Heterocyclic compounds, their production methods and uses

Abstract

We provide KRAS G12C inhibitors. Provided are compounds having Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof. Also provided are methods for making the compounds and methods for using the compounds, for example, in inhibiting KRAS G12C in cells and / or in treating various cancers, such as pancreatic cancer, endometrial cancer, colorectal cancer, or lung cancer (e.g., non-small cell lung cancer). TIFF2022130631000160.tif57128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to international application PCT / CN2019 / 123,223, filed December 5, 2019, PCT / CN2019 / 087772, filed May 21, 2019, and PCT / CN2019 / 095947, filed July 15, 2019, the contents of each of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION In various embodiments, the present invention relates to entirely new heterocyclic compounds, their compositions, methods of manufacture, and methods of use, e.g., for the inhibition of RAS and / or the treatment of various diseases or disorders, such as pancreatic cancer, colorectal cancer, and lung cancer. [Background technology]

[0003] background RAS proteins regulate important cellular pathways that transmit signals received from cell membrane receptors to downstream molecules such as Raf, MEK, ERK and PI3K, and are important for cell proliferation and survival. RAS cycles between an inactive form bound to GDP and an active form bound to GTP. There are three genetic isoforms of RAS proteins, KRAS, NRAS and HRAS, which share extensive homology (>90%) in the N-terminal domain (amino acids 1-165). RAS is a frequently 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). Hotspot mutations in RAS occur at codons 12, 13, and 61, and 75% of KRAS mutations occur at codon 12 (glycine) (DK Simanshu, DV Nissley and F. McCormick, 2017, Cell, 170:17-33 (Non-Patent Document 2)).

[0004] There is a medical need for treatments for cancer patients with RAS mutations, such as the KRAS G12C mutation. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] F. McCormick, 2017, Clin Cancer Res 21:1797-1801 [Non-Patent Document 2] DK Simanshu, DV Nissley and F. McCormick, 2017, Cell, 170:17-33 Summary of the Invention

[0006] BRIEF SUMMARY OF THE INVETION In various embodiments, the present disclosure provides new compounds, pharmaceutical compositions, their preparation methods and use methods.Typically, the compounds described herein are RAS inhibitors, for example KRAS G12C inhibitors.The compounds and compositions herein are useful for treating various diseases or disorders, such as cancers associated with KRAS G12C mutation.

[0007] In various embodiments, the disclosure provides a compound of Formula I or Formula II, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000001.tif57128

[0008] The variables in the formula are defined herein. In some embodiments, the compound of formula I can 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 numbers 1-186, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound can be present in a mixture of atropisomers in any ratio, if applicable. In some embodiments, if applicable, the compound can exist as an isolated single atropisomer substantially free of other atropisomers (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, by HPLC area, or both).

[0009] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds 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 pharma- ceutically acceptable salt thereof), and optionally a pharma- ceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for various routes of administration, such as oral administration, parenteral administration, or inhalation.

[0010] Certain embodiments relate to methods of treating diseases or disorders associated with RAS, e.g., KRAS G12C. In some embodiments, the methods include 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein. In some embodiments, methods of treating cancer are provided. In some embodiments, the methods include 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 may be pancreatic, endometrial, colorectal, or lung cancer (e.g., non-small cell lung cancer). In some embodiments, the cancer is a hematological cancer (e.g., those described herein). In some embodiments, the cancer is MYH-associated polyposis. In some embodiments, the cancer may be gallbladder, thyroid, or cholangiocarcinoma. Administration is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, and parenteral administration. The compounds of the present disclosure can be used as monotherapy or combination therapy. In some embodiments, the combination therapy includes treating the subject with a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, or immunotherapy.

[0011] It should be noted that the above summary and the following detailed description are both exemplary and explanatory and are not intended to limit the invention. [The present invention 1001] A compound of formula I or a pharma- ceutically acceptable salt thereof: TIFF0007679338000002.tif61128In formula, X is O, NR 10 , S, S.O.2 or an optionally substituted 4- to 7-membered heterocycle; R 1 is hydrogen, optionally substituted C 1-4 Alkyl, or L-R 20 and where L is absent or optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring; Here, R 20 is hydrogen, 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- to 7-membered heterocyclyl; Or XR 1 -COOH, -COOR 23 , -CONR 21 R 22 , -CN,C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 represents cycloalkyl, 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl includes, for example, F, OH, protected OH, and C 1-4 each of which is optionally substituted with 1 to 3 groups independently selected from alkoxy; Here, R 10 , R 21 , and R 22 Each of the following is independently selected from the group consisting of hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C1-4 Heteroalkyl, optionally substituted C 3-6 R is a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; 23 is independently at each occurrence 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; A 1 , A 2 , A 3 , A 4 , and A 5 Each of the following may be independently 30 or N, Here, R 30 are independently hydrogen, F, Cl, C 1-4 Alkyl, or C 1-4 is alkoxy; Or, R 1 , X, and A 1 taken together form an optionally substituted heterocyclic or heteroaryl ring; R 2 and R 3 are each independently hydrogen, halogen, -OH, -CN, or 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- to 7-membered heterocyclic ring, or optionally substituted C 1-4 is alkoxy; Het is a 4- to 10-membered heterocycle and is selected from one or more independently selected R 4 Group, (R 4 ) n where n is 0, 1, 2 or 3; R 4 is expressed independently for each occurrence as C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl; or two R 4 The groups may be linked together to form a 3- to 6-membered ring structure; U represents an electrophilic moiety capable of forming a covalent bond with a cysteine ​​residue of a KRAS protein, e.g., a KRAS G12C mutant protein; R 7 is hydrogen, halogen, -CN, a 3- to 4-membered ring (e.g., cyclopropyl), an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 is alkoxy; and R 8 is optionally substituted aryl or optionally substituted heteroaryl. [The present invention 1002] Formula I-1 or Formula I-2: TIFF0007679338000003.tif68128, During the ceremony, X is O, S, N, or NR 10 and J 1 and J. 2 each of which is independently O, S, N, CR 40 , and N.R. 41 where R 40 and R 41 Each of the following is independently selected from 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 1-4Heteroalkyl, optionally substituted C 3-6 a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring; R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 Forms a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is, independently at each occurrence, 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; wherein the dashed lines represent each link being a single or double bond, provided that the bicyclic ring as a whole is aromatic. A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1003] Formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C: TIFF0007679338000004.tif249158, In the formula, A 2 is CH or N, and R 10 , R 40 and R 41 Each of 1-4 is alkyl, The compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1004] Formula I-5 or I-6: TIFF0007679338000005.tif89166, During the ceremony, R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 Forms a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4Heteroalkyl, optionally substituted C 3-6 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is, independently at each occurrence, 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; L is absent or optionally substituted C 1-4 alkylene or an optionally substituted 4- to 7-membered heterocycle containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms); Here, R 20 is hydrogen, optionally substituted C 1-4 Alkyl, -NR 21 R 22 , -OR 23 an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms); R 21 , R 22 and R 23 Each of the following is independently hydrogen or an optionally substituted C 1-4 is alkyl, A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1005] -OLR 20 The residue is The compound of the present invention 1004, which is TIFF0007679338000006.tif64128, or a pharma- ceutically acceptable salt thereof. [The present invention 1006] Formula I-7 or I-8: TIFF0007679338000007.tif83166, During the ceremony, R 5 and R6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 may form a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is, independently at each occurrence, 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; L is absent or optionally substituted C 1-4 alkylene or an optionally substituted 4- to 7-membered heterocycle containing one or two ring heteroatoms (e.g., one or two ring nitrogen atoms); Here, R 20 is hydrogen, optionally substituted C 1-4 Alkyl, -NR21 R 22 , -OR 23 an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms); wherein ring B is a 4- to 7-membered heterocycle containing one or two ring heteroatoms (e.g., one or two ring nitrogen atoms) and one or more R 42 Group, (R 42 ) m where R 42 is, independently at each occurrence, hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, -NR 21 R 22 OR 23 where m is 0, 1, or 2; R 10 , R 21 and R 22 Each of the following is independently selected from the group consisting of hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 alkynyl, or a nitrogen protecting group; and R 23 is, independently at each occurrence, hydrogen or optionally substituted C 1-4 is alkyl, A compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1007] having a formula according to I-7, The TIFF0007679338000008.tif26128 part is -NH 2 , -NHCH 3 , -NHC(O)CH 3 , -N(CH 3 )SO 2 CH 3 , -N(CH 3 ) 2 , and Selected from TIFF0007679338000009.tif27128, The compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1008] I-8, wherein ring B is optionally one or more substituents R 42 Together, TIFF0007679338000010.tif33128, The compound of the present invention, or a pharma- ceutically acceptable salt thereof. [The present invention 1009] -XR 1 But -C(CH 3 ) 2 OH, or a pharma- ceutically acceptable salt thereof. [The present invention 1010] If applicable, A 1 and A 2 and R are each independently 0 or 1. The compound of the present invention, wherein both of R and R are N, or a pharma- ceutically acceptable salt thereof. [The present invention 1011] If applicable, A 1 and A 2 One of the two is N, and A 1 and A 2 The compound according to any one of 1001 to 1009 of the present invention, or a pharma- ceutically acceptable salt thereof, wherein the other is CH. [The present invention 1012] R 2 and R 3 C optionally substituted with hydrogen or 1 to 3 fluorines 1-4 Alkyl, C 3-6 The compound of any one of 1001 to 1011 of the present invention, which is independently selected from cycloalkyl, and halogen, or a pharma- ceutically acceptable salt thereof. [The present invention 1013] R 2 and R 3is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl, or a pharma- ceutically acceptable salt thereof. [The present invention 1014] R 2 and R 3 The compound of any one of the present inventions 1001 to 1013, or a pharma- ceutically acceptable salt thereof, wherein [The present invention 1015] R 2 and R 3 are both isopropyl or both cyclopropyl, or a pharma- ceutically acceptable salt thereof. [The present invention 1016] R 2 and R 3 is different, R 2 and R 3 The compound of any one of the present invention 1001 to 1013, or a pharma- ceutically acceptable salt thereof, wherein one of [The present invention 1017] Het in formula I is (R 4 ) n and together with U. TIFF0007679338000011.tif37128, where n is 0, 1, or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 The compound according to any one of claims 1001 to 1016, which is CN, or a pharma- ceutically acceptable salt thereof. [The present invention 1018] Het in formula I is (R 4 ) n and together with U. The compound of the present invention 1017 represented by TIFF0007679338000012.tif26129, or a pharma- ceutically acceptable salt thereof. [The present invention 1019] R 5 and R 6 and R 1 and R 2 are each independently hydrogen, or a pharma- ceutically acceptable salt thereof. [The present invention 1020] A 3 is N, or a pharma- ceutically acceptable salt thereof. [The present invention 1021] A 4 The compound of any one of the present invention 1001 to 1020, or a pharma- ceutically acceptable salt thereof, wherein [The present invention 1022] A 5 is N, or a pharma- ceutically acceptable salt thereof. [The present invention 1023] R 7 is hydrogen, F, Cl, methyl, or CF 3 The compound of any one of the present inventions 1001 to 1022, or a pharma- ceutically acceptable salt thereof. [The present invention 1024] R 8 F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 The compound of any one of the present invention Nos. 1001 to 1023, wherein the compound is phenyl optionally substituted by 1 to 3 groups each independently selected from alkoxy, or a pharma- ceutically acceptable salt thereof. [The present invention 1025] R 8 F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 The compound of any one of the present invention 1001 to 1023, or a pharma- ceutically acceptable salt thereof, wherein the compound is a bicyclic heteroaryl (e.g., indazolyl) optionally substituted by 1 to 3 groups each independently selected from alkoxy. [The present invention 1026] R 8 but, Any one of the compounds of the present invention 1001 to 1023 selected from TIFF0007679338000013.tif17128 or a pharma- ceutically acceptable salt thereof. [The present invention 1027] A compound of formula II, or a pharma- ceutically acceptable salt thereof: TIFF0007679338000014.tif58128In formula, G 1 is hydrogen, -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 said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl is F, OH, protected OH, and C 1-4 alkoxy; or G 1 -XR 1 and; where X is O, NR 10 , S, S.O. 2 or an optionally substituted 4- to 7-membered heterocycle; R 1 is hydrogen, optionally substituted C 1-4 Alkyl, or L-R 20 and where L is absent or optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring; Here, R 20 is hydrogen, 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- to 7-membered heterocyclyl; Here, R 10 , R 21 and R 22 Each of the following is independently selected from the group consisting of 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 R is a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; 23 is, independently at each occurrence, 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; A 1 , A 2 , A 3 , A 4 , and A 5 Each of the following may be independently 30 or N, Here, R 30 are independently hydrogen, F, Cl, C 1-4 Alkyl, or C 1-4is alkoxy; Alternatively, if applicable, R 1 , X, and A 1 together form an optionally substituted heterocyclic or heteroaryl ring; Het is one or more R 4 Group, (R 4 ) n is a 4- to 10-membered heterocycle optionally substituted with Here, R 4 is expressed independently for each occurrence as C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl, and n is 0, 1, 2, or 3; or two R 4 The groups may be linked together to form a 3- to 6-membered ring structure; U represents an electrophilic moiety capable of forming a covalent bond with a cysteine ​​residue of a KRAS protein, e.g., a KRAS G12C mutant protein; R 7 is hydrogen, halogen, -CN, a 3- to 4-membered ring (e.g., cyclopropyl), an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 is alkoxy; and R 8 is optionally substituted aryl or optionally substituted heteroaryl. [The present invention 1028] G 1 is hydrogen, methyl, cyclopropyl, -C(CH 3 ) 2 OH, -CF 3 or CN, preferably G 1 is hydrogen, or a pharma- ceutically acceptable salt thereof. [The present invention 1029] If applicable, A 1 and A 2 and R are each independently 0 or 1. The compound of any one of claims 1027 to 1028, or a pharma- ceutically acceptable salt thereof. [The present invention 1030] If applicable, A 1 and A 2 One of the two is N, and A 1 and A 2 and the other is CH, or a pharma- ceutical acceptable salt thereof. [The present invention 1031] U, TIFF0007679338000015.tif15128, wherein R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 may form a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of 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 carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R23A is, independently at each occurrence, 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; Any one of the compounds of the present invention Nos. 1027 to 1030, or a pharma- ceutically acceptable salt thereof. [The present invention 1032] Het in formula I is (R 4 ) n and together with U. TIFF0007679338000016.tif36128, where n is 0, 1, or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 The compound of the present invention 1031, which is CN, or a pharma- ceutically acceptable salt thereof. [The present invention 1033] Het in formula I is (R 4 ) n and together with U. The compound of the present invention 1032 represented by TIFF0007679338000017.tif26129, or a pharma- ceutically acceptable salt thereof. [The present invention 1034] R 5 and R 6 and R 1 and R 2 are each independently hydrogen, or a pharma- ceutically acceptable salt thereof. [The present invention 1035] A 3 is N, or a pharma- ceutically acceptable salt thereof. [The present invention 1036] A 4The compound of any one of 1027 to 1035, or a pharma- ceutically acceptable salt thereof, of the present invention, wherein [The present invention 1037] A 5 The compound of any one of claims 1027 to 1036, or a pharma- ceutically acceptable salt thereof, according to the present invention, wherein [The present invention 1038] R 7 is hydrogen, F, Cl, methyl, or CF 3 and preferably R 7 is F or Cl, or a pharma- ceutically acceptable salt thereof. [The present invention 1039] R 8 F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 The compound of any one of claims 1027 to 1038, or a pharma- ceutically acceptable salt thereof, wherein the compound is phenyl optionally substituted by 1 to 3 groups each independently selected from alkoxy. [The present invention 1040] R 8 F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 The compound according to any one of claims 1027 to 1038, wherein the compound is a bicyclic heteroaryl (e.g., indazolyl) optionally substituted by 1 to 3 groups each independently selected from alkoxy, or a pharma- ceutically acceptable salt thereof. [The present invention 1041] R 8 but, TIFF0007679338000018.tif17128, preferably R 8 but, Any of the compounds of the present invention 1027 to 1038, which is TIFF0007679338000019.tif15128, or a pharma- ceutically acceptable salt thereof. [The present invention 1042] A compound selected from any of compound numbers 1 to 186, or a pharma- ceutically acceptable salt thereof. [The present invention 1043] A pharmaceutical composition comprising any one of the compounds of the present invention 1001 to 1042 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient. [The present invention 1044] A method for inhibiting KRAS G12C mutant protein in a cell, comprising contacting the cell with any one of the compounds of the present invention 1001 to 1042 or a pharma- ceutically acceptable salt thereof. [The present invention 1045] A method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of any one of the compounds of the present invention 1001 to 1042 or a pharma- ceutically acceptable salt thereof, or the pharmaceutical composition of the present invention 1043. [The present invention 1046] The method of claim 1045, wherein said 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 colorectal cancer. [The present invention 1047] The method of any one of claims 1045 to 1046, further comprising treating said subject with an additional therapy. [The present invention 1048] The method of claim 1047, wherein said additional therapy is a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, or immunotherapy. [The present invention 1049] The method of any one of claims 1045 to 1048, wherein the subject has a G12C mutation in KRAS, HRAS, and / or NRAS. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 shows tumor volume growth profiles versus days following treatment with vehicle, AMG510 (60 mg / kg), Compound No. 44 (60 mg / kg) or Compound No. 126 (30 mg / kg) in a colorectal adenocarcinoma SW837 xenograft model. [Diagram 2] FIG. 2 shows tumor volume growth profiles versus days following treatment with vehicle, AMG510 (30 mg / kg), Compound No. 44 (30 mg / kg) or Compound No. 126 (30 mg / kg) in an NSCLC H358 xenograft model. [Diagram 3] FIG. 3 shows tumor volume growth profiles versus days following treatment with vehicle, AMG510 (60 mg / kg) or Compound No. 126 (60 mg / kg) in an NSCLC H2122 xenograft model. [Figure 4] FIG. 4 shows tumor volume growth profiles versus days following treatment with vehicle, carboplatin (30 mg / kg), Compound No. 145 (5 mg / kg), or carboplatin (30 mg / kg) and Compound No. 145 (5 mg / kg) in an NSCLC H358 xenograft model. [Diagram 5] FIG. 5 shows tumor volume growth profiles versus days following treatment with vehicle, cisplatin (2 mg / kg), RMC-4550 (10 mg / kg), Compound No. 126 (5 mg / kg), cisplatin (2 mg / kg) and Compound No. 126 (5 mg / kg), or RMC-4550 (10 mg / kg) and Compound No. 126 (5 mg / kg) in an NSCLC H358 xenograft model. [Figure 6] FIG. 6 shows tumor volume growth profiles versus days following treatment with vehicle, trametinib (1 mg / kg), Compound No. 44 (30 mg / kg), or trametinib (1 mg / kg) and Compound No. 44 (30 mg / kg) in a colorectal adenocarcinoma SW837 xenograft model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Detailed Description of the Invention In various embodiments, the present specification provides novel compounds, pharmaceutical compositions, methods of manufacture and methods of use.

[0014] compound Some embodiments of the present disclosure relate to novel compounds. The compounds herein may typically be inhibitors of KRAS protein, particularly KRAS G12C mutant protein.

