KRAS G12C Inhibitors for Treating Cancer

Abstract

To provide compounds useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.SOLUTION: Specifically, a KRAS G12C inhibitor represented by, for example, the following structural formula, and a composition thereof are provided.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application is filed with a sequence listing in electronic format. The sequence listing is provided in a file named A-2262-WO-PCT_SeqList_061019_ST25.txt, created on June 10, 2019, which is 16kb in size. The information in the electronic sequence listing is incorporated herein by reference in its entirety.

[0002] The present invention relates to compounds that inhibit the KRAS G12C protein, methods of using the compounds to treat diseases or conditions, such as cancer, and pharmaceutical compositions containing the compounds. [Background technology]

[0003] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colon cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have shown that KRAS mutations are a negative prognostic factor for patients with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colon cancer, and thus, the mutation status of KRAS can provide important information before prescribing TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colon cancer, including those diagnosed with such cancers characterized by KRAS mutations and those who have progressed after chemotherapy. Summary of the Invention [Means for solving the problem]

[0004] The compounds disclosed herein may be in the form of pharma- ceutically acceptable salts.The compounds provided herein may be formulated into pharmaceutical preparations comprising the compounds disclosed herein and pharma- ceutically acceptable excipients.

[0005] Also provided is a method of inhibiting KRAS G12C in a cell, comprising contacting the cell with a compound or composition disclosed herein.Further provided is a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.In some embodiments, the cancer is lung cancer, pancreatic cancer or colon cancer.

[0006] In one aspect of the present invention, the present invention provides a compound represented by formula (I): [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; [ka] are the single or double bonds necessary to give every atom its normal valence; R 1 are independently H, hydroxy, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Alkoxy, -NH-C 1~6 Alkyl, -N(C 1~4 alkyl)2, cyano or halo; R 2 ,Halo,-C 1~6 Alkyl, -C 1~6 Haloalkyl, -OR 2a , -N(R 2a )2, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, -C 0~3 Alkylene-C 6~14 Aryl or -C 0~3 Alkylene-C 2~14heteroaryl, and each R 2a are independently H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 3~14 Cycloalkyl, -C 2~14 Heterocycloalkyl, -C 2~6 Alkenyl, -C 2~6 alkynyl, aryl, or heteroaryl, or two R 2a the substituents, together with the nitrogen atom to which they are attached, form a 3- to 7-membered ring; R 3 ,Halo,-C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Alkoxy, C 3~6 Cycloalkyl, -C 2~14 Heterocycloalkyl, -C 2~6 Alkenyl, -C 2~6 alkynyl, aryl or heteroaryl; R 4 teeth, [ka] and; Ring A is a monocyclic 4-7 membered ring or a bicyclic bridged, fused or spiro 6-11 membered ring; L is a bond, -C 1~6 Alkylene, -OC 0~6 Alkylene, -SC 0~6 Alkylene or -NH-C 0~6 alkylene, and -C 2~6 Alkylene, -OC 2~6 Alkylene, -SC 2~6 Alkylene and NH-C 2~6 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4a , H, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 is aryl, or [ka] Selected from; R 5 and R 6 are each independently H, halo, -C 1~6 Alkyl, -C 2~6 Alkynyl, -C 1~6 Alkylene-OC 1~4 Alkyl, -C 1~6 Alkylene -OH, -C 1~6 Haloalkyl, -C 1~6 Alkyleneamines, -C 0~6 Alkylene-amide, -C 0~3 Alkylene -C(O)OH, -C 0~3 Alkylene-C(O)OC 1~4 Alkyl, -C 1~6 Alkylene-O-aryl, -C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, -C 0~3 Alkylene-C 6~14 Aryl, -C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~6 alkyl or R 7 and R 5form a 4- to 6-membered ring together with the atoms to which they are attached; R 8 -H, -C 1~6 Alkyl, -C 0~3 Alkylene-C 6~14 Aryl, -C 0~3 Alkylene-C 3~14 Heteroaryl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, -C 1~6 Alkoxy, -OC 0~3 Alkylene-C 6~14 Aryl, -OC 0~3 Alkylene-C 3~14 Heteroaryl, -OC 0~3 Alkylene-C 3~14 Cycloalkyl, -OC 0~3 Alkylene-C 2~14 Heterocycloalkyl, -NH-C 1~8 Alkyl, -N(C 1~8 Alkyl)2, -NH-C 0~3 Alkylene-C 6~14 Aryl, -NH-C 0~3 Alkylene-C 2~14 Heteroaryl, -NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, -NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 is an alkylene-amine; R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 and R 8Any of the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of the substituents have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups can contain a S=O or SO2 group; R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , L, R 5 , R 6 , R 7 and R 8 Any -C in the substituent 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl and -OC 1~6 Alkyl is unsubstituted or is substituted with OH, -OC 1~6 Alkyl, -C 1~6 Alkyl-OC 1~6 Alkyl, Halo, -O-HaloC 1~6 Alkyl, -CN, -NR a R b , -(NR a R b R c ) n , -OSO2R a , -SO2R a , -(CH2CH2O) n CH3, -(=O), -C(=O), -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -O-SiR a R b R c , -SiR a R b R cone, two or three R independently selected from -O-(3- to 10-membered heterocycloalkyl), 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group; 9 Substituted by substituents, the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups can contain an S=O or SO2 group; R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , R 8 and R 9 Any of the substituents aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be unsubstituted or may be substituted with OH, halo, -NR c R d , -C 1~6 Alkyl, -OC 1~6 Alkyl, -C 1~6 Alkyl-OH, -C 1~6 Alkyl-OC 1~6 Alkyl, C 1~6 Haloalkyl, -O-HaloC 1~6 Alkyl, -SO2R c , -CN, -C(=O)NR c R d , -C(=O)R c , -OC(=O)R a , -C(=O)OR c, one, two, three, or four R independently selected from 6-12 membered aryl or heteroaryl, 5-12 membered spirocycloalkyl or spiroheterocycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered monocyclic or bicyclic cycloalkyl, or 3-12 membered monocyclic or bicyclic heterocycloalkyl group; 10 R may be substituted with a substituent. 10 The heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of the formula (I) have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and R 10 or R 10 The heterocycloalkyl groups may contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups may contain an S=O or SO2 group; Each R a , R b , R c and R d are independently hydrogen, OH, -C 1~6 Alkyl, -(CH2CH2O) n CH3, -NR 11 R 11 , -C 1~6 Alkyl-NR 11 R 11 , Phenyl, -C 1~6 Alkyl-C(=O)OH, -C 1~6 Alkyl-C(=O)-OC 1~6 Alkyl, -C 1~6 Alkyl-3 to 12-membered cycloalkyl, -C 1~6 Alkyl-3 to 12 membered heterocycloalkyl, -C 1~6 alkyl-6 to 12 membered heteroaryl, 6 to 12 membered aryl or heteroaryl, 3 to 12 membered monocyclic or bicyclic cycloalkyl, or 3 to 12 membered monocyclic or bicyclic heterocycloalkyl group; R a , R b , R c and R d a heteroaryl group, a heterocycloalkyl group, or R a , R b , Rc and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group has 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S; R a , R b , R c and R d and R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group may contain a double bond, and further, R a , R b , R c and R d and R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group may contain a C=O group; and R a , R b , R c and R d or R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group is unsubstituted or contains one, two, three or four R 12 Each R 12 H, OH, halo, -C 1~6 Alkyl, N(CH3)2, -C 1~6 Haloalkyl, C(=O)CH3, C(=O)OCH3 or -C 1~6 Alkyl-OC 1~6 alkyl) or a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, or a pharma- ceutically acceptable salt of the atropisomer.

[0007] In another aspect of the present invention, the present invention relates to a compound represented by formula (Ia) [ka] or a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, or a pharma- ceutically acceptable salt of the atropisomer.

[0008] One aspect of the present invention provides various compounds, stereoisomers, atropisomers, pharma- ceutically acceptable salts, pharma- ceutically acceptable salts of stereoisomers, and pharma- ceutically acceptable salts of atropisomers, as described in the embodiments below.

[0009] Another aspect of the invention provides a pharmaceutical composition comprising a compound of any of the embodiments, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier or diluent.

[0010] Another aspect of the invention provides a method of treating cancer. Such a method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of any of the embodiments or a pharma- ceutically acceptable salt thereof. In some such methods, the cancer is a hematological malignancy. In some such methods, the cancer is selected from the group consisting of breast cancer, colon cancer, skin cancer, melanoma, ovarian cancer, renal cancer, lung cancer, non-small cell lung cancer, lymphoma, non-Hodgkin's lymphoma, myeloma, multiple myeloma, leukemia, and acute myeloid leukemia. In some other such methods, the cancer is multiple myeloma. In some other such methods, the cancer is acute myeloid leukemia. In some other such methods, the cancer is non-Hodgkin's lymphoma.

[0011] In another embodiment, the method further comprises administering to a patient in need thereof a therapeutically effective amount of one or more additional pharma- ceutically active compounds. For example, in some such methods, the one or more additional pharma-ceutically active compounds are carfilzomib. In other such methods, the one or more additional pharma-ceutically active compounds are venetoclax. In still other such methods, the one or more additional pharma-ceutically active compounds are cytarabine. In still other such methods, the one or more additional pharma-ceutically active compounds are daratumumab. In still other such methods, the one or more additional pharma-ceutically active compounds are MCl-1 inhibitors. In still other such methods, the MCl-1 inhibitor is AMG-176. In still other such methods, the one or more additional pharma-ceutically active compounds are immunomodulatory agents (IMiDs).

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Methods and materials are described herein for use in this disclosure, and other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references described herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0013] Other features and advantages of the present disclosure will become apparent from the following detailed description and figures, and from the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition

[0015] [Table 1]

[0016] [Table 2]

[0017] [Table 3]

[0018] In connection with the description of the present invention (particularly in connection with the claims), the use of the terms "a", "an", "the" and similar referents should be construed to encompass both the singular and the plural unless otherwise indicated. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. The use of any examples or exemplary language provided herein (e.g., "such as") is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise asserted. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0019] As used herein, the term "alkyl" refers to straight-chain and branched C1-C8 hydrocarbon groups, including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. m~nThe term "alkylene" refers to an alkyl group having from "m" to "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. The alkyl (e.g., methyl) or alkylene (e.g., -CH2-) groups can be independently selected from a group consisting of halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -NC, amino, -CO2H, -CO2C1-C6 alkyl, -OCOC1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 10 Aryl and C5-C 10 The heteroaryl can be substituted with one or more, typically 1 to 3. The term "haloalkyl" specifically refers to an alkyl group in which at least one, e.g., 1 to 6 or all, of the hydrogens on the alkyl group have been replaced with a halo atom.

[0020] The terms "alkenyl" and "alkynyl" refer to alkyl groups that further contain double or triple bonds, respectively.

[0021] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo. The term "alkoxy" is defined as -OR, where R is alkyl.

[0022] As used herein, the terms "amino" or "amine" refer interchangeably to the -NR2 group, where each R is, for example, H or a substituent. In some embodiments, the amino group is further substituted to provide an ammonium ion, for example, NR3 +The ammonium moiety is specifically included in the definition of "amino" or "amine". The substituents can be, for example, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amido, or carboxylate. The R group can be further substituted with one or more, e.g., 1 to 4, groups selected from, for example, halo, cyano, alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amido. An "amide" or "amido" group refers interchangeably to a group similar to an amine or amino group, but further including a C(O), e.g., -C(O)NR2. Some possible amino or amide groups (some with an optional alkylene group, e.g., alkylene-amino or alkylene-amide) are CH2NH2, CH(CH3)NH2, CH(CH3)2NH2, CH2CH2NH2, CH2CH2N(CH3)2, CH2NHCH3, C(O)NHCH3, C(O)N(CH3)2, CH2C(O)NHphenyl, CH2NHC(O)CH3, CH2NH CH2CH2OH, CH2NHCH2CO2H, CH2NH(CH3)CH2CO2CH3, CH2NHCH2CH2OCH3, CH2NH(CH3)CH2CH2OCH3, CH2NH(CH3)CH2C (O)N(CH3)2, CH2NH(CH3)CH2C(O)NHCH3, CH2CH2CCH, CH2NMe2, CH2NH(CH3)CH2CH2OH, CH2NH(CH3)CH2CH2F, CH2N + (CH3)3, CH2NHCH2CHF2, CH2NHCH2CH3, [ka] Includes.

[0023] Collectively, antibodies form a family of plasma proteins known as immunoglobulins and contain immunoglobulin domains. (Janeway et al., Immunobiology: The Immune System in Health and Disease, 4 thed., Elsevier Science Ltd. / Garland Publishing, 1999). As used herein, the term "antibody" refers to a protein having a conventional immunoglobulin type, including heavy and light chains, and including a variable region and a constant region. For example, an antibody may be an IgG, which has a "Y-shaped" structure with two pairs of identical polypeptide chains, each pair having one "light" chain (usually having a molecular weight of about 25 kDa) and one "heavy" chain (usually having a molecular weight of about 50-70 kDa). An antibody has a variable region and a constant region. In the IgG type, the variable region is generally about 100-110 or more amino acids, includes three complementarity determining regions (CDRs), and is primarily responsible for antigen recognition and is substantially different from other antibodies that bind to different antigens. The constant region enables the antibody to recruit cells and molecules of the immune system. The variable region is made up of the N-terminal region of each light and heavy chain, and the constant region is made up of the C-terminal portion of each heavy and light chain. (Janeway et al., “Structure of the Antibody Molecule and the Immunoglobulin Genes”, Immunobiology: The Immune System in Health and Disease, 4 th ed.Elsevier Science Ltd. / Garland Publishing, (1999)).

[0024] The general structure and properties of antibody CDRs have been described in the art. Briefly, in the antibody framework, CDRs are embedded within the framework in the variable regions of heavy and light chains, where they constitute the regions that play a major role in antigen binding and recognition. A variable region usually comprises at least three heavy or light chain CDRs (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service NIH, Bethesda, Md.; see also Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:877-883), which are located within framework regions (referred to as framework regions 1-4, FR1, FR2, FR3 and FR4 by Kabat et al., 1991; see also Chothia and Lesk, 1987, supra).

[0025] The antibody may comprise any constant region known in the art. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, defining the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. The embodiments of the present disclosure include all such classes or isotypes of antibodies. The light chain constant region may be, for example, a kappa- or lambda-type light chain constant region, such as a human kappa- or lambda-type light chain constant region. The heavy chain constant region may be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region, such as a human alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region. Thus, in exemplary embodiments, the antibody is of the isotype IgA, IgD, IgE, IgG or IgM, including any one of IgG1, IgG2, IgG3 or IgG4.

[0026] The antibody may be a monoclonal or polyclonal antibody. In some embodiments, the antibody comprises sequences substantially similar to natural antibodies produced by mammals, such as mice, rabbits, goats, horses, chickens, hamsters, and humans. In this regard, the antibody may be considered a mammalian antibody, such as a mouse antibody, a rabbit antibody, a goat antibody, a horse antibody, a chicken antibody, a hamster antibody, and a human antibody. In certain aspects, the antibody is a human antibody. In certain aspects, the antibody is a chimeric or humanized antibody. The term "chimeric antibody" refers to an antibody that contains domains from two or more different antibodies. A chimeric antibody can, for example, contain a constant domain from one species and a variable domain from a second species, or more commonly, can contain stretches of amino acid sequences from at least two species. A chimeric antibody can also contain domains from two or more different antibodies within the same species. The term "humanized", when used in reference to an antibody, refers to an antibody with at least the CDR regions from a non-human source that have been engineered to have a structure and immune function more similar to a true human antibody than the original source antibody. For example, humanization can include the transplantation of CDRs from a non-human antibody, such as a murine antibody, into a human antibody. Humanization can also include selected amino acid substitutions to make the non-human sequence more similar to a human sequence.

[0027] Antibodies can be cleaved into fragments by enzymes such as, for example, papain and pepsin. Papain cleaves antibodies to produce two Fab fragments and a single Fc fragment. Pepsin cleaves antibodies to produce F(ab')2 and pFc' fragments. As used herein, the term "antigen-binding antibody fragment" refers to a portion of an antibody molecule capable of binding to the antigen of the antibody, also known as an "antigen-binding fragment" or "antigen-binding portion." In an illustrative example, the antigen-binding antibody fragment is a Fab fragment or a F(ab')2 fragment.

[0028] The structure of antibodies has been exploited to create a wide range of alternative formats, spanning a molecular weight range of at least about 12-150 kDa, from monomers (n=1) to dimers (n=2), trimers (n=3), tetramers (n=4) and potentially even higher valency (n) ranges, referred to herein as "antibody protein products." Antibody protein products include those based on the complete antibody structure and those that mimic antibody fragments that retain complete antigen-binding capacity, such as scFv, Fab and VHH / VH (discussed below). The smallest antigen-binding antibody fragment that retains an intact antigen-binding site is the Fv fragment, consisting exclusively of the variable (V) region. Either the V region is linked to the scFv (single chain fragment variable) fragment using a soluble, flexible amino acid peptide linker to stabilize the molecule, or a constant (C) domain is added to the V region to generate a Fab fragment [fragment, antigen-binding]. Both scFv and Fab fragments can be easily produced in host cells, e.g., prokaryotic host cells. Other antibody protein products include dimeric and multimeric antibody formats such as diabodies, triabodies and tetrabodies or minibodies (miniAbs), including disulfide bond stabilized scFv (ds-scFv), single chain Fab (scFab) and different formats consisting of scFv linked to oligomerization domains. The smallest fragments are the VHH / VH of camelid heavy chain Abs and single domain Abs (sdAbs). The building blocks most frequently used to generate novel antibody formats are single chain variable (V)-domain antibody fragments (scFv), which contain the V domains from heavy and light chains (VH and VL domains) linked by a peptide linker of about 15 amino acid residues. Peptibodies or peptide-Fc fusions are yet another antibody protein product. The structure of a peptibody consists of a biologically active peptide grafted onto an Fc domain. Peptibodies have been described in detail in the art, see, e.g., Shimamoto et al., mAbs 4(5):586-591 (2012).

