Improved synthesis method for key intermediates of KRAS G12C inhibitor compounds

Abstract

This provides an improved synthetic method for important intermediates of KRAS G12C inhibitor compounds. [Solution] The present invention provides, JPEG2026109623000156.jpg43150 Structures useful for the synthesis of compounds targeting the KRAS G12C mutation, such as JPEG2026109623000157.jpg32150 The present invention relates to an improved, efficient, and scalable method for preparing intermediate compounds such as compound 5M, which have the following characteristics.

Description

[Technical Field]

[0001] The present invention relates to an improved, efficient, and scalable method for preparing intermediate compounds, such as compound 5M, having the following structure, which are useful for the synthesis of compounds that inhibit the KRAS G12C mutation. [ka] [Background technology]

[0002] KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gallbladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in approximately 25% of NSCLC patients, and several studies have shown that KRAS mutations are a negative prognostic factor in NSCLC patients. Recently, V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS) mutations have been found to confuse resistance to epidermal growth factor receptor (EGFR) targeted therapy in colorectal cancer, and therefore, the KRAS mutation status can provide important information before prescribing TKI therapy. In summary, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, particularly those diagnosed with cancer characterized by KRAS mutations, and including patients whose cancer has progressed to the point of chemotherapy. [Brief explanation of the drawing]

[0003] [Figure 1] Figure 1 shows the crystal arrangement of composition 4a. [Figure 2-1] Figure 2-1 shows the XRPD overlays for Zion racemic types A through E. [Figure 2-2] Figure 2-2 shows the XRPD overlay of the (1S)-(-)-camphanic acid cocrystal. [Figure 2-3] Figure 2-3 shows the XRPD overlay of the (+)-2,3-dibenzoyl-D-tartaric acid cocrystal. [Figure 2-4]Figure 2-4 shows the XRPD overlay of the D-(+)-malate cocrystal. [Figure 2-5] Figure 2-5 shows XRPD overlays of M-zion cocrystals at different temperatures. [Figure 2-6] Figure 2-6 shows XRPD overlays of P-dione cocrystals at different temperatures. [Figure 2-7] Figure 2-7 shows XRPD overlays of mixtures of M-dione and P-dione cocrystals at different temperatures. [Figure 2-8] Figure 2-8 shows the XRPD overlay of the dion racemite at different temperatures (I / II). [Figure 2-9] Figure 2-9 shows the XRPD overlay of a dion racemite at different temperatures (II / II). [Figure 2-10] Figure 2-10 shows the ternary phase diagram of the M / P-dione cocrystal. [Figure 2-11] Figure 2-11 shows the ternary phase diagram of M / P-Zeon. [Figure 3-1] Figure 3-1 shows the XRPD of a Zion racemic A-type. [Figure 3-2] Figure 3-2 shows the TGA / DSC overlay of Zeon racemic type A. [Figure 3-3] Figure 3-3 shows the 1H NMR spectrum of the dione racemic A-type. [Figure 3-4] Figure 3-4 shows a PLM image of a dion racemic A-type. [Figure 3-5] Figure 3-5 shows the XRPD of a Zion racemic B-type. [Figure 3-6] Figure 3-6 shows the TGA / DSC overlay of Zeon racemic type B. [Figure 3-7] Figure 3-7 shows the 1H NMR spectrum of the dione racemic mixture type B. [Figure 3-8] Figure 3-8 shows the XRPD of a Zion Racemic C-type. [Figure 3-9] Figure 3-9 shows a TGA / DSC overlay of a Zeon racemic C-type. [Figure 3-10]Figure 3-10 shows the 1H NMR spectrum of the dione racemic C-type. [Figure 3-11] Figure 3-11 shows the XRPD of a D-type zion racemic mixture. [Figure 3-12] Figure 3-12 shows the TGA / DSC overlay of Zeon racemic type D. [Figure 3-13] Figure 3-13 shows the 1H NMR spectrum of the D-type dione racemic mixture. [Figure 3-14] Figure 3-14 shows the XRPD overlay of a Zeon racemic E-type. [Figure 3-15] Figure 3-15 shows a TGA / DSC overlay of a Zeon racemic E-type. [Figure 3-16] Figure 3-16 shows the 1H NMR spectrum of the E-type dione racemic mixture. [Figure 3-17] Figure 3-17 shows the XRPD of type A of the M-zion cocrystal. [Figure 3-18] Figure 3-18 shows a TGA / DSC overlay of M-zion cocrystal type A. [Figure 3-19] Figure 3-19 shows the 1H NMR spectrum of the M-dione cocrystal type A. [Figure 3-20] Figure 3-20 shows the XRPD of type A, a P-dione cocrystal. [Figure 3-21] Figure 3-21 shows a TGA / DSC overlay of type A P-zion cocrystal. [Figure 3-22] Figure 3-22 shows the 1H NMR spectrum of type A P-dione cocrystal. [Figure 3-23] Figure 3-23 shows the XRPD overlay of the Zeon racemic form. [Figure 3-24] Figure 3-24 shows the XRPD of competing slurry samples. [Figure 3-25] Figure 3-25 shows the XRPD overlay of the prepared P-dione cocrystal. [Figure 3-26] Figure 3-26 shows the 1H NMR spectrum overlay of the M / P-dione cocrystal. [Figure 3-27]Figure 3-27 shows the XRPD overlay of the prepared P-dione cocrystal. [Figure 4-1] Figure 4-1 shows the inter-crystallization of the crystalline morphology of the M-zion DBTA cocrystal. [Figure 5-1] Figure 5-1 shows XRPD overlays of the crystal morphologies (types A to E) of M-zion DBTA cocrystals. [Figure 5-2] Figure 5-2 shows the XRPD overlay of the crystal morphology (F-K type) of M-zion DBTA cocrystals. [Figure 5-3] Figure 5-3 shows the XRPD overlay of the crystal morphology (L to Q type) of M-zion DBTA cocrystals. [Figure 5-4] Figure 5-4 shows the XRPD pattern of type A. [Figure 5-5] Figure 5-5 shows the A-type TGA / DSC curve. [Figure 5-6] Figure 5-6 shows the 1H NMR spectrum of type A. [Figure 5-7] Figure 5-7 shows the XRPD overlay of type B. [Figure 5-8] Figure 5-8 shows the B-type TGA / DSC curve. [Figure 5-9] Figure 5-9 shows the 1H NMR spectrum of type B. [Figure 5-10] Figure 5-10 shows the C-type XRPD pattern. [Figure 5-11] Figure 5-11 shows a C-type TGA / DSC curve. [Figure 5-12] Figure 5-12 shows the 1H NMR spectrum of the C type. [Figure 5-13] Figure 5-13 shows a D-type XRPD pattern. [Figure 5-14] Figure 5-14 shows a D-type TGA / DSC curve. [Figure 5-15] Figure 5-15 shows the 1H NMR spectrum of type D. [Figure 5-16] Figure 5-16 shows the E-type XRPD pattern. [Figure 5-17] Figure 5-17 shows the E-type TGA / DSC curve. [Figure 5-18]Figure 5-18 shows the 1H NMR spectrum of type E. [Figure 5-19] Figure 5-19 shows the F-type XRPD pattern. [Figure 5-20] Figure 5-20 shows the F-type TGA / DSC curve. [Figure 5-21] Figure 5-21 shows the 1H NMR spectrum of the F type. [Figure 5-22] Figure 5-22 shows the G-type XRPD pattern. [Figure 5-23] Figure 5-23 shows a G-type TGA / DSC curve. [Figure 5-24] Figure 5-24 shows the 1H NMR spectrum of the G type. [Figure 5-25] Figure 5-25 shows an H-shaped XRPD pattern. [Figure 5-26] Figure 5-26 shows an H-shaped TGA / DSC curve. [Figure 5-27] Figure 5-27 shows the 1H NMR spectrum of the H type. [Figure 5-28] Figure 5-28 shows a type I XRPD pattern. [Figure 5-29] Figure 5-29 shows the type I TGA / DSC curve. [Figure 5-30] Figure 5-30 shows the 1H NMR spectrum of type I. [Figure 5-31] Figure 5-31 shows a J-type XRPD pattern. [Figure 5-32] Figure 5-32 shows a J-type TGA / DSC curve. [Figure 5-33] Figure 5-33 shows the 1H NMR spectrum of the J type. [Figure 5-34] Figure 5-34 shows the K-type XRPD pattern. [Figure 5-35] Figure 5-35 shows the K-type TGA / DSC curve. [Figure 5-36] Figure 5-36 shows the 1H NMR spectrum of the K-type. [Figure 5-37] Figure 5-37 shows an L-shaped XRPD pattern. [Figure 5-38] Figure 5-38 shows an L-shaped TGA / DSC curve. [Figure 5-39]Figure 5-39 shows the 1H NMR spectrum of the L-type. [Figure 5-40] Figure 5-40 shows the M-type XRPD pattern. [Figure 5-41] Figure 5-41 shows an M-type TGA / DSC curve. [Figure 5-42] Figure 5-42 shows the 1H NMR spectrum of the M type. [Figure 5-43] Figure 5-43 shows an N-type XRPD pattern. [Figure 5-44] Figure 5-44 shows the N-type TGA / DSC curve. [Figure 5-45] Figure 5-45 shows the N-type 1H NMR spectrum. [Figure 5-46] Figure 5-46 shows the XRPD pattern of type O. [Figure 5-47] Figure 5-47 shows the O-type TGA / DSC curve. [Figure 5-48] Figure 5-48 shows the 1H NMR spectrum of type O. [Figure 5-49] Figure 5-49 shows the P-type XRPD pattern. [Figure 5-50] Figure 5-50 shows a P-type TGA / DSC curve. [Figure 5-51] Figure 5-51 shows the 1H NMR spectrum of the P-type. [Figure 5-52] Figure 5-52 shows a Q-type XRPD pattern. [Figure 5-53] Figure 5-53 shows a Q-type TGA / DSC curve. [Figure 5-54] Figure 5-54 shows the 1H NMR spectrum of the Q type. [Figure 6-1] Figure 6-1 shows the HPLC analysis of M-5 after resolution with 1,3-diphenyl-3-oxopropanesulfonic acid. [Figure 6-2] Figure 6-2 shows the HPLC of 5 (with excess P-atropisomer) after resolution with 1,3-diphenyl-3-oxopropanesulfonic acid. [Overview of the project] [Means for solving the problem]