[0015] In some embodiments, the disclosure provides a compound of formula I, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000020.tif55128In formula, X is O, NR 10 , S, S.O. 2 or an optionally substituted heterocycle (e.g., a 4- to 7-membered heterocycle); R 1 is hydrogen, optionally substituted alkyl (e.g., C 1-4 alkyl group), or LR 20 and where L is absent or an optionally substituted alkylene (e.g., C 1-4 alkylene), optionally substituted heteroalkylene (e.g., C 1-4 heteroalkylene), optionally substituted carbocycles (e.g., C 3-6 carbocyclic ring) or an optionally substituted heterocyclic ring (e.g., a 4- to 7-membered heterocyclic ring); Here, 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 (e.g., 4- to 7-membered heterocyclyl); Or XR 1 -COOH, -COOR 23 , -CONR 21 R 22 , -CN, optionally substituted alkyl, alkenyl, alkynyl, or carbocycle (e.g., cycloalkyl), such as, for example, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 represents cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl can be, for example, each independently F, OH, protected OH, and C. 1-4 optionally substituted with 1 to 3 groups selected from alkoxy; Here, R 10 , R 21 , and R 22 Each of the following is independently selected from each occurrence: hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, e.g., 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 carbocycles (e.g., C 3-6 carbocycle), an optionally substituted heterocycle (e.g., a 4- to 7-membered heterocycle), or a nitrogen protecting group; 23 are independently hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, e.g., 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 carbocycles (e.g., C 3-6carbocyclic ring), an optionally substituted heterocyclic ring (e.g., a 4- to 7-membered heterocyclic ring), or an oxygen protecting group; A 1 , A 2 , A 3 , A 4 , and A 5 Each of the following may be independently 30 or N, Here, R 30 is independently at each occurrence hydrogen, halogen (e.g., F, Cl), optionally substituted C 1-4 Alkyl, or optionally substituted alkoxy (e.g., C 1-4 alkoxy); Or, R 1 , X, and A 1 may be linked together to form an optionally substituted ring structure, such as an optionally substituted heterocyclic or heteroaryl ring; R 2 and R 3 are each independently hydrogen, halogen, -OH, -CN, optionally substituted alkyl, alkenyl, or alkynyl, e.g., optionally substituted C 1-4 Alkyl, C 2-4 Alkenyl, or C 2-4 Alkynyl, optionally substituted carbocyclic rings (e.g., C 3-6 carbocyclic ring), optionally substituted heterocyclic ring (e.g., 4- to 7-membered heterocyclic ring), or optionally substituted alkoxy (e.g., C 1-4 alkoxy); TIFF0007679338000021.tif10128 (hereinafter sometimes abbreviated as "Het") is a heterocycle (e.g., a 4- to 10-membered heterocycle) that can be, for example, one or more independently selected R 4 Group, (R 4 ) n where n is 0, 1, 2, or 3; R 4 is independently at each occurrence an optionally substituted alkyl, alkenyl, or alkynyl or a 3- or 4-membered ring, e.g., R 4 For each occurrence, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl; or two R 4 The groups may be linked together to form a ring structure, for example a 3- to 6-membered ring structure; U represents an electrophilic moiety capable of forming a covalent bond with a cysteine ​​residue of a KRAS protein (e.g., a KRAS G12C mutant protein); R 7 is hydrogen, halogen, -CN, a 3-4 membered ring (e.g., cyclopropyl), an optionally substituted alkyl, alkenyl, alkynyl, or alkoxy, e.g., an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 is alkoxy; and R 8 is optionally substituted aryl or optionally substituted heteroaryl.

[0016] In some embodiments, X in formula I can be or include a heteroatom. For example, in some embodiments, X can be O. In some embodiments, X can be NR 10 In some embodiments, X may be S or SO 2 In some embodiments, X may be a heterocycle, such as an optionally substituted 4- to 7-membered heterocycle. In some embodiments, the 4- to 7-membered heterocycle has 1 or 2 heteroatoms, such as 1 or 2 nitrogen atoms. A variety of heterocycles are suitable. Non-limiting suitable examples include: TIFF0007679338000022.tif23128, each of which is, for example, halogen, —OH, oxo, C 1-4 Alkyl, and C1-4 alkoxy; 1-4 Alkyl or C 1-4 The alkoxy is optionally substituted with one to three fluorines, where the heterocycle may be attached to the remainder of formula I at any two available positions. For example, when X in formula I is an optionally substituted piperazine, the piperazine ring may be bonded to two nitrogen atoms, two carbon atoms, a single carbon atom, or a nitrogen atom and a carbon atom, e.g., TIFF0007679338000023.tif23128 (not showing any substituents) may be attached to the remainder of formula I. Other heterocycles are similarly understood.

[0017] Different R 1 A group can be attached to X in formula I. In some embodiments, R 1 may be hydrogen. In some embodiments, R 1 is an optionally substituted C 1-4 Alkyl, e.g., methyl, ethyl, isopropyl, CHF 2 , C.F. 3 etc.

[0018] In some embodiments, R 1 -LR 20 In some embodiments, L may be absent. In some embodiments, L may be a linker, e.g., an optionally substituted C 1-4 Alkylene, optionally substituted C 1-4 Heteroalkylene, optionally substituted C 3-6 In some embodiments, L is a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring. 1-4 Alkylene, for example, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-CH 2In some embodiments, L can be an optionally substituted C, each independently having one or two substituents such as F, OH, or methyl. 1-4 As used herein, optionally substituted C 1-4 Alkylene also includes two geminal substituents, where the two substituents form a cyclic structure, e.g. C form TIFF0007679338000024.tif10128 1-4 In some embodiments, L is C 1-4 Heteroalkylene, for example, -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 Typically, L is C 1-4 When it is a heteroalkylene, it has one or two heteroatoms, such as one oxygen atom, one nitrogen atom, or two oxygen atoms. 20 In some embodiments, L is an optionally substituted C, each of which independently has one or two substituents, such as F, OH, or methyl. 1-4 Similarly, as used herein, optionally substituted C 1-4 Heteroalkylene also includes two geminal substituents, where the two substituents are cyclic structures, e.g. C form TIFF0007679338000025.tif14128 1-4 In some embodiments, L is an optionally substituted C3-6 It may be a carbon ring. For example, in some embodiments, L may be cyclopropylene, cyclobutylene, cyclopentylene, etc. In some embodiments, a heterocyclic ring is also suitable. For example, L may be a 4- to 7-membered heterocyclic ring having one or two heteroatoms independently selected from O, N, and S, where any two available positions of the heterocyclic ring are X and R 20 and can be used to connect with. Non-limiting suitable heterocyclic rings include those described herein, such as azetidinyl, tetrahydrofuryl, pyrrolidinyl, piperazinyl, morpholinyl, etc. The heterocyclic ring may be substituted with, for example, halogen, -OH, oxo, C 1-4 alkyl, and C 1-4 alkoxy, each independently selected from 1 to 3 substituents, where C 1-4 alkyl or C 1-4 alkoxy may be substituted with 1 to 3 fluorines.

[0019] R 20 is typically hydrogen, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, -NR 21 R 22 , -OR 23 , or optionally substituted 4- to 7-membered heterosilyl. For example, in some embodiments, R 20 may be hydrogen. In some embodiments, R 20 may be C 1-4 alkyl such as methyl, ethyl, isopropyl, etc. In some embodiments, R 20 is selected from 1 to 3 substituents independently selected from F, -OH, -NH 2 , -NH(C 1-4 alkyl) such as -NHMe, and -NMe 2 or -N(C 1-4 alkyl)(C 1-4 alkyl) such as -N(Me)(Et), and is substituted C 1-4For example, in some embodiments, R 20 is -CH 2 -OH, -CH 2 -NMe 2 etc. In some embodiments, R 20 -OR 23 For example, in some embodiments, R 20 is -OH or OC 1-4 In some embodiments, R 20 is -OC(O)-C 1-4 It may be a protected OH, such as an alkyl or silyl protected hydroxyl, such as -O-TMS. In some embodiments, such a protected OH may be converted to R 20 Using a compound having as R 20 In some embodiments, compounds can be provided in which R 20 -NR 21 R 22 For example, in some embodiments, R 20 is -NH 2 , -NH(C) 1-4 alkyl), or -NMe 2 Or N(C) such as N(Me)(Et) 1-4 Alkyl)(C 1-4 In some embodiments, R 21 and R 22 One or both of R may be a nitrogen protecting group. 21 and R 22 are nitrogen protecting groups, TIFF0007679338000026.tif20128, etc. 21 and R 22 In some embodiments, such protected NH(R) or NH 2 R 20 Using a compound having as R 20 is NH(R) or NH 2In some embodiments, R 20 may 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. Heterocyclyls include, for example, halogen, -OH, oxo, C 1-4 Alkyl, and C 1-4 alkoxy, wherein C 1-4 Alkyl or C 1-4 The alkoxy may be substituted with 1 to 3 fluorine atoms.

[0020] In some embodiments, X, R in formula I 1 , and A 1 may be linked 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 taken together to form a 4-, 5-, or 6-membered heterocyclic ring structure, or a 5- or 6-membered heteroaryl ring structure. 1 , and A 1 When taken together, they form a ring structure, It is understood that X, R and R are shared to form a fused bicyclic ring in Formula I. Non-limiting suitable ring structures include the following, for illustration purposes: 1 , and A 1 merely instead of the ring structure formed from the fused ring structure, and no optional substituents are shown. TIFF0007679338000028.tif101128 In some embodiments, A 2 is CH. In some embodiments, A 2 is N.

[0021] In some embodiments, -XR in formula I1 may represent a carbon-linked moiety, where X is not a heteroatom. For example, in some embodiments, -XR 1 -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, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 3-6 Cycloalkyl includes, for example, F, -OH, protected OH, and C 1-4 In some embodiments, the -XR 1 is a hydroxyl-substituted C 1-6 It may be an alkyl group, for example, -C(CH 3 ) 2 It may also be -OH.

[0022] In some embodiments, A in formula I 1 and A 2 In some embodiments, both of A in formula I may be N. 1 and A 2 One of the two may be N, and A 1 and A 2 The other may be CH.

[0023] R in Formula I 2 and R 3 may be the same or different. Typically, R 2 and R 3 are each independently a hydrogen atom or a C group optionally substituted with 1 to 3 fluorines. 1-4 Alkyl, C 3-6 cycloalkyl, or halogen. For example, in some embodiments, R 2 and R 3is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some specific embodiments, R 2 and R 3 In some embodiments, both R 2 and R 3 In some embodiments, both of R 2 and R 3 are the same. In some embodiments, R 2 and R 3 are different. In some embodiments, R 2 and R 3 One of the groups is hydrogen or methyl.

[0024] Various heterocycles are suitable as Het in formula I. Note that in the formulae of this specification: Although depicted as TIFF0007679338000029.tif10128, it is made clear that Het is not to be construed as including only 6-membered monocyclic heterocycles. Typically, Het may be a 4-9 membered heterocycle, which may be monocyclic or polycyclic (e.g., bicyclic, fused or spiro bicyclic). Het generally contains one or two ring heteroatoms, such as one or two ring nitrogen atoms. Non-limiting examples of suitable heterocycles are: TIFF0007679338000030.tif20142, where the attachment point may be at any available position. In general, where applicable, the two ring nitrogen atoms are attached to the 6,6-bicyclic structure and the electrophilic moiety U in formula I. For example, in some embodiments, Het is piperazine and is attached through the two nitrogen atoms to the remainder of formula I: TIFF0007679338000031.tif25128 (optional substituents not shown).

[0025] The compounds herein include an electrophilic moiety, U, that can react with a cysteine ​​residue of a KRAS protein to form a covalent bond. In some embodiments, U can be an electrophilic moiety that includes a Michael acceptor. For example, in some embodiments, U can be TIFF0007679338000032.tif20128, wherein R 5 and R 6 is defined herein. In some embodiments, U is linked to the nitrogen atom of Het, for example, to the following structural moiety: TIFF0007679338000033.tif30128, where R 5 and R 6 is defined herein. In some embodiments, U is TIFF0007679338000034.tif109146, wherein R 5 and R 6 is defined herein. In some embodiments, U is TIFF0007679338000035.tif18128, wherein R 5 and R 6 is defined herein. In some embodiments, U is TIFF0007679338000036.tif19128, wherein R 5 and R 6 is defined herein.

[0026] Various R 5 and R 6 For example, in some embodiments, R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 may form a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A is independently at each occurrence 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is, at each occurrence, 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 It is a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group.

[0027] 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 In some embodiments, R 6 may be hydrogen. In some embodiments, R 6 are F, -OH, -NH 2 , -NH(C) 1-4 Alkyl), -NMe 2 or -N(C) such as N(Me)(Et) 1-4 Alkyl)(C 1-4C optionally substituted by 1 to 3 substituents independently selected from alkyl, 4- to 7-membered heterocyclyl having 1 or 2 ring heteroatoms independently selected from O, N and S; 1-4 For example, in some embodiments, R 6 is -CH 2 -OMe, -(CH 2 ) n -OH, -(CH 2 ) n -NMe 2 , TIFF0007679338000037.tif18128, etc., where n is an integer from 1 to 4. In some embodiments, R 6 may be a halogen, such as F or Cl. In some embodiments, R 6 may be -CN. In some embodiments, R 6 -COOR 23A For example, -COO(C 1-4 In some embodiments, R 6 -CONR 21A R 22A For example, -CON(C 1-4 Alkyl)(C 1-4 alkyl), -CONH(C 1-4 alkyl), or CONH 2 In some embodiments, R 6 is optionally substituted phenyl or 5- or 6-membered heteroaryl, e.g. It could also be TIFF0007679338000038.tif22128.

[0028] In some specific embodiments, R 5 and R 6 In some specific embodiments, both of R 5 is F or OMe, and R 6 is hydrogen. In some specific embodiments, R 5 is hydrogen and R6 is -CH 2 -OMe or The file is TIFF0007679338000039.tif17128.

[0029] As shown in formula I, Het is substituted with an electrophilic moiety U and independently selected R 4 Group, (R 4 ) n where 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.

[0030] Typically, if present, R 4 is expressed independently for each occurrence as C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl; or two R 4 The groups may be linked together to form a 3- to 6-membered ring structure. For example, in some embodiments, R 4 is represented by methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, n may be 1 and R 4 is methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, n may be 2, and one of R 4 may be methyl, and the other R 4 Methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH2 It may also be CN.

[0031] In some embodiments, Het of formula I is (R 4 ) n and together with U: TIFF0007679338000040.tif26129, where R 5 and R 6 is defined herein, for example, R 5 and R 6 may both be hydrogen.

[0032] A in Formula I 3 is typically N, but in some embodiments, A 3 CR 30 For example, in some embodiments, A 3 may be CH.

[0033] A in Formula I 4 is typically CH, but in some embodiments, A 4 may be N.

[0034] A in Formula I 5 is typically N, but in some embodiments, A 5 CR 30 For example, in some embodiments, A 5 may be CH.

[0035] In some embodiments, R in formula I 7 is hydrogen, halogen, -CN, a 3- to 4-membered ring (e.g., cyclopropyl), an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 For example, in some embodiments, R 7 is hydrogen, F, Cl, methyl, -CN, or CF 3In some embodiments, R 7 may be F. In some embodiments, R 7 may be Cl.

[0036] R in Formula I 8 is typically an optionally substituted phenyl or naphthyl or an optionally substituted 5-10 membered heteroaryl. In some embodiments, R 8 are F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 phenyl, optionally substituted with 1 to 3 groups, each independently selected from alkoxy. In some embodiments, R 8 is substituted with F and -OH, -NH 2 , a protected hydroxyl group, or a protected amino group. In some embodiments, the phenyl substituents may be ortho to the 6,6-bicyclic structure in formula I.

[0037] In some embodiments, R 8 are F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 It may also form a bicyclic heteroaryl (eg, indazolyl) which is optionally substituted by 1 to 3 groups each independently selected from alkoxy.

[0038] In some embodiments, R 8 teeth, It could also be TIFF0007679338000041.tif16128.

[0039] In some embodiments, the disclosure provides exemplary compounds of formula I having formula I-1 or I-2, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000042.tif63128In formula, X is O, S, N, or NR 10 and J 1 and J. 2 each of which is independently O, S, N, CR 40 , and N.R. 41 Selected from Here, R 40 and R 41 Each of the following is independently selected from 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 a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring; where the dashed lines indicate that each link is a single or double bond, and provided that the bicyclic ring as a whole is aromatic, where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 ,Het,n,A 3 , A 4 , and A 5 may be any of those defined herein for each variable.

[0040] In some embodiments, for each occurrence, R 40 and R41 Each of the groups is independently a C, such as hydrogen or methyl. 1-4 It is an alkyl.

[0041] In some specific embodiments, the disclosure also provides exemplary compounds of formula I having formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C, or a pharma- ceutically acceptable salt thereof: TIFF0007679338000043.tif224154In formula, A 2 is CH or N; In the formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 40 , R 41 ,Het,n,A 3 , A 4 , and A 5 may be any of the definitions herein for each variable. In some embodiments, R 10 , R 40 , and R 41 Each of 1-4 In some embodiments, A is an alkyl (e.g., methyl). 2 is CH. In some embodiments, A 2 is N. In some embodiments, A 3 is N and A 4 is CH and A 5 is N.

[0042] In some specific embodiments, the disclosure also provides exemplary compounds of formula I having formula I-5 or I-6, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000044.tif84166 formula, R 2 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , L, R 20 ,Het,n,A 3 , A 4 , and A 5 In some embodiments, L is an optionally substituted or absent C 1-4 alkylene, or an optionally substituted 4- to 7-membered heterocycle containing one or two ring heteroatoms (e.g., one or two ring nitrogen atoms). 20 is hydrogen, optionally substituted C 1-4 Alkyl, -NR 21 R 22 , -OR 23 , an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), where R 21 , R 22 , and R 23 may be any of the definitions herein for each variable. In some embodiments, R 21 , R 22 , and R 23 Each of the following is independently hydrogen or an optionally substituted C 1-4 In some embodiments, -OLR in formula I-5 or I-6 is alkyl. 20 The residue is It could also be TIFF0007679338000045.tif50128.

[0043] In some specific embodiments, the disclosure also provides exemplary compounds of formula I having formula I-7 or I-8, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000046.tif78166In formula, Ring B is a 4-7 membered heterocycle containing one or two ring heteroatoms, such as one or two ring nitrogen atoms, which is optionally joined by one or more R 42 Group, (R 42 ) mwhere R 42 is independently at each occurrence hydrogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, -NR 21 R 22 OR 23 where m is 0, 1 or 2; and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , L, R 10 , R 20 , R 21 , R 22 , R 23 ,Het,n,A 1 , A 2 , A 3 , A 4 , and A 5 In some embodiments, L is an optionally substituted or absent C 1-4 alkylene or an optionally substituted 4- to 7-membered heterocycle containing one or two ring heteroatoms (e.g., one or two ring nitrogen atoms). 20 is hydrogen, optionally substituted C 1-4 Alkyl, -NR 21 R 22 , -OR 23 , an optionally substituted 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms (e.g., 1 or 2 ring nitrogen atoms), where R 21 , R 22 , and R 23 may be any of the definitions herein for each variable. In some embodiments, R 10 , R 21 , and R 22 Each of the groups in each occurrence is independently hydrogen, optionally substituted C 1-4In some embodiments, R is an alkyl, or a nitrogen protecting group, where applicable. 23 Each occurrence represents hydrogen or optionally substituted C 1-4 In some embodiments, in formula I-7, The TIFF0007679338000047.tif17128 part is -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 I-8, ring B is selected from any one or more substituents R 42 Together, The file is TIFF0007679338000049.tif25128.