[0029] Other antibody protein products include single chain antibodies (SCAs), diabodies, triabodies, tetrabodies, and bispecific or triabodies. Bispecific antibodies can be divided into five major classes: BsIgG, adduct IgG, BsAb fragments, bispecific fusion proteins, and BsAb conjugates. See, e.g., Spiess et al., Molecular Immunology 67(2)Part A:97-106(2015).

[0030] As used herein, the term "aryl" refers to 6~14 Monocyclic or polycyclic aromatic groups, preferably C 6~10 Monocyclic or bicyclic aromatic group or C 10~14 It refers to a polycyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl refers to a C cyclic aromatic ring in which one ring is aromatic and the other ring is saturated, partially unsaturated, or aromatic. 10~14 It also refers to bicyclic and tricyclic carbocycles, such as dihydronaphthyl, indenyl, indanyl or tetrahydronaphthyl (tetralinyl). Unless otherwise indicated, aryl groups are unsubstituted or substituted with, for example, halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -CF3, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C6 alkyl, -OCOC1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 10 Aryl and C5-C 10 It may be substituted with one or more, particularly 1 to 4, groups independently selected from heteroaryl.

[0031] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic carbocyclic ring, which may be fused, bridged, or spiro. Carbocyclic rings can have from 3 to 10 carbon ring atoms. Possible carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

[0032] As used herein, the term "heterocycloalkyl" means a monocyclic or polycyclic (e.g., bicyclic), saturated or partially unsaturated ring system containing a total of three or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7) atoms, of which one to five (e.g., one, two, three, four, or five) atoms are independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, and diazacycloheptyl.

[0033] Unless otherwise indicated, a cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with one or more, particularly one to four, groups. Some possible substituents include halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C6 alkyl, -OCOC1-C8 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 10 Aryl and C5-C 10 Examples of such radicals include heteroaryl.

[0034] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic ring system (e.g., bicyclic) containing one to three aromatic rings and containing one to four (e.g., one, two, three, or four) heteroatoms in the aromatic rings selected from nitrogen, oxygen, and sulfur. In certain embodiments, a heteroaryl group has 5 to 20, 5 to 15, 5 to 10, or 5 to 7 atoms. Heteroaryl refers to a C aryl group in which one ring is aromatic and the other ring is saturated, partially unsaturated, or aromatic. 10~14 It also refers to bicyclic and tricyclic rings. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothio, benzophenyl ... Examples of heteroaryl groups include phenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, thiazolinyl, thiadiazolopyrimidyl and thienopyridyl. Unless otherwise indicated, heteroaryl groups can be unsubstituted or substituted with one or more, particularly 1 to 4 or 1 or 2, substituents. Possible substituents include halo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C6 alkyl, -OCOC1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5-C 10 Aryl and C5-C 10 Examples of such radicals include heteroaryl.

[0035] As used herein, the term Boc means: [ka] Refers to the structure of.

[0036] As used herein, the term Cbz means [ka] Refers to the structure of.

[0037] As used herein, the term Bn means [ka] Refers to the structure of.

[0038] As used herein, the term trifluoroacetamide means [ka] Refers to the structure of.

[0039] As used herein, the term trityl means [ka] Refers to the structure of.

[0040] As used herein, the term tosyl means [ka] Refers to the structure of.

[0041] As used herein, the term Troc means: [ka] Refers to the structure of.

[0042] As used herein, the term Teoc means: [ka] Refers to the structure of.

[0043] As used herein, the term Alloc means: [ka] Refers to the structure of.

[0044] As used herein, the term Fmoc means: [ka] Refers to the structure of.

[0045] Compounds of the Disclosure The compounds disclosed herein include all pharma- ceutically acceptable isotopically labeled compounds in which one or more atoms of the compounds disclosed herein are replaced by an atom having the same atomic number, but a different atomic mass or mass number than that usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125I. These radiolabeled compounds may be useful, for example, to facilitate the determination or measurement of the efficacy of a compound by identifying the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of the present disclosure, for example those incorporating a radioisotope, are useful in studying tissue distribution of drugs and / or substrates. The radioisotope tritium, i.e. 3 H and carbon-14, i.e. 14 C is particularly useful for this purpose in view of its ease of incorporation and rapid means of detection.

[0046] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, can confer certain therapeutic advantages resulting from increased metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances.

[0047] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of structure (I) can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described in the Preparations and Examples below, substituting the appropriate isotopically labeled reagents for the non-labeled reagents previously used.

[0048] Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described in the accompanying Examples and Schemes, substituting an appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0049] Some of the compounds disclosed herein may exist as stereoisomers (i.e., isomers that differ only in the spatial arrangement of atoms), including optical isomers and conformers (or conformers). The compounds disclosed herein include all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations, as well as racemic mixtures of such stereoisomers, as well as individual diastereomers and enantiomers that can be separated according to methods known to those skilled in the art. Additionally, the compounds disclosed herein include all tautomeric forms of those compounds.

[0050] Some of the compounds disclosed herein may exist as atropisomers, which are conformational stereoisomers that arise when rotation around a single bond in a molecule is hindered or greatly slowed down as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, both as pure individual atropisomer preparations, preparations enriched in each, or unspecified mixtures of each. If the barrier to rotation around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of isomeric species may be possible. For example, but not limited to, the following R 8 basis [ka] Each group such as may exhibit restrictions of rotation.

[0051] Embodiment EMBODIMENT 1 In one embodiment of the present invention, the present invention provides a compound of formula (I) [ka] (In the formula, E 1 and E 2 are each independently N or CR 1 and; [ka] are the single or double bonds necessary to give every atom its normal valence; R 1 are independently H, hydroxy, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Alkoxy, -NH-C 1~6 Alkyl, -N(C 1~4 alkyl)2, cyano or halo; R 2 ,Halo,-C 1~6 Alkyl, -C 1~6 Haloalkyl, -OR 2a , -N(R 2a )2, -C 2~6 Alkenyl, -C 2~6 Alkynyl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, -C 0~3 Alkylene-C 6~14 Aryl or -C 0~3 Alkylene-C 2~14 heteroaryl, and each R 2a are independently H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 3~14 Cycloalkyl, -C 2~14 Heterocycloalkyl, -C 2~6 Alkenyl, -C 2~6 alkynyl, aryl, or heteroaryl, or two R 2a the substituents, together with the nitrogen atom to which they are attached, form a 3- to 7-membered ring; R 3 ,Halo,-C 1~6 Alkyl, -C 1~6 Haloalkyl, -C 1~6 Alkoxy, C 3~6 Cycloalkyl, -C 2~14 Heterocycloalkyl, -C 2~6 Alkenyl, -C 2~6 alkynyl, aryl or heteroaryl; R4 teeth, [ka] and; Ring A is a monocyclic 4-7 membered ring or a bicyclic bridged, fused or spiro 6-11 membered ring; L is a bond, -C 1~6 Alkylene, -OC 0~6 Alkylene, -SC 0~6 Alkylene or -NH-C 0~6 alkylene, and -C 2~6 Alkylene, -OC 2~6 Alkylene, -SC 2~6 Alkylene and NH-C 2~6 For alkylene, one carbon atom of the alkylene group can be optionally substituted with O, S, or NH; R 4a , H, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Alkylene-OC 1~4 Alkyl, C 1~6 Alkylene-OH, C 1~6 Haloalkyl, cycloalkyl, heterocycloalkyl, C 0~3 Alkylene-C 3~14 Cycloalkyl, C 0~3 Alkylene-C 2~14 Heterocycloalkyl, aryl, heteroaryl, C 0~3 Alkylene-C 6~14 is aryl, or [ka] Selected from; R 5 and R 6 are each independently H, halo, -C 1~6 Alkyl, -C 2~6 Alkynyl, -C 1~6 Alkylene-OC 1~4 Alkyl, -C 1~6 Alkylene -OH, -C 1~6 Haloalkyl, -C 1~6Alkyleneamines, -C 0~6 Alkylene-amide, -C 0~3 Alkylene -C(O)OH, -C 0~3 Alkylene-C(O)OC 1~4 Alkyl, -C 1~6 Alkylene-O-aryl, -C 0~3 Alkylene-C(O)C 1~4 Alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, -C 0~3 Alkylene-C 6~14 Aryl, -C 0~3 Alkylene-C 2~14 heteroaryl or cyano, or R 5 and R 6 form a 4- to 6-membered ring together with the atoms to which they are attached; R 7 is H or C 1~6 alkyl or R 7 and R 5 form a 4- to 6-membered ring together with the atoms to which they are attached; R 8 -H, -C 1~6 Alkyl, -C 0~3 Alkylene-C 6~14 Aryl, -C 0~3 Alkylene-C 3~14 Heteroaryl, -C 0~3 Alkylene-C 3~14 Cycloalkyl, -C 0~3 Alkylene-C 2~14 Heterocycloalkyl, -C 1~6 Alkoxy, -OC 0~3 Alkylene-C 6~14 Aryl, -OC 0~3 Alkylene-C 3~14 Heteroaryl, -OC 0~3 Alkylene-C 3~14 Cycloalkyl, -OC 0~3 Alkylene-C 2~14Heterocycloalkyl, -NH-C 1~8 Alkyl, -N(C 1~8 Alkyl)2, -NH-C 0~3 Alkylene-C 6~14 Aryl, -NH-C 0~3 Alkylene-C 2~14 Heteroaryl, -NH-C 0~3 Alkylene-C 3~14 Cycloalkyl, -NH-C 0~3 Alkylene-C 2~14 Heterocycloalkyl, halo, cyano or C 1~6 is an alkylene-amine; R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 and R 8 Any of the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of the substituents have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups can contain a S=O or SO2 group; R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , L, R 5 , R 6 , R 7 and R 8 Any -C in the substituent 1~6 Alkyl, -C 2~6 Alkenyl, -C 2~6 Alkynyl and -OC 1~6 Alkyl is unsubstituted or is substituted with OH, -OC 1~6 Alkyl, -C 1~6 Alkyl-OC 1~6 Alkyl, Halo, -O-HaloC 1~6 Alkyl, -CN, -NR a Rb , -(NR a R b R c ) n , -OSO2R a , -SO2R a , -(CH2CH2O) n CH3, -(=O), -C(=O), -C(=O)R a , -OC(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -O-SiR a R b R c , -SiR a R b R c one, two or three R independently selected from -O-(3- to 10-membered heterocycloalkyl), 6- to 12-membered aryl or heteroaryl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, or 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group; 9 Substituted by substituents, the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups can contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups can contain an S=O or SO2 group; R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , R 8 and R 9 Any of the substituents aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups may be unsubstituted or may be substituted with OH, halo, -NR c R d , -C1~6 Alkyl, -OC 1~6 Alkyl, -C 1~6 Alkyl-OH, -C 1~6 Alkyl-OC 1~6 Alkyl, C 1~6 Haloalkyl, -O-HaloC 1~6 Alkyl, -SO2R c , -CN, -C(=O)NR c R d , -C(=O)R c , -OC(=O)R a , -C(=O)OR c , one, two, three, or four R independently selected from 6-12 membered aryl or heteroaryl, 5-12 membered spirocycloalkyl or spiroheterocycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered monocyclic or bicyclic cycloalkyl, or 3-12 membered monocyclic or bicyclic heterocycloalkyl group; 10 R may be substituted with a substituent. 10 The heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of the formula (I) have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, and R 10 or R 10 The heterocycloalkyl groups may contain a C=O group, and further, the spiroheterocycloalkyl and heterocycloalkyl groups may contain an S=O or SO2 group; Each R a , R b , R c and R d are independently hydrogen, OH, -C 1~6 Alkyl, -(CH2CH2O) n CH3, -NR 11 R 11 , -C 1~6 Alkyl-NR 11 R 11 , Phenyl, -C 1~6 Alkyl-C(=O)OH, -C 1~6 Alkyl-C(=O)-OC 1~6 Alkyl, -C 1~6 Alkyl-3 to 12-membered cycloalkyl, -C1~6 Alkyl-3 to 12 membered heterocycloalkyl, -C 1~6 alkyl-6 to 12 membered heteroaryl, 6 to 12 membered aryl or heteroaryl, 3 to 12 membered monocyclic or bicyclic cycloalkyl, or 3 to 12 membered monocyclic or bicyclic heterocycloalkyl group; R a , R b , R c and R d a heteroaryl group, a heterocycloalkyl group, or R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group has 1, 2, 3, or 4 heteroatoms independently selected from O, N, or S; R a , R b , R c and R d and R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group may contain a double bond, and further, R a , R b , R c and R d Cycloalkyl and heterocycloalkyl groups of the formula R a , R b , R c and R d -C 1~6 The heterocycloalkyl group of the alkyl-heterocycloalkyl group may contain a C=O group; and R a , R b , R c and R d or R a , R b , R c and R d -C 1~6The heterocycloalkyl group of the alkyl-heterocycloalkyl group is unsubstituted or contains one, two, three or four R 12 Each R 12 H, OH, halo, -C 1~6 Alkyl, N(CH3)2, -C 1~6 Haloalkyl, C(=O)CH3, -C(=O)OCH3 or -C 1~6 Alkyl-OC 1~6 alkyl) or a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, or a pharma- ceutically acceptable salt of the atropisomer.

[0052] EMBODIMENT 2 In another embodiment of the present invention, the present invention relates to a compound represented by formula (Ia) [ka] or a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, or a pharma- ceutically acceptable salt of the atropisomer.

[0053] EMBODIMENT 3 In another embodiment of the present invention, the present invention provides a method for producing 1 is N.

[0054] EMBODIMENT 4 In another embodiment of the present invention, the present invention provides a method for producing 2 CR 1

[0033] The present invention includes compounds as described in embodiment 1, wherein

[0055] EMBODIMENT 5 In another embodiment of the present invention, the present invention provides 1 is H.

[0056] EMBODIMENT 7 In another embodiment of the present invention, the present invention provides2 Includes compounds according to embodiment 6, wherein is substituted aryl.

[0057] EMBODIMENT 8 In another embodiment of the present invention, the present invention provides 2 is a fluorinated phenyl.

[0058] EMBODIMENT 9 In another embodiment of the present invention, the present invention provides 2 Includes compounds as described in embodiment 6, wherein is Cl.

[0059] EMBODIMENT 10 In another embodiment of the present invention, the present invention provides 2 but, [ka]

[0023] The compounds of embodiment 6 include those compounds described in embodiment 6, wherein

[0060] EMBODIMENT 11 In another embodiment of the present invention, the present invention provides 2 but, [ka]

[0023] The compounds of embodiment 6 include those compounds described in embodiment 6, wherein

[0061] EMBODIMENT 12 In another embodiment of the present invention, the present invention provides 3 Includes compounds according to any one of embodiments 1-11, wherein is halo.

[0062] EMBODIMENT 13 In another embodiment of the present invention, the present invention provides 3 Includes compounds as described in embodiment 12, wherein is Cl.

[0063] EMBODIMENT 14 In another embodiment of the present invention, the present invention provides 3 is F.

[0064] EMBODIMENT 15 In another embodiment of the present invention, the present invention provides 4 but, [ka] The present invention includes a compound according to any one of embodiments 1 to 14, wherein

[0065] EMBODIMENT 16 In another embodiment of the invention, the invention includes compounds according to embodiment 15, wherein L is a bond.

[0066] EMBODIMENT 17 In another embodiment of the invention, the invention encompasses compounds according to embodiment 15, wherein ring A is a monocyclic 4-7 membered ring.

[0067] EMBODIMENT 18 In another embodiment of the present invention, the present invention includes compounds according to embodiment 17, wherein A is an unsubstituted or substituted heterocycle.

[0068] EMBODIMENT 19 In another embodiment of the present invention, the present invention provides 4 but, [ka] The compound according to any one of embodiments 1 to 18 is selected from the group consisting of:

[0069] EMBODIMENT 20 In another embodiment of the present invention, the present invention provides 4 but, [ka]

[0042] In some embodiments, the compounds are as described in embodiment 19, wherein

[0070] EMBODIMENT 21 In another embodiment of the present invention, the present invention provides 4 but, [ka]

[0042] In some embodiments, the compounds are as described in embodiment 19, wherein

[0071] EMBODIMENT 22 In another embodiment of the present invention, the present invention provides 4 but, [ka]

[0042] In some embodiments, the compounds are as described in embodiment 19, wherein

[0072] EMBODIMENT 23 In another embodiment of the present invention, the present invention provides 8 Ga-C 0~3 Alkylene-C 6~14 Aryl or -C 0~3 Alkylene-C 3~14 Includes compounds according to any one of embodiments 1 to 22, which is heteroaryl.

[0073] EMBODIMENT 24 In another embodiment of the present invention, the present invention provides 8 Ga-C 3~14 Includes compounds according to embodiment 23, which are heteroaryl.

[0074] EMBODIMENT 25 In another embodiment of the present invention, the present invention provides 8 but, [ka] The compound according to embodiment 23 is selected from the group consisting of:

[0075] EMBODIMENT 26 In another embodiment of the present invention, the present invention provides a compound of formula: [ka] [ka] [ka] [ka] or a stereoisomer thereof, an atropisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, or a pharma- ceutically acceptable salt of the atropisomer.

[0076] EMBODIMENT 27 In another embodiment of the invention, the invention comprises a compound according to any one of embodiments 1 to 26 in the form of a pharma- ceutically acceptable salt.

[0077] EMBODIMENT 28 In another embodiment of the invention, the invention comprises a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 27 and a pharma- ceutically acceptable excipient.

[0078] EMBODIMENT 29 In another embodiment of the invention, the invention comprises a method of inhibiting KRAS G12C in a cell, comprising the step of contacting a cell with a compound according to any one of embodiments 1 to 27 or a composition according to embodiment 28.

