/kg and Compound #126 at 30 mg/kg are more effective than AMG510 at 60 mg/kg in reducing tumor volume in vivo in colorectal adenocarcinoma xenograft model SW837 throughout the treatment period. FIG. 2 illustrates that Compound #44 at 30 mg/kg and Compound #126 at a dose of 30 mg/kg is more effective than AMG510 at a dose of 30 mg/kg in reducing tumor volume in vivo in the NSCLC xenograft model H358. FIG. 3 illustrates that compound #126 at a dose of 60 mg/kg is more effective than AMG510 at a dose of 60 mg/kg in reducing tumor volume in vivo in the NSCLC xenograft model H2122.

[268] FIGS. 4-6 illustrate that the compounds of the present invention can be used in combination with other anticancer therapies to achieve a synergistic effect against various cancers. FIG. 4 illustrates that in the H358 NSCLC xenograft model, combination treatment with carboplatin and Compound #145 shows significantly better tumor volume reduction over the course of treatment compared to treatment with carboplatin or Compound #145 alone. In this study, the treatments included: carboplatin at 30 mg/kg; Compound 145 at 5 mg/kg; or carboplatin at 30 mg/kg and Compound 145 at 5 mg/kg. FIG. 5 shows that in the H358 NSCLC xenograft model, combination treatment with cisplatin and Compound 126 shows significantly better tumor volume reduction throughout the course of treatment compared to treatment with cisplatin or Compound 126 alone. Similarly, combination treatment with RMC-4550 and Compound 126 shows significantly better tumor volume reduction throughout the course of treatment compared to treatment with RMC-4550 or Compound 126 alone. In this study, treatment included: cisplatin at a dose of 2 mg/kg; RMC-4550 at a dose of 10 mg/kg; Compound 126 at 5 mg/kg; cisplatin at a dose of 2 mg/kg and Compound 126 at a dose of 5 mg/kg; or RMC-4550 at a dose of 10 mg/kg and Compound 126 at a dose of 5 mg/kg. FIG. 6 illustrates that in the SW837 colorectal adenocarcinoma xenograft model, combination treatment with trametinib and compound 44 shows significantly better tumor volume reduction over the course of treatment compared to treatment with trametinib or compound 44 alone. In this study, treatments include: trametinib at 1 mg/kg; compound 44 at 30 mg/kg; or trametinib at 1 mg/kg and compound 44 at 30 mg/kg.

[269] The Summary and Abstract sections may indicate one or more, but not all, illustrative embodiments of the present invention as contemplated by the inventor(s) and, thus, are not intended to limit the present invention and the appended claims in any way.

[270] The present invention has been described above using functional building blocks illustrating the implementation of said functions and their interrelations. The boundaries of these functional building blocks have been arbitrarily defined in this document for convenience of description. Alternative boundaries may be defined as long as the said functions and their relationships are properly performed.

[271] With respect to aspects of this disclosure described as a genus, all distinct species are individually considered distinct aspects of this disclosure. When aspects of this disclosure are described as "comprising" a feature, embodiments are also considered to "consist of" or "consist essentially of" that feature.

[272] The foregoing description of specific embodiments is intended to fully express the general nature of the invention, which others, using knowledge within the scope of the art, can easily modify and/or adapt to various applications of such specific embodiments without undue experimentation, without departing from the general concept of the invention. Accordingly, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments based on the teachings and instructions provided herein. It should be understood that the language or terminology herein is intended to be descriptive and not limiting, so that the terminology or language of the present description should be interpreted by one skilled in the art in light of the teachings and instructions.

[273] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[274] All of the various aspects, embodiments, and variants described herein may be combined in any and all variations.

[275] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to the term in this document controls.

Claims (11)

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is: 3. A pharmaceutical composition that inhibits the mutant KRAS G12C protein, containing a therapeutically effective amount of a compound according to any one of claims 1, 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 4. A method for inhibiting a mutant KRAS G12C protein in a cell, comprising contacting the cell with a compound according to any one of claims 1, 2 or a pharmaceutically acceptable salt thereof. 5. A method for treating cancer associated with a G12C mutation in KRAS in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1, 2 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3. 6. The method according to claim 5, wherein the cancer is a hematological malignancy, lung cancer, pancreatic cancer, endometrial cancer, gallbladder cancer, thyroid cancer, bile duct cancer and/or colon cancer. 7. The method of claim 6, wherein the lung cancer is non-small cell lung cancer. 8. The method according to any one of paragraphs 5-7, further comprising treating the subject with additional therapy. 9. The method according to claim 8, characterized in that the additional therapy is a chemotherapeutic agent, a therapeutic antibody, radiation therapy, cell therapy or immunotherapy.