[0044] As noted above, the variables in the subformulas of formula I (e.g., formulas I-1, I-2, I-3A, I-3B, I-3C, I-4A, I-4B, I-4C, I-5, I-6, I-7, or I-8) can have any of the applicable respective definitions defined for formula I. For example, in some embodiments, R in formula I and any of its subformulas can have any of the applicable respective definitions defined for formula I. 2 and R 3 is hydrogen, C optionally substituted with 1 to 3 fluorines 1-4 Alkyl, C 3-6 In some embodiments, R in formula I and any of its subformulas is independently selected from cycloalkyl, cycloalkyl, and halogen. 2 and R 3 may be independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some embodiments, R in formula I and any of its subformulas is 2 and R 3In some embodiments, R in formula I and any of its subformulas may both be isopropyl or both be cyclopropyl. 2 and R 3 may be different, R 2 and R 3 is hydrogen or methyl. In some embodiments, in formula I and any of its subformulas, Het is (R 4 ) n and together with U. TIFF0007679338000050.tif28128, where n is 0, 1, or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, in formula I and any of its subformulas, Het is (R 4 ) n and together with U. In some embodiments, in formula I and any of its subformulas, Het is (R 4 ) n and together with U. TIFF0007679338000052.tif26129. In some embodiments, R 5 and R 6 and R may both 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, in formula I and any applicable subformulas, A 1 and A 2In some embodiments, in formula I and any applicable subformulas, A 1 and A 2 may be different, for example, A 1 and A 2 One of the two is N, and A 1 and A 2 and the other is CH. In some embodiments, in formula I and any subformula, A 3 may be N. In some embodiments, in formula I and any subformula, A 4 In some embodiments, in formula I and any subformula, A 5 may be N. In some embodiments, in formula I and any subformula, R 7 is hydrogen, F, Cl, methyl, or CF 3 In some embodiments, R 7 may be F. In some embodiments, R 7 In some embodiments, in formula I and any subformula, R 8 are each independently F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, in formula I and any subformula, R 8 are each independently F, Cl, -OH, or -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, in formula I and any subformula, R may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1 to 3 groups selected from alkoxy. 8 teeth, TIFF0007679338000054.tif17128.

[0045] To further illustrate, using a subformula of formula I-3A as an example, some specific embodiments of the present disclosure include exemplary compounds of formula I having formula I-3A-C or formula I-3A-N, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000055.tif92154In formula, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 40 , Het and n may be any of the definitions herein for each variable. For example, typically, R 2 and R 3 are each independently a hydrogen atom or a C group optionally substituted with 1 to 3 fluorines. 1-4 Alkyl, C 3-6 In some embodiments, R in Formula I-3A-C or I-3A-N may be selected from cycloalkyl, cycloalkyl, and halogen. 2 and R 3 may be independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some embodiments, R in Formula I-3A-C or Formula I-3A-N 2 and R 3 In some embodiments, R in formula I-3A-C or I-3A-N may both be isopropyl or both be cyclopropyl. 2 and R 3may be different, for example, R 2 and R 3 is hydrogen, F or methyl, and R 2 and R 3 In some embodiments, in Formula I-3A-C or Formula I-3A-N, R 2 and R 3 One of the two may be F, and R 2 and R 3 The other 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 In some embodiments, in formula I-3A-C or formula I-3A-N, R 2 and R 3 can be methyl, and R 2 and R 3 The other 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. As will be appreciated by those of skill in the art, R 2 and R 3 When the atropisomers are different, the compound of formula I-3A-C or formula I-3A-N may, for example, exist as a mixture of atropisomers in any proportion. In some embodiments, the compound of formula I-3A-C or formula I-3A-N, as applicable, may exist as isolated individual atropisomers that are substantially free of other atropisomers (e.g., contain less than 20%, less than 10%, less than 5%, less than 1%, or contain undetectable amounts by weight, HPLC area, or both). Exemplary methods for isolating atropisomers are described herein, see, for example, the Examples section.

[0046] Typically, R in formula I-3A-C or formula I-3A-N 10 and R 40 are independently hydrogen and C 1-4 In some embodiments, R in formula I-3A-C or I-3A-N may be selected from alkyl. 40 In some embodiments, R in formula I-3A-C or formula I-3A-N may be hydrogen. 10 is C 1-4 It may be alkyl, preferably methyl.

[0047] Typically, in formula I-3A-C or formula I-3A-N, Het is (R 4 ) n and Together with TIFF0007679338000056.tif17128, TIFF0007679338000057.tif28128, where n is 0, 1 or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, in formula I-3A-C or I-3A-N, Het is (R 4 ) n and Together with TIFF0007679338000058.tif17128, the following formula is obtained: In some embodiments, in formula I-3A-C or formula I-3A-N, Het may be represented by (R 4 ) n and Together with TIFF0007679338000060.tif17128, this gives the following formula: TIFF0007679338000061.tif26129. In some embodiments, R 5 and R 6 In some embodiments, both R5 is F or OMe, and R 6 is hydrogen. In some embodiments, R 5 is hydrogen and R 6 Ha-CH 2 -OMe or TIFF0007679338000062.tif17128. In some embodiments, in formula I-3A-C or formula I-3A-N, Het is (R 4 ) n and Together with TIFF0007679338000063.tif17128, this gives the following formula: It may also be represented as TIFF0007679338000064.tif30128.

[0048] R in formula I-3A-C or formula I-3A-N 7 is typically hydrogen, F, Cl, methyl, or CF 3 In some embodiments, R 7 may be F. In some embodiments, R 7 may be Cl.

[0049] R in formula I-3A-C or formula I-3A-N 8 is typically F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in Formula I-3A-C or Formula I-3A-N may be phenyl optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 are F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in Formula I-3A-C or Formula I-3A-N may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 teeth, In some embodiments, R in Formula I (e.g., any subformula in 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) can be selected from the group consisting of: 8 teeth, The file is TIFF0007679338000066.tif15128.

[0050] Some embodiments of the present disclosure also relate to compounds of formula II, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000067.tif55128In formula, G 1 is hydrogen, -COOH, -COOR 23 , -CONR 21 R 22 , -CN, optionally substituted alkyl, alkenyl, alkynyl, or carbocycle (e.g., cycloalkyl), such as C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 cycloalkyl, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl is F, OH, protected OH, and C 1-4 alkoxy; or G1 -XR 1 and; where X is O, NR 10 , S, S.O. 2 or an optionally substituted 4- to 7-membered heterocycle; R 1 is hydrogen, optionally substituted alkyl (e.g., C 1-4 alkyl), or L-R 20 and where L is absent or optionally substituted alkylene (e.g., C 1-4 alkylene), optionally substituted heteroalkylene (e.g., C 1-4 heteroalkylene), optionally substituted carbocycles (e.g., C 3-6 carbocyclic ring) or an optionally substituted heterocyclic ring (e.g., a 4- to 7-membered heterocyclic ring); Here, R 20 is hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, e.g., 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- to 7-membered heterocyclyl; Here, R 10 , R 21 , and R 22 Each of the following is independently selected from each occurrence: hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, e.g., 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 R is a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; 23 is independently at each occurrence hydrogen, optionally substituted alkyl, alkenyl, or alkynyl, e.g., optionally substituted C1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; A 1 , A 2 , A 3 , A 4 , and A 5 Each of the following may be independently 30 or N, Here, R 30 is independently at each occurrence hydrogen, halogen (e.g., F, Cl), optionally substituted C 1-4 Alkyl, optionally substituted alkoxy (e.g., C 1-4 alkoxy); Alternatively, where applicable, R 1 , X, and A 1 taken together form an optionally substituted ring structure, e.g., an optionally substituted heterocyclic or heteroaryl ring; Het is one or more R 4 Group, (R 4 ) n is a 4- to 10-membered heterocycle optionally substituted with Here, R 4 is independently at each occurrence an optionally substituted alkyl, alkenyl or alkynyl, or a 3- or 4-membered ring, e.g., R 4 For each occurrence, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl; or two R 4 The groups may be linked together to form a ring structure, for example a 3- to 6-membered ring structure; U represents an electrophilic moiety capable of forming a covalent bond with a cysteine ​​residue of a KRAS protein, e.g., a KRAS G12C mutant protein; R 7 is hydrogen, halogen, -CN, a 3- to 4-membered ring (e.g., cyclopropyl), an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 is alkoxy; and R 8 is optionally substituted aryl or optionally substituted heteroaryl.

[0051] Various groups are represented by G in formula II. 1 In some embodiments, G 1 may be hydrogen. In some embodiments, G 1 -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, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 Cycloalkyl includes, for example, F, -OH, protected OH, and C 1-4 In some embodiments, G in Formula II is optionally substituted with 1 to 3 groups each independently selected from alkoxy. 1 is a hydroxyl-substituted C 1-6 Alkyl, e.g., -C(CH 3 ) 2 Hydroxyl-substituted C such as -OH 1-4 In some embodiments, G in formula II may be alkyl. 1 is a hydroxyl-substituted C 3-6 Cycloalkyl, e.g., hydroxyl-substituted C 3-5In some embodiments, G in formula II can be cycloalkyl. 1 -XR 1 which may have any of the definitions defined in the context of formula I and its subformulas. In some embodiments, G in formula II 1 is hydrogen, methyl, -COOH, OCF 2 H, -OCF 3 , cyclopropyl, -C(CH 3 ) 2 OH, CF 3 In some preferred embodiments, G in formula II may be 1 is hydrogen.

[0052] In some embodiments, the variable R in formula II 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.

[0053] For example, in some embodiments, U in formula II is TIFF0007679338000068.tif15128, where R 5 and R 6 is defined herein. For example, in some embodiments, R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 may form a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is, independently at each occurrence, 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 In some embodiments, in formula II, Het is a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group. 4 ) n and together with U. TIFF0007679338000069.tif28128, where n is 0, 1, or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, in formula II, Het is (R 4 ) n and together with U. TIFF0007679338000070.tif It may be represented by 26129. In some embodiments, in Formula II, Het is (R 4 ) n and together with U, TIFF0007679338000071.tif It may be represented by 25129. In some embodiments, both R 5 and R 6 may 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 TIFF0007679338000072.tif is 17128. In some embodiments, A 1 and A 2 in Formula II may be N. In some embodiments, A 1 and A 2 in Formula II may be different, if applicable, 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 3 in Formula II may be N. In some embodiments, A 4 in Formula II may be CH. In some embodiments, A 5 in Formula II may be N. In some embodiments, R 7 in Formula II may be hydrogen, F, Cl, methyl, or CF 3 . In some preferred embodiments, R 7 is F or Cl. In some embodiments, R 7 may be F. In some embodiments, R 7 may be Cl. In some embodiments, R 8 in Formula II is F, Cl, -OH, -NH 2 , a protected hydroxyl group, a protected amino group, C1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in Formula II may be phenyl, optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 are F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in Formula II may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 teeth, In some preferred embodiments, R in formula II may be selected from the group consisting of 8 teeth, The file is TIFF0007679338000074.tif15128.

[0054] Introducing a dicyclopropyl group into formula II provides various advantages. As shown in the Examples section and Figures 1-3, certain compounds of formula II, such as compounds 44 and 126, have better anticancer efficacy in some animal models than the current clinical compound AMG-510. The introduction of a 4,6-dicyclopropylpyrimidin-5-yl group may also lead to improved in vitro inhibition of RAS proteins (e.g., KRAS G12C). As discussed herein, data exists showing that changing an isopropylpyrimidin-5-yl group to the corresponding cyclopropylpyrimidin-5-yl leads to a 2- to 6-fold decrease in potency. However, the trend is consistent with the introduction of R in formula II. 8The reverse occurs when the group is a 2-amino-6-fluoro-phenyl group. For example, compounds 44 and 126 have been found to have better potency in inhibiting KRAS G12C than their corresponding isopropyl analogues. Furthermore, the introduction of a 4,6-dicyclopropylpyrimidin-5-yl group may also lead to improved in vivo profiles, such as efficacy and / or safety profiles in the treatment of cancer. As discussed herein, when compared to the control compounds, compounds 44 and 126 have better overall pharmacokinetic ("PK") profiles, such as better human hepatocyte clearance profiles and better overall rat PK profiles with significantly improved oral bioavailability. These data are also expected to provide better in vivo profiles, such as efficacy and / or safety profiles.

[0055] In some embodiments, the disclosure also provides a compound of formula III, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000075.tif48128In formula, 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, for example, any of those defined herein for each variable in the context of Formula I and its subformulas or Formula II.

[0056] For example, in some embodiments, in formula III, G 1 is hydrogen, methyl, cyclopropyl, -C(CH 3 ) 2 OH, CF 3 In some embodiments, U in formula III can be: TIFF0007679338000076.tif13128, where R 5 and R6 is defined herein. In some embodiments, in formula III, Het is (R 4 ) n and together with U. TIFF0007679338000077.tif27128, where n is 0, 1 or 2, where R 4 is independently for each occurrence methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 In some embodiments, in formula III, Het is (R 4 ) n and together with U. In some embodiments, in formula III, Het may be represented by the formula: 4 ) n and together with U. TIFF0007679338000079.tif26129. In some embodiments, R 5 and R 6 In some specific embodiments, both R 5 is F or OMe, and R 6 is hydrogen. In some specific embodiments, R 5 is hydrogen and R 6 Ha-CH 2 -OMe or TIFF0007679338000080.tif17128. In some embodiments, R 2 and R 3 may be independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some specific embodiments, R 2 and R 3 In some embodiments, both of R 2 and R 3 In some embodiments, both of R2 and R 3 are the same. In some embodiments, R 2 and R 3 are different. In some embodiments, R 2 and R 3 In some embodiments, one of A in formula III is hydrogen or methyl. 1 and A 2 In some embodiments, A in formula III can be N. 1 and A 2 may be different, for example, A 1 and A 2 One of them is N and the other is A 1 and A 2 The other of A in formula III is CH. 3 In some embodiments, A in formula III may be N. 4 In some embodiments, A in formula III can be CH. 5 may be N. In some embodiments, R in formula III 7 is hydrogen, F, Cl, methyl, or CF 3 In some embodiments, R 7 may be F. In some embodiments, R 7 may be Cl.

[0057] In some embodiments, the disclosure also provides a compound of formula IV, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000081.tif61128In formula, G 1 , R 2 , R 3 , R 7 , R 8 , A 1 , A 2 , A 3 , A 4 , and A 5 may be, for example, any of the variables defined herein in the context of Formula I and its subformulas or Formula II.

[0058] For example, in some embodiments, G in formula IV 1 is hydrogen, methyl, cyclopropyl, -C(CH 3 ) 2 OH, -CF 3 In some embodiments, R 2 and R 3 may be independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl. In some specific embodiments, R 2 and R 3 In some embodiments, both of R 2 and R 3 In some embodiments, both of R 2 and R 3 are the same. In some embodiments, R 2 and R 3 are different. In some embodiments, R 2 and R 3 In some embodiments, one of A in formula IV is hydrogen or methyl. 1 and A 2 In some embodiments, A in formula IV may be N. 1 and A 2 may be different, for example, A 1 and A 2 One of the two is N, and A 1 and A 2 In some embodiments, the other of A in formula IV is CH. 3 In some embodiments, A in formula IV can be N. 4 In some embodiments, A in formula IV can be CH. 5 may be N. In some embodiments, R in formula IV 7 is hydrogen, F, Cl, methyl, or CF 3 In some embodiments, R 7 may be F. In some embodiments, R 7 In some embodiments, R in formula IV can be Cl.8 are F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in formula IV may be phenyl, optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 are F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 In some embodiments, R in formula IV may be a bicyclic heteroaryl (e.g., indazolyl) optionally substituted with 1 to 3 groups each independently selected from alkoxy. 8 teeth, In some embodiments, R in formula IV may be selected from the group consisting of: 8 teeth, The file is TIFF0007679338000083.tif15128.

[0059] In some embodiments, the present disclosure also provides a compound selected from any of compound numbers 1-186, or a pharma- ceutically acceptable salt thereof. TIFF0007679338000084.tif228159TIFF0007679338000085.tif216165TIFF0007679338000086.tif227156TIFF0007679338 000087.tif237159TIFF0007679338000088.tif207167TIFF0007679338000089.tif230167TIFF0007679338000090.tif40161

[0060] In some embodiments, the disclosure also provides a compound selected from any of compound numbers 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 pharma- ceutically acceptable salt thereof. In any embodiment described herein, unless otherwise specified or contradicted by context, the compound of the disclosure may be compound number 44, 126, or 145, or a pharma- ceutically acceptable salt thereof.

[0061] 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 WO2019 / 213516.

[0062] Further exemplary embodiments In some embodiments, the present disclosure provides the following alternative exemplary embodiments.

[0063] Embodiment 1. A compound of formula I-3A-1, I-3B-1, I-3C-1, I-4A-1, I-4B-1 or I-4C-1, or a pharma- ceutically acceptable salt thereof: In the formula TIFF0007679338000091.tif237154, in each corresponding formula, A 2 is CH or N; R 2 and R 3 are each independently hydrogen, halogen, -OH, -CN, or 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- to 7-membered heterocyclic ring, or optionally substituted C 1-4 is alkoxy; Het is an independently selected R 4 Group, (R 4 ) n where n is 0, 1, 2, or 3, and R 4 is expressed independently for each occurrence as C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3- or 4-membered ring (e.g., cyclopropyl), fluorine-substituted C 1-4 Alkyl, Hydroxyl Substituted C 1-4 Alkyl or cyano substituted C 1-4 alkyl; or two R 4 The groups may be linked together to form a 3- to 6-membered ring structure; R 5 and R 6 are each independently hydrogen, halogen, -CN, -COOR 23A , -CONR 21A R 22A , optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 3-6 carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R 5 and R 6 are linked together and optionally substituted C 3-6 may form a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R 21A and R 22A Each of the following is independently selected from the group consisting of hydrogen, optionally substituted C 1-4Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 23A is independently at each occurrence 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or an oxygen protecting group; R 7 is hydrogen, halogen, CN, a 3- to 4-membered ring (e.g., cyclopropyl), an optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4 Alkynyl, or optionally substituted C 1-4 is alkoxy; 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 a carbocycle, an optionally substituted 4- to 7-membered heterocycle, or a nitrogen protecting group; and R 40 and R 41 Each of the following is independently selected from hydrogen, OH, CN, halogen, optionally substituted C 1-4 Alkyl, optionally substituted C 2-4 Alkenyl, optionally substituted C 2-4Alkynyl, optionally substituted C 1-4 Alkoxy, optionally substituted C 1-4 Heteroalkyl, optionally substituted C 3-6 It is a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring.

[0064] Embodiment 2. In each formula, A 2 is CH, or a pharma- ceutically acceptable salt thereof.

[0065] Embodiment 3. In each formula, A 2 is N, or a pharma- ceutically acceptable salt thereof.

[0066] Embodiment 4. In each formula, R 2 and R 3 are each independently substituted with hydrogen or 1 to 3 fluorines; 1-4 Alkyl, C 3-6 The compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is selected from cycloalkyl, and halogen.

[0067] Embodiment 5. In each formula, R 2 and R 3 is independently selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, F, and Cl; or a pharma- ceutically acceptable salt thereof.

[0068] Embodiment 6. In each formula, R 2 and R 3 are both isopropyl or both cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0069] Embodiment 7. In each formula, R 2 and R 3 is hydrogen, F or methyl, and R 2 and R 3and the other is isopropyl or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0070] Embodiment 8. In each formula, R 2 and R 3 One of them is F and the other is R 2 and R 3 The other of R 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 The compound according to any one of embodiments 1-3, wherein is isopropyl or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0071] Embodiment 9. In each formula, R 2 and R 3 is methyl, and R 2 and R 3 the other is isopropyl or cyclopropyl, e.g., R 2 is methyl and R 3 is isopropyl or cyclopropyl; or R 3 is methyl and R 2 The compound according to any one of embodiments 1-3, wherein is isopropyl or cyclopropyl, or a pharma- ceutically acceptable salt thereof.