[0079] EMBODIMENT 30 In another embodiment of the invention, the invention comprises a method of treating cancer in a subject, comprising the step of administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1-27 or a composition described in embodiment 28.

[0080] EMBODIMENT 31 In another embodiment of the invention, the invention encompasses the method of embodiment 30, wherein the cancer is lung cancer, pancreatic cancer, or colon cancer.

[0081] EMBODIMENT 32 In another embodiment of the invention, the invention comprises the method of embodiment 31, wherein the cancer is lung cancer.

[0082] EMBODIMENT 33 In another embodiment of the invention, the invention comprises the method of embodiment 31, wherein the cancer is pancreatic cancer.

[0083] EMBODIMENT 34 In another embodiment of the invention, the invention comprises the method of embodiment 31, wherein the cancer is colon cancer.

[0084] EMBODIMENT 35 In another embodiment of the invention, the invention comprises the method of embodiment 30, further comprising the step of administering to a patient in need thereof a therapeutically effective amount of one or more additional pharma- ceutical active compounds.

[0085] EMBODIMENT 36 In another embodiment of the invention, the invention comprises the method of embodiment 35, wherein the one or more additional pharma- ceutically active compounds is an anti-PD-1 antibody.

[0086] EMBODIMENT 37 In another embodiment of the invention, the invention comprises the method of embodiment 36, wherein the anti-PD-1 antibody is pembrolizumab.

[0087] EMBODIMENT 38 In another embodiment of the invention, the invention comprises the method of embodiment 36, wherein the anti-PD-1 antibody is nivolumab.

[0088] EMBODIMENT 39 In another embodiment of the invention, the invention comprises the method of embodiment 36, wherein the anti-PD-1 antibody is AMG404.

[0089] EMBODIMENT 40 In another embodiment of the invention, the invention comprises the method of embodiment 35, wherein the one or more additional pharma- ceutical active compounds is a MEK inhibitor.

[0090] EMBODIMENT 41 In another embodiment of the invention, the invention comprises the method of embodiment 35, wherein the one or more additional pharma- ceutically active compounds is daratumumab.

[0091] EMBODIMENT 42 In another embodiment of the invention, the invention comprises the method of embodiment 35, wherein the one or more additional pharma- ceutical active compounds is an immunomodulatory agent.

[0092] EMBODIMENT 43 In another embodiment of the invention, the invention comprises the use of a compound according to any one of embodiments 1 to 27 for treating cancer in a subject.

[0093] EMBODIMENT 44 In another embodiment of the invention, the invention comprises a compound according to any one of the embodiments 1 to 27 in the preparation of a medicament for treating cancer.

[0094] EMBODIMENT 45 In another embodiment of the invention, the invention encompasses compounds as described in embodiment 44, wherein the cancer is non-small cell lung cancer.

[0095] Synthesis of the Disclosed Compounds The compounds disclosed herein can be synthesized by a number of specific methods. The examples outlined in the specific synthetic routes and the general schemes below are intended to provide guidance to a synthetic chemist of ordinary skill, who will readily understand that solvents, concentrations, reagents, protecting groups, order of synthetic steps, times and temperatures, etc., can be varied as necessary and well within the skill and judgment of the artisan.

[0096] Pharmaceutical Compositions, Administration and Routes of Administration Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein together with a pharma- ceutically acceptable excipient, such as a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an amount effective to achieve its intended purpose. Administration of the compounds is described in more detail below.

[0097] Suitable pharmaceutical formulations can be determined by those skilled in the art depending on the route of administration and the desired dosage. For example, see Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). Formulations may affect the physical state, stability, in vivo release rate and in vivo excretion rate of the administered drug. Depending on the route of administration, suitable doses can be calculated according to body weight, body surface area or organ size. Further refinement of calculations required to determine appropriate treatment doses can be routinely performed by those skilled in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein and pharmacokinetic data available from animal or human clinical trials.

[0098] The phrase "pharmacologically acceptable" or "pharmacologically acceptable" refers to molecular entities and compositions that do not produce adverse, allergic or other untoward reactions when administered to animals or humans. As used herein, "pharmacologically acceptable" includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, as well as isotonic and absorption delaying agents and the like. The use of such excipients for pharma-ceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the therapeutic composition, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In an exemplary embodiment, the formulation includes corn syrup solids, high oleic safflower oil, coconut oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM (emulsifier), L-glutamine, L-valine, dipotassium phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-asparagine monohydrate, L-serine, potassium citrate, L-threonine, sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride, L-triptyline, L-cystine dihydrochloride, L-trimethylsilyl ether ... Ingredients may include: tophan, L-aspartic acid, choline chloride, taurine, m-inositol, ferrous sulfate, ascorbyl palmitate, zinc sulfate, L-carnitine, alpha-tocopheryl acetate, sodium chloride, niacinamide, tocopherol mixture, calcium pantothenate, copper sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, beta-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0099] The compounds may be present in the pharmaceutical composition as pharma- ceutically acceptable salts. As used herein, "pharmaceutically acceptable salts" includes, for example, base addition salts and acid addition salts.

[0100] Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Pharmaceutically acceptable salts of compounds can also be prepared with pharma- ceutically acceptable cations. Suitable pharma-ceutically acceptable cations are well known to those skilled in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations include sodium, potassium, magnesium, ammonium, calcium or iron. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine and procaine.

[0101] Pharmaceutically acceptable acid addition salts include inorganic acid salts or organic acid salts. Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate. Other suitable pharma-ceutically acceptable salts are well known to those skilled in the art, such as salts with formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; salts with organic carboxylic acids, sulfonic acids, sulfoacids, or phosphoric acids, or N-substituted sulfamic acids, such as acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, and salts with amino acids, such as the 20 alpha amino acids involved in the synthesis of natural proteins, such as glutamic acid or aspartic acid, and also salts with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane 1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene 2-sulfonic acid, naphthalene 1,5-disulfonic acid, 2- or 3-phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamate) or other acid organic compounds, such as ascorbic acid.

[0102] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured in a conventional manner, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. Proper formulation depends on the route of administration chosen.

[0103] For oral administration, suitable compositions can be easily formulated by combining the compounds disclosed herein with pharma- ceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers allow the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compounds disclosed herein with solid excipients, optionally grinding the resulting mixture, and processing the granulated mixture, after adding suitable auxiliaries as necessary, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants can be added as necessary. Pharmaceutically acceptable ingredients are well known for various types of formulations, and can be, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavorings, coating materials, preservatives, dyes, thickeners, adjuvants, antibacterial agents, antioxidants, and carriers for various formulation types.

[0104] When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition will typically be in the form of a solid formulation (e.g., a tablet, capsule, pill, powder or lozenge) or a liquid formulation (e.g., an aqueous suspension, solution, elixir or syrup).

[0105] When administered in tablet form, the composition may further contain a functional solid and / or solid carrier such as gelatin or an adjuvant. Tablets, capsules and powders may contain about 1 to about 95% of the compound, preferably about 15 to about 90% of the compound.

[0106] When administered in liquid or suspension form, functional liquids and / or liquid carriers such as water, petroleum, or oils of animal or plant origin can be added. The liquid form of the composition can further contain physiological saline, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in liquid or suspension form, the composition can contain about 0.5 to about 90% by weight of the compound disclosed herein, preferably about 1 to about 50% of the compound disclosed herein. In one contemplated embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition can be provided as a rapidly dissolving solid formulation for dissolution or suspension immediately prior to administration.

[0107] When a therapeutically effective amount of the compounds disclosed herein is administered by intravenous, cutaneous or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, with due consideration of pH, isotonicity, stability, and the like, is within the skill of the art. A preferred composition for intravenous, cutaneous or subcutaneous injection typically contains an isotonic vehicle in addition to the compounds disclosed herein. Such compositions can be prepared for administration as an aqueous solution of a free base or a pharmacologically acceptable salt suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations can optionally contain a preservative to prevent the growth of microorganisms.

[0108] Injectable compositions may include sterile aqueous solutions, suspensions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions, suspensions or dispersions. In all embodiments, the form must be sterile and fluid to the extent that easy syringability exists. The form must be stable under the conditions of manufacture and storage and must be resistant to the contaminating action of microorganisms such as bacteria and fungi, optionally including preservatives. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one possible embodiment, the carrier is non-aqueous or substantially non-aqueous. The proper fluidity can be maintained, for example, by the use of a coating agent such as lecithin, by maintaining the particle size of the compound required in the embodiment of the dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many embodiments, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0109] Sterile injection is prepared by incorporating the active compound in the required amount in a suitable solvent together with various other ingredients as listed above, as necessary, followed by sterilization by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains a basic dispersion medium and other desired ingredients from the ingredients listed above.In the embodiment of sterile powder for preparing sterile injection, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient plus any additional desired ingredients from the solution that has been previously sterilized and filtered.

[0110] Slow or sustained release formulations can also be prepared to achieve controlled release of active compounds in contact with fluids in the digestive tract and provide a substantially constant and effective level of active compounds in plasma. For example, release can be controlled by one or more of dissolution, diffusion and ion exchange. In addition, slow release techniques can enhance absorption through saturable or restricted pathways in the digestive tract. For example, the compounds can be embedded in a polymer matrix of biodegradable polymers, water-soluble polymers or a mixture of both, and optionally a suitable surfactant, for this purpose. In this case, embedding can mean incorporating microparticles in a polymer matrix. Controlled release formulations can also be obtained by encapsulation of dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

[0111] For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray dispensed from a pressurized pack or nebulizer using a suitable propellant.In pressurized aerosol embodiments, the dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges, for example of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0112] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion).The preparation for injection can be provided in unit dosage form (e.g., in ampoules or multi-dose containers) with added preservative.The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents.

[0113] Pharmaceutical preparations for parenteral administration include aqueous solutions of the compound in water-soluble form. Additionally, suspensions of the compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Alternatively, the composition can be in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0114] The compounds disclosed herein can also be formulated into rectal compositions such as suppositories or retention enemas (e.g., containing a conventional suppository base). In addition to the above formulations, the compounds can also be formulated as depot preparations. Such long-acting formulations can be administered by injection (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or can be formulated as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0115] In particular, the compounds disclosed herein can be administered orally, bucally or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid preparations can be prepared with pharma- ceutically acceptable additives, such as suspending agents. The compounds can also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronarily. For parenteral administration, the compounds are most often used in the form of a sterile aqueous solution, which may contain other substances, such as salts or sugar alcohols, such as mannitol or glucose, to make the solution isotonic with blood.

[0116] For veterinary use, the compounds disclosed herein are administered in a suitably acceptable formulation in accordance with normal veterinary practice, and a veterinarian can readily determine the most appropriate dosing regimen and route of administration for a particular animal.

[0117] In some embodiments, all components necessary for the treatment of KRAS-related disorders, either alone or in combination with another drug or intervention conventionally used for the treatment of KRAS-related diseases, can be packaged in a kit. Specifically, the present invention provides a kit for use in the therapeutic intervention of a disease, comprising a pharmaceutical product, comprising a compound disclosed herein, and buffers and other components for preparing a deliverable form of said pharmaceutical product, and / or a device for delivering such a pharmaceutical product, and / or any drug used in combination therapy with the compound disclosed herein, and / or a packaged set of instructions for the treatment of the disease packaged with the pharmaceutical product. The instructions can be fixed on any tangible medium of expression, such as printed paper or a computer-readable magnetic or optical medium, or can be instructions that refer to a remote computer data source, such as a World Wide Web page accessible via the Internet.

[0118] "Therapeutically effective amount" refers to an amount effective to treat or prevent the progression of current symptoms or to alleviate current symptoms of the subject being treated. Determining an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. In general, "therapeutically effective dose" refers to the amount of a compound that achieves a desired effect. For example, in a preferred embodiment, a therapeutically effective amount of a compound disclosed herein reduces KRAS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% compared to a control.

[0119] The amount of compound administered may depend on the subject being treated, the subject's age, health, sex and weight, type of concurrent treatment (if any), severity of the affliction, the nature of the desired effect, the mode and frequency of treatment, and the judgment of the prescribing physician. The frequency of administration may also depend on the pharmacodynamic effect on arterial oxygen pressure. However, the most preferred dosage can be adjusted for each individual subject, as can be understood and determined by those skilled in the art without undue experimentation. This usually involves adjusting the standard dosage (e.g., reducing the dosage if the patient is underweight).

[0120] While individual needs vary, determining the optimal range of effective amounts of the compounds is within the skill of the art. For administration to humans in the curative or prophylactic treatment of conditions and disorders identified herein, for example, a typical dosage of the compounds of the invention may be about 0.05 mg / kg / day to about 50 mg / kg / day, such as at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which may be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound may be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day The dose may be about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 1500 mg / day, about 5 mg / day to about 1000 mg / day, about 10 mg / day to about 750 mg / day, about 3 mg / day to about 350 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.

[0121] How to Use KRAS G12C Inhibitors The present disclosure provides a method for inhibiting RAS-mediated cell signaling, comprising contacting a cell with an effective amount of one or more compounds disclosed herein. Inhibition of RAS-mediated signaling can be assessed and demonstrated by a variety of methods known in the art. Non-limiting examples include: (a) showing a decrease in the GTPase activity of RAS; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in the Koff of GTP or a decrease in the Koff of GDP; (d) a decrease in the level of downstream signaling molecules of the RAS pathway, such as a decrease in the level of pMEK, pERK or pAKT; and / or (e) a decrease in the binding of the RAS complex to downstream signaling molecules, including but not limited to Raf. Kits and commercially available assays can be utilized to determine one or more of the above.

[0122] The present disclosure also provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including, but not limited to, conditions resulting from the effects of G12C KRAS, HRAS or NRAS mutations (e.g., cancer).

[0123] In some embodiments, a method of treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound disclosed herein. In some embodiments, the cancer is mediated by KRAS, HRAS, or NRAS G12C mutations. In various embodiments, the cancer is pancreatic cancer, colon cancer, or lung cancer. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and bile duct cancer.

[0124] In some embodiments, the disclosure provides a method of treating a disorder in a subject in need thereof, comprising determining whether the subject has a KRAS, HRAS or NRAS G12C mutation, and if the subject is determined to have a KRAS, HRAS or NRAS G12C mutation, administering to the subject a therapeutically effective dose of at least one compound disclosed herein, or a pharma- ceutical acceptable salt thereof.

[0125] The disclosed compounds have the potential to inhibit anchorage-independent cell proliferation and therefore tumor metastasis. Thus, in another embodiment, the present disclosure provides a method of inhibiting tumor metastasis, comprising administering an effective amount of a compound disclosed herein.

[0126] KRAS, HRAS or NRAS G12C mutations have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow and / or lymph nodes). Thus, certain embodiments are directed to the administration of the disclosed compounds (e.g., in the form of a pharmaceutical composition) to patients in need of treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemias and lymphomas. For example, the disclosed compounds can be used to treat diseases such as acute lymphocytic 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 other embodiments, the compounds are useful for treating lymphomas, such as all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma. In various embodiments, the compounds are useful in the treatment of plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom's macroglobulinemia.

[0127] Determining whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation can be made by evaluating the nucleotide sequence encoding the KRAS, HRAS or NRAS protein, by evaluating the amino acid sequence of the KRAS, HRAS or NRAS protein, or by evaluating the characteristics of a putative KRAS, HRAS or NRAS mutant protein. Wild-type human KRAS, HRAS or NRAS sequences are known in the art (e.g., Accession No. NP203524).

[0128] Methods for detecting mutations in the nucleotide sequence of KRAS, HRAS or NRAS are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high resolution melting assay and microarray analysis. In some embodiments, samples are evaluated for G12C KRAS, HRAS or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific for KRAS, HRAS or NRAS G12C mutations is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, KRAS, HRAS, or NRAS G12C mutations are identified using direct sequencing of specific regions in the KRAS, HRAS, or NRAS genes (e.g., exon 2 and / or exon 3). This technique identifies all possible mutations in the sequenced region.

[0129] Methods for detecting mutations in KRAS, HRAS or NRAS proteins are known to those of skill in the art, including, but not limited to, detection of mutant KRAS, HRAS or NRAS proteins using binding agents (e.g., antibodies) specific for the mutant proteins, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0130] A variety of samples can be used in the method of determining whether a tumor or cancer contains a G12C KRAS, HRAS or NRAS mutation. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0131] The present disclosure also relates to a method of treating a hyperproliferative disorder in a mammal, comprising the step of administering to said mammal a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof.In some embodiments, the method is directed to treating acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancer (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, embryonal tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic bile duct intraepithelial carcinoma (DCIS), germinoma, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, cardiac cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer , lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer of unknown primary site, midline ductal carcinoma, oral cavity cancer, multiple 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 and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity The present invention relates to the treatment of subjects suffering from cancer, such as cancer of the parathyroid gland, 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, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumor, atypical cancer of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virally induced cancer.In some embodiments, the methods relate to the treatment of non-cancerous hyperproliferative disorders such as benign hyperplasia of the skin (eg, psoriasis), restenosis or prostate (eg, benign prostatic hyperplasia (BPH)).

[0132] In some embodiments, the method of treatment is directed to treating lung cancer, the method comprising administering an effective amount of any of the above compounds (or pharmaceutical compositions comprising same) to a subject in need thereof. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer or large cell lung cancer. In some embodiments, the lung cancer is small cell lung cancer. Other lung cancers treatable with the disclosed compounds include, but are not limited to, ductal tumors, carcinoid tumors and undifferentiated carcinomas.