[0004] The present invention relates to the following chemical structure [ka] Compounds having the following chemical structure, as well as important intermediates thereof, i.e., the following chemical structure [ka] This invention relates to compositions containing and improved preparation methods for compounds.

[0005] This invention further relates to the following chemical structure [ka] This relates to a method for preparing compound 5M having the following properties.

[0006] This invention further, structure [ka] This relates to compositions containing the following: [Modes for carrying out the invention]

[0007] definition Abbreviations: The following abbreviations may be used in this specification:

[0008] [Table 1]

[0009] [Table 2]

[0010] [Table 3]

[0011] In the context describing the present invention (particularly in the context of the claims), the use of terms “a,” “an,” “the,” and similar referents should be interpreted as encompassing both singular and plural forms unless otherwise indicated. The descriptions of value ranges in this specification are intended merely as a concise way of referring individually to each distinct value falling within that range, unless otherwise indicated, and each distinct value is incorporated herein as if it were individually enumerated. Any use of examples or illustrative language provided herein (e.g., “such as”) is intended to better illustrate the present invention and, unless otherwise specified, does not limit the scope of the invention. Language herein should not be interpreted as indicating that any element not mentioned is essential for the practice of the invention.

[0012] As used herein, the term “alkyl” refers to linear 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~n This means that the alkyl group has m to n carbon atoms. The term "alkylene" refers to alkyl groups with substituents. Alkyl (e.g., methyl) or alkylene (e.g., -CH2-) groups include, for example, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, and C. 1~8 Alkyl, C 2~8 Alkenil, C 2~8 Alkinyl, -NC, amino, -CO2H, -CO2C1~C8 alkyl, -OCOC1~C8 alkyl, C3~C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5~C10 Aryl, and C5-C 10 One or more, usually 1 to 3, selected independently from heteroaryl, may be substituted. The term "haloalkyl" specifically refers to an alkyl group in which at least one, for example, 1 to 6, or all of the hydrogen atoms of the alkyl group are substituted with halo atoms.

[0013] The terms "alkenyl" and "alkynyl" each denote an alkyl group further containing a double bond or a triple bond.

[0014] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo. The term "alkoxy" is defined as -OR (where R is alkyl).

[0015] As used herein, the term "amino" or "amine" interchangeably refers to a -NR2 group (where each R is, for example, H or a substituent). In some embodiments, the amino group is further substituted to form an ammonium ion, for example, NR3 + is formed. The ammonium moiety is specifically included in the definition of "amino" or "amine". The substituent can be, for example, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amide, or carboxylate. The R group can further be substituted with one or more, for example, 1 to 4 groups selected from, for example, halo, cyano, alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amide. The term "amide" or "amide" group is similar to an amine or amino group but interchangeably refers to a group further containing C(O), for example, -C(O)NR2. [[ID=二十一]]

[0016] [[ID=二十二]] [[ID=二十三]]As used herein, the term "aryl" refers to C[[ID=二十四]] 6~14 [[ID=二十五]]A monocyclic or polycyclic aromatic group, preferably C[[ID=二十六]] 6~10 [[ID=二十七]]A monocyclic or bicyclic aromatic group, or C[[ID=二十八]] 10~14This refers to a polycyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azlenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to a group where one ring is an aromatic ring and the other is a saturated, partially unsaturated, or aromatic ring. 10~14 This refers to bicyclic and tricyclic carbon rings, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). Unless otherwise specified, aryl groups refer to, for example, halo, C 1-8 Alkyl, C 2~8 Alkenil, C 2~8 Alkinyl, -CF3, -OCF3, -NO2, -CN, -NC, -OH, Alkoxy, Amino, -CO2H, -CO2C1~C8 alkyl, -OCOC1~C8 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 groups, particularly 1 to 4 groups, independently selected from the heteroaryl.

[0017] As used herein, the term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic carbocyclic rings (where the polycyclic ring may be condensed, cross-linked, or spiro). A carbocyclic ring may have 3 to 10 carbocyclic atoms. Possible carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

[0018] As used herein, the term "heterocycloalkyl" means a ring system containing three or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7) total atoms, of which 1 to 5 (e.g., 1, 2, 3, 4, or 5) atoms are monocyclic or polycyclic (e.g., bicyclic) saturated or partially unsaturated rings 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.

[0019] Unless otherwise specified, cycloalkyl groups or heterocycloalkyl groups may be unsubstituted or substituted with one or more groups, particularly 1 to 4 groups. Some possible substituents include halo, C 1~8 Alkyl, C 2~8 Alkenil, C 2~8 Alkinyl, -OCF3, -NO2, -CN, -NC, -OH, Alkoxy, Amino, -CO2H, -CO2C1~C8 alkyl, -OCOC1~C8 alkyl, C3~C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5~C 10 Aryl, and C5~C 10 Heteroaryls are one example.

[0020] As used herein, the term “heteroaryl” refers to a monocyclic or polycyclic (e.g., bicyclic) ring system comprising 1 to 3 aromatic rings, the aromatic rings containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, 5 to 10, or 5 to 7 atoms. A heteroaryl is also a ring in which one ring is aromatic and the other is saturated, partially unsaturated, or aromatic. 10~14This refers to bicyclic and tricyclic rings. Examples of heteroaryl groups include furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, and benzotriazoli Examples of heteroaryl groups include, but are not limited to, halo, benzoxazolyl, flopyridyl, imidazopyridinyl, imidazothiazolyl, indolidinyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, chiazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise specified, heteroaryl groups may be unsubstituted or substituted with one or more substituents, particularly 1 to 4 or 1 or 2 substituents. Possible substituents include halo, C 1~8 Alkyl, C 2~8 Alkenil, C 2~8 Alkinyl, -OCF3, -NO2, -CN, -NC, -OH, Alkoxy, Amino, -CO2H, -CO2C1~C8 alkyl, -OCOC1~C8 alkyl, C3~C 10 Cycloalkyl, C3-C 10 Heterocycloalkyl, C5~C 10 Aryl, and C5~C 10 Heteroaryls are one example.

[0021] As used herein, the term Boc refers to the following structure: [ka]

[0022] Embodiment Embodiment 1 In one embodiment of the present invention, the present invention is a composition comprising Formula 4 [ka] Compounds of formula B [ka] The composition includes the compound.