[0072] Embodiment 10. The compound according to any one of embodiments 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein, where applicable, in each formula, the compound is present as an isolated individual atropisomer substantially free of other atropisomers (e.g., containing less than 20%, less than 10%, less than 5%, less than 1%, or having undetectable amounts by weight, by HPLC area, or both).

[0073] Embodiment 11. Where applicable, in each formula, R 10 , R 40 , and R 41 are independently hydrogen and C1-4 11. The compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein R is selected from alkyl.

[0074] Embodiment 12. In each formula, R 40 The compound of any one of embodiments 1-11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0075] Embodiment 13. Where applicable, in each formula, R 10 C 1-4 The compound according to any one of embodiments 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein R is alkyl, preferably methyl.

[0076] In each of the formulas, Het is (R 4 ) n and Together with TIFF0007679338000092.tif17128, TIFF0007679338000093.tif28128, where n is 0, 1, or 2, where R 4 independently for each occurrence, methyl, ethyl, -CF 3 , -CF 2 H, -CH 2 OH, or CH 2 The compound according to any one of embodiments 1-13, wherein R is CN, or a pharma- ceutically acceptable salt thereof.

[0077] In each of the formulas, Het is (R 4 ) n and Together with TIFF0007679338000094.tif17128, A compound according to any one of embodiments 1 to 13, represented by TIFF0007679338000095.tif26129, or a pharma- ceutically acceptable salt thereof.

[0078] In each of the formulas, Het is (R 4 ) n and Together with TIFF0007679338000096.tif17128, A compound according to any one of embodiments 1 to 13, represented by TIFF0007679338000097.tif26129, or a pharma- ceutically acceptable salt thereof.

[0079] Embodiment 17. In each formula, R 5 and R 6 17. The compound of any one of embodiments 1-16, or a pharma- ceutically acceptable salt thereof, wherein both are hydrogen.

[0080] Embodiment 18. In each formula, R 5 is F or OMe, and R 6 The compound of any one of embodiments 1-16, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

[0081] Embodiment 19. In each formula, R 5 is hydrogen and R 6 Ga-CH 2 -OMe or TIFF0007679338000098.tif17128, or a pharma- ceutically acceptable salt thereof.

[0082] In each of the formulae, Het is (R 4 ) n and Together with TIFF0007679338000099.tif17128, A compound according to any one of embodiments 1 to 13, represented by TIFF0007679338000100.tif30128, or a pharma- ceutically acceptable salt thereof.

[0083] Embodiment 21. In each formula, R 7 is hydrogen, F, Cl, methyl or CF 3 21. The compound of any one of embodiments 1-20, wherein:

[0084] Embodiment 22. In each formula, R 7 The compound according to any one of embodiments 1-20, wherein is F, or a pharma- ceutically acceptable salt thereof.

[0085] Embodiment 23. In each formula, R 7 The compound according to any one of embodiments 1-20, or a pharma- ceutically acceptable salt thereof, wherein is Cl.

[0086] Embodiment 24. In each formula, R 8 F, Cl, -OH, NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 24. The compound of any one of embodiments 1-23, or a pharma- ceutically acceptable salt thereof, wherein phenyl is optionally substituted with 1 to 3 groups, each independently selected from alkoxy.

[0087] Embodiment 24.R 8 F, Cl, -OH, -NH 2 , protected hydroxyl group, protected amino group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), C 1-4 Alkoxy, Fluorine-substituted C 1-4 Alkyl and fluorine substituted C 1-4 The compound of any one of embodiments 1-23, which is bicyclic heteroaryl (e.g., indazolyl), optionally substituted with 1 to 3 groups, each independently selected from alkoxy, or a pharma- ceutically acceptable salt thereof.

[0088] Embodiment 25. In each formula, R 8 but, TIFF0007679338000101.tif17128, preferably TIFF0007679338000102.tif15128, or a pharma- ceutically acceptable salt thereof.

[0089] Embodiment 26. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0090] Embodiment 27. A method for inhibiting KRAS G12C mutant protein in a cell, comprising contacting said cell with a compound according to any one of embodiments 1 to 25, or a pharma- ceutically acceptable salt thereof.

[0091] 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 to 25, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 26.

[0092] Embodiment 29. The method of 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 colorectal cancer.

[0093] Embodiment 30 The method of embodiment 28 or 29, further comprising treating the subject with an additional therapy.

[0094] Embodiment 31 The method of embodiment 30, wherein the additional therapy is a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, or immunotherapy.

[0095] Embodiment 32. The method of any one of embodiments 28 to 31, wherein the subject has a G12C mutation in KRAS, HRAS, and / or NRAS.

[0096] Synthesis method The compounds of the present disclosure can be readily synthesized by one of skill in the art in light of the present disclosure, and exemplary syntheses are also provided in the Examples section.

[0097] The following synthetic methods for formula I are exemplary and will be understood by those skilled in the art to be capable of synthesizing XR 1 The starting material or intermediate having a group is converted to the corresponding G 1 The same can be applied to the synthesis of compounds of formula II by replacing starting materials or intermediates with groups. Compounds of formula III or IV can also 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 shown in the schemes herein.

[0098] As shown in Scheme 1, in some embodiments, compounds of formula I can be prepared by reacting intermediate S-2 with heterocyclic compound S-1 under appropriate conditions, where Lg 1 is a leaving group such as a halide or a triflate (CF 3 SO 3 -) or a sulfonate leaving group such as a tosylate. In some embodiments, S-1 can be reacted with S-2 in a suitable solvent with a base such as an amine base (e.g., diisopropylethylamine) or an inorganic base such as, for example, a carbonate base. In some embodiments, R 8A and R 8 are the same. However, in some embodiments, R 8A and R 8 may be different, and the synthesis method may include 8A R 8 For example, in some embodiments, R 8A may be a leaving group such as a halide or sulfonate leaving group, and the reaction product of S-1 and S-2 may be coupled, via one or more steps, with a suitable partner to give the desired R 8 Typically, R 8The introduction of the group is mediated by a metal-catalyzed coupling reaction, such as the palladium-catalyzed coupling reactions exemplified herein. Reagents and reaction conditions useful for palladium-catalyzed coupling reactions are generally known, see, for example, WO2019 / 051291, WO2018 / 119183, and WO2018 / 217651. In some embodiments, a suitable partner is R 8 -B(OH) 2 In some embodiments, R 8A is converted to a boronic acid or ester and then reacted with R 8 -Lg 2 where Lg 2 is a leaving group such as a halide or sulfonate leaving group. Other suitable coupling reactions, such as Stille or Negishi coupling, are known in the art and can be applied in light of the present invention to synthesize the compounds described herein. Example 4 provides an example of the reaction of S-1 and S-2, where A 3 is N and Lg 1 is Cl. Other compounds of formula I can be prepared similarly. The variables X, R in Scheme 1 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 may be any of those defined herein. TIFF0007679338000103.tif64143

[0099] In some cases, R 8 and / or the introduction of U groups can proceed after the incorporation of a heterocycle that does not have a U group. For example, as shown in Scheme 2, the heterocycle of S-3 can be reacted with S-2 to form intermediate S-4. 1is typically hydrogen or a nitrogen protecting group such as Boc. Typically, S-4 can be deprotected under appropriate conditions to introduce a U group. This deprotection step generates an NH moiety, which can be reacted with a suitable U group donor to obtain formula I. In general, such a U group donor is of the formula U-Lg 3 where Lg 3 is OH, Cl, or other suitable leaving group, and exemplary U group donors are TIFF0007679338000104.tif16128 molecule, or acyl chloride, TIFF0007679338000105.tif16128, where R 5 and R 6 may be any of those defined herein. As in Scheme 1, R 8A is R 8 It may be the same as or different from R. 8A R 8 If different from R, the synthesis method also 8A R 8 As mentioned above, R 8A may be a leaving group such as a halide or sulfonate leaving group, and may be coupled with an appropriate partner via one or more steps to give the desired R 8 If applicable, R 8A R 8 The conversion to can be carried out either before or after the introduction of the heterocycle and / or U group of S-3. 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 may be any of those defined herein. TIFF0007679338000106.tif60164

[0100] In some embodiments, the -XR 1 Groups may be derived from other compounds of formula I. For example, in some embodiments, -XR 1 The group is -SO 2 Me, and such compounds may be -XR 1 It can be prepared from the corresponding compound of formula I, where the group is -S-Me, via an oxidation process. 1 The group is -SO 2 The compound of formula I in which Me is a methyl group may also be used as a starting material for the synthesis of other compounds of formula I. As will be apparent to one skilled in the art, such conversions may be carried out on any of the suitable intermediates described herein. 1 Other derivatizations of groups are also possible and in some cases can be used to prepare compounds of the disclosure.

[0101] The intermediate compound S-2 can typically be prepared by a method that includes forming a 6,6-bicyclic ring. For example, Scheme 3 shows A 3 and A 5 A typical process for preparing compound S-2, where Lg is N, is shown. Thus, compound S-5 can be coupled with compound S-6 via a carbonyl group donor such as oxalyl chloride to form intermediate S-7, where Lg is N. 4 is a leaving group such as a halide (e.g., Cl) or a sulfonate leaving group. Compounds of S-8 can then be formed, typically by base-mediated cyclization of S-7. S-8 can then be reacted with, for example, POCl 3 or other suitable reagents to form compounds of S-9. Exemplary syntheses of various compounds of S-5 are provided in the Examples section. Other compounds of S-5 can be similarly synthesized in light of the present invention. Compounds of S-6 may be commercially available or may be prepared by one of ordinary skill in the art. The variables X, R in Scheme 3 are 1 , R 2 , R3 , R 7 , R 8A , A 1 , A 2 , and A 4 may be any of those defined herein. TIFF0007679338000107.tif95139

[0102] As will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis" (4th Edition, PGM Wuts, TW Greene, John Wiley, 2007) and references cited therein. The reaction reagents described therein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures 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 supplements (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) or the latest editions available at the time of filing this application, or obvious modifications thereof.

[0103] Pharmaceutical Compositions Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0104] The pharmaceutical composition may optionally include a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition includes a compound of the present disclosure (e.g., a compound of any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof) and a pharma- ceutically acceptable excipient. Pharmaceutically acceptable excipients are known in the art. Non-limiting suitable excipients include, for example, encapsulating agents or additives, such as absorption enhancers, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrants, emulsifiers, swelling agents, fillers, flavoring agents, humectants, lubricants, flavoring agents, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. Also refer to Remington's The Science and Practice of Pharmacy, 21st Edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in the formulation of pharmaceutical compositions and known techniques for their preparation.

[0105] The pharmaceutical composition may include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition includes a compound of formula I (e.g., any compound 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), formula II, formula III, formula IV, compound numbers 1-186, or a pharma- ceutically acceptable salt thereof), e.g., in a therapeutically effective dose. In any of the embodiments described herein, the pharmaceutical composition may include a therapeutically effective amount of a compound selected from compound numbers 1-186, or a pharma- ceutically acceptable salt thereof.

[0106] Pharmaceutical compositions can be formulated for delivery via any known route of administration, including, but not limited to, oral, parenteral, inhalation, and the like.

[0107] In some embodiments, pharmaceutical composition can be formulated for oral administration.Oral formulation can be presented as individual units such as capsules, pills, cachets, lozenges or tablets, each of which contains a predetermined amount of active compound; as powder or granules; as a solution or suspension in aqueous or non-aqueous liquid; or as oil-in-water or water-in-oil emulsion.Excipients for preparing compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, corn ... corn oil, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethylcellulose, oil), potassium phosphates, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium laurate sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0108] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous injection or intramuscular injection, etc.). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for the manufacture of parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut 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.

[0109] In some embodiments, the pharmaceutical composition is formulated for inhalation. Inhalable formulations can be formulated as aerosols that can be administered via nasal sprays, dry powders, or metered dose inhalation. Excipients for preparing inhalation formulations are known in the art. Non-limiting suitable excipients include, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, and mixtures of these substances. Sprays can further include propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0110] The pharmaceutical composition can include various amounts of the compound of the present disclosure, depending on various factors such as the use, potency and selectivity of the compound. In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of a compound of the present disclosure (e.g., any of the compounds 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 V, compound numbers 1-186, or a pharma- ceutically acceptable salt thereof). In some embodiments, the pharmaceutical composition includes a therapeutically effective amount of a compound of the present disclosure and a pharma- ceutically 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 described herein, which may depend on the person receiving the treatment, the disease or disorder being treated and its severity, the composition 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 clearance rate, and whether other drugs are used concomitantly.

[0111] For veterinary use, the compounds of the present disclosure can be administered in an appropriately acceptable formulation in accordance with normal veterinary practice. A veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0112] In some embodiments, the compounds of the present disclosure can be used alone or in combination with another therapeutic agent or intervention conventionally used to treat such diseases, and all components necessary for the treatment of KRAS-related diseases can be packaged in a kit. Specifically, in some embodiments, the present invention provides a kit for use in therapeutic intervention of a disease, including a packaged pharmaceutical, the pharmaceutical comprising a compound disclosed herein, buffers and other components for preparing the pharmaceutical in a deliverable form, and / or a device for delivering such pharmaceutical, and / or any therapeutic agent used in combination therapy with the compounds of the present disclosure, and / or instructions for treating the disease packaged with the pharmaceutical. The instructions may be fixed on any tangible medium, such as printed paper, computer-readable magnetic or optical media, or may be instructions that refer to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0113] Treatment method The compounds of the present disclosure are useful as therapeutically active substances for the treatment and / or prevention of diseases or disorders associated with RAS, eg, KRAS G12C.

[0114] In some embodiments, the disclosure provides methods of inhibiting RAS-mediated cell signaling comprising contacting a cell with an effective amount of one or more compounds of the disclosure (e.g., any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof). Inhibition of RAS-mediated signaling can be assessed and demonstrated by a variety of methods known in the art. Non-limiting examples include: (a) a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) a decrease in the K off or GDP growth rateoff (d) decreased levels of downstream signaling molecules in the RAS pathway, such as decreased levels of pMEK, pERK, or pAKT; and / or (e) decreased binding of the RAS complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays are available to measure one or more of the above.

[0115] In some embodiments, the disclosure provides 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 disclosure (e.g., a compound of any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof).

[0116] In some embodiments, the disclosure provides a method of treating a disease or disorder, e.g., a cancer associated with a G12C mutation in KRAS, HRAS, and / or NRAS, such as a KRAS G12C associated cancer, in a subject in need thereof. In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound of the disclosure (e.g., a compound of any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof) or a therapeutically effective amount of a pharmaceutical composition described herein.

[0117] In some embodiments, a method of treating cancer is provided, the method comprising administering to a subject in need thereof an effective amount of a compound of the disclosure (e.g., a compound of any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound of the disclosure. In some embodiments, the cancer comprises a G12C mutation in KRAS, HRAS and / or NRAS, e.g., a G12 mutation in KRAS. Methods for determining whether a tumor or cancer contains a G12C mutation in KRAS, HRAS and / or NRAS are known in the art, 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., those described herein). In some embodiments, the cancer is MYH-associated polyposis. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, or cholangiocarcinoma.Non-limiting examples of cancers also include acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, atypical teratoma, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders (CHD), chronic myeloproliferative disorders (MMD), chronic myeloproliferative disorders (MMR ... Reproductive disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, DCIS, embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancer, fibrous histiocytic osteoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, cardiac cancer, hepatic cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumors, pancreatic neuroendocrine tumors Tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, primary lobular carcinoma (LCIS), lung cancer, lymphoma, metastatic squamous cell carcinoma with occult primary, midline ductal carcinoma, oral cancerMultiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of bone, nasal cavity cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer , ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymic and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic carcinoma, abnormal cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0118] In some embodiments, the disclosure provides a method of treating a disease or disorder (e.g., a cancer as described herein) in a subject in need of such treatment, the method comprising determining whether the subject has a KRAS, HRAS and / or NRAS G12C mutation, e.g., a KRAS G12C mutation, and determining whether the subject has a KRAS, HRAS and / or NRAS G12C mutation, e.g., a KRAS If the subject is determined to have a G12C mutation, administering to the subject a therapeutically effective dose of at least one compound of the present disclosure (e.g., a compound of any 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, Compound Nos. 1-186, or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition comprising at least one compound of the present disclosure.

[0119] G12C mutations in KRAS, HRAS and / or NRAS have also been identified in hematological malignancies (e.g., cancers affecting blood, bone marrow and / or lymph nodes). Thus, certain embodiments relate to a method for treating hematological malignancies in a subject in need thereof, 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 myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL) and / or other leukemias. In some embodiments, hematological malignancies may further include lymphomas, such as Hodgkin's lymphoma or non-Hodgkin's lymphoma, multiple myeloma, plasma cell malignancies, such as mantle cell lymphoma, and Waldenstrom's macroglubnemia.

[0120] The compounds of the present disclosure may be used as monotherapy or combination therapy. In some embodiments, the combination therapy includes treating the subject with a chemotherapeutic agent, a therapeutic antibody, radiation, cell therapy, or immunotherapy. In some embodiments, the compounds of the present disclosure may also be co-administered to a subject in need thereof (e.g., a subject having a cancer associated with the KRAS G12C mutation described herein) simultaneously or sequentially in any order with additional pharmacoactive compounds. In some embodiments, the additional pharmacoactive compounds may be chemotherapeutic agents, therapeutic antibodies, and the like. Any known chemotherapeutic agent may be used in combination with the compounds of the present disclosure. In some embodiments, the compounds of the present disclosure may be used in combination with radiation therapy, hormone therapy, cell therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0121] Many chemotherapeutic agents are 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 are chemotherapeutic agents such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), venetoclax and adriamycin, and numerous chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules. Non-limiting examples of chemotherapeutic agents include alkylating agents, such as thiotepa and cyclosphosphamide (CYTOXAN™); alkylsulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; aziridines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide, and trimethylolomelamine. ethylenimines and methylamelamines; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Aclacinomycins, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, CasodexTM, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, keramycin Antibiotics such as sirolimus, lodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; frolinic acid Folic acid supplements such as aceglatone, aldophosphamide glycosides, aminolevulinic acid, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elfomithine, elliptinium acetate, etoglucide, gallium nitrate, hydroxyurea, lentinan, lonidamine, mitoguazone, mitoxantrone, mopidamol, nitracrine, pentostatin, phenamet, pirarubicin;These include podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK; razoxane; schizophyllan; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'''-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes such as paclitaxel and docetaxel; retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0122] Suitable chemotherapy cell conditioners also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as tamoxifen (Nolvadex™), raloxifene, 4(5)-imidazoles that inhibit aromatase, 4-hydroxytamoxifen, trioxifene, keoxifene, LY antiestrogens such as 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogues such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11); the topoisomerase inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0123] If desired, the compounds or pharmaceutical compositions of the present disclosure can be administered in combination with commonly prescribed anti-cancer drugs, such as, for example, Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, Avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone ... thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic drugs, antineoplastic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, afatinib 2992, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic drugs, dichloroacetic acid, discordermolide, elsamitrucin, enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, in Drocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucantone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, Proteasome Inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford VV), Swainsonine, Talaporfin, Tariquidar, Tegafur uracil, Temodar, Tesetaxel, Triplatin Tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

[0124] The compounds of the present disclosure may also be used in combination with additional pharmacoactive compounds that interrupt or inhibit RAS-RAF-ERK or PI3K-AKT-TOR signaling pathways. In other such combinations, the additional pharmacoactive compounds are PD-1 and PD-L1 antagonists. The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with an amount of one or more substances selected from EGFR inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, Mcl-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapies including monoclonal antibodies, immunomodulatory imids (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents, GITR agonists, CAR-T cells and BiTEs.