[0133] The present disclosure further provides a method of modulating the activity of a protein by contacting the G12C mutant KRAS, HRAS or NRAS protein with an effective amount of a compound of the present disclosure. Modulation can inhibit or activate the activity of the protein. In some embodiments, the present disclosure provides a method of inhibiting the activity of a protein by contacting the G12C mutant KRAS, HRAS or NRAS protein with an effective amount of a dissolved compound of the present disclosure. In some embodiments, the present disclosure provides a method of inhibiting the activity of a G12C mutant KRAS, HRAS or NRAS protein by contacting a cell, tissue or organ expressing the protein of interest. In some embodiments, the present disclosure provides a method of inhibiting the activity of a protein in a subject by administering an effective amount of a compound of the present disclosure to a subject, including but not limited to rodents and mammals (e.g., humans). In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0134] In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS or NRAS G12C in a cell by contacting the cell with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the cell. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS or NRAS G12C in a tissue by contacting the tissue with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the tissue. In some embodiments, the present disclosure provides a method of inhibiting the activity of KRAS, HRAS or NRAS G12C in an organ by contacting the organ with a compound of the present disclosure in an amount sufficient to inhibit the activity of KRAS, HRAS or NRAS G12C in the organ. In some embodiments, the present disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in an animal by contacting the animal with a compound of the present disclosure in an amount sufficient to inhibit KRAS, HRAS or NRAS G12C activity in the animal. In some embodiments, the present disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a mammal by contacting the mammal with a compound of the present disclosure in an amount sufficient to inhibit KRAS, HRAS or NRAS G12C activity in the mammal. In some embodiments, the present disclosure provides a method of inhibiting KRAS, HRAS or NRAS G12C activity in a human by contacting the human with a compound of the present disclosure in an amount sufficient to inhibit KRAS, HRAS or NRAS G12C activity in the human. The present disclosure provides a method of treating a disease mediated by KRAS, HRAS or NRAS G12C activity in a subject in need of such treatment.

[0135] Combination therapy: The present disclosure also provides a method of combination therapy, in which drugs known to regulate other pathways or other components of the same pathway or even overlapping sets of target enzymes are combined with the compounds of the present disclosure or their pharma- ceutically acceptable salts. In one embodiment, such treatment includes, but is not limited to, the combination of one or more compounds of the present disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatments to produce synergistic or additive therapeutic effects.

[0136] Currently, 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 antimitotic agents, 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, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), Venclexta™ (venetoclax), and Adriamycin™, (doxorubicin), as well as a host of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan™); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphazine, chlorocyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Aclacinomycin, Actinomycin, Ausramycin, Azaserine, Bleomycin, Cactinomycin, Calicheamicin, Carabicin, Carminomycin, Carzinophilin, Casodex™, Chromomycin, Dactinomycin, Daunorubicin, Detorubicin, 6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epirubicin, Esorubicin, Idarubicin, Marcellomycin, Mitomycin, Mycophenolic acid, Nogalamycin, Olivomycin, Peplomycin, Potofilomycin, Puromycin, Antibiotics such as sirolimus, keramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; metabolic antagonists 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; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, and eno Pyrimidine analogues such as citabine, floxuridine, androgens such as calcitonin, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diazicon; elfomitine; elliptinium acetate; etoglucide; gallium nitrate; hydroxy Urea;Lentinan;Lonidamine;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Pentostatin;Phenamet;Pirarubicin;Podophyllic acid;2-Ethylhydrazide;Procarbazine;PSK;Razoxane;Sizofiran;Spirogermanium;Tenuazonic acid;Triazicon;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; esperamycin; capecitabine; and pharma- ceutically acceptable salts, acids, or derivatives of any of the above.

[0137] Also included are suitable chemotherapeutic cytoregulatory agents, such as antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens including tamoxifen (Nolvadex™), raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxyphene, ketoxifene, LY117018, 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);Topoisomerase inhibitors RFS2000;Difluoromethylornithine (DMFO).

[0138] Optionally, the compounds or pharmaceutical compositions of the present disclosure are selected from the group consisting of Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, , 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxin, antineoplastic agent, antineoplastic herb, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, biricoderm, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, cell cycle nonspecific antineoplastic agent, dichloroacetic acid, discodermolide, elsamitrucin , enocitabine, epothilone, eribulin, everolimus, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, papaya, pixantro It can be used in combination with commonly prescribed anticancer drugs such as rifampin, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, or zosuquidar.

[0139] The present disclosure further relates to a method of using a compound or pharmaceutical composition provided herein in combination with radiation therapy to inhibit abnormal cell growth or treat hyperproliferative disorders in a mammal. Methods for administering radiation therapy are known in the art, and these methods can be used in the combination therapy described herein. The administration of the compound disclosed herein in this combination therapy can be determined as described herein.

[0140] Radiation therapy can be administered by one or a combination of several methods, including, but not limited to, external beam radiation therapy, internal beam radiation therapy, implant radiation, stereotactic radiosurgery, total body radiation therapy, radiation therapy, and permanent or temporary interstitial brachytherapy. The term "brachytherapy" as used herein refers to radiation therapy delivered by spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. The term is intended to include, but is not limited to, exposure to radioisotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioisotopes of Lu). Suitable radiation sources for use as cell regulators of the present disclosure include both solid and liquid. As non-limiting examples, the radioactive source can be a radionuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic radiation. The radioactive material can be a fluid made from any solution of the radionuclide, such as a solution of I-125 or I-131, or the radioactive fluid can be made using a slurry of a suitable fluid containing small particles of a solid radionuclide such as Au-198, Y-90, etc. Additionally, the radionuclide can be embodied as a gel or radioactive microspheres.

[0141] The compounds or pharmaceutical compositions of the present disclosure may be used in combination with an amount of one or more substances selected from an antiangiogenic agent, a signal transduction inhibitor, an antiproliferative agent, a glycolysis inhibitor, or an autophagy inhibitor.

[0142] Antiangiogenic agents such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used with the compounds of the present disclosure and the pharmaceutical compositions described herein. Antiangiogenic agents include, for example, rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are those described in WO 96 / 33172, WO 96 / 27583, EP 0818442, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 606046, EP 931788, No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 0,780,386, all of which are incorporated herein by reference in their entireties. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferably, they selectively inhibit MMP-2 and / or MMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).Some specific examples of MMP inhibitors useful in the present disclosure are AG-3340, RO32-3555, and RS13-0830.

[0143] The compound is selected from the group consisting of acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, and cetrole. Rix, cladribine, clotrimazole, cytarabine ocphosphate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa Fa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin, gimeracil / oteracil / tegafur combination, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronate, idarubicin, imiquimod, interferon alpha, natural interferon alpha, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon alpha-N1, interferon alpha- n3, interferon alfacon-1, natural interferon alpha, interferon beta, interferon beta-1a, interferon beta-1b, interferon gamma, natural interferon gamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguan, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil Rasil, Liarozole, Lobaplatin, Lonidamine, Lovastatin, Masoprocol, Melarsoprol, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mismatched base pair double stranded RNA, Mitoguazone, Mitolactol, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel erythropoiesis stimulating protein, NSC631570 Octreotide, Oprelvekin, Osateron, Oxaliplatin, Paclitaxel, Pamidronate, Pegaspar glycerol, peginterferon alpha-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alpha-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium Re186 etidronate, RII retinamide, rituximab, romurtide, samarium (153Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, so Nerumin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, native tumor necrosis factor alpha, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer or zoledronic acid; abarelix; AE941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Am gen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin-2, iproxifen, LDI200 (Milkhaus), religistim, lintuzumab, CA125MAb (Biomira), cancer MAb (Nihon Yakuhin Kaihatsu Co., Ltd.), HER-2 and Fc MAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafine gadolinium, MX6 (Galderma), nelarabine, nolatrexed, P30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysis product vaccine (New York Medical College),It may also be used in combination therapy with other antineoplastic agents such as viral melanoma lysate vaccine (Royal Newcastle Hospital) or valspodar.

[0144] The compounds of the present invention may further be used with VEGFR inhibitors.Other compounds described in the following patents and patent applications may be used in combination therapy: U.S. Pat. No. 6,258,812, U.S. Patent Application Publication No. 2003 / 0105091, WO 01 / 37820, U.S. Pat. No. 6,235,764, WO 01 / 32651, U.S. Pat. No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat. No. 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, U.S. Pat. No. 5,747,498, WO 02 / 68406, and the like. FRET, WO 02 / 66470, WO 02 / 55501, WO 04 / 05279, WO 04 / 07481, WO 04 / 07458, WO 04 / 09784, WO 02 / 59110, WO 99 / 45009, WO 00 / 59509, WO 99 / 61422, U.S. Pat. No. 5,990,141, WO 00 / 12089 and WO 00 / 02871.

[0145] In some embodiments, the combination comprises the composition of the present invention in combination with at least one antiangiogenic agent.The agent includes, but is not limited to, chemical compositions prepared by synthesis in vitro, antibodies, antigen-binding regions, radionuclides, and combinations and conjugates thereof.The agent may be an agonist, antagonist, allosteric regulator, toxin, or more generally act to inhibit or stimulate its target (e.g., activate or inhibit a receptor or enzyme), thereby promoting cell death or stopping cell proliferation.

[0146] Exemplary anti-angiogenic agents include ERBITUX™ (IMC-C225), KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen binding regions that specifically bind to kinase domain receptors), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind to VEGF or a soluble VEGF receptor or its ligand binding region) and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as AVASTIN™ or VEGF-TRAP™, EGFR inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto) such as Vectibix (panitumumab), IRESSA™ (gefitinib), TARCEVA™ (erlotinib), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen binding regions that specifically bind thereto or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto). The pharmaceutical compositions of the invention may also include one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind and inhibit the activity of a growth factor, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor) and antibodies or antigen-binding regions that specifically bind to the receptor "c-met."

[0147] Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (Ceretti et al., U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932), anti-TWEAK agents (e.g., antibodies or antigen binding regions that specifically bind or soluble TWEAK receptor antagonists; Wiley, U.S. Patent No. 6,727,225), ADAM disintegrin domains that antagonize the binding of integrins to their ligands (Fanslow et al., U.S. Patent No. 6,727,225), and agonists that specifically bind integrins to their ligands (Fanslow et al., U.S. Patent No. 6,727,225). al., U.S. Patent Application Publication No. 2002 / 0042368), specifically binding anti-eph receptor and / or anti-ephrin antibodies or antigen binding regions (U.S. Pat. Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen binding regions that specifically bind) as well as antibodies or antigen binding regions that specifically bind PDGF-BB ligands and PDGFR kinase inhibitors (e.g., antibodies or antigen binding regions that specifically bind thereto).

[0148] Further antiangiogenic / antitumor agents include SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EP 770622); pegaptanib octasodium (Gilead Sciences, USA); alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S. Pat. No. 5,712,291); ilomastat (Arriva, USA, U.S. Pat. No. 5,892,112); emaxanib (Pfizer, USA, U.S. Pat. No. 5,792,783); vatalanib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); Anecortave acetate (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands); DAC: Antiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E fragment (BioActa, UK); Angiogenesis inhibitors (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); Angiogenesis inhibitors (Tripep, Sweden); Maspin (Sosei Corporation, Japan); 2-Methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IVAX, USA); Benefin (Lane Labs, USA); Tz-93 (Tsumura Corporation, Japan); TAN-1120 (Takeda Pharmaceutical Co., Japan); FR-111142 (Fujisawa Pharmaceutical Co., Japan, JP 02233610 A);Platelet factor 4 (RepliGen, USA, EP 407122); Vascular endothelial growth factor antagonists (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis inhibitors (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); MAb, alpha 5 beta 3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); Gene therapy, retinopathy (Oxford BioMedica, UK); Enzastaurin hydrochloride (USAN) (Lilly, USA); CEP7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC1 (Genoa Institute of Cancer Research, Italy);angiogenesis inhibitors (Alchemia, Australia);VEGF antagonists (Regeneron, USA);rBPI21 and BPI-derived antiangiogenic drugs (XOMA, USA);PI88 (Progen, Australia);cilengitide (pINN) (Merck KGaA, Germany;Munich Technical University, Germany;Scripps Clinic and Research Foundation, USA);cetuximab (INN) (Aventis, France);AVE8062 (Ajinomoto Co., Japan);AS1404 (Cancer Research Laboratory, New Zealand);SG292 (Telios, USA);endostatin (Boston Children's Hospital, USA);ATN161 (Attenuon, USA);ANGIOSTATIN (Boston Children's Hospital, USA);2-methoxyestradiol (Boston Children's Hospital, USA);ZD6474 (AstraZeneca, UK);ZD6126 (Angiogene Pharmaceuticals, UK); PPI2458 (Praecis, USA); AZD9935 (AstraZeneca, UK); AZD2171 (AstraZeneca, UK);Vatalanib (pINN) (Novartis, Switzerland and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA); Pegaptanib (Pinn) (Gilead Sciences, USA); Xanthorrhizol (Yonsei University, Korea); Gene Vaccine, VEGF-2 (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX103 (University of California, San Diego, USA); PX478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU6668 (SUGEN, USA); OXI4503 (OXiGENE, USA); o-Guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, Canada); CDP791 (Celltech Group, UK); atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai Co., Ltd., Japan); CYC381 (Harvard University, USA); AE941 (Aeterna, Canada); Vaccines, Angiogenesis (EntreMed, USA); Urokinase Plasminogen Activator Inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-1 alpha inhibitors (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR31372 (Korea Research Institute of Chemical Technology, Korea);GW2286(GlaxoSmithKline, UK);EHT0101(ExonHit, France);CP868596(Pfizer, USA);CP564959(OSI, USA);CP547632(Pfizer, USA);786034(GlaxoSmithKline, UK);KRN633(Kirin Holdings Company, Ltd., Japan);Intraocular drug delivery system, 2-methoxyestradiol (EntreMed, USA); anginex (Maastricht University, The Netherlands and University of Minnesota, USA); ABT510 (Abbott, USA); AAL993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitors (National Institute on Aging, USA); SU11248 (Pfizer, USA and SUGEN, USA); ABT518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5beta1 (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK and Johnson & Johnson, USA); GFB116 (University of South Florida, USA and Yale University, USA); CS706 (Daiichi Sankyo Co., Ltd., Japan); Combretastatin A4 prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES2690 (Bayer, Germany); AGM1470 (Harvard University, USA, Takeda Pharmaceutical Co., Japan and TAP, USA); AG13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS100 (Wayne State University, USA) CV247 (Ivy Medical, UK); CKD732 (Chong Kun Dang, Korea); MAb, vascular endothelial growth factor (Xenova, UK); irsogladine (INN) (Nippon Shinyaku Co., Ltd., Japan); RG13577 (Aventis, France); WX360 (Wilex, Germany); squalamine (pINN) (Genaera, USA); RPI4610 (Sirna, USA); cancer treatment (Marinova, Australia);Heparanase inhibitors (InSight, Israel); KL3106 (Kolon, Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK229561 (Novartis, Switzerland and Schering AG, Germany); XMP300 (XOMA, USA); VGA1102 (Taisho Pharmaceutical Co., Ltd., Japan); VEGF receptor modulators (Pharmacopoeia, USA); VE-cadherin-2 antagonists (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Vaccine, Flk-1 (ImClone Systems, USA); TZ93 (Tsumura Corporation, Japan); Tumstatin (Beth Israel These include truncated soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck&Co, USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0149] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatases, analogs of cAMP, and drugs that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Additionally, antisense or siRNA that inhibit the expression of proteins, including but not limited to ATG5 (involved in autophagy), can also be used.

[0150] Further pharma- ceutically active compounds / agents that may be used in the treatment of cancer and may be used in combination with one or more compounds of the present invention include epoetin alfa; darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim; denosumab; ancestim; AMG102; AMG176; AMG386; AMG479; AMG655; AMG745; AMG951; and AMG706 or a pharma- ceutically acceptable salt thereof.

[0151] In certain embodiments, the compositions provided herein are administered in combination with a chemotherapeutic agent. Suitable chemotherapeutic agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, doxorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-aspartate, cyclosporine ... L-asparaginase, which metabolizes asparagine systemically and deprives cells of the ability to synthesize their own asparagine), antiplatelet agents, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan and chlorambucil), antiproliferative / antimitotic alkylating agents such as ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-75 19, RGB286638 and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs and streptozocin), triazenes-dacarbazine (DTIC), folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin and 2-chlorodeoxyadenosine) Antimetabolites, aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole) and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidin, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus,ridafolimus and sirolimus), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitors (e.g., CAL-130), multi-targeted kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and luteinizing hormone releasing hormone (LHRH) agonists (e.g., Golgi, Hormonal agonists such as cerelin, leuprolide and triptorelin, BAFF-neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNTO328), telomerase inhibitors (e.g., GRN163L), Aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CS1 (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torc1 / 2 specific kinase inhibitors (e.g., INK128), kinase inhibitors (e.g., GS-1101), ER / UPR targeting agents (e.g., MKC-3946), c FMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), BCL-2 antagonists. Other chemotherapeutic agents may include mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or analogs or derived versions of any of the above.

[0152] The compounds of the present invention may also be used in combination with radiation therapy, hormone therapy, surgery, and immunotherapy, all of which are well known to those skilled in the art.

[0153] In certain embodiments, the pharmaceutical compositions provided herein are administered in combination with a steroid. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, flupred These may include nisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednibar, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts and / or derivatives thereof. In certain embodiments, the compounds of the present invention may be used in combination with additional pharma- ceutically active agents to treat nausea. Examples of agents that can be used to treat nausea include dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or pharma- ceutically acceptable salts thereof.

[0154] The compounds of the present invention can also be used in combination with additional pharmacologic active compounds that interrupt or inhibit the RAS-RAF-ERK signaling pathway or the PI3K-AKT-TOR signaling pathway. In such other combinations, the additional pharmacologic active compounds are antagonists of PD-1 and PD-L1. The compounds or pharmaceutical compositions of the present disclosure can 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 immunotherapy, including monoclonal antibodies, immunomodulatory agents (IMiDs) (e.g., thalidomide, lenalidomide, and pomalidomide), anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents, GITR agonists, CAR-T cells, and BiTEs.