[0023] Embodiment 2 In another embodiment of the present invention, the present invention relates to a compound of formula 4 that is of formula 5M [ka] The composition of Embodiment 1 comprises the compound of [the compound].

[0024] Embodiment 3 In another embodiment of the present invention, the present invention relates to a compound of formula 4 that is of formula 5P [ka] The composition of Embodiment 1 comprises the compound of [the compound].

[0025] Embodiment 4 In another embodiment of the present invention, the present invention relates to a compound of formula B being of formula B1 [ka] The present invention comprises one of the compositions of Embodiments 1 to 3, which is a compound of the present invention.

[0026] Embodiment 5 In another embodiment of the present invention, the present invention relates to a compound of formula B being of formula B2 [ka] The present invention comprises one of the compositions of Embodiments 1 to 3, which is a compound of the present invention.

[0027] Embodiment 6 In another embodiment of the present invention, the present invention includes any one of the compositions of Embodiments 1 to 5, wherein the composition comprises a compound of Formula 4 and a compound of Formula B in a ratio of 2:1.

[0028] Embodiment 7 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The present invention comprises any one of the compositions of Embodiments 1 to 6, further comprising 2-methyltetrahydrofuran having .

[0029] Embodiment 8 In another embodiment of the present invention, the present invention comprises any one of the compositions of Embodiments 1 to 7, wherein the ratio of 2-methyltetrahydrofuran to the compound of formula B is 2:1.

[0030] Embodiment 9 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 1 comprises having the following characteristics.

[0031] Embodiment 10 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 9 includes having the following:

[0032] Embodiment 11 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 9 includes having the following:

[0033] Embodiment 12 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 9 includes having the following:

[0034] Embodiment 13 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 9 includes having the following:

[0035] Embodiment 14 In another embodiment of the present invention, the present invention includes one of the compositions from Embodiments 1 to 13, wherein the composition is in a crystalline state.

[0036] Embodiment 15 In another embodiment of the present invention, the present invention is a method for producing a composition of formula 4a, wherein the following chemical structure [ka] Compound 4 having the formula was prepared in the presence of 2-methyltetrahydrofuran. [ka] When compound B1 having the structure is reacted with the compound, [ka] The method includes forming a composition of formula 4a having the following properties:

[0037] Embodiment 16 In another embodiment of the present invention, the present invention relates to the following chemical structure [ka] A method for obtaining a compound of formula 5M having the following characteristics: a) The following chemical structure [ka] Compound 4 having the formula was prepared in the presence of 2-methyltetrahydrofuran. [ka] When compound B1 having the structure is reacted with the compound, [ka] Forming a composition of formula 4a having the following as a crystal; b) Isolate composition 4a; c) Treat the isolated composition 4a with a base to produce the compound of formula 5M. This includes methods that include [specific methods].

[0038] Embodiment 17 In another embodiment of the present invention, the present invention includes the method of Embodiment 16, wherein the base is Na2HPO4.

[0039] Embodiment 18 In another embodiment of the present invention, the present invention includes the method of Embodiment 16, wherein the base is NaHCO3.

[0040] Embodiment 19 In another embodiment of the present invention, the present invention is a composition comprising formula 4 [ka] Compounds of formula 11 [ka] The composition includes the compound.

[0041] Embodiment 20 In another embodiment of the present invention, the present invention relates to a compound of formula 4 that is of formula 5M [ka] The composition of Embodiment 19 comprises the compound of [the compound].

[0042] Embodiment 21 In another embodiment of the present invention, the present invention relates to a compound of formula 4 that is of formula 5P [ka] The composition of Embodiment 19 comprises the compound of [the compound].

[0043] Embodiment 22 In another embodiment of the present invention, the present invention relates to a compound of formula 11 that is of formula 11a [ka] The present invention comprises one of the compositions from Embodiments 19 to 21, which is a compound of the present invention.

[0044] Embodiment 23 In another embodiment of the present invention, the present invention relates to a compound of formula 11 that is of formula 11b [ka] The present invention comprises one of the compositions from Embodiments 19 to 21, which is a compound of the present invention.

[0045] Embodiment 24 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 19 comprises having [the specified element].

[0046] Embodiment 25 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 19 comprises having [the specified element].

[0047] Embodiment 26 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 19 comprises having [the specified element].

[0048] Embodiment 27 In another embodiment of the present invention, the present invention relates to a composition of formula [ka] The composition of Embodiment 19 comprises having [the specified element].

[0049] Embodiment 28 In another embodiment of the present invention, the present invention includes any one of the compositions of Embodiments 19 to 27, comprising a compound of Formula 4 and a compound of Formula 11 in a 1:1 ratio.

[0050] Embodiment 29 In another embodiment of the present invention, the present invention uses a compound of formula 5M, [ka] The method of Embodiment 16 includes producing a compound having [a specific characteristic].

[0051] Compounds of the Disclosure This specification provides KRAS inhibitors having a structure described in more detail below.

[0052] The compounds disclosed herein include all pharmaceutically acceptable isotope-labeled compounds in which one or more atoms of the disclosed compound are substituted with atoms having the same atomic number but with an atomic mass or mass number different from those commonly 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, for example, 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 125 I is an example. These radiolabeled compounds may be useful for helping to determine or measure the efficacy of a compound by characterizing, for example, the site or mode of action, or the binding affinity to a pharmacologically important site of action. Certain isotope-labeled compounds of this disclosure, for example, compounds incorporating radioisotopes, are useful in studies of drug and / or substrate tissue distribution. Radioisotopes such as tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose in terms of the ease of their incorporation and the ease of detection.

[0053] Deuterium, that is 2 Substitution with heavier isotopes, such as 1H, is preferable in some situations because it can provide greater metabolic stability, for example, certain therapeutic benefits resulting from an increased in vivo half-life or reduced drug requirements.

[0054] 11 C, 18 F, 15 O and 13Substitution with positron-emitting isotopes such as 1N may be useful in positron-emitting topography (PET) studies to investigate substrate-receptor occupancy. The isotope-labeled compound of structure (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described below, using appropriate isotope-labeling reagents instead of previously used unlabeled reagents.

[0055] The isotope-labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and schemes, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0056] 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 conformational isomers (or conformers). The compounds disclosed herein include all stereoisomers as pure individual stereoisomer preparations, as each as a Rich preparation, as a racemic mixture of such stereoisomers, or as individual diastereomers and enantiomers that can be divided according to methods known to those skilled in the art. Furthermore, the compounds disclosed herein include all tautomers of those compounds.

[0057] Some of the compounds disclosed herein may exist as atropisomers, which are conformational isomers that arise when rotation around a single bond in the molecule is hindered or very slowed as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers as pure individual atropisomer preparations, as Richie preparations for each, or as nonspecific mixtures thereof. If the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation and isolation of the isomer species may be possible. For example, the following groups may restrict rotation: [ka]

[0058] The term "monohydrate" refers to a salt of compound 9 to which approximately one water molecule is bonded. Those skilled in the art will understand that the exact number of bonded water molecules can change slightly at any time as temperature, pressure, and other environmental influences change. All slight variations in the number of bonded water molecules are considered to be within the scope of the present invention.

[0059] The term "dihydrate" refers to a salt of compound 9, which is composed of approximately two water molecules. Those skilled in the art will understand that the exact number of water molecules bonded can change slightly at any time as temperature, pressure, and other environmental influences change. All slight variations in the number of water molecules bonded are considered to be within the scope of the present invention.

[0060] The term "cocrystal" refers to a crystalline material containing two or more compounds at ambient temperature (20°C to 25°C, preferably 20°C), where at least two of the compounds are bonded by weak interactions, at least one of the compounds is a cocrystal-forming agent, and the others are compound 5. Weak interactions are defined as interactions that are neither ionic nor covalent, such as hydrogen bonds, van der Waals forces, and π-π interactions.

[0061] The term "amorphous form" or "amorphous" refers to a material that lacks long-range order and does not exhibit a distinct X-ray diffraction peak, i.e., a Bragg diffraction peak. The XRPD pattern of an amorphous material is characterized by one or more amorphous halos. The term "amorphous halo" refers to a nearly bell-shaped maximum in the X-ray powder pattern of an amorphous material.