[0125] Exemplary anti-PD-1 or anti-PDL-1 antibodies and methods of use thereof 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 (Disclosure No. WO 2006 / 121168), each of which is expressly incorporated herein by reference. A1), and includes pembrolizumab (Keytruda®), nivolumab (Opdivo®), Yervoy™ (ipilimumab) or tremelimumab (anti-CTLA-4), galiximab (anti-B7.1), M7824 (bifunctional anti-PD-L1 / TGF-β Trap fusion protein), AMP224 (anti-B7DC), BMS-936559 (anti-B7-H1), MPDL3280A (anti-B7-H1), MEDI-570 (anti-ICOS), AMG 404, AMG557 (anti-B7H2), MGA271 (anti-B7H3), IMP321 (anti-LAG-3), BMS-663513 (anti-CD137), PF-05082566 (anti-CD137), CDX-1127 (anti-CD27), anti-OX40 (Providence Health Services), huMAbOX40L (anti-OX40L), Ataccept (anti-TACI), CP-870893 (anti-CD40), Lucatumumab (anti-CD40), Dacetuzumab (anti-CD40), Muromonab-CD3 (anti-CD3), Ipilumumab (anti-CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs). Non-limiting useful additional agents also include anti-EGFR antibodies and small molecule EGFR inhibitors, such as cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib (Tarceva), lapatinib (TykerB), and the like.Non-limiting useful 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. Non-limiting useful 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 lists 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.

[0126] As shown in the Examples section, the combination of Compound Nos. 44, 126, and 145 with various agents including platinum-based drugs (cisplatin or carboplatin), SHP2 inhibitors (RMC-4550, (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspirocyclo[4.5]decan-8-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl)methanol), and MEK inhibitors (trametinib) has been shown to produce synergistic effects in reducing tumor volume in several animal models. Thus, in some embodiments, a compound 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), an SHP2 inhibitor (e.g., RMC-4550, RMC-4630, TNO155), and / or a MEK inhibitor (e.g., trametinib).

[0127] In this specification, administration is not limited to a specific administration route.For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal and parenteral administration.In some embodiments, administration is oral administration.

[0128] Dosage regimens, including dosage, can vary and be adjusted depending on the person being treated, the disease or disorder being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether it is used in conjunction with other drugs.

[0129] definition It is understood that appropriate valence is maintained for all moieties and combinations thereof.

[0130] It is also understood that a particular embodiment of a variable site herein may be the same or different from another particular embodiment having the same identifier.

[0131] The atoms or groups suitable for the variables herein are independently selected. The definitions of the variables may be combined. For example, in Formula I, 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 the formula I, 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" may be combined with any of the other definitions of ", ", ", ", ", ", ", ", ", ", ", ", ", ")")

[0132] Definitions of specific functional groups and chemical terms are discussed in more detail below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover), and specific functional groups are generally defined as described herein. Additionally, general principles of organic chemistry, and specific functional groups and reactivity are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0133] The compounds of the present disclosure may contain one or more asymmetric centers and / or axial asymmetry and therefore may exist in various isomeric forms (e.g., enantiomers and / or diastereomers). For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, atropisomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from 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; alternatively, 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); and Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically depicted, it is understood that with respect to that particular chiral center or axial asymmetry, the compound will exist predominantly as the depicted stereoisomer, e.g., the amount of other stereoisomers is less than 20%, less than 10%, less than 5%, less than 1%, or undetectable by weight, HPLC area, or both. The presence and / or amount of stereoisomers can be determined by one of skill in the art in light of this disclosure, including the use of chiral HPLC.

[0134] The compounds of the present disclosure can have atropisomers. In any of the embodiments described herein, if applicable, the compounds of the present disclosure can exist as a mixture of atropisomers in any ratio. In some embodiments, if applicable, the compounds can exist as isolated single atropisomers that are substantially free of other atropisomers (e.g., less than 20%, less than 10%, less than 5%, less than 1%, or undetectable amounts by weight, HPLC area, or both). The Examples section provides some exemplary isolated atropisomers of the compounds of the present disclosure. As will be understood by those skilled in the art, if rotation is restricted around a single bond, e.g., a biaryl single bond, the compound may exist as a mixture of atropisomers, with each of the individual atropisomers being isolable.

[0135] When a range of values ​​is stated, it is intended to encompass each value and subrange within the range. For example, "C 1-6 " is 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 is intended to encompass.

[0136] As used herein, the term "compound of the present disclosure" or "compound of the present invention" refers to any 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 numbers 1 to 186, and isomers thereof. By "compound number 1-186" is meant any of the compounds described herein according to their isomer-labeled compounds (e.g., deuterium analogs in which one of the hydrogen atoms is replaced with a deuterium atom at or above natural abundance), their possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), their geometric isomers, their atropisomers, their tautomers, their conformers, and / or their pharma-ceutically acceptable salts (e.g., acid addition salts such as HCl salts, or base addition salts such as Na salts). For the avoidance of doubt, Compound No. 1-186 or Compounds 1-186 means the compounds described herein labeled as 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 compositions of the present disclosure in which the compounds are associated with water or a solvent, respectively.

[0137] The compounds of the present disclosure can exist in isotopically labeled or isotopically enriched forms, including one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. The isotopes can be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine include: 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl and 125 Compounds that contain other isotopes of these atoms and / or other atoms are within the scope of this invention.

[0138] As used herein, the terms "administration" of a compound, "administering" a compound, or other variations thereof, refer to providing the compound or a prodrug of the compound to an individual in need of treatment.

[0139] As used herein, the term "alkyl" by itself or as part of another group means a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, alkyl is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl) or the specified number of carbon atoms (i.e., C 1 Alkyl (e.g., methyl), C 2 Alkyl (e.g., ethyl), C 3 In one embodiment, the alkyl group can include a linear C 1-10 In another embodiment, the alkyl is a branched C 3-10 In another embodiment, the alkyl is a linear C 1-6 In another embodiment, the alkyl is a branched C 3-6 In another embodiment, the alkyl is a linear C 1-4 For example, C 1-4 Alkyl means a group selected from methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. 1-4 Alkyl is as defined herein, optionally substituted with one or more permissible substituents as described herein. 1-4 As used herein, the term "alkylene" by itself or as part of another group refers to a divalent group derived from an alkyl. For example, a non-limiting straight chain alkylene is -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH2 -, -CH 2 -CH 2 -etc.

[0140] As used herein, the term "heteroalkyl" refers to an alkyl as defined above in which one or more carbons have been replaced with a heteroatom (e.g., O or N). A heteroalkyl may be specified by its number of carbons. For example, C 1-4 Heteroalkyl means a heteroalkyl containing 1 to 4 carbons. If optionally substituted, any heteroatom or carbon atom of a heteroalkyl may be substituted with an acceptable substituent. As used herein, the term "heteroalkylene" by itself or as part of another group means a divalent group derived from a heteroalkyl.

[0141] As used herein, the term "alkenyl" by itself or as part of another group refers to an alkyl, as defined above, having one, two or three carbon-carbon double bonds. In one embodiment, an alkenyl is 2-6 In another embodiment, the alkenyl is C 2-4 Alkenyl. Non-limiting exemplary alkenyls include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0142] As used herein, the term "alkynyl" by itself or as part of another group refers to an alkyl, 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, an alkynyl is C 2-6 In another embodiment, the alkynyl is C 2-4 Alkynyl. Non-limiting exemplary alkynyls include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0143] As used herein, the term "alkoxy" refers to Ra1 is alkyl; a1 means the group

[0144] As used herein, the term "haloalkyl" by itself or as part of another group means an alkyl substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl substituted with one, two or three fluorine atoms. In one embodiment, a haloalkyl is a C 1-10 In one embodiment, the haloalkyl is C 1-6 In one embodiment, the haloalkyl is C 1-4 It is haloalkyl.

[0145] "Carbocyclyl" or "carbocycle", by itself or as part of another group, refers to a ring system having from 3 to 10 ring carbon atoms ("C 3-10 "Carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 120, 132, 140, 142, 150, 162, 170, 183, 194, 195, 196, 197, 198, 199, 102, 199, 103, 199,

[0146] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group is a group having 3 to 8 ring carbon atoms ("C 3-8In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl").

[0147] "Heterocyclyl" or "heterocycle", by itself or as part of another group, means a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms ("3- to 10-membered heterocyclyl"), each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyls containing one or more nitrogen atoms, the point of attachment may be at either a carbon atom or a nitrogen atom, as valence permits. Heterocyclyls may be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle as defined above is fused to one or more carbocyclyl groups, where the point of attachment is on either the carbocyclyl or the heterocycle, or in which a heterocyclic ring as defined above is fused to one or more aryl or heteroaryl rings, where the point of attachment is on the heterocycle, in which case the number of ring members continues to specify the number of ring members of the heterocyclic ring system.

[0148] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrole-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolane, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. C 6 Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0149] "Aryl," used by itself or as part of another group, refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10 or 14 pi electrons shared in the ring arrangement) having 6 to 14 carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group refers to a group having 6 ring carbon atoms ("C 6 In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl. In some embodiments, an aryl has 14 ring carbon atoms ("C 14 "Aryl"; for example, anthracyl). "Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyls or heterocyclyls, where the radical or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to designate the number of carbon atoms in the aryl ring system.

[0150] "Aralkyl," used by itself or as part of another group, means an alkyl substituted with one or more aryls, preferably one aryl. Examples of aralkyls include benzyl, phenethyl, and the like. Where an aralkyl is optionally substituted, either the alkyl or aryl portion of the aralkyl may be substituted.

[0151] "Heteroaryl" by itself or as part of another group refers to a group of 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 pi electrons shared in the ring arrangement) with ring carbon atoms provided to the aromatic ring system and 1-4 ring heteroatoms each independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the point of attachment may be at either a carbon atom or a nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may contain 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 carbocyclyls or heterocyclyls, and the point of attachment is on the heteroaryl ring, in such cases the number of ring members continues to specify the number of ring members of 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 either on the aryl or heteroaryl ring, and in such cases the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., the ring may contain a heteroatom (e.g., 2-indolyl) or may not contain a heteroatom (e.g., 5-indolyl).

[0152] Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryls containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryls containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0153] "Heteroaralkyl" by itself or as part of another group means an alkyl substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl is designated as being optionally substituted, either the alkyl or the heteroaryl portion of the heteroaralkyl may be substituted.

[0154] As commonly understood by those of ordinary skill in the art, alkylene, alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the divalent radicals corresponding to alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0155] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, refer to the respective groups that are unsubstituted or substituted. In general, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous 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 multiple positions of any given structure are substituted, the substituent may be the same or different at each position. Typically, when substituted, the optionally substituted groups herein may be substituted with 1 to 5 substituents. The substituents may be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents, where applicable.

[0156] Unless specified to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain unchanged or essentially unchanged for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0157] In some embodiments, the "optionally substituted" non-aromatic groups herein are unsubstituted or substituted with F, Cl, -OH, oxo (where applicable), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 and n is 0, 1, 2, or 3 substituents selected from cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, and 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl (e.g., CF 3 ), C 1-4 Alkoxy and fluorine substituted C 1-4 In some embodiments, the "optionally substituted" aromatic groups (including aryl and heteroaryl) herein are unsubstituted or substituted with one, two, or three substituents independently selected from the group consisting of F, Cl, -OH, -CN, -C, -C- ... 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C3-6 and optionally substituted with 1, 2, or 3 substituents independently selected from cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, and 4- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 Alkoxy and fluorine substituted C 1-4 It may be substituted with 1, 2 or 3 substituents independently selected from alkoxy.

[0158] Exemplary carbon atom substituents are 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 、-SO 2 R 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)(ORcc ) 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 + X - 、-P(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 アルキル、C1-10 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, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group; where X - is a counter ion; or the two geminal hydrogens on the carbon atom are groups =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 is replaced by; R aa Each instance of 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- to 14-membered heteroaryl; or two R aa The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently 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- to 14-membered heteroaryl; or two R bb The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd group; where X - is the counter ion; R cc Each instance of is independently hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each example is independently a 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)R ee , -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(=O)(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, and 5- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or two geminal R ddThe substituents may be linked to form =O or =S; where X - is the counterion; R ee Each instance of 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of is independently 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- to 10-membered heteroaryl; or two R ff The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R gg substituted with a group: R gg Each example is independently a 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(C1-6 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(=NH)(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 1-6alkyl), -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 O.C. 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- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R ggThe substituents may be linked to form =O or =S; where X - is the counter ion.

[0159] A "counterion" or "anionic counterion" is a negatively charged group associated with a positively charged group to maintain electrical neutrality. Anionic counterions may be monovalent (i.e., contain one formal negative charge). Anionic counterions may be multivalent (i.e., contain more than one formal negative charge), such as divalent or trivalent. Exemplary counterions are halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , 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, etc.), carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, etc.), BF 4 - , P.F. 4 - , P.F. 6 - , AsF 6 - , SbF 6 - , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 ] - , B.P.h. 4 - , Al(OC(CF 3 )3 ) 4 - and carborane anions (e.g., CB 11 H 12 - or (HCB 11 Me 5 Br 6 ) - Exemplary counter ions, which may be multiply charged, include CO 3 2- , H.P.O. 4 2- , P.O. 4 3- , B 4 O 7 2- , S.O. 4 2- , S 2 O 3 2- , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalate, aspartate, glutamate, etc.), and carboranes.

[0160] "Halo" or "halogen" means fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0161] "Acyl" means -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)SR aa where R aa and R bb is defined herein.

[0162] Nitrogen atoms can be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are 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(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)(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 6-14aryl, and 5- to 14-membered heteroaryl; or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined above.

[0163] In certain embodiments, the substituent present on a nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include -OH, -OR aa , -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)SR cc , -C(=S)SR cc , C 1-10 Alkyl, ar-C 1-10 Alkyl, Heteroar-C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd group, where R aa , R bb , R cc , and R dd is as defined herein. Nitrogen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0164] Exemplary oxygen atom substituents are -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)(Raa ) 2 ,-P(=O)(OR cc ) 2 and P(=O)(N(R bb ) 2 ) 2 In particular, the following are included: - , R aa , R bb and R cc is as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are described in Protective Groups in Organic Synthesis, TW Greene and PG M Huts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl (e.g., 4-methoxybenzyl), methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), and the like, silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), and the like, acetals or ketals, such as tetrahydropyranyl (THP), esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, and the like, carbonates, sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), and the like.

[0165] The term "leaving group" has its ordinary meaning in the field of organic synthetic chemistry and means, for example, an atom or group that can be substituted by a nucleophile. See, e.g., Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyl (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate.

[0166] The term "pharmaceutically acceptable salt" means a salt that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that has a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0167] The terms "tautomer" or "tautomerism" mean two or more interconvertible compounds that result from the formal migration of at least one hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, from a triple bond to a single bond, or vice versa). The exact ratio of tautomers depends on several factors such as temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides the tautomeric pair) can be catalyzed by an acid or a base. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactim, enamine-imine, and enamine-(different enamine).

[0168] As used herein, the term "subject" (alternatively referred to herein as "patient") means an animal, preferably a mammal, most preferably a human, that is the subject of treatment, observation, or experiment.

[0169] As used herein, the terms "treat", "treating", "treatment" and the like refer to the elimination, alleviation, or amelioration of a disease or condition and / or symptoms associated therewith. Although not excluded, treating a disease or condition does not require the complete elimination of the disease, condition, or symptoms associated therewith. As used herein, the terms "treat", "treating", "treatment" and the like can include "prophylactic treatment", which refers to reducing the likelihood of re-developing a disease or condition or the recurrence of a previously controlled disease or condition in a subject who does not have the disease or condition but who is at risk or may be at risk of re-developing the disease or condition or of recurrence of the disease or condition. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment. EXAMPLES

[0170] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified, if necessary, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of these compounds can be performed using conventional methods such as melting point, mass spectrum, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for carrying out the synthesis of the products described herein are described in more detail below.

[0171] Example 1: Synthesis of Compound 1 TIFF0007679338000108.tif77163

[0172] Step 1: 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) 3A mixture of 1-(4.6 g, 5 mmol) and Sphos (4.1 g, 10 mmol) was stirred at 95° C. under nitrogen atmosphere for 30 min. The reaction 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=4 / 1) to give 1-1.

[0173] Step 2: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol) in dichloromethane (100 mL) at room temperature, oxalyl chloride (11 g, 88 mmol) and 15 drops of dry DMF were added. After 30 min, the resulting solution was concentrated to give a residue that was dissolved in dioxane (40 mL). 100 mL of aqueous ammonia (28% NH in water) was added at 0 °C. 3 ) was added dropwise and the reaction mixture was stirred for an additional 10 min, filtered and washed with water. The filter cake was collected and lyophilized to give 1-2.

[0174] 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 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 solution was stirred at room temperature overnight and then concentrated. The residue was purified by silica gel flash column chromatography (ethyl acetate / petroleum ether=1 / 9 to 1 / 3) to give 1-3.

[0175] Step 4: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL) was added KHMDS (5 mL, 1 M in tetrahydrofuran (THF), 5.0 mmol) at -20°C. The resulting mixture was then stirred at room temperature for 2 h. Saturated NH 4The reaction was quenched with Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (ethyl acetate / petroleum ether=1 / 9 to 2 / 1) to give 1-4.

[0176] Step 5: 1-4 (250 mg, 0.64 mmol), DIEA (107.6 mg, 0.83 mmol) and POCl in MeCN (3 mL) 3 (117.9 mg, 0.77 mmol) 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 dropwise addition of a solution of tert-butyl (3S)-3-methylpiperazine-1-carborate (384.9 mg, 1.92 mmol) in MeCN (1 mL). The resulting solution was stirred at room temperature for 1 h. The reaction 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 silica gel flash column chromatography (ethyl acetate / petroleum ether=1 / 4 to 1 / 1) to give 1-5.

[0177] Step 6: 1,4-dioxane (2 mL) and H 2 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)Cl in O (3 drops). 2 A mixture of (12.8 mg, 0.017 mmol) was heated at 90 °C with N 2 The mixture was stirred at ambient temperature for 1.5 hours. The mixture was cooled and extracted with EtOAc. The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated. 2 Cl 2 The residue was purified by hexane / MeOH=15 / 1) to give 1-6.

[0178] 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 and the resulting residue was dissolved in DCM (3 mL). DIEA (171.7 mg, 1.33 mmol) was added at 0° C., followed by dropwise addition of a solution of acryloyl chloride (10.2 mg, 0.11 mmol) in DCM (1 mL). The mixture was stirred at 0° C. for 10 min, the resulting residue was concentrated and the residue was purified by preparative HPLC (NH 4 HCO 3 Purification with aqueous solution (10 mM) and acetonitrile (30%-54%) gave compound 1 (30 mg). LCMS (ESI, m / z): [M+H] + = 586.3; HNMR (300MHz, 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=10.4,2.4Hz,1H),4.98(brs,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=6.7Hz,3H),0.97-0.81(m,8H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -113.10(1F).