[0155] EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotides or siRNAs. Useful antibody inhibitors of EGFR include cetuximab (Erbitux), panitumumab (Vectibix), zalutumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently lapatinib (TykerB). See, e.g., Yan L, et.al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005;39(4):565-8 and Paez JG, et.al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004;304(5676):1497-500.

[0156] Non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications and all pharma- ceutically acceptable salts and solvates of said EGFR inhibitors: EP 520722, published December 30, 1992; EP 566226, published October 20, 1993; WO 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, published May 5, 1998; U.S. Patent No. 5,747,498, published October 3, 1996; WO 96 / 30347, published on August 6, 1997; EP 787772, published on August 6, 1997; WO 97 / 30034, published on August 21, 1997; WO 97 / 30044, published on August 21, 1997; WO 97 / 38994, published on October 23, 1997; WO 97 / 49688, published on December 31, 1997; EP 837063, published on April 22, 1998 WO 98 / 02434 published January 22, 1998;WO 97 / 38983 published October 23, 1997;WO 95 / 19774 published July 27, 1995;WO 95 / 19970 published July 27, 1995;WO 97 / 13771 published April 17, 1997;WO 98 / 02437 published January 22, 1998;WO 97 / 38983 published October 23, 1997;WO 95 / 19774 published July 27, 1995;WO 95 / 19970 published April 17, 1997;WO 97 / 13771 published January 22, 1998 WO 98 / 02438;WO 97 / 32881 published September 12, 1997;GER 19629652 published January 29, 1998;WO 98 / 33798 published August 6, 1998;WO 97 / 32880 published September 12, 1997;WO 97 / 32880 published September 12, 1997;EP 682027 published November 15, 1995;WO 97 / 02266, published January 23, 1997;WO 97 / 27199, published July 31, 1997;WO 98 / 07726, published February 26, 1998;WO 97 / 34895, published September 25, 1997;WO 96 / 31510, published October 10, 1996;WO 98 / 14449, published April 9, 1998;WO 98 / 14450, published April 9, 1998;WO 98 / 14451, published April 9, 1998;WO 95 / 09847, published April 13, 1995 ;WO 97 / 19065, published May 29, 1997;WO 98 / 17662, published April 30, 1998;U.S. Patent No. 5,789,427, issued August 4, 1998;U.S. Patent No. 5,650,415, issued July 22, 1997;U.S. Patent No. 5,656,643, issued August 12, 1997;WO 99 / 35146, published July 15, 1999;WO 99 / 35132, published July 15, 1999;WO 99 / 07701, published February 18, 1999; and WO 92 / 20642, published November 26, 1992. Further non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.

[0157] Antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1:1311-1318; Huang, SM, et al., 1999, Cancer Res. 15:59(8):1935-40; and Yang, X., et al., 1999, Cancer Res. 59:1236-1243. Thus, the EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra) or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.

[0158] MEK inhibitors include, but are not limited to, trametinib, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, ARRY-438162, and PD-325901.

[0159] PI3K inhibitors include, but are not limited to, wortmannin, 17-hydroxywortmannin analogs described in WO 06 / 044453, 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC0941, described in WO 09 / 036,082 and WO 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydropyridine ... Hydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, described in WO 06 / 122806), (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO 2008 / 070740), LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, Axon Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, available from Axon Medchem), PIK75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfono-hydrazide hydrochloride, available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, available from Axon Medchem). Medchem), GDC-0941 bismesylate (2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine bismesylate, available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione, available from Axon Medchem) and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one, available from Axon Medchem), XL-765 and XL-147. Other PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907 and AEZS-136.

[0160] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Ak1 and 2) (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine (e.g., interferes with membrane localization of Akt; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and triciribine (TCN or API-2 or NCI, identifier: NSC154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0161] TOR inhibitors include, but are not limited to, AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30 and Torin1). Other TOR inhibitors include FKBP12 enhancers, including rapamycin and its derivatives: CCI-779 (temsirolimus), RAD001 (everolimus; WO 9409010) and AP23573; rapalogs, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, such as AP23573, AP23464 or AP23841; 40-(2-aminobutyric acid) inhibitors, such as those disclosed in WO 98 / 02441 and WO 01 / 14387, such as AP23573, AP23464 or AP23841; hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolito)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentynyloxy-32(S)-dihydrorapamycin and other derivatives disclosed in WO 05005434; U.S. Pat. No. 5,258,389, WO 94 / 09010 No. 1, International Publication No. 92 / 05179, U.S. Patent No. 5,118,677, U.S. Patent No. 5,118,678, U.S. Patent No. 5,100,883, U.S. Patent No. 5,151,413, U.S. Patent No. 5,120,842, International Publication No. 93 / 111130, International Publication No. 94 / 02136, International Publication No. 94 / 02485, International Publication No. 95 / 14023 rapamycin derivatives containing phosphorus (e.g., WO 05016252); 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0162] MCl-1 inhibitors include, but are not limited to, AMG-176, AMG397, MIK665 and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the important anti-apoptotic members of B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely related to tumor progression and is closely related to resistance not only to conventional chemotherapy but also to targeted therapy, including BCL-2 inhibitors such as ABT-263.

[0163] SHP inhibitors include, but are not limited to, SHP099.

[0164] Proteasome inhibitors include, but are not limited to, Kyprolis® (carfilzomib), Velcade® (bortezomib), and oprozomib.

[0165] Immunotherapies include, but are not limited to, anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA-4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0166] Monoclonal antibodies include, but are not limited to, Darzalex® (daratumumab), Herceptin® (trastuzumab), Avastin® (bevacizumab), Rituxan® (rituximab), Lucentis® (ranibizumab), and Eylea® (aflibercept).

[0167] Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs (drugs that modify the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0168] Exemplary anti-PD-1 antibodies and their methods of use are described in Goldberg et al., Blood 110(1):186-192 (2007), Thompson et al., Clin. Cancer Res. 13(6):1757-1761 (2007), and Korman et al., International Application PCT / 2006 / 309606 (WO 2006 / 121168 A1), each of which is expressly incorporated herein by reference, and include: Keytruda® (pembrolizumab), Opdivo® (nivolumab), Yervoy™ (ipilimumab) or tremelimumab (against CTLA-4), galiximab (against B7.1), BMS-936558 (against PD-1), MK-3 475 (against PD-1), AMP224 (against B7DC), BMS-936559 (against B7-H1), MPDL3280A (against B7-H1), MEDI-570 (against ICOS), AMG557 (against B7H2), MGA271 (against B7H3), IMP321 (against LAG-3), BMS-663513 (against CD137), PF-05082566 (against CD137), CDX-1127 (against CD27), anti-OX40 (Providence Health Services), huMAbOX40L (against OX40L), atacicept (against TACI), CP-870893 (against CD40), lucatumumab (against CD40), dacetuzumab (against CD40), muromonab-CD3 (against CD3), ipilimumab (against CTLA-4). Immunotherapies also include genetically engineered T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTEs).

[0169] In certain embodiments, the compounds of the invention are used in combination with an anti-PD-1 antibody, such as AMG404. In certain embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises one, two, three, four, five, or all six of the CDR amino acid sequences of SEQ ID NOs: 1-6 (representing HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively). In certain embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises all six of the CDR amino acid sequences of SEQ ID NOs: 1-6. In other embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises (a) a heavy chain variable region amino acid sequence of SEQ ID NO: 7 or a variant thereof (which differs in only one or two amino acids or has at least or about 70% sequence identity), or (b) a light chain variable region amino acid sequence of SEQ ID NO: 8 or a variant thereof (which differs in only one or two amino acids or has at least or about 70% sequence identity). In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises a heavy chain variable region amino acid sequence of SEQ ID NO: 7 and a light chain variable region amino acid sequence of SEQ ID NO: 8. In other embodiments, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises (a) a heavy chain amino acid sequence of SEQ ID NO: 9, or a variant thereof (which differs by only one or two amino acids or which has at least or about 70% sequence identity); or (b) a light chain amino acid sequence of SEQ ID NO: 10, or a variant thereof (which differs by only one or two amino acids or which has at least or about 70% sequence identity). In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding antibody fragment thereof) comprises a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10.

[0170] The disclosure further provides nucleic acid sequences encoding anti-PD-1 antibodies (or antigen-binding portions thereof). In exemplary embodiments, the antibodies comprise one, two, three, four, five, or all six of the CDRs (representing HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, respectively) encoded by the nucleic acids of SEQ ID NOs: 11-16. In another exemplary embodiment, the antibodies comprise all six of the CDRs encoded by the nucleic acids of SEQ ID NOs: 11-16. In some embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises (a) a heavy chain variable region encoded by SEQ ID NO: 17, or a variant thereof (which differs in only one, two, three, four, five, or six nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity), or (b) a light chain variable region encoded by SEQ ID NO: 18, or a variant thereof (which differs in only one, two, three, four, five, or six nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity). In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises a heavy chain variable region encoded by SEQ ID NO: 17 and a light chain variable region encoded by SEQ ID NO: 18. In other embodiments, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises (a) a heavy chain encoded by SEQ ID NO: 19, or a variant thereof (which differs in only one, two, three, four, five, or six nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity), or (b) a light chain encoded by SEQ ID NO: 20, or a variant thereof (which differs in only one, two, three, four, five, or six nucleic acids or has at least or about 70%, 85%, 90%, or 95% sequence identity). In an exemplary embodiment, the anti-PD-1 antibody (or antigen-binding portion thereof) comprises a heavy chain encoded by SEQ ID NO: 19 and a light chain encoded by SEQ ID NO: 20.

[0171] GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., anti-GITR bivalent antibodies), such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090box.c, EP 090505B1, U.S. Pat. No. 8,586,023, WO 2010 / 003118 and WO 2011 / 090754, or the antibodies described in, for example, U.S. Pat. No. 7,025,962, EP 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, EP 1866339, Examples of such antibodies include the anti-GITR antibodies described in the specification, WO 2011 / 028683, WO 2013 / 039954, WO 2005 / 007190, WO 2007 / 133822, WO 2005 / 055808, WO 99 / 40196, WO 2001 / 03720, WO 99 / 20758, WO 2006 / 083289, WO 2005 / 115451, U.S. Patent No. 7,618,632, and WO 2011 / 051726.

[0172] The compounds described herein can be used in combination with the drugs disclosed herein or other suitable drugs depending on the condition to be treated. Thus, in some embodiments, one or more compounds of the present disclosure will be administered in combination with the other drugs described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second drug. This combination administration can include simultaneous administration of the two drugs in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compounds described herein and any of the drugs described above can be formulated together in the same dosage form and administered at the same time. Alternatively, the compounds disclosed herein and any of the drugs described above can be administered simultaneously, where both drugs are in separate formulations. In another option, the compounds disclosed herein can be administered, followed by any of the drugs described above, or vice versa. In some embodiments of the separate administration protocol, the compounds disclosed herein and any of the drugs described above are administered minutes apart, hours apart, or days apart.

[0173] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharma- ceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit comprises a container, such as a divided bottle or a divided foil packet, for containing the separate compositions. Further examples of containers include syringes, boxes and bags. In some embodiments, the kit comprises instructions for using the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), when administered at different dosing intervals, or when dosage adjustment of the individual components of the combination is desired by the prescribing medical professional.

[0174] SECTION 1 - GENERAL PROCEDURES 1. 4,6-Diisopropylpyrimidin-5-amine (Intermediate A) [ka] A solution of 4,6-dichloro-5-aminopyrimidine (3.00 g, 18.3 mmol, Combi-Blocks Inc., San Diego, CA) in THF (18 mL) was degassed by bubbling argon into the mixture for 5 min. 2-Propylzinc bromide (0.5 M solution in THF, 91.0 mL, 45.5 mmol, Sigma-Aldrich, St. Louis, MO) was added via syringe followed by Xantphos Pd G3 (434 mg, 0.5 mmol, Sigma-Aldrich, St. Louis, MO). The resulting mixture was stirred at room temperature for 16 h and then filtered through a pad of Celite. The filter cake was rinsed with EtOAc and the filtrate was collected and concentrated in vacuo to give 4,6-diisopropylpyrimidin-5-amine (Intermediate A, 3.45 g). m / z (ESI, positive ion): 180.2 (M+H)+.

[0175] 2. 2-Isopropyl-4-methylpyridin-3-amine (Intermediate B) [ka] To a slurry of 3-amino-2-bromo-4-picoline (360 mg, 1.9 mmol, Combi-Blocks, San Diego, CA) in THF (4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (79 mg, 0.1 mmol). The resulting slurry was degassed with argon for 2 min, then 2-propylzinc bromide (0.5 M solution in THF, 5.4 mL, 2.7 mmol, Sigma-Aldrich, St. Louis, MO) was added. The resulting solution was heated at 60°C for 17 h, then heating was stopped and the reaction was cooled to room temperature. The reaction mixture was quenched with water (10 mL) and 1N NaOH solution (20 mL) and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel (eluent: 0-15% MeOH / DCM) to give 2-isopropyl-4-methylpyridin-3-amine (Intermediate B).1 H NMR(400MHz,DMSO-d6)δ ppm 7.66(d,J=4.6Hz,1H),6.78(d,J=4.8Hz,1H),4.72(br s,2H),3.14-3.25(m,1H),2.08(s,3H),1.14(d,J=6.8Hz,6H).m / z(ESI, cation):151.1(M+H)+.

[0176] 3. 2-Chloro-N,N-dimethyl-3-nitropyridin-4-amine (Intermediate C) and 4-chloro-N,N-dimethyl-3-nitropyridin-2-amine (Intermediate D) [ka] To 2,4-dichloro-3-nitropyridine (7.0 g, 36 mmol, Ark Pharm, Inc.) in 10 ml acetonitrile was added triethylamine (6 ml, 43 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was cooled to 0° C. and 2N dimethylamine in THF (19 ml, 38 mmol) was added slowly. After 2.5 hours, LCMS showed the reaction was complete. 100 ml ethyl acetate was added, washed with brine, dried and evaporated. After purification by chromatography on silica gel (0-100% ethyl acetate / heptane), 4-chloro-N,N-dimethyl-3-nitropyridin-2-amine (Intermediate D) was obtained as the less polar peak: 1 H NMR (400 MHz, chloroform-d) δ ppm 7.98-8.22 (m, 1H) and 2-chloro-N,N-dimethyl-3-nitropyridin-4-amine (Intermediate C) as the more polar peak: 1 H NMR (400 MHz, chloroform-d) δ ppm 3.01-3.05 (m, 6H) 6.61-6.70 (m, 1H) 6.85-6.95 (m, 1H) 7.80-7.87 (m, 1H) 7.97-8.06 (m, 1H).

[0177] 4. 2-Isopropyl-N,N-4-dimethylpyridine-3,4-diamine (Intermediate E) [ka] Step 1: N,N-Dimethyl-3-nitro-2-(prop-1-en-2-yl)pyridin-4-amine. To a three-neck flask was added 2-chloro-N,N-dimethyl-3-nitropyridin-4-amine (Intermediate C) (4.66 g, 23.1 mmol), 30 ml dioxane, and 15 ml water. The mixture was stirred under nitrogen for 10 minutes. Powdered anhydrous sodium carbonate (7.35 g, 69.3 mmol, Sigma-Aldrich, St. Louis, MO), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (1.0 g, 1.4 mmol, Sigma-Aldrich, St. Louis, MO), and 2-isopropenylboronic acid, pinacol ester (8.3 g, 49.4 mmol, Combi-Blocks Inc.) were added and heated in a 100°C bath. After 5 hours, LCMS showed the reaction was complete and the mixture was cooled to room temperature. Ethyl acetate (200 ml) was added, washed with 50 ml brine, dried, and evaporated. Purification by chromatography on silica gel (eluent: 30-40% ethyl acetate / heptane) gave N,N-dimethyl-3-nitro-2-(prop-1-en-2-yl)pyridin-4-amine as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 2.11-2.21 (m, 3H) 2.95-3.01 (m, 6H) 4.99-5.06 (m, 1H) 5.16-5.23 (m, 1H) 6.59-6.69 (m, 1H) 8.19-8.28 (m, 1H).

[0178] Step 2: 2-Isopropyl-N,N-4-dimethylpyridine-3,4-diamine. To a solution of N,N-dimethyl-3-nitro-2-(prop-1-en-2-yl)pyridin-4-amine (4.8 g, 23.2 mmol) in EtOH (60 ml) was added palladium 10% on carbon (0.6 g, 5.6 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was hydrogenated at 45 PSI for 3 days. The mixture was filtered through a pad of Celite, washed with ethyl acetate, evaporated, and purified by chromatography on silica gel eluting with 30-40% (3 / 1 EtOAc / EtOH) / heptane to give 2-isopropyl-N,N-4-dimethylpyridine-3,4-diamine (Intermediate E).

[0179] Following the same sequence 4-isopropyl-N,N-2-dimethylpyridine-2,3-diamine (Intermediate F) was prepared from 4-chloro-N,N-dimethyl-3-nitropyridin-2-amine (Intermediate D).

[0180] 5. 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isopropylpyridin-3-amine (Intermediate G) [ka] Step 1: Methyl 3-amino-2-isopropyl isonicotinate. To a 1 L three-necked round bottom flask equipped with a Findenser condenser was added 3-amino-2-chloro-4-(methoxycarbonyl)pyridine (10.6 g, 56.8 mmol, Combi-Blocks Inc., San Diego, CA) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (2.69 g, 2.8 mmol, Sigma-Aldrich, St. Louis, MO) in tetrahydrofuran (114 ml) under argon. 2-Propylzinc bromide 0.5 M in tetrahydrofuran (148 ml, 73.8 mmol, Sigma-Aldrich, St. Louis, MO) was added via addition funnel over 4 min. The reaction mixture was then stirred at 50° C. for 40 min. The reaction mixture was cooled in an ice-water bath. Ice (ca. 100 g) and Celite (ca. 100 g) were added with stirring and the mixture was filtered through a fine fritted glass filter, washing with DCM to remove insoluble emulsion. The two layers were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give a brown oil. The crude material was purified by chromatography on silica gel eluting with a gradient of 0% to 70% EtOAc in heptane to give methyl 3-amino-2-isopropyl isonicotinate as a yellow oil.