[0062] The term "substantially pure" refers to the solid form of compound 9 having a purity of approximately 95%, particularly approximately 99.5%, more particularly approximately 99.8%, and even more particularly approximately 99.9%.

[0063] The term "patient" refers to animals such as dogs, cats, cows, horses, sheep, and humans. Certain patients are mammals. The term "patient" includes both males and females.

[0064] Terms such as "treating," "treating," or "treatment" include preventative (e.g., prophylactic) and palliative treatments.

[0065] The term "excipients" refers to pharmaceutically acceptable additives, carriers, diluents, adjuvants, or other components other than the active pharmaceutical ingredient (API), which are typically included for formulation and / or administration to a patient.

[0066] Pharmaceutical composition, dosage, and route of administration Furthermore, provided herein are pharmaceutical compositions comprising the compounds disclosed herein together with pharmaceutically acceptable excipients, such as diluents or carriers. Compounds and pharmaceutical compositions suitable for use in the present invention include those in which the compound can be administered in an effective amount to achieve its intended purpose. The administration of the compounds is described in more detail below.

[0067] Those skilled in the art can determine the appropriate pharmaceutical dosage form depending on the route of administration and the desired dose. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). The dosage form may affect the physical state, stability, in vivo release rate, and in vivo elimination rate of the administered drug. Depending on the route of administration, the appropriate dose may be calculated according to body weight, body surface area, or organ size. Further refinements to the calculations necessary to determine the appropriate therapeutic dose are routinely made by those skilled in the art without excessive experimentation, particularly in light of the dose information and analyses disclosed herein, as well as pharmacokinetic data obtained through animal or human clinical trials.

[0068] The terms "pharmaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that, when administered to animals or humans, do not produce harmful allergic or other adverse reactions. In this specification, "pharmaceutically acceptable" includes any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such excipients for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in a therapeutic composition unless it is incompatible with the therapeutic composition. Auxiliary active ingredients may also be incorporated into the composition. In exemplary embodiments, the formulation includes corn syrup solid, 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 - May contain tryptophan, 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 hydrochloride, vitamin A palmitate, manganese sulfate, riboflavin, pyridoxine hydrochloride, folic acid, β-carotene, potassium iodide, phylloquinone, biotin, sodium selenite, chromium chloride, sodium molybdate, vitamin D3, and cyanocobalamin.

[0069] The compounds may be present in pharmaceutical compositions as pharmaceutically acceptable salts. In this specification, “pharmaceutically acceptable salts” include, for example, base addition salts and acid addition salts.

[0070] pharmaceutically acceptable base addition salts can be produced using metals or amines such as alkalis and alkaline earth metals or organic amines. pharmaceutically acceptable salts of compounds can also be prepared using pharmaceutically acceptable cations. Suitable pharmaceutically 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 ferric. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N,N'-dibenzylethylenediamine, procaine chloride, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.

[0071] Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Examples of suitable acid salts include hydrochloride, formate, acetate, citrate, salicylate, nitrate, and phosphate. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art, and include, for example, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid; organic carboxylic acids, sulfonic acids, sulfoacids, or phosphoacids 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, embonic acid, and ni This includes substances containing chotinic acid or isonicotinic acid; and substances containing 20 alpha amino acids involved in the synthesis of natural proteins, such as glutamic acid or aspartic acid; and also substances containing 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 cyclamate formation), or other acidic organic compounds such as ascorbic acid.

[0072] Pharmaceutical compositions containing the compounds disclosed herein can be manufactured by conventional methods, for example, by conventional mixing, dissolution, granulation, sugar-coated tablet manufacturing, powdering, emulsification, encapsulation, encapsulation, or lyophilization processes. The appropriate dosage form depends on the chosen route of administration.

[0073] For oral administration, suitable compositions can be readily formed by combining the compounds disclosed herein with pharmaceutically acceptable excipients, such as carriers well known in the art. Such excipients and carriers enable the compounds of the present invention to be formed into dosage forms such as tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by patients being treated. Pharmaceutical preparations for oral use can be obtained by adding a solid excipient to the compounds disclosed herein, optionally grinding the resulting mixture, and, if necessary, adding suitable adjuvants to obtain a tablet or coated tablet core, and then processing the granular mixture. Suitable excipients include, for example, fillers and cellulose preparations. Disintegrants may be added as needed. Pharmaceutically acceptable ingredients are well known in various types of formulations and may include, for example, binders (e.g., natural or synthetic polymers), lubricants, surfactants, sweeteners and flavorings, coating materials, preservatives, dyes, thickeners, adjuvants, antimicrobial agents, antioxidants, and carriers for various formulation types.

[0074] When a therapeutically effective dose of the compounds disclosed herein is administered orally, the compositions are typically in the form of solids (e.g., tablets, capsules, pills, powders, or lozenges) or liquid formulations (e.g., aqueous suspensions, solutions, elixirs, or syrups).

[0075] 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%.

[0076] When administered in liquid or suspension form, functional liquids and / or liquid carriers, such as water, petroleum, or oils of animal or plant origin, may be added. The liquid form of the composition may further contain physiological saline, sugar alcohol solutions, dextrose or other sugar solutions, or glycols. When administered in liquid or suspension form, the composition may contain about 0.5 to about 90% by weight of the compounds disclosed herein, preferably about 1 to about 50% of the compounds disclosed herein. In one possible embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. When administered in liquid form, the composition may be supplied as a rapidly dissolving solid formulation for dissolution or suspension immediately before administration.

[0077] When a therapeutically effective dose of the compounds disclosed herein is administered intravenously, cutaneously, or subcutaneously, the composition is in the form of a parenterally acceptable aqueous solution that does not contain pyrogens. Preparing such parenterally acceptable solutions, taking into account pH, isotonicity, stability, etc., is within the scope of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle in addition to the compounds disclosed herein. Such compositions may be prepared for administration as a solution of a free base or a pharmacokinetically acceptable salt in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof, as well as in oil. Under normal storage and use conditions, these preparations may optionally contain preservatives to prevent microbial growth.

[0078] The injectable composition may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions, suspensions, or dispersions. In all embodiments, this form must be sterile and fluid enough to pass easily through an injection needle. It must be stable under manufacturing and storage conditions and resistant to microbial contamination, such as bacteria and fungi, by optionally including preservatives. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. In one possible embodiment, the carrier is non-aqueous or substantially non-aqueous. Adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, maintaining the required particle size of the compound in the dispersion embodiment, and the use of surfactants. Prevention of microbial activity can be provided by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many embodiments, it is preferable to include an isotonic agent, such as sugar or sodium chloride. The extension of absorption of an injectable composition can be achieved by using absorption-delaying agents, such as aluminum monostearate and gelatin, in the composition.

[0079] Sterile injectable solutions are prepared by incorporating the required amount of active compound, along with various other components listed above if necessary, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing the basic dispersion medium and other necessary components listed above. In embodiments of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying, in which the powders of the active ingredients and any additional desired ingredients are obtained from their pre-sterilized filtered solutions.

[0080] Sustained-release or sustained-release formulations can also be prepared to achieve controlled release of the active compound in contact with body fluids within a GI tube, thereby providing a substantially constant and effective plasma concentration of the active compound. For example, release can be controlled by one or more of the following: dissolution, diffusion, and ion exchange. Furthermore, sustained-release approaches can enhance absorption via saturable or restricted pathways within the GI tube. For example, the compound can be embedded for this purpose in a matrix of biodegradable polymers, water-soluble polymers, or mixtures thereof, and optionally in a suitable surfactant. Embedding in this context means incorporating microparticles into a polymer matrix. Controlled-release formulations can also be obtained by encapsulating dispersed microparticles or emulsified microdroplets using well-known dispersion or emulsification coating techniques.

[0081] For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray from a pressurized container or nebulizer using a suitable propellant. In the pressurized aerosol embodiment, the dose unit can be determined by providing a valve for delivering a measured amount. For use in inhalers or injectors, for example, gelatin capsules and cartridges can be formulated containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0082] The compounds disclosed herein can be formulated for parenteral administration by injection (e.g., bolus injection or serial infusion). Injectable formulations can be provided in unit dose form (e.g., ampoules or multi-dose containers) with added preservatives. Compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants.

[0083] Pharmaceutical formulations for parenteral administration contain aqueous solutions of water-soluble compounds. Furthermore, suspensions of compounds can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, suspensions may also contain suitable stabilizers or agents that increase the solubility of the compound and enable the preparation of highly concentrated solutions. Alternatively, the composition may be in powder form for preparation with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.