[0179] Example 2: Synthesis of Compound 42 TIFF0007679338000109.tif62165

[0180] Step 1: tert-Butyl-(2S,5R)-2,5-dimethylpiperazine-1-carborate (2.14 g, 10 mmol) and acrylic acid chloride (990 mg, 11 mmol) were added to a stirred solution of THF (30 mL) at −10° C. and N 2A solution of triethylamine (3.03 g, 30 mmol) in THF (10 mL) was added at room temperature. The mixture was gradually heated 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 silica gel (petroleum ether / ethyl acetate=1 / 10) flash column chromatography to give 42-1.

[0181] Step 2: To a solution of 42-1 (804 mg, 3 mmol) in dichloromethane (DCM) (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1.5 h and concentrated to give 42-2.

[0182] Step 3: In a solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol) in acetonitrile (20 mL) was added POCl at room temperature. 3 (367 mg, 2.4 mmol) was added dropwise. 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 and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel (DCM to DCM / MeOH=10 / 1) column chromatography to give 42-4.

[0183] 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)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol) in 1,4-dioxane (3 mL) and water (3 drops) was stirred at 90° C. under nitrogen atmosphere for 3 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (acetonitrile containing 0.05% aqueous TFA: 25% to 95%) to give compound 42 (58 mg). LCMS (ESI, m / z): [M+H] += 584.1; HNMR (400MHz, 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(376MHz,DMSO-d 6 ,ppm):δ -113.32(1F),-128.68(1F).

[0184] Example 3: Synthesis of Compound 13 TIFF0007679338000110.tif61157

[0185] Step 1: In a 250 mL sealed tube, 2,6-dimethylheptane-3,5-dione (10 g, 64.0 mmol), urea (7.69 g, 128.0 mmol), EtOH (120 mL), and concentrated HCl (50 mL) were added 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, the organic layer was separated, and the mixture was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 13-1.

[0186] Step 2: Concentrate 13-1 (8.40 g, 46.6 mmol) 2 SO 4 (100 mL) of fuming HNO 3 (11.75 g, 186.4 mmol) was added dropwise. 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 and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated to give 13-2.

[0187] Step 3: 13-2 (4 g, 17.8 mmol) and K 2 CO 3 To a stirred solution of 2-bromo-N,N-dimethylethan-1-amine hydrobromide (4.96 g, 21.3 mmol) (4.9 g, 35.5 mmol) in acetone (80 mL) was added in portions. The resulting mixture was stirred at 60 °C under nitrogen for 16 h, cooled to room temperature, and concentrated. The residue was diluted with water and extracted with DCM / MeOH (10 / 1). The combined organic layers were washed with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to give 13-3.

[0188] Step 4: A mixture of 13-3 (300 mg, 1.0 mmol), 10% Pd / C (38.1 mg) and MeOH (10 mL) was dissolved in H 2 The mixture was stirred at room temperature overnight at room temperature, and the resulting mixture was filtered and the filtrate was concentrated to give 13-4.

[0189] 13 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 677.4; HNMR (400MHz, DMSO-d 6 ,ppm):δ 8.48(s,1H),7.60-7.44(m,1H),7.32(m,2H),7.20(t,J=6.7Hz,1H),6.98-6.79(m,1H), 6.22(d,J=15.6Hz,1H),5.78(d,J=10.2Hz,1H),4.98(brs,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,4H),2.21(s,6H),1. 35(d,J=6.6Hz,3H),1.06(d,J=6.5Hz,6H),0.91(d,J=6.4Hz,6H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -114.70(1F).

[0190] Example 4: Synthesis of Compound 8 TIFF0007679338000111.tif52163

[0191] 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)ferrocene]dichloropalladium(II) (58 mg, 0.08 mmol) in 1,4-dioxane (7 mL) and water (0.2 mL) was stirred at 90 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2 / 1) to give 8-4.

[0192] Step 2: A solution of 8-4 (82 mg, 0.17 mmol) and DIEA (360 mg, 2.8 mmol) in acetonitrile (3 mL) was added with POCl at room temperature. 3 (135 mg, 0.88 mmol) was added dropwise. 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 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 containing 0.05% aqueous TFA: 5% to 65%) to give compound 8 (26.2 mg). LCMS (ESI, m / z): [M+H] + = 620.1; HNMR (400MHz, 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=10.4,2.4Hz,1H),4.94(brs,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=6.4Hz,3H),1.02(d,J=6.8Hz,6H),0.87(d,J=6.4Hz,6H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -114.78(1F).

[0193] Example 5: Synthesis of Compound 6 TIFF0007679338000112.tif65159

[0194] Step 1: In a solution of 13-2 (7 g, 31 mmol) in phosphoryl chloride (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, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 6-1.

[0195] Step 2: A mixture of 6-1 (0.95 g, 3.7 mmol) and aqueous 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 brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-2.

[0196] Step 3: A mixture of 6-2 (1.1 g, 4.9 mmol), di-tert-butyl carbonate (3.2 g, 14.7 mmol) and 4-dimethylaminopyridine (0.6 g, 4.9 mmol) in tetrahydrofuran (30 mL) was refluxed for 0.5 h. 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=10 / 1) to give 6-3.

[0197] Step 4: A mixture of 6-3 (1.7 g, 4 mmol), aqueous ammonia (0.05 mL) and 10% Pd / 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.

[0198] 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 with 0.05% aqueous TFA: 25% to 95%) to give compound 6 (17.8 mg). LCMS (ESI, m / z): [M+H] + = 605.1; HNMR (400MHz, 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),6.85-6.8 1(m,1H),6.20-6.15(m,1H),5.73(dd,J=10.4,2.4Hz,1H),4.92(brs,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=6.8Hz,3H),0.98(d,J=6.4Hz,6H),0.83(d,J=6.8Hz,6H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -114.67(1F).

[0199] Example 6: Synthesis of Compound 20 TIFF0007679338000113.tif52165

[0200] Step 1: In a solution of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (2.4 g, 12.5 mmol) in ethanol (50 mL) was added stannous chloride (8.3 g, 43.7 mmol) and the reaction mixture was heated at 80° C. for 4 h. The reaction 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=5 / 1) to give 20-1.

[0201] Step 2: Toluene (60 mL) and H 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 20 mL of N 2 Tris(dibenzylideneacetone)-dipalladium (789 mg, 0.86 mmol) was added under atmospheric pressure. 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=5 / 1) to give 20-2.

[0202] Step 3: To a solution of 20-2 (1.4 g, 6.3 mmol) in dichloromethane (70 mL) at 0° C., 3-chloroperoxybenzoic acid (3.3 g, 19.0 mmol) was added, 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=2 / 1) to give 20-3.

[0203] Step 4: To a solution of 2-(dimethylamino)ethanol (1.5 g, 18 mmol) in tetrahydrofuran (50 mL) at 0° C., sodium hydride (1.4 g, 36 mmol) was added. The reaction mixture was stirred at 0° C. for 15 min, and 20-3 (1.4 g, 5.5 mmol) was added. After stirring at room temperature for 3 h, the mixture was quenched with water and concentrated. The residue was purified by preparative HPLC (acetonitrile containing 0.05% aqueous TFA: 5% to 25%) to give 20-4 as a TFA salt.

[0204] 20 was synthesized in the same manner as in Examples 1 and 4. LCMS (ESI, m / z): [M+H] + = 673.1; HNMR (400MHz, DMSO-d 6 ,ppm):δ 9.46(brs,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=16.8Hz,1H),5.74(dd,J=10.8,2.0Hz,1H),4.92(brs,1H),4.52-4.46(m ,2H),4.38-3.98(m,3H),3.78-3.57(m,2H),3.44-3.32(m,3H),2.80(d,J=4.4Hz,6H ),1.71-1.67(m,2H),1.31(d,J=6.8Hz,3H),1.08-0.80(m,8H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -113.43(1F).

[0205] Example 7: Synthesis of Compound 33 TIFF0007679338000114.tif50165

[0206] Step 1: Toluene (60 mL) and H 2 A mixture of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine (2.4 g, 10 mmol), cyclopropyl-boronic acid (3.7 g, 42.8 mmol), sodium carbonate (3.2 g, 30.2 mmol) in 20 mL of N 2 Under atmospheric conditions, Pd(PPh3 ) 4 (1.1 g, 1.0 mmol) was added. The reaction mixture was stirred at 95° C. for 3 h. Then 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=6 / 1) to give 33-1.

[0207] Step 2: In a solution of 33-1 (2.0 g, 8.0 mmol) in dichloromethane (80 mL) at 0° C., 3-chloroperoxy-benzoic acid (3.5 g, 20.0 mmol) was added, 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=4 / 1) to give 33-2.

[0208] Step 3: In a solution of 33-2 (940 mg, 5.0 mmol) and DIEA (1.29 g, 10.0 mmol) in tetrahydrofuran (12 mL), N,N-dimethylethylenediamine (510 mg, 5.8 mmol) was added, and the mixture was stirred at room temperature for 2 h. Then, the reaction solution was concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate = 2 / 1) to give 33-3.

[0209] Step 4: Ethanol (20 mL) and saturated NH 4 A mixture of 33-3 (700 mg, 3.6 mmol) and Zn powder (1.3 g, 20.0 mmol) in 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 silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=1 / 1) to give 33-4.

[0210] 33 was synthesized in the same manner as in Examples 1 and 4. LCMS (ESI, m / z): [M+H] + = 656.2; HNMR (400MHz, methanol-d4 ,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=16.8,3.2Hz,1H),5.79(dd,J=10.8,1.6Hz,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),1.6 2-1.50(m,2H),1.45(d,J=6.0Hz,3H),1.05-1.01(m,4H),0.88-0.73(m,4H).FNMR(376MHz,methanol-d 4 ,ppm):δ -115.0(1F),-129.2(1F).

[0211] Example 8: Synthesis of Compound 26 TIFF0007679338000115.tif78161

[0212] 26-1 was synthesized in the same manner as in Example 1.

[0213] Step 1: To a solution of 26-1 (500 mg, 0.75 mmol) in dichloromethane (8 mL) at 0° C., 3-chloroperoxybenzoic acid (260 mg, 1.5 mmol) was added, 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 silica gel flash column chromatography (ethyl acetate / dichloromethane=1 / 1 to ethyl acetate) to give 26-2.

[0214] Step 2: To a solution of 26-2 (300 mg, 0.43 mmol) in DMSO (4 mL) at 0° C., NaCN (106 mg, 2.2 mmol) was added, and the reaction mixture was stirred at room temperature for 18 h. Then, 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 silica gel flash column chromatography (petroleum ether / ethyl acetate=1 / 1) to give 26-3.

[0215] 26 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 595.3; HNMR (300MHz, 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),6.2 1(d,J=17.0Hz,1H),5.78(dd,J=10.4,2.4Hz,1H),4.98(brs,1H),4.39-4.32(m,2 H),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=6.7Hz,3H),1.15-0.90(m,8H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -113.63(1F),-128.34(1F).

[0216] Example 9: Synthesis of Compound 71 TIFF0007679338000116.tif73128

[0217] Step 1: To a solution of 5-nitro-1,3-benzothiazole (8.0 g, 44.4 mmol) in tetrahydrofuran (50 mL) at 0° C., a solution of isopropylmagnesium bromide in tetrahydrofuran (2 M, 24.4 mL, 48.8 mmol) was added. The mixture was stirred at 0° C. for 0.5 h. Then, a solution of DDQ (12.1 g, 53.2 mmol) in tetrahydrofuran (10 mL) was added. The resulting mixture was stirred at 0° C. for 1 h and at room temperature for another 2 h. The mixture was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 71-1.

[0218] HNMR (300MHz, DMSO-d 6 ,ppm):δ 9.62(s,1H),8.27(d,J=6.0Hz,1H),7.84(d,J=9.0Hz,1H),3.56-3.47(m,1H),1.54(d,J=6.9Hz,6H).

[0219] Step 2: MeOH (100 mL) and H 2 71-1 (79 mg, 0.35 mmol) in NH2O (10 mL) 4 A mixture of Cl (189 mg, 3.5 mmol) and Zn (231 mg, 3.5 mmol) 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 silica gel flash column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 71-2.

[0220] 71 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 603.3; HNMR (300MHz, DMSO-d 6,ppm):δ 9.42(s,1H),8.46-8.42(m,1H),8.05(d,J=8.4Hz,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=17.4Hz,1H),5.79(dd,J=10.2,2.4Hz,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(282MHz,DMSO-d 6 ,ppm):δ -114.01(1F).

[0221] Example 10: Synthesis of Compound 68 TIFF0007679338000117.tif82128

[0222] Step 1: To a solution of 71-2 (2.0 g, 10.6 mmol) in HOAc (40 mL) at 0° C., Br 2 (1.7 g, 10.6 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The mixture was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=99 / 1) to give 68-1.

[0223] Step 2: 71-2 (2.4 g, 8.8 mmol) in 20 mL 1,4-dioxane / H 2 In a 5 / 1 O solution, trimethyl-1,3,5,2,4,6-trioxatriborinane (2.2 g, 17.6 mmol) and Na 2 CO 3 (2.35 g, 22.1 mmol) and Pd(PPh 3 ) 4 (1.0 g, 0.89 mmol) was added. The resulting mixture was then heated in a 300-mL flask. 2 The mixture was stirred at 100° C. for 5 hours under atmospheric pressure. After cooling to room temperature, the mixture was washed with water and extracted with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 It was dried at 40° C., concentrated and purified by preparative TLC (petroleum ether / ethyl acetate=5 / 1) to give 68-2.

[0224] 68 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 617.1; HNMR (300MHz, DMSO-d 6 ,ppm):δ 9.33(s,1H),8.49(s,1H),7.95(d,J=0.9Hz,1H),7.51-7.44(m,1H),7.31-7.16(m,3H),6.98-6.81(m,1H),6. 22(d,J=16.7Hz,1H),5.78(dd,J=10.2,2.4Hz,1H),4.97(brs,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=6.9,1.8Hz,3H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -114.35(1F).

[0225] Example 11: Synthesis of Compound 70 TIFF0007679338000118.tif105141

[0226] Step 1: 2,6-Dibromo-3-nitropyridine (50 g, 177 mmol) and Na in EtOH (500 mL) 2 CO 3 (37.6 g, 355 mmol) at 0 °C in CH 3 NH 2 A solution of (107 mL, 214 mmol) in THF was added dropwise. 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.

[0227] 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 dropwise a solution of isopropylzinc bromide in THF (0.5 M, 33 mL, 66 mmol) at room temperature. The resulting mixture was stirred at 30 °C under argon atmosphere for 3 h. The reaction was quenched with saturated NH 4 The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at rt, concentrated and purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=20 / 1) to give 70-2.

[0228] Step 3: At 0° C., a solution of 70-2 (1.5 g, 7.7 mmol) in DMF (15 mL) was added dropwise with a solution of NBS (1.64 g, 9.2 mmol) in DMF (15 mL). The resulting mixture was stirred at 0° C. for 2 h, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated to give a residue, which was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=10 / 1) to give 70-3.

[0229] Step 4: Methanol (15 mL) / H 2 70-3 (1.5 g, 5.5 mmol) in NH2O (8 mL) 4 A mixture of Cl (2.34 g, 43.7 mmol) and Zn (1.8 g, 27.4 mmol) 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 and washed with anhydrous Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to give 70-4.

[0230] 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 with NaOH to pH=7. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried at rt and concentrated to give 70-5.

[0231] Step 6: A mixture of 70-5 (2.9 g, 11.4 mmol) and Cu (362 mg, 5.7 mmol) in aqueous ammonia (40 mL) was stirred at room temperature for 0.5 h, then at 100° C. overnight. The resulting mixture was extracted with ethyl acetate and washed with anhydrous Na 2 SO 4 The mixture was dried at rt, concentrated and purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=3 / 1) to give 70-6.

[0232] 70 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 601.4; HNMR (400MHz, 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=16.4Hz,1H),5.78(dd,J=10.4,2.4Hz,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(d d,J=13.1,6.6Hz,3H),1.16(d,J=6.7Hz,3H),1.06(dd,J=6.7,2.3Hz,3H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -114.16(1F).

[0233] Example 12: Synthesis of Compound 65 TIFF0007679338000119.tif75128

[0234] Step 1: 70-6 (30 mg, 1.57 mmol) in HOAc (15 mL) and CHCl 3 (6 mL) solution at 0°C. 2 A solution of (252 mg, 1.57 mmol) in HOAc (1 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h, and then saturated NaHCO 3 The reaction was quenched with ethyl acetate. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at rt, concentrated and purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=1 / 9) to give 65-1.

[0235] Step 2: Dioxane / H 2 A mixture of 65-1 (200 mg, 0.74 mmol), trimethyl-1,3,5,2,4,6-trioxaborinane (559 mg, 4.45 mmol), Pd(PPh) in 2H2O (5 / 1, 2 mL) 3 ) 4 (85mg, 0.074mmol), Na 2 CO 3 (196 mg, 1.85 mmol) was stirred under nitrogen atmosphere at 110° C. for 3 h. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate=1 / 1) to give 65-2.

[0236] 65 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 615.3; HNMR (400MHz, 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(brs,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=6.8Hz,3H),1.14(d,J=6.8Hz,3H),1.02(dd,J=6.4,1.8Hz,3H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -114.52(1F).

[0237] Example 13: Synthesis of Compound 72 TIFF0007679338000120.tif81154

[0238] Process 1:N 1 To a solution of 25 g (149 mmol) of 4-methyl-4-nitrobenzene-1,2-diamine and 200 mL of trimethyl orthoformate in 300 mL of DMF was added dropwise concentrated HCl (16 mL) at room temperature. After stirring overnight at room temperature, the mixture was concentrated. The residue was dissolved in ethyl acetate. The mixture was diluted with Et 3 The organic layer was washed with anhydrous Na 2 SO 4 Drying at rt and concentration gave a residue which was purified by silica gel flash column chromatography (dichloromethane / methanol=12 / 1) to give 72-1.

[0239] Step 2: To a solution of 72-1 (32 g, 180 mmol) in tetrahydrofuran (80 mL) at 0° C. was added i-PrMgCl.LiCl (210 mL, 1.3 M in THF, 271 mmol). The mixture was stirred at 0° C. for 0.5 h. Then, a solution of DDQ (49.2 g, 216 mmol) in tetrahydrofuran (40 mL) was added. The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water at 0° C. The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated, and the residue was purified by silica gel column chromatography to give 72-2.

[0240] 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 under hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to give 72-3.

[0241] 72 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 600.4; HNMR (300MHz, 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=8.4Hz,1H),7.27-7.14( m,3H),7.02-6.98(dd,J=10.5,2.1Hz,1H),6.91-6.85(m,1H),6.24-6.19(d,J=16.2Hz,1H), 5.79-5.75(dd,J=12.9,2.4Hz,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(282MHz,DMSO-d 6 ,ppm):δ -114.19(1F).

[0242] Example 14: Synthesis of Compound 69 TIFF0007679338000121.tif132155

[0243] Method A Step 1: A solution of 4-isopropyl-1-methyl-1,3-benzodiazol-5-amine (6.0 g, 31.7 mmol) in HOAc (20 mL) was added at 0° C. with Br 2 A solution of (5.1 g, 31.7 mmol) in HOAc (2 mL) was added dropwise. After stirring for 1 h, the mixture was concentrated. The residue was partitioned between ethyl acetate and 2M NaOH. The organic layer was washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=4 / 1) to give 69-1.

[0244] Step 2: 30 mL of dioxane / H 2 69-1 (3.8 g, 14.2 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (3.6 g, 28.4 mmol), Na in O(5 / 1) 2 CO 3 (3.0 g, 28.4 mmol) and Pd(PPh 3 ) 4 A mixture of (1.64 g, 1.42 mmol) was added to N 2 The mixture was stirred at 100° C. under atmospheric pressure for 5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and diluted with MgSO 4 The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1) to give 69-2.