[0181] Step 2: 3-Amino-2-isopropylpyridin-4-yl)methanol. A 1 L three-neck flask was equipped with a condenser and charged with methyl 3-amino-2-isopropyl isonicotinate (18.2 g, 94 mmol) and THF (185 mL). 2 M lithium borohydride in THF (94 ml, 187 mmol, Sigma-Aldrich, St. Louis, MO) was added dropwise. The mixture was stirred at room temperature for 15 min. Methanol (30.3 ml) was then added slowly and the mixture was stirred at room temperature for 3.5 h until the temperature reached 40° C. Saturated NH4Cl (ca. 100 mL) was added slowly. The reaction mixture was concentrated in vacuum to remove most of the THF. The residual mixture was diluted with water and extracted with EtOAc (4×150 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated to give crude 3-amino-2-isopropylpyridin-4-yl)methanol, which was used directly in the next step.

[0182] Step 3: 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isopropylpyridin-3-amine. A 1 L RBF was charged with (3-amino-2-isopropylpyridin-4-yl)methanol (15.6 g, 94 mmol), DIPEA (57.3 ml, 328 mmol, Sigma-Aldrich, St. Louis, MO) and 4-(dimethylamino)pyridine (0.57 g, 4.7 mmol, Sigma-Aldrich, St. Louis, MO) in dichloromethane (187 ml). tert-Butyldiphenylchlorosilane (31.7 ml, 122 mmol, Sigma-Aldrich, St. Louis, MO) was added dropwise. The mixture was stirred at room temperature for 3 hours. The mixture was washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by chromatography on silica gel eluting with a gradient of 0% to 50% EtOAc in heptane to give 4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isopropylpyridin-3-amine (Intermediate G, 28.1 g, 69.4 mmol, 74.1% yield) as a white solid.

[0183] 6. 2,5-Dichloro-6-(2-fluorophenyl)nicotinic acid (Intermediate H) [ka] 2,5-Dichloro-6-(2-fluorophenyl)nicotinic acid. A mixture of 2,5,6-trichloronicotinic acid (1.03 g, 4.54 mmol, Combi-Blocks, San Diego, CA), palladium tetrakis (0.13 g, 0.1 mmol, Sigma-Aldrich, St. Louis, MO), (2-fluorophenyl)boronic acid (0.70 g, 5.0 mmol, TCI America, Portland, OR) and sodium carbonate (2 M in water, 6.8 mL, 13.6 mmol) in 1,4-dioxane (11 mL) was purged with nitrogen and heated to 80° C. for 1 h, then at 90° C. for 5 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with 1 N aqueous citric acid (2×100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo to give 2,5-dichloro-6-(2-fluorophenyl)nicotinic acid (Intermediate H, 1.27 g, 4.4 mmol, 97% yield) as an amber oil. m / z (ESI, positive ion): 285.8 (M+H). + .

[0184] 7. 6,7-Dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate I) [ka] Step 1: 2-cyano-N-(4,6-diisopropylpyrimidin-5-yl)acetamide. To 4,6-diisopropylpyrimidin-5-amine (6.9 g, 38.5 mmol, intermediate A) and cyanoacetic acid (4.86 g, 57.1 mmol, Sigma-Aldrich, St. Louis, MO) was added DCE (35 ml), a 50 wt% solution of 1-propanephosphonic acid cyclic anhydride in ethyl acetate (45.8 ml, 77 mmol, Sigma-Aldrich, St. Louis, MO) and anhydrous triethylamine (16.2 ml, 115 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was heated to 50° C. for 30 min. The mixture was cooled to room temperature and 300 ml of ethyl acetate and saturated NaHCO3 (150) were added and stirred for 5 min. The organic layer was separated, washed with saturated NH4Cl, dried and evaporated. Purification by chromatography on silica gel eluting with 0-50% (3 / 1 EtOAc / EtOH) / heptane gave 2-cyano-N-(4,6-diisopropylpyrimidin-5-yl)acetamide as a white solid.

[0185] Step 2: 2,5,6-Trichloronicotinoyl chloride. To a suspension of 2,5,6-trichloronicotinic acid (2.92 g, 12.9 mmol) in DCM (20 mL) was added DMF (0.3 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (9.67 mL, 19.3 mmol, Sigma-Aldrich, St. Louis, Mo.) The mixture was stirred at room temperature for 45 min, evaporated, and dried in vacuo to give crude 2,5,6-trichloronicotinoyl chloride, which was used in the next step.

[0186] Step 3: 6,7-Dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To 2-cyano-N-(4,6-diisopropylpyrimidin-5-yl)acetamide (3.1 g, 12.6 mmol) in THF (30 ml) was added 60% sodium hydride (1.51 g, 37.8 mmol, Sigma-Aldrich, St. Louis, MO) in portions. The mixture was stirred for 15 min and 2,5,6-trichloronicotinoyl chloride (3.08 g, 12.6 mmol, Combi-Blocks, San Diego, CA) in THF (30 ml) was added slowly. After 15 min, the mixture was heated in a 70° C. bath for 1 h. An additional 0.5 g of 60% NaH was added and the mixture was stirred for 10 min and heated at 90° C. for 6 h. The mixture was cooled to room temperature and water (5 ml) was added slowly followed by 2N HCl (50 ml). The mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine (3x), dried, evaporated, and purified by chromatography on silica gel eluting with 0-60% (3 / 1 EtOH / EtOAc) / heptane to give 6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate I) as a yellow solid.

[0187] [Table 4]

[0188] [Table 5]

[0189] 8. 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate R) [ka] To 6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate I, 0.97 g, 2.3 mmol) in 10 mL of acetonitrile was added diisopropylethylamine (1.2 mL, 7 mmol, Sigma-Aldrich, St. Louis, MO) and phosphorus oxychloride (0.3 mL, 3.4 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was heated at 90° C. for 30 minutes. The mixture was cooled, evaporated, and dried in vacuum. This was dissolved in 10 mL of acetonitrile and cooled in an ice-water bath. Diisopropylethylamine (1.22 ml, 6.96 mmol) and 1-(t-butoxycarbonyl)-piperazine (0.490 ml, 2.63 mmol, Sigma-Aldrich, St. Louis, MO) were added and the mixture was stirred at 0° C. for 1 h and at room temperature for 16 h. Ethyl acetate (60 ml) was added and the solution was washed with brine (3×), dried and evaporated. Purification by chromatography on silica gel eluting with 0-40% ethyl acetate / heptane gave 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate R) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.92-1.00(m,6H)1.04-1.13(m,6H)1.40-1.55(m,9H)2.60-2.73(m,2H)3.56-3.70(m ,4H)3.73-3.86(m,4H)8.38-8.65(m,1H)9.07-9.35(m,1H);m / z(ESI, cation):586(M+H) + . EXAMPLES

[0190] Example 1 4-(4-Acryloylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: tert-Butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-formylphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. tert-Butyl 4-(6,7-dichloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (Intermediate R, 0.42 g, 0.7 mmol), 2-formylphenylboronic acid (0.127 g, 0.8 mmol, Sigma-Aldrich, St. Louis, MO), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.067 g, 0.09 mmol, Sigma-Aldrich, St. Louis, MO) and cesium acetate salt (0.13 g, 0.7 mmol, Sigma-Aldrich, St. Louis, MO) were placed in a two-neck flask, flushed with N2 for 5 min and THF (4 ml) was added. The mixture was heated at 90° C. for 1.5 h. It was cooled to room temperature and EtOAc (15 mL) and 8 mL of brine were added. The two layers were separated and the organic layer was dried and evaporated. Purification by chromatography on silica gel eluting with 0-40% (3 / 1 EtOH / EtOAc) / heptane gave tert-butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-formylphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a white solid.

[0191] Step 2: tert-Butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To tert-butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-formylphenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.2 g, 0.3 mmol) in DCE (3 ml) was added dimethylamine (0.4 ml, 0.8 mmol) (2 M in THF, Sigma-Aldrich, St. Louis, MO), sodium triacetoxyborohydride (0.18 g, 0.8 mmol, Sigma-Aldrich, St. Louis, MO) and HOAc (1 ml). After 5 h, 10 ml each of DCM and 10% K2CO3 solution were added. The organic layer was separated, dried and evaporated. Purification by chromatography on silica gel eluting with 0-30% (3 / 1 EtOH / EtOAc) / heptane gave tert-butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate.

[0192] Step 3: 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. tert-Butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (62 mg, 0.09 mmol) and TFA (1 ml) (Sigma-Aldrich, St. Louis, MO) were stirred in DCM (2 ml) for 30 min and evaporated. This was co-evaporated with DCM (4×10 ml). The residue was dissolved in DCM (6 ml), cooled to °C, and anhydrous triethylamine (50 μl, 0.3 mmol, Sigma-Aldrich, St. Louis, MO) and acryloyl chloride (400 μl, 0.2 mmol, Sigma-Aldrich, St. Louis, MO) were added. The mixture was stirred for 15 min, evaporated and purified by chromatography on silica gel eluting with 0-80% (3 / 1 EtOH / EtOAc) / heptane to give a yellow oil. Further purification by chromatography on silica gel eluting with 0-90% (8% (2N NH3 in MeOH) in DCM) / DCM gave 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-((dimethylamino)methyl)phenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ ppm 1.02-1.13 (m, 6H) 1.19-1.27 (m, 6H) 1.94-2.05 (m, 6H) 2.05-2.15 (m, 2H) 2.44-2.77 (m, 2H) 3.79-4.12 (m, 8H) 5.71-6.04 (m, 1H) 6.29-6.54 (m, 1H) 6.57-6.80 (m, 1H) 6.90-7.08 (m, 1H), 1H overlaps with CHCL3, 7.36-7.45 (m, 1H) 7.45-7.52 (m, 1H) 8.00-8.36 (m, 1H) 8.97-9.33 (m, 1H). m / z (ESI, positive ion): 638.9 (M+H) + .

[0193] Example 2 4-(4-Acryloylpiperazin-1-yl)-6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: 6-chloro-7-(2-fluorophenyl)-1-(4-formyl-2-isopropylpyridin-3-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To 1-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isopropylpyridin-3-yl)-6-chloro-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate O, 3.0 g, 4.2 mmol) in THF (40 ml) was added nBu4NF (1 M in THF, 5.2 ml, Sigma-Aldrich, St. Louis, MO). After 22 h, 200 ml of ethyl acetate and 60 ml of saturated ammonium chloride were added. The organic layer was separated, washed with 2× saturated NH4Cl, dried, and evaporated. Purification by chromatography on silica gel eluting with 20-90% (3 / 1 EtOAc / EtOH) / heptane gave the alcohol. 6-Chloro-7-(2-fluorophenyl)-4-hydroxy-1-(4-(hydroxymethyl)-2-isopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.48 g, 3.1 mmol) in DCM (40 ml) was stirred with manganese(IV) oxide (7.4 g, 85 mmol, Sigma-Aldrich, St. Louis, Mo.) at room temperature for 2 days. The mixture was filtered through Celite and evaporated to give the crude aldehyde.

[0194] Step 2: 6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To 6-chloro-7-(2-fluorophenyl)-1-(4-formyl-2-isopropylpyridin-3-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (1.05 g, 2.2 mmol) in DCE (12 ml) was added 2M dimethylamine in THF (2.3 ml, 4.6 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was stirred for 5 min and sodium triacetoxyborohydride (0.80 g, 3.7 mmol, Sigma-Aldrich, St. Louis, MO) was added. After 2 h, the mixture was diluted with DCM (20 ml) and saturated NaHCO3 (20 ml). The organic layer was separated, dried and evaporated. Purification by chromatography on silica gel eluting with 20-100% (7% 2M NH3 / MeOH in 3 / 1 EtOAc / EtOH) / heptane gave 6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid.

[0195] Step 3: tert-Butyl 4-(6-chloro-3-cyano-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To a suspension of 6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.82 g, 1.6 mmol) in 12 ml of acetonitrile was added anhydrous triethylamine (3 ml, 21.3 mmol, Sigma-Aldrich, St. Louis, MO) and phosphoroxychloride (0.5 ml, 5.3 mmol, Sigma-Aldrich, St. Louis, MO). The mixture was heated to 75° C. for 30 min. The mixture was cooled to room temperature, evaporated, and dissolved in DCM (20 ml). TEA (1.5 ml) and 1-(t-butoxycarbonyl)-piperazine (0.621 g, 3.3 mmol, Sigma-Aldrich, St. Louis, MO) were added. After 6 hours, LCMS showed chloride starting material was still present. 1-(t-butoxycarbonyl)-piperazine (0.3 g) was added and the mixture was stirred for a further 16 hours. DCM (40 ml) and 10 ml of brine were added and the organic layer was separated, dried and evaporated. Purification by chromatography on silica gel eluting with 10-40% (10% 2N NH3 / MeOH (3 / 1 EtOAc / EtOH)) / heptane gave tert-butyl 4-(6-chloro-3-cyano-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate.

[0196] Step 4: 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To tert-butyl 4-(6-chloro-3-cyano-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.8 g, 1.2 mmol) in DCM (6 ml) was added TFA (4 ml) (Sigma-Aldrich, St. Louis, MO). The mixture was stirred for 10 min, evaporated, and dried in vacuum. The residue was dissolved in DCM (6 ml), cooled in an ice-water bath, and anhydrous triethylamine (1.0 ml, 7 mmol) was added. 0.5 M acryloyl chloride (ready-made) in DCM (4.5 ml, 2.2 mmol, Sigma-Aldrich, St. Louis, MO) was added. After 10 min, the mixture was evaporated. Purification by chromatography on silica gel eluting with 10-30% (10% 2N NH3 in MeOH (3 / 1 EtOAc / EtOH)) / heptane gave 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(4-((dimethylamino)methyl)-2-isopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid. 19 F NMR (376MHz, DMSO-d6) δ ppm -114.33(s, 1F). 1 H NMR (400MHz, DMSO-d6) δ ppm 0.89-0.98(m,3H)1.04-1.11(m,3H)1.82-1.95(m,6H)2.65-2.77(m,1 H)2.92-3.09(m,2H)3.77-3.97(m,8H)5.75-5.81(m,1H)6.16-6.25(m, 1H)6.85-6.97(m,1H)7.09-7.17(m,1H)7.21-7.32(m,2H)7.33-7.37(m,1H)7.45-7.54(m,1H)8.39-8.63(m,2H).m / z(ESI, cation):614.0(M+H) + .

[0197] Example 3 (E)-6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: tert-Butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. 6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate Q, 0.37 g, 0.7 mmol) in 6 mL of acetonitrile was heated at 90° C. for 45 min with diisopropylethylamine (0.5 mL, 2.8 mmol, Sigma-Aldrich, St. Louis, MO) and phosphorus oxychloride (0.1 mL, 1.0 mmol, Sigma-Aldrich, St. Louis, MO). The reaction mixture was evaporated and dried in vacuo. The residue was dissolved in DCM (8 mL), cooled to 0° C., and 1 mL of Hunig's base and 1-(t-butoxycarbonyl)-piperazine (0.18 g, 0.9 mmol, Sigma-Aldrich, St. Louis, MO) were added. After 30 min, DCM (25 ml) was added. The organic layer was washed with brine, dried and evaporated. Purification by chromatography on silica gel eluting with 0-20% (3 / 1 EtOH / EtOAc) / heptane gave tert-butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a yellow solid: 1H NMR(400MHz,DMSO-d6)δ ppm 0.87-0.94(m,6H)1.03-1.13(m,6H)1.43-1.51(m,9H)2.64-2.75(m,2H)3.60-3.71(m,4H)3.77-3.8 9(m,4H)7.11-7.19(m,1H)7.23-7.36(m,2H)7.45-7.56(m,1H)8.47-8.54(m,1H)9.05-9.13(m,1H). 19 F NMR (376MHz, DMSO-d6) δ ppm -114.61(s, 1F).

[0198] Step 2: 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-4-(piperazin-1-yl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. tert-Butyl 4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.3 g, 2.0 mmol) and trifluoroacetic acid (8 mL, 107 mmol, Sigma-Aldrich, St. Louis, MO) in DCM (12 mL) were stirred for 1 h and evaporated. The residue was dissolved in EtOAc (50 mL) and stirred with saturated NaHCO3. The organic layer was separated, washed with brine, dried and evaporated to give 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-4-(piperazin-1-yl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a yellow solid.

[0199] Step 3: (E)-6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To 6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-4-(piperazin-1-yl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.1 g, 0.18 mmol) in DMF (1 ml) was added trans-4-dimethylaminocrotonic acid hydrochloride (0.056 g, 0.3 mmol, Matrix Scientific), diisopropylethylamine (0.25 ml, 1.431 mmol) and COMU (0.23 g, 0.5 mmol, Combi-Blocks, San Diego, Calif.). After 17 h, EtOAc (30 ml) was added and the organic layer was washed with brine, dried and evaporated. Purification by chromatography on silica gel eluting first with 0-60% (3 / 1 EtOH / EtOAc) / heptane then 60% (15% (2N NH3 in MeOH) in DCM) / heptane gave (E)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-4-(4-(4-(dimethylamino)but-2-enoyl)piperazin-1-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.82-0.98(m,6H)1.08(br d,J=4.35Hz,6H)2.09-2.29(m,6H)2.63-2.78(m,2H)3.01-3.16(m,2H)3.74-4.0 8(m,8H)6.48-6.91(m,2H)7.08-7.65(m,4H)8.41-8.71(m,1H)8.94-9.30(m,1H). 19 F NMR(376MHz,DMSO-d6)δ ppm -114.60(br s,1F).m / z(ESI, cation):656.9(M+H) + .