[0084] The compounds disclosed herein can also be formulated into rectal compositions such as suppositories or retaining enemas (e.g., including conventional suppository bases). In addition to the formulations described above, the compounds can also be formulated as depot formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Accordingly, for example, the compounds can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil), or with an ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0085] In particular, the compounds disclosed herein may be administered orally, orally, or sublingually, in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules, alone or in mixtures with excipients, or in the form of elixirs or suspensions containing flavoring agents or coloring agents. Such liquid preparations may be prepared with pharmaceutically acceptable additives such as suspensions. The compounds may also be administered parenterally, for example, by injection intravenously, intramuscularly, subcutaneously, or into the coronary artery. For parenteral administration, the compounds are most often used in the form of sterile aqueous solutions that may contain other substances, such as salts, or sugar alcohols such as mannitol, or glucose, in order to make the solution isotonic with blood.

[0086] For veterinary use, the compounds disclosed herein are administered as appropriately acceptable formulations in accordance with normal veterinary practice. Veterinarians can easily determine the most appropriate administration plan and route for a particular animal.

[0087] In some embodiments, all components necessary for the treatment of KRAS-related disorders, either used alone or in combination with other agents or therapeutic interventions traditionally used for the treatment of such disorders, can be packaged in a kit. Specifically, the present invention provides a kit for use in a therapeutic intervention for a disorder, comprising a packaged set of agents including the compounds disclosed herein, buffers and other components for preparing the agents into a deliverable form, and / or a device for delivering such agents, and / or any agents used in combination therapy with the compounds disclosed herein, and / or instructions for the treatment of the disorder packaged together with the agents. The instructions may be fixed on printed paper or any tangible medium such as computer-readable magnetic or optical media, or the instructions may refer to a data source on a remote computer, such as a World Wide Web page accessible via the Internet.

[0088] “Therapeutic dose” means an amount that is effective in treating, slowing the progression of, or alleviating the current symptoms of the subject being treated. Determining the effective dose is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, “therapeutic dose” refers to the amount of compound that results in the achievement of the desired effect. For example, in one preferred embodiment, a therapeutic dose 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.

[0089] The amount of compound administered may depend on the subject being treated, their age, health, sex, and weight, the type of concomitant therapy (if any), the severity of the distress, the nature of the desired effect, the method 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 dose can be determined to suit the individual subject without excessive experimentation, as can be understood and determined by those skilled in the art. This usually involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0090] While individual needs vary, determining the optimal range of effective amounts of the compound is within the realm of those skilled in the art. For administration to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical doses of the compounds of the present invention can be about 0.05 mg / kg / day to about 50 mg / kg / day, for example, 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 × 5 kg) to about 5000 mg / day (50 mg / kg × 100 kg). For example, the dosage of the compound ranges from approximately 0.1 mg / kg / day to approximately 50 mg / kg / day, approximately 0.05 mg / kg / day to approximately 10 mg / kg / day, approximately 0.05 mg / kg / day to approximately 5 mg / kg / day, approximately 0.05 mg / kg / day to approximately 3 mg / kg / day, approximately 0.07 mg / kg / day to approximately 3 mg / kg / day, approximately 0.09 mg / kg / day to approximately 3 mg / kg / day, and approximately 0.05 mg / kg / day to approximately 0.1 mg / kg / day. The dosage can be approximately 0.1 mg / kg / day to approximately 1 mg / kg / day, approximately 1 mg / kg / day to approximately 10 mg / kg / day, approximately 1 mg / kg / day to approximately 5 mg / kg / day, approximately 1 mg / kg / day to approximately 3 mg / kg / day, approximately 3 mg / day to approximately 500 mg / day, approximately 5 mg / day to approximately 250 mg / day, approximately 10 mg / day to approximately 100 mg / day, approximately 3 mg / day to approximately 10 mg / day, or approximately 100 mg / day to approximately 250 mg / day. Such dosages may be administered as a single dose or divided into multiple doses.

[0091] How to use KRAS G12C inhibitors This disclosure provides a method for inhibiting RAS-mediated cell signaling, comprising contacting cells with an effective amount of one or more compounds disclosed herein. Inhibition of RAS-mediated signaling can be evaluated and demonstrated by a wide range of methods well known in the art. Non-limiting examples include (a) a decrease in RAS GTPase activity; (b) a decrease in GTP binding affinity or an increase in GDP binding affinity; (c) an increase in K-off of GTP or a decrease in K-off of GDP; (d) a decrease in the levels of downstream signaling molecules of the RAS pathway, such as a decrease in pMEK, pERK, or pAKT levels; 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.

[0092] The disclosure also provides methods of using the compounds or pharmaceutical compositions of the disclosure to treat disease conditions, including but not limited to, those associated with G12C KRAS, HRAS, or NRAS mutations (e.g., cancer).

[0093] In some embodiments, a method for treating cancer is provided, which comprises administering an effective amount of any of the aforementioned pharmaceutical compositions containing the compounds disclosed herein to a subject in need. In some embodiments, the cancer is mediated by a G12C mutation in KRAS, HRAS, or NRAS. In various embodiments, the cancer is pancreatic cancer, colorectal cancer, or lung cancer. In some embodiments, the cancer is gallbladder cancer, thyroid cancer, and bile duct cancer.

[0094] In some embodiments, the Disclosure provides a method for treating a disorder in a subject requiring treatment, comprising determining whether the subject has a G12C mutation in KRAS, HRAS, or NRAS, and if it is determined that the subject has a G12C mutation in KRAS, HRAS, or NRAS, administering to the subject a therapeutically effective dose of at least one compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0095] The disclosed compounds have the potential to inhibit anchorage-independent cell proliferation and therefore tumor metastasis. Accordingly, in another embodiment, the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount of the compounds disclosed herein.

[0096] G12C mutations in KRAS, HRAS, or NRAS have also been identified in hematological malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, certain embodiments relate to the administration of the disclosed compounds (e.g., in the form of pharmaceutical compositions) to patients requiring treatment for hematological malignancies. Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the compounds of this disclosure can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In another embodiment, the compounds are useful for the treatment of lymphoma, e.g., all subtypes of Hodgkin lymphoma or non-Hodgkin lymphoma. In various embodiments, the compounds are useful in treating plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenström macroglobulinemia.

[0097] The determination of 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 characterizing the putative KRAS, HRAS, or NRAS mutant protein. The sequences of wild-type human KRAS, HRAS, or NRAS are well known in the art (e.g., accession number NP203524).

[0098] Methods for detecting mutations in KRAS, HRAS, or NRAS nucleotide sequences are well known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting curve analysis, and microarray analysis. In some embodiments, a sample is evaluated for G12C KRAS, HRAS, or NRAS mutations by real-time PCR. In real-time PCR, a fluorescent probe specific to G12C mutations in KRAS, HRAS, or NRAS is used. If a mutation is present, the probe binds and fluorescence is detected. In some embodiments, G12C mutations in KRAS, HRAS, or NRAS are identified using direct sequencing of a specific region (e.g., exon 2 and / or exon 3) within the KRAS, HRAS, or NRAS gene. This method identifies all possible mutations in the sequenced region.

[0099] Methods for detecting mutations in KRAS, HRAS, or NRAS proteins are well known to those skilled in the art. These methods include, but are not limited to, the detection of KRAS, HRAS, or NRAS variants using mutant protein-specific binders (e.g., antibodies), protein electrophoresis and Western blotting, and direct peptide sequencing.

[0100] Various samples can be used in a method for determining whether a tumor or cancer contains a G12C KRAS, HRAS, or NRAS mutation. In some embodiments, the sample is taken from a subject having 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.