[0245] Method B Step 1: H of 2-fluoro-4-methylaniline (10.0 g, 79.9 mmol) 2 SO 4 (100 mL) solution at 0 °C with concentrated HNO 3 (5.66g, 87.9mmol) of H 2 SO 4(11.2 mL) solution was added dropwise. After stirring at 0° C. for 3 h, the reaction mixture was poured into ice water (600 mL) and the resulting mixture was made basic by slow addition of NaOH solution (180 g dissolved in 240 mL water), then filtered and dried to give 69-3.

[0246] Step 2: To a solution of 69-3 (5 g, 29.4 mmol) in DMSO (35 mL), Cs 2 CO 3 (47.88 g, 146.9 mmol) and methylamine hydrochloride (5.95 g, 88.2 mmol) were added. 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 washed with Na 2 SO 4 It was dried at rt, 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.

[0247] Step 3: To a solution of 69-4 (3.2 g, 15.9 mmol) in toluene (12 mL) was added trimethoxymethane (3.54 g, 33.4 mmol) and 4-methylbenzenesulfonic acid (60.5 mg, 0.35 mmol). 2 The solution was stirred under atmosphere for 2 h at 100° C. 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.

[0248] 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 under hydrogen atmosphere at room temperature for 6 h, then filtered and the filtrate was concentrated to give 69-6.

[0249] 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 2The solution was diluted with O and basified to pH=8 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate. The combined organic layers were washed with Na 2 SO 4 It was dried at rt, 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.

[0250] Step 6: 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 Cs in dioxane (16 mL) and water (3 mL). 2 CO 3 (5.41 g, 16.6 mmol) in a mixture of N 2 Bottom, Pd(dppf)Cl 2 (243 mg, 0.33 mmol) was added. The mixture was stirred at 80° C. for 2.5 h under nitrogen atmosphere. The solution was diluted with ethyl acetate and H 2 The organic layer was diluted with Na 2 SO 4 Drying at rt and concentration gave a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 1 to 1 / 3) to give 69-8.

[0251] 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 under hydrogen atmosphere at room temperature for 2 h, then filtered and the filtrate was concentrated to give 69-2.

[0252] 69 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 614.1; HNMR (300MHz, 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=16.4Hz,1H),5.78(dd,J=10.4,2.4Hz,1H), 4.92(brs,1H),4.46-4.04(m,3H),3.78(s,3H),3.70-3.05(m,3H),2.78(d,J=7.1Hz,1H),1.98(s,3H),1.43-1.20(m,9H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -114.52(1F).

[0253] Example 15: Synthesis of Compound 117 TIFF0007679338000122.tif98139

[0254] Step 1: Dioxane (100 mL) and H 2 6-Bromo-4-methylpyridin-2-amine (10 g, 53.5 mmol) in O (20 mL), 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) were added to a mixture of Pd(dppf)Cl at room temperature under an argon atmosphere. 2 (3.91 g, 5.35 mmol) was added. The resulting mixture was stirred at 90° C. for 2 h under argon atmosphere. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=5 / 1) to give 117-1.

[0255] 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 overnight at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to give 117-2.

[0256] Step 3: H of 117-2 (3.0 g, 20 mmol) 2 SO 4 (35 mL) solution at 0 °C with fuming HNO 3 (4.5 mL, 71 mmol) was added dropwise. The mixture was stirred at 50° C. for 2 h. The reaction was quenched with ice at 0° C. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and anhydrous Na 2 SO 4 Drying at rt and concentration gave 117-3.

[0257] 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 atmosphere. The mixture was filtered and the filter cake was washed with acetonitrile. The filtrate was concentrated to give 117-4.

[0258] 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 under argon atmosphere at 120° C. for 2 days. 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.

[0259] 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 overnight at room temperature under hydrogen atmosphere. The mixture was filtered and the filter cake was washed with MeOH. The filtrate was concentrated to give 117-6.

[0260] 117 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 602.4; HNMR (300MHz, 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,1H),6.25( d,J=16.8Hz,1H),5.78(dd,J=10.4,2.4Hz,1H),4.99(brs,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),3.27-3.12(m,1H),2.84-2.78(m,1H),2.20(d,J=2. 4Hz,3H),1.34(d,J=6.6Hz,3H),1.10(d,J=6.6Hz,3H),1.00-0.98(m,3H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -114.30(1F).

[0261] Example 16: Synthesis of Compound 44 TIFF0007679338000123.tif69155

[0262] 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). Then, oxalyl chloride (33 g, 0.26 mol) was added slowly at room temperature over 30 min. The mixture was stirred at room temperature for 1 h and then concentrated to give an oil, which was dissolved in dioxane (50 mL). This solution was added to ammonium hydroxide (150 mL) over 30 min at 0° C. 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.

[0263] 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 was concentrated. The residue was dissolved in acetonitrile (100 mL) and cooled to −10° C., after which 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. This solution was diluted with saturated NaHCO 3 The mixture was diluted with aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether to petroleum ether / ethyl acetate=4 / 1) to give 42-6.

[0264] 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 was purified by elution with saturated NH 4 The mixture was quenched with aqueous Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether to petroleum ether / ethyl acetate=2 / 1) to give 42-3.

[0265] Step 4: A solution of 42-3 (746 mg, 2 mmol) and DIEA (387 mg, 3 mmol) in MeCN (20 mL) was added at room temperature to POCl 3 (367 mg, 2.4 mmol) was added dropwise. The resulting mixture was stirred at 80° C. for 45 min, and then a solution of DIEA (3.87 g, 30 mmol) and 42-2 (1.58 g, 4 mmol) in MeCN (10 mL) was added dropwise at −10° C. After stirring at room temperature for 1 h, the reaction was quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (dichloromethane to dichloromethane / methanol=10 / 1) to give 42-4.

[0266] Step 5: Dioxane (3 mL) / H2 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)Cl in O (1 drop). 2 A mixture of (13 mg, 0.018 mmol) and KOAc (40 mg, 0.41 mmol) was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (acetonitrile (30% to 65%) containing 0.05% aqueous TFA) to give 44. LCMS (ESI, m / z): [M+H] + = 599.1; HNMR (400MHz, methanol-d 4 ,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=8.4Hz,1H),6.42-6.3 8(m,1H),6.30-6.24(m,1H),5.83-5.78(m,1H),5.01(brs,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=6.8Hz,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(376MHz,methanol-d 4 ,ppm):δ -114.9(1F),-125.6(1F).

[0267] Example 17: Synthesis of Compound 126 TIFF0007679338000124.tif63164

[0268] Step 1: To a suspension of 2,5,6-trichloronicotinic acid (10 g, 44 mmol) in dichloromethane (100 mL) at room temperature was 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 aqueous ammonia (28% NH 3 Aqueous solution) was added dropwise and the reaction mixture was stirred for an additional 10 min, then filtered and washed with water. The filter cake was collected and lyophilized to give 1-2.

[0269] 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) and cooled to −10° C., then 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 silica gel flash column chromatography (ethyl acetate / petroleum ether=1 / 9 to 1 / 3) to give 1-3.

[0270] Step 3: To a stirred solution of 1-3 (845 mg, 1.98 mmol) in THF (40 mL) at -20°C, KHMDS (5 mL, 1 M in THF, 5.0 mmol) was added. The resulting mixture was then stirred at room temperature for 2 h. Saturated NH 4 The reaction was quenched with aqueous Cl solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (ethyl acetate / petroleum ether=1 / 9 to 2 / 1) to give 1-4.

[0271] Step 4: 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 at room temperature to POCl 3(790 mg, 5.12 mmol) was added dropwise. The resulting solution was stirred at 80° C. for 45 min, and then a solution of DIEA (6.62 g, 51.25 mmol) and 42-2 (1.45 g, 5.12 mmol) in MeCN (5 mL) was added dropwise at −10° C. After stirring at room temperature for 1 h, the reaction was quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (ethyl acetate / petroleum ether=0 / 1 to 3 / 1) to give 126-1.

[0272] Step 5: Dioxane (3 mL) / H 2 126-1 (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 in O (1 drop). 2 A mixture of (16 mg, 0.022 mmol) and KOAc (108 mg, 1.11 mmol) was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (acetonitrile (34% to 45%) with 0.05% aqueous TFA) to give 126. LCMS (ESI, m / z): [M+H] + = 615.3; HNMR (400MHz, DMSO-d 6 ,ppm):δ 8.74(s,1H),8.52-8.35(m,1H),7.16-7.07(m,1H),6.94-6.76(m,1H),6. 51(d,J=6.0Hz,1H),6.38(t,J=6.6Hz,1H),6.20(dd,J=12.6,1.8Hz,1H), 5.76(dd,J=12.6,1.6Hz,1H),4.91-4.80(m,2H),4.51-3.50(m,6H),1.91 -1.65(m,1H),1.45-1.15(m,6H),1.10-0.70(m,8H).FNMR(376MHz,DMSO-d 6 ,ppm):δ -114.30(1F).

[0273] Example 18: Synthesis of Compound 127 TIFF0007679338000125.tif41128

[0274] Step 1: Dioxane (3 mL) / H 2 126-1 (200 mg, 0.37 mmol), 2-fluoro-6-hydroxyphenylboronic acid (115 mg, 0.74 mmol), Pd(dppf)Cl in O (1 drop). 2 A mixture of (27 mg, 0.037 mmol) and KOAc (181 mg, 1.85 mmol) was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (acetonitrile with 0.05% TFA in water: 25% to 48%) to give 127. LCMS (ESI, m / z): [M+H] + = 616.2; HNMR (300MHz, DMSO-d 6 ,ppm):δ 10.16(s,1H),8.71(s,1H),8.50-8.40(m,1H),7.31-7.23(m,1H),6.86-6.67(m,3H),6.2 0(d,J=16.5Hz,1H),5.79-5.74(m,1H),4.99-4.78(m,1.5H),4.55-4.45(m,0.5H),4.40- 4.05(m,1.5H),3.95-3.68(m,2H),3.55-3.45(m,0.5H),1.80-1.60(m,2H),1.34(s,3H), 1.30-1.23(m,3H),0.95(d,J=5.7Hz,2H),0.90(s,4H),0.82(s,2H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -115.33(1F).

[0275] Example 19: Synthesis of Compound 124 TIFF0007679338000126.tif47139

[0276] Step 1: A solution of 8-1 (900 mg, 2.3 mmol) and DIEA (1.2 g, 9.3 mmol) in MeCN (3 mL) was added at room temperature to POCl 3 (707 mg, 4.6 mmol) was added dropwise. The resulting solution was stirred at 80° C. for 45 min, and then a solution of DIEA (6.62 g, 51.25 mmol) and 8-1 (889 mg, 5.8 mmol) in MeCN (2 mL) was added dropwise at −10° C. After stirring at room temperature for 1 h, the reaction was quenched with ice water, and the mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (ethyl acetate / petroleum ether=0 / 1 to 3 / 1) to give 124-1.

[0277] Step 2: Dioxane (3 mL) / H 2 124-1 (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 in O (1 drop). 2 A mixture of (36 mg, 0.048 mmol) and KOAc (158 mg, 1.61 mmol) was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (10 mM NH 4 HCO 3 aqueous solution and acetonitrile (26% to 42%) to give 124. LCMS (ESI, m / z): [M+H] + = 601.4; HNMR (300MHz, 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=8.1Hz,1H) ,6.38(t,J=9.0Hz,1H),6.22(d,J=16.8Hz,1H),5.78(dd,J=10.5,2.4Hz,1H),5.22(brs,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,1 H),1.90-1.75(m,2H),1.35(dd,J=23.7,6.4Hz,3H),1.15-0.75(m,8H).FNMR(282MHz,DMSO-d 6 ,ppm):δ -114.17(1F).

[0278] Example 20: Synthesis of Compound 151 and Compound 152 TIFF0007679338000127.tif97150

[0279] 151-1 was synthesized in the same manner as in Example 1. 151-1 (1.7 g) was subjected to SFC (Dr. Maisch MIC, 250 x 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).

[0280] 151 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 629.3; HNMR (400MHz, DMSO-d 6,ppm):δ 8.45-8.40(m,1H),8.07(s,1H),7.27(s,1H),7.01(dd,J=15.2,8.0Hz,1H),6.90-6.86(m,1H),6.40(d, J=8.0Hz,1H),6.34-6.18(m,2H),5.77(dd,J=10.4,2.4Hz,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).

[0281] 152 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 629.1; HNMR (400MHz, DMSO-d 6 ,ppm):δ 8.40(s,1H),8.06(s,1H),7.27(s,1H),7.01(dd,J=15.2,7.9Hz,1H),6.95-6.80( m,1H),6.40(d,J=8.2Hz,1H),6.29(t,J=8.8Hz,1H),6.21(d,J=16.4Hz,1H),5.77( dd,J=10.4,2.3Hz,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).

[0282] Example 21: Synthesis of Compound 157 and Compound 158 TIFF0007679338000128.tif113152

[0283] Step 1: 2-Chloro-6-methyl-3-nitropyridine (25 g, 144.5 mmol) and K in DMSO (200 mL) 2 CO 3(59.8 g, 433.5 mmol) was added dropwise with 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 layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt and concentrated to give 157-1.

[0284] 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 at room temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 Drying at rt and concentration gave 157-2.

[0285] Step 3: 157-2 (32g, 131mmol), Zn powder (85g, 1310mmol), NH 4 A mixture of Cl (34.7 g, 655 mmol) in water (30 mL) and dichloromethane / methanol (1 / 1, 150 mL) was added to a flask with N 2 The mixture was stirred at room temperature under atmospheric pressure for 2 hours. The mixture was filtered and the filter cake was washed with dichloromethane. The combined filtrate was diluted with water and extracted with dichloromethane. The combined organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 Drying at rt and concentration gave 157-3.

[0286] 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 dissolved in N 2 The mixture was stirred at 100° C. for 2 hours under atmospheric pressure. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine and diluted with anhydrous Na 2 SO 4 Drying at rt and concentration gave a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 1 / 1) to give 157-4.

[0287] Step 5: 157-4 (11 g, 48.9 mmol), diphenylmethanimine (13.3 g, 73.3 mmol), cesium carbonate (31.9 g, 97.8 mmol), Pd in ​​DMF (100 mL) 2 (dba) 3 (2.23 g, 2.44 mmol) and Xantphos (2.83 g, 4.88 mmol) were mixed with N 2 The mixture was stirred at 120° C. under atmospheric pressure overnight. The resulting mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine and diluted with Na 2 SO 4 It was dried at rt 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.

[0288] Step 6: To a solution of 157-5 (12.80 g, 39.26 mmol) in dichloromethane (60 mL), a solution of HCl in dioxane (4 M, 30 mL) was added dropwise. The mixture was stirred at room temperature for 1 h. Acetonitrile (30 mL) was added to the solution, which was then filtered to give 157-6.

[0289] Step 7: In a solution of 157-6 (8.8 g, 54.3 mmol) in acetic acid (150 mL), Br 2 (8.7 g, 54.3 mmol) was added dropwise. 2 The mixture was stirred at room temperature for 2 hours under atmospheric conditions. The resulting solution was adjusted to pH=7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine and diluted with Na 2 SO 4 It was dried at rt 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.

[0290] Step 8: 1,4-dioxane (60 mL) and H 2157-7 (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 in O (12 mL). 2 A mixture of (1.54 g, 2.1 mmol) was added to N 2 The mixture was stirred at 80° C. under atmospheric pressure overnight. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine and added with Na 2 SO 4 It was dried at rt 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.

[0291] 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 under hydrogen atmosphere at room temperature overnight. The mixture was filtered and the solid was washed with tetrahydrofuran. The filtrate was concentrated to give 157-9.

[0292] 157-10 was synthesized in the same manner as in Example 1. 157-10 (1.15 g) was purified by supercritical fluid chromatography (SFC) (Dr. Maisch MIC, 250 x 25 mm, 10 μm, 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).

[0293] 157 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 614.6; HNMR (400MHz, 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).

[0294] Compound 158 was synthesized in the same procedure as in Example 1. LCMS (ESI, m / z): [M + H] + = 614.2; 1H 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).

[0295] Example 22: Synthesis of Compound 145 and Compound 146 TIFF0007679338000129.tif149165

[0296] Step 1: To a solution of 1,5-difluoro-2,4-dinitrobenzene (50.0 g, 245 mmol) in DCM (500 mL) at 0° C. was added triethylamine (49.5 g, 490 mmol), 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 and concentrated with Na 2 SO 4 It was dried at rt and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 1) to give 145-1.

[0297] Step 2: To a solution of 145-1 (34.0 g, 158 mmol) in ethyl acetate (500 mL) was added 10% Pd(OH) 2 3.4 g of 145-C was added. The resulting mixture was stirred under hydrogen atmosphere at room temperature overnight. It was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give 145-2.

[0298] 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 and extracted with Na 2 SO 4 It was dried at rt and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 3) to give 145-3.

[0299] Step 4: To a solution of 145-3 (9 g, 54.5 mmol) in dichloromethane (100 mL) at 0° C. was added N-bromosuccinimide (9.7 g, 54.5 mmol) in portions. The resulting solution was heated 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 and concentrated to 100° C. with 100% NaCl. 2 SO 4 It was dried at rt and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 2) to give 145-4.

[0300] Step 5: Dioxane (60 mL) and H 2 145-4 (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)Cl in O (12 mL). 2 (1.71 g, 2.34 mmol) was stirred overnight at 90° C. under argon atmosphere. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine and added Na 2 SO 4 It was dried at rt and concentrated to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=1 / 1) to give 145-5.

[0301] 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 under hydrogen atmosphere at room temperature overnight. The mixture was filtered and the solid was washed with tetrahydrofuran. The filtrate was concentrated to give 145-6.

[0302] 145-7 was synthesized in the same manner as in Example 1. 145-7 (1.08 g) was subjected to SFC (Dr. Maisch MIC, 250 x 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).

[0303] 145 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 631.4; HNMR (400MHz, DMSO-d 6 ,ppm):δ 8.28-8.20(m,1H),8.20(s,1H),7.43(d,J=9.6Hz,1H),7.08(dd,J=15.2,8.0Hz,1H),6. 91-6.78(m,1H),6.44(d,J=8.4Hz,1H),6.37(t,J=8.0Hz,1H),6.19(d,J=16.8Hz,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).

[0304] 146 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 631.3; HNMR (400MHz, DMSO-d 6 ,ppm):δ 8.33(d,J=9.6Hz,1H),8.20(s,1H),7.44(d,J=9.6Hz,1H),7.09(dd,J=15.2,8.0Hz,1H),6.90 -6.79(m,1H),6.45(d,J=8.0Hz,1H),6.37(t,J=8.0Hz,1H),6.19(dd,J=16.8,2.0Hz,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).

[0305] Example 23: Synthesis of Compound 179 and Compound 180 TIFF0007679338000130.tif75157

[0306] Step 1: 145-4 (1 g, 4.1 mmol), cyclopropylboronic acid (2.8 g, 32.9 mmol), Pd(dtbpf)Cl in dioxane (50 mL) and water (10 mL) 2 (270 mg, 0.4 mmol) and K 2 CO 3 A mixture of (1.4 g, 10.1 mmol) was stirred overnight at 90° C. under nitrogen atmosphere. The mixture was cooled and concentrated to give a residue which was purified by reverse phase HPLC (acetonitrile with 0.05% aqueous TFA: 18% to 20%) to give 179-1.