[0200] [Table 6]

[0201] Example 4 (E)-6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile trifluoroacetate [ka] Step 1: tert-Butyl (E)-(4-(4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazin-1-yl)-4-oxobut-2-en-1-yl)(methyl)carbamate. 6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-4-(piperazin-1-yl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.33 g, 0.6 mmol, from Example 3, step 2) in DMF (3 ml) was added with (E)-4-((tert-butoxycarbonyl)(methyl)amino)but-2-enoic acid (0.24 g, 1.1 mmol) (can be synthesized as described for Example 17b in U.S. Pat. No. 9,951,077), COMU (0.55 g, 1.2 mmol, Combi-Blocks, San Diego, CA) and diisopropylethylamine (0.3 ml, 1.7 mmol). The mixture was stirred at room temperature for 1 hour. EtOAc (50 ml) was added, washed with brine (3×), dried and evaporated. Purification by chromatography on silica gel eluting with 0-40% (3 / 1 EtOAc-EtOH) / heptane gave tert-butyl (E)-(4-(4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazin-1-yl)-4-oxobut-2-en-1-yl)(methyl)carbamate.

[0202] Step 2: (E)-6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile trifluoroacetate. To tert-butyl (E)-(4-(4-(6-chloro-3-cyano-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazin-1-yl)-4-oxobut-2-en-1-yl)(methyl)carbamate (0.16 g, 0.2 mmol) in DCM (3 ml) was added TFA (2 ml). After 1.5 h the mixture was evaporated, 5×DCM was added and evaporated to give (E)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-(4-(4-(methylamino)but-2-enoyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile trifluoroacetate as a colored foam. 19 F NMR (376 MHz, methanol-d4) δ ppm -115.72 (s, 1F) -77.42 (s, 1F). 1 H NMR(400MHz, methanol-d4)δ ppm 0.93-1.02(m,6H)1.12-1.18(m,6H)1.98-2.00(m,3H)2.66-2.73(m,2H)3.82-3.89(m,2H)3.91-4.04(m,8H)6.70-6.82(m, 1H)6.89-6.99(m,1H)7.10-7.24(m,3H)7.42-7.54(m,1H)8.46-8.52(m,1H)8.99-9.06(m,1H).m / z(ESI, cation):643.1(M+H) + .

[0203] Example 4.1: (E)-4-(4-(4-aminobut-2-enoyl)piperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] The compound was prepared according to the procedure of Example 4 from (E)-4-((tert-butoxycarbonyl)amino)but-2-enoic acid (which can be synthesized as described for intermediate 34 in International Application PCT / US2016 / 065954; WO2017100662). 1 F NMR showed the presence of 2TFA. 19 F NMR (376MHz, DMSO-d6) δ ppm -114.60(s,1F), -74.47(s,1F). 1 H NMR(400MHz,DMSO-d6)δ ppm 0.88-0.93(m,6H)1.05-1.11(m,6H)2.64-2.72(m,2H)3.65-3.75(m,2H)3.81-3.96(m,8H)6.64-6.77(m,1H)6.83-6.93(m,1H)7.09- 7.18(m,1H)7.23-7.36(m,2H)7.46-7.66(m,1H)7.89-8.18(m,3H)8.38-8.65(m,1H)8.95-9.20(m,1H).m / z(ESI, cation):629.2(M+H) + .

[0204] Example 5 (E)-6-Chloro-4-(4-(4-(cyclopropylamino)but-2-enoyl)piperazin-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: (E)-4-(4-(4-bromobut-2-enoyl)piperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To (E)-4-bromobut-2-enoic acid (0.25 g, 1.5 mmol, enamine) in DCM (3 ml) was added a few drops of DMF and a 2.0 M solution of oxalyl chloride in methylene chloride (1.5 ml, 3.0 mmol). After 30 min at room temperature, the mixture was evaporated to dryness in vacuum. The residue was dissolved in THF (6 ml) and DCM (6 ml) and added slowly to a pre-cooled solution of (S)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-(2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (from Example 3, step 2, 0.63 g, 1.2 mmol) and anhydrous triethylamine (0.33 ml, 2.3 mmol) in THF (12 ml) (the solution was cooled in an ice / NaCl bath, the temperature alone was −10° C. to −15° C., after the addition the bath temperature rose to −5° C. to −10° C.). The cooling bath was allowed to warm to room temperature. After 3 h, EtOAC (150 ml) and brine / saturated NaHCO3 were added. The organic layer was separated, dried and evaporated. Purification by chromatography on silica gel eluting with 0-60% EtOAc / heptane gave (E)-4-(4-(4-bromobut-2-enoyl)piperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile.

[0205] Step 2: (E)-6-chloro-4-(4-(4-(cyclopropylamino)but-2-enoyl)piperazin-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. A mixture of (E)-4-(4-(4-bromobut-2-enoyl)piperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.18 g, 0.26 mmol) and cyclopropylamine (77 μl, 1.1 mmol) in 1.5 ml of acetonitrile was stirred at room temperature for 5 hours. The mixture was evaporated and purified by preparative HPLC (Phenomenex Gemini C18 column, 150×30 mm, 10 u, 110 A, 0.1% TFA in 10-100% MeCN / HO) to give (E)-6-chloro-4-(4-(4-(cyclopropylamino)but-2-enoyl)piperazin-1-yl)-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as bis-TFA. 1 H NMR(400MHz, methanol-d4)δ ppm 0.86-0.99(m,4H)1.00-1.06(m,6H)1.16-1.23(m,6H)2.66-2.80(m,2H)2.81-2.90(m,1H)3.91-4.15(m,10H) 6.74-6.90(m,1H)6.95-7.06(m,1H)7.14-7.29(m,3H)7.43-7.57(m,1H)8.48-8.58(m,1H)9.00-9.12(m,1H). 19 F NMR (376 MHz, methanol-d4) δ ppm -119.71 - -118.25 (m, 6F) -83.14 - -71.43 (m, 1F). m / z (ESI, positive ion): 669.0 (M+H) + .

[0206] Example 5.1: (E)-6-Chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-4-(4-(4-(isopropylamino)but-2-enoyl)piperazin-1-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] The compound was prepared following the procedure of Example 5, using isopropylamine in step 2. 1 H NMR(400MHz, methanol-d4)δ ppm 0.97-1.06(m,6H)1.16-1.22(m,6H)1.37-1.43(m,6H)2.69-2.80(m,2H)3.88-3.95(m,2H)3.95-4.07(m,8H)4.09-4.1 6(m,1H)6.75-6.87(m,1H)6.97-7.06(m,1H)7.14-7.26(m,3H)7.44-7.59(m,1H)8.50-8.56(m,1H)9.02-9.12(m,1H). 19 F NMR (376 MHz, methanol-d4) δ ppm -115.73 (s, 6F) -79.92 - -74.06 (m, 1F). 2 Consistent with TFA. m / z (ESI, positive ion): 671.2 (M+H) + .

[0207] Example 5.2: (E)-4-(4-(4-(tert-butylamino)but-2-enoyl)piperazin-1-yl)-6-chloro-1-(4,6-diisopropylpyrimidin-5-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] The compound was prepared according to the procedure of Example 5 using tert-butylamine. m / z (ESI, positive ion): 685.3 (M+H) + . 1 H NMR(400MHz, methanol-d4)δ ppm 0.95-1.00(m,6H)1.14-1.18(m,6H)1.40-1.44(m,9H)2.61-2.76(m,2H)3.84-3.90(m,2H)3.92-4.06(m,8H) 6.70-6.83(m,1H)6.94-7.03(m,1H)7.07-7.27(m,4H)7.42-7.52(m,1H)8.41-8.57(m,1H)8.95-9.11(m,1H). 19F NMR (376MHz, methanol-d4) δ ppm -115.73 (s, 1F) -78.45 - -76.11 (m, 1F)

[0208] Example 6 4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: tert-Butyl 4-(6-chloro-3-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To a solution of 6-chloro-7-(2-fluorophenyl)-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate P, 250 mg, 0.5 mmol) and iPr2EtN (0.29 mL, 1.6 mmol) in acetonitrile (5 mL) was added phosphorus oxychloride (0.08 mL, 0.8 mmol, Sigma-Aldrich, St. Louis, MO), and the resulting solution was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The resulting residue was dissolved in acetonitrile (4 mL), and iPr2EtN (0.29 mL, 1.6 mmol) was added. The mixture was cooled to 0° C. and tert-butyl piperazine-1-carboxylate (207 mg, 1.1 mmol, Sigma-Aldrich, St. Louis, MO) in acetonitrile (0.5 mL) was added. After stirring at room temperature for 20 min, saturated NaHCO3 (5 mL) and EtOAc (5 mL) were added. The organic layer was collected, washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-25% EtOAc:EtOH (3:1) in heptane) gave tert-butyl 4-(6-chloro-3-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate as a pale yellow solid: m / z (ESI, cation) 617.0 (M+H). + .

[0209] Step 2: 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To a 50 mL round bottom flask was added tert-butyl 4-(6-chloro-3-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (246 mg, 0.4 mmol), trifluoroacetic acid (2 mL, 17.5 mmol) and DCM (4 mL). The reaction mixture was stirred at room temperature for 30 min and the solvent was removed under reduced pressure to give 6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-4-(piperazin-1-yl)-1,2-dihydro-1,8-naphthyridin-3-carbonitrile as the trifluoroacetate salt: m / z (ESI, positive ion) 517.0 (M+H). + The crude salt was dissolved in DCM (5 mL) and iPr2EtN (0.28 mL, 1.6 mmol) was added. The reaction mixture was cooled to 0 °C and acryloyl chloride (0.036 mL, 0.44 mmol, Sigma-Aldrich, St. Louis, MO) in DCM (0.5 mL) was added. The reaction mixture was stirred at 0 °C for 30 min, quenched with a saturated aqueous solution of NaHCO3 (5 mL) and extracted with EtOAc (10 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 50% EtOAc:EtOH (3:1) in heptane) afforded 4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as a pale yellow solid. 1H NMR(400MHz,DMSO-d6)δ 8.50(s,1H),8.44(d,J=4.77Hz,1H),7.47-7.57(m,1H),7.25-7.34(m,2H),7.22(d,J=5 .18Hz,1H),7.19(td,J=7.26,1.45Hz,1H),6.92(dd,J=16.59,10.37Hz,1H),6.21(dd,J =16.79,2.28Hz,1H),5.75-5.80(m,1H),3.79-4.00(m,8H),2.66(quintet,J=6.63Hz,1H),1 .93(s,3H),1.07(d,J=6.63Hz,3H),0.91(d,J=6.63Hz,3H).m / z(ESI,cation)571.0(M+H) + .

[0210] Following the route above, the following compounds were prepared from the substituted 1-Boc-piperazines in step 1:

[0211] [Table 7]

[0212] Example 7 4-(4-Acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: Racemic tert-butyl 4-(6,7-dichloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To a 250 mL round bottom flask was added 6,7-dichloro-1-(2,4-diisopropylpyridin-3-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate K, 2.8 g, 6.7 mmol) and diisopropylethylamine (3.5 ml, 20.1 mmol) in CH3CN (24 mL). POCl3 (0.94 ml, 10.1 mmol) was then added dropwise. The reaction mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure.

[0213] The residue was redissolved in CH3CN (24 mL) and diisopropylethylamine (3.5 ml, 20.1 mmol) was added. The reaction was cooled to 0° C. and 1-Boc-piperazine (1.63 g, 8.7 mmol, Aldrich) was added in one portion. The reaction mixture was stirred at 0° C. for 1 h, warmed to room temperature, treated with saturated NaHCO3, and extracted with EtOAc (3×). The organic extracts were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with a gradient of 0% to 25% 3:1 EtOAc:EtOH in heptane to give tert-butyl 4-(6,7-dichloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (1.48 g, 2.5 mmol, 38% yield) as a yellow solid. m / z (ESI, positive ion): 585.0 (M+1).

[0214] (M)-tert-butyl 4-(6,7-dichloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate and (P)-tert-butyl 4-(6,7-dichloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate The above material was purified by preparative SFC purification to give both (M) and (P) isomers: [OX-H (5um, 21x250mm) column, F=80ml, 35% methanol, 65% carbon dioxide, backpressure=90bar, 1.2ml injection] gave: Peak 1: 580mg, chemical purity: >99.0%, DE>99.0%. 1 H NMR (400 MHz, chloroform-d) δ 8.67 (d, J = 5.18 Hz, 1H), 8.11 (s, 1H), 7.22 (d, J = 5.18 Hz, 1H), 3.67-3.81 (m, 8H), 2.26-2.56 (m, 2H), 1.52 (s, 9H), 1.19 (dd, J = 6.84, 12.02 Hz, 6H), 1.03 (dd, J = 6.84, 18.45 Hz, 6H) and peak 2: 650 mg, chemical purity: > 99.0%, DE 96.3%. 1 H NMR(400MHz,chloroform-d)δ 8.67(d,J=5.18Hz,1H),8.11(s,1H),7.22(d,J=4.98Hz,1H),3.67-3.84(m,8H),2.29-2. 53(m,2H),1.52(s,9H),1.19(dd,J=6.84,12.02Hz,6H),1.03(dd,J=6.84,18.45Hz,6H).

[0215] Step 2: tert-Butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To a vial containing tert-butyl 4-(6,7-dichloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (210 mg, 0.36 mmol, one isomer) was added o-tolylboronic acid (54 mg, 0.4 mmol, Sigma-Aldrich Corporation), Pd(PPh3)4 (25 mg, 0.022 mmol) and potassium carbonate (99 mg, 0.72 mmol). The vial was evacuated under reduced pressure and then flushed with nitrogen. 1,4-dioxane (897 μl) and water (299 μl) were then added and the reaction mixture was heated at 100° C. for 1 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and brine. The aqueous layer was back-extracted with EtOAc (2x) and the combined organics were dried (Na2SO4) and concentrated. The crude material was purified by chromatography on silica gel eluting with a gradient of 0% to 50% 3:1 EtOAc / EtOH in heptane to give tert-butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (164 mg, 0.26 mmol, 71% yield) as a pale yellow solid. m / z (ESI, cation): 641.3 (M+1).

[0216] Step 3: 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile To tert-butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (164 mg, 0.26 mmol) dissolved in dichloromethane (1.3 ml) was added trifluoroacetic acid (400 μl, 5.4 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was redissolved in dichloromethane (1.3 mL) and 1,1'-dimethyltriethylamine (134 μl, 0.77 mmol) was added followed by acryloyl chloride (23 μl, 0.28 mmol, Sigma-Aldrich Corporation) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was purified by chromatography on silica gel eluting with a gradient of 0% to 60% EtOAc in heptane to give 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (63 mg, 0.1 mmol, 41.4% yield) as a white solid. m / z (ESI, positive ion): 595.3 (M+1). 1 H NMR(400MHz,chloroform-d)δ 8.53(d,J=5.18Hz,1H),8.15(s,1H),8.03(s,1H),7.16(d,J=7.67Hz,2H),7.10(d,J=5.18H z,1H),6.96(d,J=7.46Hz,1H),6.57-6.66(m,1H),6.39(dd,J=1.76,16.69Hz,1H),5.81(dd ,J=1.76,10.47Hz,1H),3.72-4.02(m,8H),2.52(quintet,J=6.63Hz,1H),2.38-2.46(m,1H),1. 94(s,3H),1.16(dd,J=6.74,11.09Hz,6H),0.97(d,J=6.84Hz,3H),0.92(d,J=6.84Hz,3H).

[0217] [Table 8]

[0218] Example 8 Racemic 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: 6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To 6,7-dichloro-1-(2,4-diisopropylpyridin-3-yl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate J, 335 mg, 0.8 mmol), potassium carbonate (222 mg, 1.6 mmol), Pd(PPh3)4 (56 mg, 0.048 mmol, Sigma-Aldrich, St. Louis, MO) and 2-fluorobenzeneboronic acid (124 mg, 0.9 mmol) was added 1,4-dioxane (2 ml) and water (669 μl) and the reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (2×) and the combined organics were dried (Na2SO4) and concentrated. The crude material was purified by chromatography on a silica gel column eluting with a gradient of 0% to 50% 3:1 EtOAc / EtOH in heptane to give 6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (326 mg, 0.68 mmol, 85% yield) as a yellow solid. m / z (ESI, cation): 477.2 (M+1).

[0219] Step 2: tert-Butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. To 6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (326 mg, 0.7 mmol), diisopropylethylamine (358 μl, 2.0 mmol) and POCl3 (96 μl, 1.0 mmol) was added CH3CN (2.3 mL). The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was redissolved in CH3CN (2.3 mL) and diisopropylethylamine (358 μl, 2.0 mmol) was added. The reaction product was cooled to 0° C. and 1-Boc-piperazine (166 mg, 0.9 mmol, Sigma-Aldrich, St. Louis, MO) was added in one portion. After stirring at room temperature for 2 h, saturated NaHCO3 was added and the aqueous layer was extracted with EtOAc (3x). The organic extracts were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel eluting with a gradient of 0% to 25% EtOAc:EtOH (3:1) in heptane to give tert-butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (270 mg, 0.4 mmol, 61% yield) as an orange solid. m / z (ESI, cation): 645.2 (M+1).