[0101] The disclosure also relates to a method for treating a mammalian hyperproliferative disorder, comprising administering a therapeutically effective dose of a compound disclosed herein or a pharmaceutically acceptable salt thereof to the mammal.In some embodiments, the method is used for acute myeloid leukemia, adolescent cancer, pediatric adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical malformations, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, atypical malformations, germ cell tumor, primary lymphoma, cervical cancer, pediatric cancer, chordoma, cardiac tumor, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, and colon cancer. Colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), germ cell tumor, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, pancreatic islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and mouth cancer Cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, recurrent metastatic cervical squamous cell carcinoma of unknown primary origin, midline cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic 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 lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillary cancer This relates to the treatment of patients suffering from cancers such as tumors, paragangliomas, sinus and nasal cavity cancers, parathyroid cancers, penile cancers, pharyngeal cancers, pleuropulmonary blastomas, primary central nervous system (CNS) lymphomas, prostate cancers, rectal cancers, transitional cell carcinomas, retinoblastomas, rhabdomyosarcomas, salivary gland cancers, skin cancers, gastric (stomach) cancers, small cell lung cancers, small intestine cancers, soft tissue sarcomas, T-cell lymphomas, testicular cancers, pharyngeal cancers, thymomas and thymic carcinomas, thyroid cancers, transitional cell carcinomas of the renal pelvis and ureters, trophoblastic tumors, pediatric abnormal cancers, urethral cancers, uterine sarcomas, vaginal cancers, vulvar cancers, or virus-induced cancers.In some embodiments, the method relates to the treatment of noncancerous hyperproliferative disorders such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate problems (e.g., benign prostatic hyperplasia (BPH)).

[0102] In some embodiments, the treatment method relates to the treatment of lung cancer, and the method comprises administering an effective amount of any of the above compounds (or pharmaceutical compositions containing them) to a subject in need. 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, adenocarcinoma, carcinoid tumors, and undifferentiated carcinomas.

[0103] The Disclosure further provides a method for modulating the activity of G12C mutant KRAS, HRAS, or NRAS proteins by contacting the protein with an effective amount of the compound of the Disclosure. Modulation may involve inhibiting or activating the protein's activity. In some embodiments, the Disclosure provides a method for inhibiting protein activity by contacting a G12C mutant KRAS, HRAS, or NRAS protein with an effective amount of the compound of the Disclosure in solution. In some embodiments, the Disclosure provides a method for 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 Disclosure provides a method for inhibiting the activity of a protein in a subject, including (but not limited to) rodents and mammals (e.g., humans), by administering an effective amount of the compound of the Disclosure to the subject. In some embodiments, the percentage of modification is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0104] In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS in cells by contacting the cells with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS in the cells. In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS in tissues by contacting the tissue with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS in the tissue. In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS inside an organism by contacting the organism with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS inside the organism. In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS within an animal by contacting the animal with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS within the animal. In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS within a mammal by contacting the mammal with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS within the mammal. In some embodiments, the Disclosure provides a method for inhibiting the G12C activity of KRAS, HRAS, or NRAS within a human by contacting the human with a compound of the Disclosure in an amount sufficient to inhibit the G12C activity of KRAS, HRAS, or NRAS within the human. The Disclosure provides a method for treating a disease mediated by the G12C activity of KRAS, HRAS, or NRAS, and a method for treating a subject in need of such treatment.

[0105] Combination therapy The Disclosure also provides methods of combination therapy in which agents known to modulate other pathways or other components of the same pathway, or sets of overlapping target enzymes, are used in combination with the compounds of the Disclosure or pharmaceutically acceptable salts thereof. In one embodiment, such therapy includes, but is not limited to, combinations of one or more compounds of the Disclosure with chemotherapeutic agents, therapeutic antibodies, and radiotherapy to provide a synergistic or additive therapeutic effect.

[0106] Many chemotherapeutic agents are currently well known in the art and can be used in combination with the compounds of this disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Kyprolis® (carfilzomib), Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), Venclexta® (venetoclax), and Adriamycin® (doxorubicin), as well as hosts for chemotherapeutic agents. Non-exclusive examples of chemotherapy drugs include alkylating agents such as thiotepa and cyclophosphamide (Cytoxan®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbocon, metsuredopa and uredopa; ethyleneimines and methylamelamamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethyloromelamamine; nitrogen mustards such as chlorambucil, chlornafadin, chlorocyclophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobembicin, fenestrine, prednimustine, trophosphamide and uracil mustard; and nitrosoureas such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine and ranimustine.Acrasinomycin, Actinomycin, Ausramycin (Anthramycin), Azaserin, Bleomycin, Kakutinomycin, Calicheamycin, Carabicin, Carminomycin, Cardinophilin, Casodex (trademark), Chromomycin, Dactinomycin, Daunorubicin, Detrubicin, 6-Diazo-5-Oxo-L-Norleucine, Doxorubicin, Epirubicin, Esolubicin, Idarubicin, Marcelomycin, Mitomycin, Mycophenolic acid, Nogaramycin, Olibomycin, Peplomycin, Potophyllomycin, Antibiotics such as puromycin, keramycin, rhodorubicin, streptonigrin, streptozocin, tubercidine, ubenimex, dinostatin, and zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, and doxifluridine Pyrimidine analogs such as enocitabine and phloxuridine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal agents such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; acegraton; aldofamide glycoside; aminolevulinic acid; amsacrin; bestrabusil; bisanthren; edatraxate; defofamine; demecolsin; diaziquan; elfomitin; eriptinium acetate; etogluside; gallium nitrate; hi Roxyurea; Lentinan; Ronidamin; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK; Lazoxane; Schizophyllan; Spirogermanium; Tenuazonic acid; Triadiquan; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitractol; Pipobroman; Gacitosine; Arabinoside ("Ara-C"); Cyclophosphamide; Thiotepa;This includes taxanes, such as paclitaxel and docetaxel; retinoic acid; esperamycin; capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the above.

[0107] Appropriate chemotherapy cell conditioners include, for example, anti-estrogens including tamoxifen (Nolvadex®), raloxifene, aromatase inhibitor 4(5)imidazole, 4-hydroxytamoxifen, trioxyfen, keoxyfen, LY117018, onapristone, and toremifene (Fareston); anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; chlorambucil; and This also includes anti-hormone agents that modulate or inhibit the hormonal effects on tumors, such as mucitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs 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 inhibitor RFS 2000; and difluoromethylornithine (DMFO).

[0108] If desired, the compounds or pharmaceutical compositions disclosed herein include Herceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, avagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alfa-lazine, arbocidibe, 3 -Aminopyridine-2-carboxyaldehyde thiosemicarbazone, amonafide, anthracendione, anti-CD22 immunotoxin, antitumor drug, antitumor-forming herb, apadicone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992, bilicodal, brostaricin, bryostatin, butionine sulfoximine, CBV (chemotherapy), kallikrin, cell cycle nonspecific antitumor agent, dichloroacetic acid, discodermolide, erusamitolucin, e Nocitabine, Epothilon, Eribulin, Everolimus, Exatecan, Exislind, Ferginol, Forodesine, Phosfestrol, ICE chemotherapy regimen, IT-101, Imexone, Imiquimod, Indocarbazole, Ilofluben, Lanikidal, Lalotaxel, Lenalidomide, Lucanton, Lulutotecan, Maphosfamide, Mitozolomide, Nafoxidin, Nedaplatin, Olaparib, Ortaxel, PAC-1, Pawpaw, Pixantrone It can be used in combination with commonly prescribed anticancer drugs such as proteasome inhibitors, rebecamycin, reximod, rubitecan, SN-38, salinosporamide A, sapacitabine, stanford V, swinesonin, talaporfin, talikidal, tegafur-uracil, temodal, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacin, uramustine, bajimezan, vinflunin, ZD6126, or zoskidal.

[0109] The present disclosure further relates to a method of combining a compound or pharmaceutical composition provided herein with radiation therapy to inhibit abnormal cell growth in a mammal or to treat a hyperproliferative disorder. Techniques for administering radiation therapy are well known in the art and those techniques can be used in the combination therapies described herein. Administration of the compounds of the present disclosure in this combination therapy can be determined as described herein.

[0110] Radiation therapy can be administered by one or a combination of several methods including, but not limited to, external beam therapy, internal radiation therapy, interstitial irradiation, stereotactic radiosurgery, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially limited radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site. This term is intended to include, but not be limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and Lu radioactive isotopes). Suitable radiation sources for use as the cell conditioner of the present disclosure include both solids and liquids. By way of non-limiting example, the radiation source can be a radioactive nuclide such as I-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solid source, or other radioactive nuclides that emit photons, beta particles, gamma rays, or other therapeutic light rays. The radioactive material can also be a fluid generated from any solution of a radioactive nuclide, e.g., a solution of I-125 or I-131, or the radioactive fluid can be generated using a suitable fluid slurry containing microparticles of a solid radioactive nuclide such as Au-198, Y-90. Further, the radioactive nuclide can be embodied in the form of a gel or radioactive microspheres.