[0307] 179-2 was synthesized in the same manner as in Example 1. 179-2 (1.34 g) was subjected to SFC (Dr. Maisch MIC, 250 x 25 mm, 10 μm, 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).

[0308] 179 was synthesized in the same manner as in Example 1. LCMS (ESI, m / z): [M+H] + = 629.3; HNMR (400MHz, 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 - 1.27 (m, 3H), 1.23 - 1.13 (m, 3H), 0.79 - 0.75 (m, 1H), 0.68 - 0.66 (m, 1H). ¹³C NMR (376 MHz, DMSO-d 6 , ppm): δ -113.81 (1F), -126.99 (1F), -127.16 (1F).

[0309] Compound 180 was synthesized as the TFA salt following the same procedure as in Example 1. LCMS (ESI, m / z): [M + H] + = 629.3; ¹H 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). ¹³C NMR (376 MHz, DMSO-d 6 , ppm): δ -116.28 (1F), -123.46 (1F), -126.84 (1F).

[0310] Compounds of formula (I) and (II) can be prepared by following the synthetic methods described herein. Representative analytical data for some of the compounds prepared similarly to the methods described in Examples 1-23 are listed in Table 1.

[0311] Table 1. Characterization of compounds of formula (I) and (II) TIFF0007679338000131.tif134166TIFF0007679338000132.tif209166TIFF0007679338000133.tif217166TIF F0007679338000134.tif217166TIFF0007679338000135.tif213166TIFF0007679338000136.tif236166TIFF000 7679338000137.tif221166TIFF0007679338000138.tif216166TIFF0007679338000139.tif221166TIFF0007679 338000140.tif217166TIFF0007679338000141.tif234166TIFF0007679338000142.tif207166TIFF00076793380 00143.tif233166TIFF0007679338000144.tif233166TIFF0007679338000145.tif238166TIFF00076793380001 46.tif217166TIFF0007679338000147.tif232166TIFF0007679338000148.tif239166TIFF0007679338000149.t if239166TIFF0007679338000150.tif234166TIFF0007679338000151.tif213166TIFF0007679338000152.tif21 8166TIFF0007679338000153.tif217166TIFF0007679338000154.tif221166TIFF0007679338000155.tif172166

[0312] Biological Examples 1. Cell Proliferation Assays Lung cancer cell line NCI-H358 (ATCC CRL-5807) containing KRas G12C mutation was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, penicillin / streptomycin. One hundred fifty microliters (150 μL) medium containing 2000 cells per well was seeded into each well of a 96-well culture plate and left overnight in a 37°C incubator with 5% CO2 to allow attachment. 0.75 μL of diluted compound was added per well with a liquid handler to a final concentration of 0.5% DMSO. Cells were treated in the incubator for 5 days. Cell proliferation was assessed using the Cell-Titer Glo (CTG) kit (Promega). 120 μL of CTG reagent was added to each well and incubated at room temperature for 10 min. Luminescence signals were then collected on an Envision 2104 plate reader.

[0313] Table 2. Inhibition of NCI-H358 cell proliferation by representative compounds TIFF0007679338000156.tif200166TIFF0007679338000157.tif132166*: Control A: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0314] The above in vitro data were 8 We show that converting the R position (see, e.g., Formulas I-IV) from a 2-fluorophenyl group to a 2-amino-6-fluorophenyl group can increase the potency of one series of compounds by about 20-fold, but not others. Compounds Nos. 126 and 128 show that R 8 Compound No. 126, which has the same structure except for the position, but has a 2-amino-6-fluorophenyl group, is approximately 15 times more effective than compound No. 128, which has a 2-fluorophenyl group, with an IC 50 Similarly, compounds No. 44 and No. 42 have R 8Compound No. 44, which has the same structure except for the position, but has a 2-amino-6-fluorophenyl group, is approximately 19 times more effective than compound No. 42, which has a 2-fluorophenyl group, with an IC 50 is 2.1 nM vs. 39.5 nM. However, this means that R 8 A compound having a 2-amino-6-fluorophenyl group at the R 8 This does not mean that the compounds have much improved potency over those having a 2-fluorophenyl group at the R 8 Compound No. 78, which has the same structure except for the position, but has a 2-amino-6-fluorophenyl group, is slightly more effective than compound No. 48, which has a 2-fluorophenyl group, with an IC 50 We also found that IC values ​​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 using the same assay (NCI-H358 assay described above). 50 were tested, and compounds with a 2-amino-6-fluorophenyl group were slightly more effective than those with a 2-fluorophenyl group, with IC 50 In addition, the IC 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 using the same assay (NCI-H358 assay described above) was 1.6 nM vs. 4.0 nM. 50was tested to be 5.3 nM, and using the same assay, the corresponding compound bearing a 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, had an IC of 19.0 nM. 50 These data were tested to have R 8 Compounds with 4,6-dicyclopropylpyrimidin-5-yl and 2-amino-6-fluorophenyl at the R position show better inhibition of the KRAS G12C enzyme. This is in contrast to data showing that changing the isopropyl to cyclopropyl on the pyrimidine ring predicts a decrease in potency of about 2-6 fold, for example, when comparing compounds nos. 2 and 5, 49 and 50, etc. This trend is consistent with the R 8 Generally observed except for compounds bearing 2-amino-6-fluorophenyl at the 5'-position, in this series the trend is reversed and the cyclopropyl-pyrimidyl compounds are more potent than the corresponding isopropyl-pyrimidyl compounds.

[0315] Biological Example 2. Human Hepatocyte Clearance Study The compounds described herein were tested for in vitro human hepatocyte clearance rates using pooled human hepatocytes purchased from Bioreclamation IVT (Westbury, NY, Cat#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 made in 100% DMSO. The thawed culture medium (50 mL) used during the study consisted of 31 mL Williams E medium (GIBCO Cat# 12551-032), 15 mL isotonic percoll (GE Healthcare Cat# 17-0891-09), 500 μL 100X GlutaMax (GIBCO Cat# 35050), 750 μL HEPES (GIBCO Cat# 15630-080), 2.5 mL FBS (Corning Cat# 35-076-CVR), 50 μL human insulin (GIBCO Cat# 12585-014) and 5 μL dexamethasone (NICPBP). The incubation medium was made from Williams E medium supplemented with 1X GlutaMax. Both the thawed culture medium and the incubation medium (serum-free) were placed in a 37°C water bath for at least 15 minutes before use. Compound stocks were diluted to 100 μM by combining 198 μL of 50% acetonitrile / 50% water with 2 μL of the 10 mM stock. Verapamil was used as a positive control. A vial of cryopreserved hepatocytes was removed from storage and thawed in a 37°C water bath by gentle rocking. The contents of the vial were poured into a 50 mL thawing medium conical tube. The vial was centrifuged at 100 g for 10 minutes at room temperature. The thawing medium was aspirated and the hepatocytes were resuspended in serum-free medium to obtain a total of approximately 1.5 × 10 6 The viability and density of hepatocytes were counted using Trypan Blue exclusion, and the cells were then cultured in serum-free medium at a concentration of 0.5 × 10 6 The cells were then diluted to a working cell density of 0.5 × 10 viable cells / mL. 6An aliquot of 100 viable cells / mL was boiled for 5 minutes before being added to the plate as a negative control to remove enzyme activity and to ensure that little substrate turnover was observed. The boiled hepatocytes were used to prepare negative samples. An aliquot of 198 μL hepatocytes was dispensed into each well of a 96-well non-coated plate. The plate was placed in an incubator on an orbital shaker at 500 rpm for approximately 10 minutes. A 2 μL aliquot of 100 μM test compound or positive control was added into each well of the non-coated 96-well plate to initiate the reaction. The assay was performed in duplicate. The plate was incubated in an incubator on an orbital shaker at 500 rpm for the indicated time points. Twenty-five microliters of the contents were transferred and mixed with six volumes (150 μL) of cold acetonitrile containing IS (200 nM imipramine, 200 nM labetalol, and 200 nM diclofenac) to terminate the reaction at 0, 15, 30, 60, 90, and 120 min. Samples were centrifuged at 3,220 g for 25 min, and 150 μL aliquots of the supernatant 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-lives (t 1 / 2 The in vitro half-life (in vitro t) was determined by regression analysis of the parent elimination rate versus time curve. 1 / 2 ): In vitro 1 / 2 = 0.693 / k was determined. In vitro t 1 / 2 Scale-up unbound intrinsic clearance (scale-up unbound CL int Conversion to the unit of mL / min / kg was performed using the following formula (average of duplicate measurements): Scale-up unbound CL int = kV / Nx scaling factor, where V = incubation volume (0.5 mL); N = number of hepatocytes per well (0.25 x 10 6 Scaling factors for in vivo intrinsic clearance rate prediction using human hepatocytes are: liver weight (g liver / kg body weight): 25.7; hepatocyte concentration (10 6cells / g liver): 99; scaling factor: 2544.3.

[0316] Table 3: Human hepatocyte clearance of exemplary compounds TIFF0007679338000158.tif171166 a : Control A: (S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)pyrido[2,3-d]pyrimidin-2(1H)-one. b : Calculated CL int < 0, T 1 / 2 and C.L. int were reported as “∞” and “0.00”, respectively. c : Working cell density is 0.5 x 10 6 viable cells / mL instead of 2 x 10 6 viable cells / mL.

[0317] Biological Example 3. Rat PK Study The pharmacokinetic (PK) profile of the compound was measured after a single ig administration to SD rats obtained from Shanghai SIPPER B&K Laboratory Animal Co.,LTD. Three female rats weighing approximately 220 g were used. The compound was prepared at 1 mg / mL in a formulation of 10% dimethyl sulfoxide (DMSO) + 10% solutol HS15 + 80% (10% HPβCD aqueous solution). After administration of the compound at a dose of 10 mg / kg, blood samples (0.2 mL) were collected at 0 hours (before administration) and 0.25, 0.5, 1, 2, 4, 8, and 24 hours.

[0318] The collected blood samples were centrifuged without delay, and the plasma was separated, transferred to test tubes, and stored at -70°C prior to analysis. Aliquots of plasma unknowns, blanks, and calibration standards were placed in 1.5 mL test tubes and mixed with acetonitrile / methanol (1 / 1, v / v) containing IS. After vortexing for 5 min, each sample was centrifuged at 14000 rpm for 10 min at 4°C. The supernatant was injected into the LC-MS / MS system.

[0319] The samples were separated at 45°C using a Simazhu LC-30D UPLC system with Shimadzu Shim-pack GIST C18 (2.1 * 50mm 2μm). The eluate was analyzed using an API4000 Q-Trap mass spectrometer with a TurboIonSpray interface. Chromatographic separation was performed with 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 delivered using a stepwise gradient elution program at a flow rate of 0.6mL / min. To improve the screening accuracy of the test compounds, an MRM method with positive electrospray ionization mode was employed. Mass spectrometry data were acquired and analyzed using AB Sciex Analyst version 1.6.2 software. Pharmacokinetic parameters were calculated by standard noncompartmental methods using 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.

[0320] Table 4. Rat PK data for selected compounds TIFF0007679338000159.tif31141 a : Control B: 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 b : Control C: 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.

[0321] Biological Example 4. In vivo studies evaluating KRAS G12C inhibitors as single agents or in combination with other agents All procedures related to the handling, care, and treatment of animals in this study were performed in accordance with the guidelines of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and approved by the Institutional Animal Care and Use Committee (IACUC) of SIPPER B&K. At the time of regular monitoring, animals were tested for the effect of tumor growth on normal behavior such as mobility, food and water intake (visual observation only), weight gain / loss (weight was measured twice weekly), eye / hair matting and other abnormal effects. Deaths and observed clinical symptoms were recorded based on the number of animals in each subset. Animals observed to be in an ever-deteriorating condition were euthanized before dying or reaching a coma.

[0322] NCI-H358, SW837, and NCI-H2122 tumor cells were purchased from the American Type Culture Collection (ATCC). Cells were cultured in RPMI-1640 or DMEM medium supplemented with 10% fetal bovine serum and 50 IU / ml penicillin / streptomycin (GIBCO) at 37°C and 5% CO in air. 2 The tumor cells were cultured as monolayers in an atmosphere of 0.1% CO and maintained in vitro. The tumor cells were treated with trypsin-EDTA and routinely subcultured twice a week. Cells in the exponential growth phase were harvested and counted for tumor inoculation.

[0323] For the tumor-bearing model, 6-8 week-old female athymic BALB / c nude mice were used bearing human cancer cell lines. The right flank of each mouse was inoculated with tumor cells (10x10) in 0.1 mL PBS. 6 The treatment was performed on mice with an average tumor size of approximately 200 to 250 mm. 3Treatment was started when the patient reached the age of 18. Carboplatin and cisplatin were administered intraperitoneally twice weekly. Vehicle and other test products were administered orally as a suspension once daily for the duration of the study or treatment period by gavage.

[0324] Tumor volumes were calculated by measuring the two perpendicular diameters using the following formula: (LxW2) / 2, where L and W represent the length and width of the tumor, respectively. Results are expressed as the mean and standard deviation of the mean.

[0325] The results of various treatments are shown in Figures 1-6. Figures 1-3 compare the efficacy of several 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 appendix cancer. AMG510 is believed to be 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-[4-methyl-2-(prop-2-yl)pyridin-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]-1H,2H-pyrido[2,3-d]pyrimidin-2-one. Figure 1 shows that a 60 mg / kg dose of Compound No. 44 and a 30 mg / kg dose of Compound No. 126 are more effective than 60 mg / kg AMG510 in reducing in vivo tumor volume in a colorectal adenocarcinoma SW837 xenograft model at all treatment periods. Figure 2 shows that a 30 mg / kg dose of Compound No. 44 and a 30 mg / kg dose of Compound No. 126 are more effective than 30 mg / kg AMG510 in reducing in vivo tumor volume in a NSCLC H358 xenograft model. Figure 3 shows that a 60 mg / kg dose of Compound No. 126 is more effective than 60 mg / kg AMG510 in reducing in vivo tumor volume in a NSCLC H2122 xenograft model.

[0326] Figures 4-6 show that the compounds of the present disclosure can be used in combination with other anti-cancer therapies to achieve synergistic effects against various cancers. Figure 4 shows that in an NSCLC H358 xenograft model, combined treatment with carboplatin and compound No. 145 shows a much better reduction in tumor volume compared to treatment with either carboplatin or compound No. 145 alone throughout the treatment period. In this study, the treatment includes 30 mg / kg carboplatin; 5 mg / kg compound 145; or 30 mg / kg carboplatin and 5 mg / kg compound 145. Figure 5 shows that in an NSCLC H358 xenograft model, combined treatment with cisplatin and compound No. 126 shows a much better reduction in tumor volume compared to treatment with either cisplatin or compound No. 126 alone throughout the treatment period. Similarly, the combination treatment of RMC-4550 and Compound No. 126 shows a much better reduction in tumor volume compared to either RMC-4550 or Compound No. 126 alone throughout the course of treatment. In this study, the treatment included 2 mg / kg cisplatin; 10 mg / kg RMC-4550; 5 mg / kg Compound 126; 2 mg / kg cisplatin and 5 mg / kg Compound 126; or 10 mg / kg RMC-4550 and 5 mg / kg Compound 126. Figure 6 shows that the combination treatment of trametinib and Compound No. 44 shows a much better reduction in tumor volume compared to either trametinib or Compound No. 44 alone throughout the course of treatment in a colorectal adenocarcinoma SW837 xenograft model. In this study, treatment included 1 mg / kg trametinib; 30 mg / kg compound 44; or 1 mg / kg trametinib and 30 mg / kg compound 44.

[0327] The Summary and Abstract sections describe one or more exemplary embodiments of the invention as contemplated by the inventors, but are not exhaustive and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0328] The present invention has been described above with the aid of functional components that demonstrate the performance of certain functions and relationships thereof. The boundaries of these functional components are arbitrarily defined herein for convenience of description. Other boundaries may be defined so long as the specified functions and relationships thereof are appropriately performed.

[0329] With respect to aspects of the invention described as genus, all individual species are considered individually as separate aspects of the invention. When an aspect of the invention is described as "comprising" a feature, it is contemplated that the embodiment also "consists of" or "consists essentially of" that feature.

[0330] The above description of the specific embodiments fully reveals the general nature of the present invention, so that others can easily modify and / or adapt such specific embodiments for various applications by applying knowledge within the skill of those skilled in the art without undue experimentation and without departing from the general concept of the present invention. Therefore, such adaptations and modifications are intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is understood that the words or terms in this specification are for the purpose of description and not for the purpose of limitation, and that the words or terms in this specification should be interpreted by those skilled in the art in light of the teaching and guidance.

[0331] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0332] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0333] 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. If a meaning or definition of a term in this document conflicts with a meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. A compound of formula I-1 or I-2, or a pharma- ceutically acceptable salt thereof: During the ceremony, X is O, S, N, or NR １０ and 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 is a carbocyclic or an optionally substituted 4- to 7-membered heterocyclic ring; A ３ , A ４ , and A ５ Each of the groups independently represents CR ３０ or N, Here, R ３０ is independently hydrogen, F, Cl, C １－４ Alkyl, or C １－４ is alkoxy; R ２ and R ３ are each independently hydrogen, halogen, —OH, —CN, or 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- to 7-membered heterocyclic ring, or optionally substituted C １－４ is alkoxy; part is, Represented by: R ７ is hydrogen, halogen, —CN, a 3- or 4-membered ring, or an optionally substituted C １－４ Alkyl, optionally substituted C ２－４ Alkenyl, optionally substituted C ２－４ Alkynyl, or optionally substituted C １－４ is alkoxy; R ８ is optionally substituted aryl or optionally substituted heteroaryl, J １ and J. ２ each independently represents O, S, N, CR ４０ , and N.R. ４１ where R ４０ and R ４１ Each of the following is independently selected from 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 a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring; R ５ and R ６ are each independently hydrogen, halogen, -CN, or -COOR. ２３Ａ , -CONR ２１Ａ R ２２Ａ , optionally substituted C １－６ Alkyl, optionally substituted C ２－６ Alkenyl, optionally substituted C ２－６ Alkynyl, optionally substituted C ３－６ carbocycle, optionally substituted phenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 4- to 7-membered heterocycle, or R ５ and R ６ are linked together to form an optionally substituted C ３－６ Forms a carbocyclic ring or an optionally substituted 4- to 7-membered heterocyclic ring, where R ２１Ａ and R ２２Ａ Each of the following is independently selected from each occurrence: 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 or an optionally substituted 4- to 7-membered heterocyclic ring; and R ２３Ａ is independently at each occurrence 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 is a carbocyclic or an optionally substituted 4- to 7-membered heterocyclic ring; Here, the dashed lines represent each link being a single or double bond, provided that the bicyclic ring as a whole is aromatic.

2. Formula I-3A, I-3B, I-3C, I-4A, I-4B, or I-4C: having In the formula, A ２ is CH or N, and R １０ , R ４０ and R ４１ Each of １－４ is alkyl, 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof.

3. R ２ and R ３ The compound according to any one of claims 1 to 2, or a pharma- ceutically acceptable salt thereof, wherein:

4. R ２ and R ３ 4. The compound of claim 3, wherein are both isopropyl or both cyclopropyl, or a pharma- ceutically acceptable salt thereof.

5. R ５ and R ６ The compound according to any one of claims 1 to 4, wherein both are hydrogen, or a pharma- ceutically acceptable salt thereof.

6. R ８ but, The compound according to any one of claims 1 to 5, selected from the group consisting of:

7. below: or a pharma- ceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

9. A pharmaceutical composition for treating cancer in a subject, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof.

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