[0220] Step 3: Racemic 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile tert-Butyl 4-(6-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.52 g, 0.8 mmol) was stirred with trifluoroacetic acid (1.3 ml, 17.4 mmol) in dichloromethane (4.1 ml) for 1 hour. The mixture was concentrated in vacuo and the residue was redissolved in dichloromethane (2 mL). 1,1'-Dimethyltriethylamine (0.43 ml, 2.4 mmol) was added followed by dropwise addition of acryloyl chloride (0.073 ml, 0.9 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes. The reaction mixture was purified by chromatography on silica gel eluting with a gradient of 0% to 50% 3:1 EtOAc / EtOH in heptane to give 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.23 g, 0.19 mmol, 46% yield). m / z (ESI, positive ion): 599.3 (M+1). 1 H NMR(400MHz,chloroform-d)δ 8.67(d,J=5.39Hz,1H),8.18(s,1H),7.36-7.46(m,1H),7.22(d,J=5.18Hz,1H),7.03-7.18(m ,3H),6.64(dd,J=10.57,16.79Hz,1H),6.41(dd,J=1.66,16.79Hz,1H),5.84(dd,J=1.66,10.5 7Hz,1H),3.78-4.10(m,8H),2.57(td,J=6.82,13.53Hz,1H),2.47(td,J=6.84,13.68Hz,1H),1 .23(d,J=6.84Hz,3H),1.18(d,J=6.84Hz,3H),1.02(d,J=6.84Hz,3H),0.95(d,J=6.84Hz,3H).

[0221] Examples 8.1 and 8.2: The above material (Example 8) was purified by preparative SFC purification [OX-H (5 um, 21 x 250 mm), F = 80 ml, 30% methanol, 70% carbon dioxide, back pressure = 90 bar, 1.0 ml injection] to give the following:

[0222] Example 8.1: As Peak 1: 14-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as an off-white solid, chemical purity: >99.0%, DE>99.0%; m / z (ESI, positive ion): 599.3 (M+1). 1 H NMR(400MHz,chloroform-d)δ 8.58(d,J=5.18Hz,1H),8.17(s,1H),7.36-7.47(m,1H),7.05-7.19(m,4H),6.64(dd,J=10.37,16.79Hz,1H),6.41(dd,J=1.66,16.79Hz,1H), 5.83(dd,J=1.76,10.47Hz,1H),3.78-4.08(m,8H),2.48-2.60(m,1H),2.38-2.48(m,1H),1.18(dd,J=6.84,10.78Hz,6H),0.90-1.02(m,6H). 19 F NMR (376 MHz, chloroform-d) δ −113.03 (s, 1F).

[0223] Example 8.2: As peak 2: 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2,4-diisopropylpyridin-3-yl)-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile as an off-white solid, chemical purity >99.0%, DE 98.2%. m / z (ESI, positive ion): 599.3 (M+1). 1H NMR(400MHz,chloroform-d)δ 8.58(d,J=5.18Hz,1H),8.17(s,1H),7.34-7.47(m,1H),7.03-7.19(m,4H),6.64(dd,J=10.57,16.79Hz,1H),6.41(dd,J=1.66,16.79Hz,1H), 5.83(dd,J=1.76,10.47Hz,1H),3.76-4.12(m,8H),2.49-2.63(m,1H),2.37-2.49(m,1H),1.18(dd,J=6.74,10.68Hz,6H),0.90-1.02(m,6H). 19 F NMR (376 MHz, chloroform-d) δ −113.03 (s, 1F).

[0224] [Table 9]

[0225] Example 9 4-(4-Acryloylpiperazin-1-yl)-7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Phosphorus oxychloride (0.334 mL, 3.57 mmol) was added dropwise to a solution of 7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (Intermediate K, 1.1 g, 2.7 mmol) and triethylamine (1.157 mL, 8.23 ​​mmol) in acetonitrile (10 mL) under argon. The mixture was heated to 80° C. for 1 h and concentrated in vacuo. The residue was dissolved in acetonitrile (10 mL) and treated with triethylamine (7.71 mL, 54.9 mmol) and 1-(piperazin-1-yl)prop-2-en-1-one bis(2,2,2-trifluoroacetate) (1.314 g, 3.57 mmol, eNovation, LLC). The reaction mixture was stirred at room temperature for 12 h, diluted with water, and extracted with EtOAc (2×). The organic extracts were combined and concentrated in vacuo, and the residue was purified by chromatography on silica gel eluting with 0-80% EtOAc / EtOH (3:1) in heptane to give 4-(4-acryloylpiperazin-1-yl)-7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.102 g, 0.098 mmol) as a mixture of atropisomers. 1 H NMR (400 MHz, chloroform-d) δ 8.71 (d, J = 5.18 Hz, 1H), 7.88 (d, J = 7.67 Hz, 1H), 7.26-7.29 (m, 1H), 6.66 (dd, J = 10.57, 16.79 Hz, 1H), 6.40-6.47 (m, 1H), 5.86 (dd, J = 1.66, 10.57 Hz, 1H), 3.99 (br s,4H),3.71-3.90(m,4H),2.36-2.54(m,2H),1.24(d,J=6.63Hz,3H),1.21(d,J=6.63Hz,3H),1.09(d,J=6.63Hz,3H),1.04(d,J=6.84Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ -124.74 (s, 1F). m / z (ESI, positive ion): 523.1 (M+H) + .

[0226] Example 9.1: 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(4,6-diisopropylpyrimidin-5-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] The compound was prepared from Intermediate I following the procedure of Example 9. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.93-1.01(m,6H)1.05-1.12(m,6H)2.61-2.75(m,2H)3.72-3.95(m,8H)5.62-5.97(m,1H)6.10- 6.38(m,1H)6.83-7.01(m,1H)8.36-8.73(m,1H)8.97-9.77(m,1H).m / z(ESI, cation):539.8(M+H) + .

[0227] Example 9.2: 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. [ka] The compound was prepared from intermediate L according to the procedure of Example 9. 1 H NMR(400MHz,DMSO-d6)δ ppm 0.95-1.02(m,3H)1.04-1.11(m,3H)1.89-1.96(m,3H)2.56-2.70(m,1H)3.74-3.95(m,8H)5.70-5.83(m, 1H)6.10-6.28(m,1H)6.82-6.99(m,1H)7.26-7.36(m,1H)8.46-8.56(m,2H).m / z(ESI, cation):511.1(M+H) + .

[0228] Example 10 4-(4-Acryloylpiperazin-1-yl)-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: tert-Butyl 4-(7-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. Following the procedure described in Example 9, 1-(t-butoxycarbonyl)-piperazine (0.657 g, 3.5 mmol, Sigma-Aldrich, St. Louis, MO) was used to give tert-butyl 4-(7-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.71 g, 1.2 mmol, 49% yield). m / z (ESI, positive ion): 569.3 (M+H). + .

[0229] Step 2: 4-(4-acryloylpiperazin-1-yl)-7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. TFA (1.86 mL, 24.9 mmol) was added to a solution of tert-butyl 4-(7-chloro-3-cyano-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (0.71 g, 1.2 mmol) in dichloromethane (5 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was suspended in DCM (5 mL) and treated with TEA (0.710 mL, 5 mmol) followed by acryloyl chloride (0.16 mL, 2 mmol). The reaction was stirred at room temperature for 10 min, quenched with water and extracted with EtOAc (2×). The organic layers were combined and concentrated, and the residue was purified by chromatography on silica gel eluting with a gradient of 0-80% EtOAc / EtOH (3:1) in heptane to give 4-(4-acryloylpiperazin-1-yl)-7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.610 g, 1.1 mmol, 93% yield). 1 H NMR(400MHz,chloroform-d)δ 8.69(d,J=5.18Hz,1H),7.86(d,J=7.67Hz,1H),7.23-7.26(m,1H),6.62(dd,J=10.57, 16.79Hz,1H),6.40(dd,J=1.76,16.69Hz,1H),5.83(dd,J=1.66,10.57Hz,1H),3.96(br s,4H),3.78(br s,4H),2.32-2.52(m,2H),1.22(br d,J=6.63Hz,3H),1.18(d,J=6.63Hz,3H),1.07(br d,J=6.43Hz,3H),1.01(d,J=6.84Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ -124.72 (s, 1F). m / z (ESI, positive ion): 523.1 (M+H) + .

[0230] Step 3: 4-(4-acryloylpiperazin-1-yl)-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. A mixture of 4-(4-acryloylpiperazin-1-yl)-7-chloro-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.250 g, 0.478 mmol), o-tolylboronic acid (0.097 g, 0.717 mmol, Sigma-Aldrich Corporation), sodium carbonate (0.15 g, 1.4 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.048 mmol) in 1,4-dioxane (3 mL) / water (2 mL) was stirred for 1 h at 90° C. The reaction mixture was diluted with water and extracted with EtOAc. The organics were concentrated and the residue was purified by chromatography on silica gel eluting with 0-90% EtOAc / EtOH (3:1) in heptane to give 4-(4-acryloylpiperazin-1-yl)-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.11 g, 0.09 mmol, 19% yield) as a mixture of atropisomers. 1 H NMR(400MHz,chloroform-d)δ 8.58(br d,J=4.98Hz,1H),7.86(d,J=9.12Hz,1H),7.26-7.32(m,1H),7.09-7.23(m,4H),6.62(dd,J=10. 57,16.79Hz,1H),6.35-6.44(m,1H),5.81(dd,J=1.66,10.57Hz,1H),3.91-4.06(m,4H),3.82(br s,4H),2.39-2.60(m,2H),1.98(s,3H),1.13-1.22(m,6H),0.97(br d,J=6.01Hz,3H),0.91(d,J=6.63Hz,3H). 19F NMR (376 MHz, chloroform-d) δ -126.76 (s, 1F). m / z (ESI, positive ion): 579.4 (M+H) + .

[0231] Example 10.1: 4-(4-acryloylpiperazin-1-yl)-1-(2,4-diisopropylpyridin-3-yl)-6-fluoro-7-(2-fluorophenyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. [ka] The compound was prepared following the procedure of Example 10 using 2-fluorophenylboronic acid (Sigma-Aldrich, St. Louis, MO). 1 H NMR(400MHz,chloroform-d)δ 8.65(d,J=5.18Hz,1H),7.92(d,J=9.12Hz,1H),7.38-7.49(m,1H),7.11-7.26(m,4H),6.66(dd,J=1 0.57,16.79Hz,1H),6.34-6.50(m,1H),5.85(dd,J=1.76,10.47Hz,1H),3.94-4.11(m,4H),3.86(br s,4H),2.44-2.63(m,2H),1.18-1.26(m,6H),1.02(br d,J=6.63Hz,3H),0.96(d,J=6.84Hz,3H). 19 F NMR (376 MHz, chloroform-d) δ -112.53 - -112.64 (s, 1F), -125.66 - -125.77 (s, 1F) (signals split due to the presence of atropisomers). m / z (ESI, positive ion): 583.4 (M+H) + .

[0232] Example 11 4-(4-Acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile [ka] Step 1: tert-Butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate. The compound was prepared from intermediate L following the procedure described for intermediate 9.

[0233] Step 2: 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. To tert-butyl 4-(6,7-dichloro-3-cyano-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl)piperazine-1-carboxylate (6.26 g, 11.2 mmol) in DCM (20 ml) was added TFA (15 ml). The mixture was stirred for 15 min and evaporated. DCM (5×20 ml) was added and evaporated. The residue was dried in vacuum, dissolved in DCM (40 ml) and cooled in an ice-water bath. Diisopropylethylamine (13 ml, 74.4 mmol) and acryloyl chloride (1.5 ml, 18.4 mmol) were added. After 10 min, DCM (100 ml) and 50 ml of brine were added and the two layers were separated. The organic layer was dried, evaporated and purified by chromatography on silica gel eluting with 25% to 70% (3 / 1 EtOAc / EtOH) / heptane to give 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. 1H NMR(400MHz,DMSO-d6)δ ppm 0.95-1.02(m,3H)1.04-1.11(m,3H)1.89-1.96(m,3H)2.56-2.70(m,1H)3.74-3.95(m,8H)5.70-5.83(m, 1H)6.10-6.28(m,1H)6.82-6.99(m,1H)7.26-7.36(m,1H)8.46-8.56(m,2H).m / z(ESI, cation):511.1(M+H) + .

[0234] Step 3: Single atropisomer of 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. 4-(4-Acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile was purified by preparative SFC using OX (250×30 mm, 5 u), a mobile phase of a 1:1 mixture of 30% iPrOH:ACN, and a flow rate of 150 mL / min, yielding peak 1 with ee>99% (chemical purity>99%) and peak 2 with ee97.53% (chemical purity 97.53%). Peak identification was determined by SFC using an OX column, using a 1:1 mixture of 30% iPrOH:ACN.

[0235] Step 4: 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile. A mixture of 4-(4-acryloylpiperazin-1-yl)-6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile, first eluting peak from SFC separation (0.156 g, 0.305 mmol), o-tolylboronic acid (0.050 g, 0.36 mmol), potassium acetate (0.090 g, 0.9 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (0.022 g, 0.03 mmol) in 1,4-dioxane (1 mL) / water (0.4 mL) was stirred for 1 h at 90° C. The resulting mixture was diluted with water and extracted with EtOAc (2×). The organics were concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with 0-80% EtOAc / EtOH in heptane, (3:1) to give 4-(4-acryloylpiperazin-1-yl)-6-chloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-7-(o-tolyl)-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (0.021 g, 0.037 mmol, 12% yield). 1 H NMR(400MHz,chloroform-d)δ 8.48(d,J=4.77Hz,1H),8.18(s,1H),7.28-7.32(m,1H),7.14-7.22(m,2H),7.01-7.12(m,2H),6.64( dd,J=10.57,16.79Hz,1H),6.40(dd,J=1.66,16.79Hz,1H),5.82(dd,J=1.55,10.47Hz,1H),3.99(br s,4H),3.84(br s,4H),2.49-2.65(m,1H),1.97(d,J=6.63Hz,6H),1.19(d,J=6.63Hz,3H),0.98(d,J=6.63Hz,3H).m / z(ESI, cation):567.4(M+H) + .

[0236] [Table 10]

[0237]

Table 11

[0238]

Table 12

[0239]

Table 13

[0240]

Table 14

[0241]

Table 15

[0242]

Table 16

[0243]

Table 17

[0244]

Table 18

[0245]

Table 19

[0246]

Table 20

[0247]

Table 21

[0248] [Table 22]

[0249] [Table 23]

[0250] biological analysis The following assay conditions were used for the compounds in Table 10.

[0251] Binding nucleotide exchange assay: Purified GDP-bound KRAS protein (aa1-169) containing both G12C and C118A amino acid substitutions and an N-terminal His-tag was pre-incubated with a dose-response titration of compounds in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl2 and 0.01% Triton X-100) for 5 minutes (see Table 10). After compound pre-incubation, purified SOS protein (aa564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 minutes. To determine the extent of inhibition of SOS-mediated nucleotide exchange, purified GST-tagged cRAF (aa1-149), nickel-chelating AlphaLISA acceptor beads (PerkinElmer AL108R) and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 minutes. The assay plates were then read on a PerkinElmer EnVision Multilabel Reader using AlphaScreen® technology and the data were analyzed using a four-parameter logistic model to determine the IC 50 The value was calculated.

[0252] Phospho-ERK1 / 2 MSD Assay: MIA PaCa-2 (ATCC® CRL-1420™) and A549 (ATCC® CCL-185™) cells were cultured in RPMI 1640 medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1× penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). MIA PaCa-2 were seeded at a density of 25,000 cells / well in 96-well cell culture plates 16 hours prior to compound treatment and incubated at 37° C., 5% CO2. Dose-response titrations of compounds were diluted in growth medium and added to the appropriate wells of the cell culture plate, then incubated at 37° C., 5% CO2 for 2 hours (see Table 10). Following compound treatment, cells were stimulated with 10 ng / mL EGF (Roche 11376454001) for 10 min and incubated with ice-cold Dulbecco's phosphate-buffered saline (Ca 2+ Mg 2+ Cells were washed with 100 mM Tris-HCl pH 7.5 (without 1% NaCl) (ThermoFisher Scientific 14190144) and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001). Phosphorylation of ERK1 / 2 in compound-treated lysates was assayed using the Phospho-ERK1 / 2 Whole Cell Lysate Kit (Meso Scale Discovery K151DWD) following the manufacturer's protocol. Assay plates were read on a Meso Scale Discovery Sector Imager 6000 and data was analyzed using a four-parameter logistic model to determine IC 50 The value was calculated.

[0253] [Table 24]

[0254] [Table 25]

[0255] The present invention has been described with respect to preferred embodiments. However, it should be understood that the present invention is not limited to the disclosed embodiments. It is understood that various modifications may be made by those skilled in the art once the description of the embodiments of the present invention is given herein. Such modifications are encompassed within the scope of the following claims.

Claims

1. The following compound: 【Chemistry 1】

2. The following compound: 【Chemistry 2】

3. The following compound: 【Chemistry 3】

4. The following compound: 【Chemistry 4】

5. The following compound: 【Chemistry 5】

6. The following compound: 【Chemistry 6】

7. A process for preparing a compound of formula Ia or a pharma- ceutically acceptable salt thereof, comprising providing a compound according to any one of claims 1 to 6 and converting said compound into a compound of formula Ia or a pharma- ceutically acceptable salt thereof, said compound of formula Ia or a pharma- ceutically acceptable salt thereof being 【Chemistry 7】 (In the formula, R ２ is halo or aryl, the aryl group being unsubstituted or selected from halo, —C １～６ Alkyl, -C ２～６ Alkenyl, -C ２～６ Alkynyl, -CF ３ , -OCF ３ , -NO ２ , -CN, -NC, -OH, alkoxy, amino, -CO ２ H, -CO ２ C １ ~C ６ Alkyl, -OCOC １ ~C ６ Alkyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Heterocycloalkyl, C ５ ~C １０ Aryl and C ５ ~C １０ substituted with one or more groups independently selected from heteroaryl; R ３ is Cl; R ４ teeth, 【Chemistry 8】 and R ８ teeth, 【Chemistry 9】 It is.) ) the manufacturing method.

8. R ２ is aryl, said aryl group being unsubstituted or selected from halo, -C １～６ The process of claim 7, wherein the compound is substituted with one or more groups independently selected from alkyl and amino.

9. R ２ is phenyl, said phenyl being halo, C １～６ The process according to claim 7 or 8, wherein the compound is substituted with one or more groups independently selected from alkyl and amino.

Images