[0111] The compounds or pharmaceutical compositions of the present disclosure can be combined with an amount of one or more substances selected from anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors.

[0112] Anti-angiogenic agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors can be used in combination with the compounds of this disclosure and the pharmaceutical compositions described herein. Examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include arecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are found in International Publication No. 96 / 33172, International Publication No. 96 / 27583, European Patent Application Publication No. 0818442, European Patent Application Publication No. 1004578, International Publication No. 98 / 07697, International Publication No. 98 / 03516, International Publication No. 98 / 34918, International Publication No. 98 / 34915, International Publication No. 98 / 33768, International Publication No. 98 / 30566, European Patent Application Publication No. 0606046, and European Patent Application Publication No. 0931788. These are described in the specifications, International Publication No. 90 / 05719, International Publication No. 99 / 52910, International Publication No. 99 / 52889, International Publication No. 99 / 29667, International Publication No. 1999 / 007675, European Patent Application Publication No. 1786785, European Patent Application Publication No. 1181017, U.S. Patent Application Publication No. 2009 / 0012085, U.S. Patent No. 5863949, U.S. Patent No. 5861510, and European Patent Application Publication No. 0780386, all of which are incorporated herein by reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity to inhibit MMP-1. More preferably, it selectively inhibits MMP-2 and / or AMP-9 compared to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP7, MMP8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in this disclosure are AG-3340, RO32-3555, and RS13-0830.

[0113] Furthermore, this compound is also known as acemannan, acralbicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amiphostin, aminolevulinic acid, amrubicin, amsacrin, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, proxuridine, capecitabine, cermoloukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphonate, DA3030 (Dong-A), daciritumab, and Nileukin difutox, Deslorerin, Dexrazoxane, Dilazep, Docetaxel, Docosanol, Doxelcalciferol, Doxifluridine, Doxorubicin, Bromocriptine, Carmustine, Cytarabine, Fluorouracil, HIT Diclofenac, Interferon Alpha, Daunorubicin, Doxorubicin, Tretinoin, Edelfosine, Edrecolomab, Eflornithine, Emitefur, Epirubicin, Epoetin Beta, Etoposide Phosphate, Exemestane, Exislind, Fadrozol, Filgrastim, Finas Teride, fludarabine phosphate, formestan, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin, gimeracil / oteracil / tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronate, idarubicin, (imiquimod, interferon alpha, interferon alpha, natural type, interferon alpha-2, interferon alpha-2a, interferon alpha-2b, interferon Alpha-N1, Interferon Alpha-n3, Interferon Alphacon-1, Interferon Alpha, Natural type, Interferon Beta, Interferon Beta-1a, Interferon Beta-1b, Interferon Gamma, Natural type Interferon Gamma-1a, Interferon Gamma-1b, Interleukin-1 Beta, Iobenguan, Irinotecan, Ilsogladine, Lanreotide, LC9018 (Yakult), Leflunomide, Lenograstim, Lentinan sulfate, Letrozole, Leukocyte alpha interferon,Leuprorelin, Levamysol + Fluorouracil, Rialozol, Lovaplatin, Ronidamin, Lovastatin, Masoprocol, Melalsoprole, Metoclopramide, Mifepristone, Miltefosine, Millimostim, Mismatch Double-Stranded RNA, Mitoguazone, Mitractol, Mitoxantrone, Morglamostim, Nafarelin, Naloxone + Pentazocine, Naltograstim, Nedaplatin, Niltamide, Noscapine, Novel Erythrocyte Production Stimulating Protein Preparation, NSC631570 Octreotide, Oprelbequin, Osateron, Oxaliplatin Paclitaxel, Pamidronic acid, PegAsparagase, PegInterferon Alpha-2b, Pentosan sodium polysulfate, Pentostatin, Picibanil, Pirarubicin, Rabbit anti-thymocyte polyclonal antibody, Polyethylene glycol interferon Alpha-2a, Porfimer sodium, Raloxifene, Larcitrexed, Rasburiembodiment, Rhenium etidronate Re186, RII retinamide, Rituximab, Romultide, Samarium (153Sm) lexidronam, Salg Ramostim, schizophyllan, sobuzoxane, sonelmin, strontium-89 chloride, suramin, tasonelmin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecoxide, thalidomide, thymalfacin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine-131, trastuzumab, treosulfan, tretinoin, trilostane, trimethrexate, triptorelin, tumor necrosis factor alpha, natural type, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysis vaccine, ba Lurubicin, verteporfin, vinorelbine, VIRULIZIN, dinostatin stimulamer, or zoledronic acid; Abarelix; AE941 (Aeterna), ambamustin, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide, diaziquan, EL532 (Elan), EM800 (Endorecherche), enyluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,Galocitabine, Gastrin 17 immune antigen, HLA-B7 gene therapy drug (Vical), granulocyte-macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM862 (Cytran), interleukin 2, iproxyfen, LDI200 (Milkhaus), religistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and FcMAb (Medarex), idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), Marimast, Menogalil, Mitsumomab, Motexafingadolinium, MX6 (Galderma), Nelarabine, Noratexed, P30 protein, Pegvisomant, Pemetrexed, Porphyromycin, Prinomast, RL0903 (Shire), Rubitecan, Satraplatin, Sodium phenylacetate, Sparfosic acid, SRL172 (SRPharma), SU5416 (SUGEN, now Pfizer.Inc.), TA077 (Tanabe), Tetrathiomolybdate, Talibrasticin, Thrombopoietin, Tin-ethylethiopurine, Tirapazamin, Cancer vaccine (Biomira), Melanoma vaccine (New York University), Melanoma vaccine (Sloan Kettering Institute), Melanoma tumor degeneration vaccine (New York Medical College), Viral melanoma cell lysate vaccine (Royal Newcastle It may be used in combination therapy with other antitumor drugs, such as Valspodar (or other antitumor drugs).

[0114] The compounds of the present invention may be further used in combination with VEGFR inhibitors. In combination therapy, other compounds described in the following patents and patent applications may be used: U.S. Patent No. 6,258,812, U.S. Patent Publication No. 2003 / 0105091, International Publication No. 01 / 37820, U.S. Patent No. 6,235,764, International Publication No. 01 / 32651, U.S. Patent No. 6,630,500, U.S. Patent No. 6,515,004, U.S. Patent No. 6,713,485, U.S. Patent No. 5,521,184, U.S. Patent No. 5,770,599, U.S. Patent No. 5,747,498, International Publication No. 02 / 68406, International Publication No. 02 / 66470 Fret, International Publication No. 02 / 55501, International Publication No. 04 / 05279, International Publication No. 04 / 07481, International Publication No. 04 / 07458, International Publication No. 04 / 09784, International Publication No. 02 / 59110, International Publication No. 99 / 45009, International Publication No. 00 / 59509, International Publication No. 99 / 61422, U.S. Patent No. 5,990,141, International Publication No. 00 / 12089, and International Publication No. 00 / 02871.

[0115] In some embodiments, the combination drug comprises the composition of the present invention in combination with at least one anti-angiogenic drug. The drug includes, but is not limited to, chemical compositions, antibodies, antigen-binding domains, radionuclides, and combinations and conjugates thereof, prepared by synthesis in vitro. The drug may be an agonist, antagonist, allosteric modulator, toxin, or, more generally, it may act to inhibit or stimulate its target (e.g., activation or inhibition of receptors or enzymes) thereby promoting cell death or inhibiting cell proliferation.

[0116] Examples of anti-angiogenic drugs 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 drugs such as AVASTIN® or VEGF-TRAP® (e.g., antibodies or antigen-binding regions that specifically bind to VEGF or soluble VEGF receptors or their ligand-binding regions), anti-VEGF receptor drugs (e.g., antibodies or antigen-binding regions that specifically bind thereto), Vectibix (panitumumab), IRESSA® (gefitinib), TARCEVA® (erlotinib), anti-Ang1 and anti-Ang2 drugs (e.g., antibodies or antigen-binding regions that specifically bind thereto or to their receptors, e.g., Tie2 / Tek), and EGFR inhibitors such as anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto). The pharmaceutical composition of the present invention may also include one or more agents (e.g., antibodies, antigen-binding domains, or soluble receptors) that specifically bind to and inhibit the activity of a growth factor, such as an antagonist of hepatocyte growth factor (HGF, also known as a dispersion factor), and an antibody or antigen-binding domain that specifically binds to the receptor "c-met".

[0117] Other anti-angiogenic drugs 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 domains that specifically bind; or soluble TWEAK receptor antagonists; see 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 Application Publication No. 2002 / 0042368), and anti-eph that specifically bind. These include receptor antibodies and / or anti-ephrin antibodies or antigen-binding regions (U.S. Patent Nos. 5,981,245; Nos. 5,728,813; Nos. 5,969,110; Nos. 6,596,852; Nos. 6,232,447; Nos. 6,057,124 and members of their patent families), and anti-PDGF-BB antagonists (e.g., antibodies or antigen-binding regions that specifically bind) and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands, and PDGFR kinase inhibitors (e.g., antibodies) and antibodies or antigen-binding regions that specifically bind to them).

[0118] Further anti-angiogenic / antinomatous agents include: SD-7784 (Pfizer, USA); Silendide (Merck KGaA, Germany, European Patent No. 770622); Pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, U.S. Patent No. 5712291); Ilomast (Arriva, USA, U.S. Patent No. 5892112); Emaxanib (Pfizer, USA, U.S. Patent No. 5792783); Batalanib (Novartis, Switzerland); 2-Methoxyestradiol (EntreMed, now CASI Pharmaceuticals, USA); TLC ELL-12 (Elan, Ireland); Anecol Acetate Tab (Alcon, USA); Alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); Anti-Vn Mab (Crucell, Netherlands); DAC: Anti-angiogenic drug (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, European Patent No. 970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); Fibrinogen-E Fragment (BioActa, UK); Angiogenesis Inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236, (Pfizer, USA); ABT-567, (Abbott, USA); Metastatin, (EntreMed, USA); Angiogenesis Inhibitor, (Tripep, Sweden); Maspin, (Sosei, Japan); 2-Methoxyestradiol, (Oncology Sciences Corporation, USA); ER-68203-00, (IVAX, USA); Benefin, (Lane Labs, USA);Tz-93 (Tsumura Co., Ltd., Japan); TAN-1120 (Takeda Pharmaceutical Company Limited, Japan); FR-111142 (Fujisawa Pharmaceutical Co., Ltd., Japan, Japanese Patent Publication No. 02-233610); Platelet Factor IV (RepliGen, USA, European Patent No. 407122); Vascular Endothelial Growth Factor Antagonist (Borean, Denmark); Bevacizumab (pINN), (Genentech, USA); Angiogenesis Inhibitor (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (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); CEP 7055, (Cephalon, USA and Sanofi-Synthelabo, France); BC 1, (Genoa Institute of Cancer Research, Italy); Angiogenesis inhibitor, (Alchemia, Australia); VEGF antagonist, (Regeneron, USA); rBPI 21 and BPI-derived anti-angiogenic agents, (XOMA, USA); PI 88, (Progen, Australia); Silenditide (pINN), (Merck KGaA, Germany; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); Cetuximab (INN), (Aventis, France); AVE 8062, (Ajinomoto Co., Inc., Japan); AS 1404, (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin, (Boston Children's Hospital, USA); ATN 161, (Attenuon, USA); Angiostatin, (Boston Children's Hospital, USA); 2-Methoxyestradiol, (Boston Children's Hospital, USA);ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitor, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthrizole, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, now CASI Pharmaceuticals, USA); Troponin I, (Harvard University, USA); SU 6668, (SUGEN, now Pfizer, Inc., USA); OXI 4503, (OXiGENE, USA); o-Guanidine, (Dimensional Pharmaceuticals, USA); Motupolamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); Atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, Eisai Co., Ltd., Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); Vaccine, Angiogenic Drug, (EntreMed, now CASI Pharmaceuticals, USA; Urokinase-type plasminogen activator inhibitor, (Dendreon, USA); Oglufanide (pINN), (Melmotte, USA); HIF-1 alpha inhibitor, (Xenova, UK); CEP 5214, (Cephalon, USA);BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery Company, Limited, Japan); Drug delivery system, intraocular drug, 2-methoxyestradiol, (EntreMed, USA); Anginex, (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510, (Abbott, USA); AAL 993, (Novartis, Switzerland); VEGI, (ProteomTech, USA); Tumor Necrosis Factor-Alpha Inhibitor, (National Institute on Aging, USA); SU 11248, (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YH16, (Yantai Rongchang, China); S-3APG, (Boston Children's Hospital, USA and EntreMed, USA); MAb, KDR, (ImClone Systems, USA); MAb, Alpha 5 Beta 1, (Protein Design, USA); KDR Kinase Inhibitor, (Celltech Group, UK and Johnson & Johnson, USA); GFB 116, (South Florida University, USA and Yale University, USA); CS 706, (Sankyo Co., Ltd., Japan); Combretastatin A4 Prodrug, (Arizona State University, USA; Chondroitinase AC, (IBEX, Canada); BAY RES 2690, (Bayer, Germany);AGM 1470 (Harvard University, USA, Takeda Pharmaceutical Company Limited, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); MAb, Vascular Endothelial Growth Factor (Xenova, UK); Irsoglandin (INN), (Nippon Shinyaku Co., Ltd., Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squalamine (pINN), (Genaera, USA); RPI 4610 (Sirna, USA); Cancer Therapy (Marinova, Australia); Heparanase Inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho Pharmaceutical Co., Ltd., Japan); VEGF receptor modulator (Pharmacopeia, USA); VE-cadherin-2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Vaccine, Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura & Co., Ltd., Japan); Tumustatin (Beth Israel Hospital, USA); Sclerolytic soluble FLT 1 (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).

[0119] Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil®), bafilomycin A1, 5-amino-4 imidazole carboxamidriboside (AICAR), okadaic acid, autophagy-suppressing algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and agents that increase cAMP levels, such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. Furthermore, antisense or siRNAs that inhibit the expression of proteins including (but not limited to) ATG5 (involved in autophagy) may also be used.

[0120] Further pharmaceutically active compounds / agents that can be used in the treatment of cancer and 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 pharmaceutically acceptable salts thereof.

[0121] In certain embodiments, the compositions provided herein are administered together with chemotherapeutic agents. Suitable chemotherapeutic agents include 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 (mitramycin), mitomycin, and enzymes (e.g., enzymes that systemically metabolize L-asparagine and synthesize asparagine itself). L-asparaginase (which eliminates cells that lack the ability to function), antiplatelet agents, antiproliferative / antimitotic alkylating agents such as nitrogen mustard (e.g., mechloretamine, cyclophosphamide and its analogs, melphalan, and chlorambucil), ethyleneimine and methylmelamine (e.g., hexamethylmelamine and thiotepa), and CDK inhibitors (e.g., sericiclib, UCN-01, P1446A-05, PD-0332991, dinacyclib, P27-00, AT-7519, RGB286638, and SCH727965). Antiproliferative / antimitotic antimetabolites such as alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and its analogues, as well as streptozocin), trazene-dacarbadinine (DTIC), folic acid analogues (e.g., methotrexate), pyrimidine analogues (e.g., fluorouracil, phloxuridine, and cytarabine), purine analogues and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine), aromatase inhibitors (e.g., ana (Strozole, exemestane, and letrozole) and platinum-coordinate complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), mTor inhibitors (e.g., temsirolimus, everolimus, ridafololimus, 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-kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and Hormone agonists such as 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., 17AA) G and KOS953), P13K / Akt inhibitors (e.g., Perifosin), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., Enzastaurin), FTIs (e.g., Zanestra®), 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), cFMS These include natural products such as inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists. Other chemotherapeutic agents may include mechloretamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, navelbine, sorafenib, or any analogues or induced variants of the above.

[0122] The compounds of the present invention can also be used in combination with radiotherapy, hormone therapy, surgery, and immunotherapy, which are well known to those skilled in the art.

[0123] In certain embodiments, the pharmaceutical compositions provided herein are administered together with a steroid. Suitable steroids include 21-acetoxypregnenolone, alclomethasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, crocortol, cloprednol, corticosterone, cortisone, cortibazole, deflazacort, desonide, dexoxymethasone, dexamethasone, diflorason, diflucortol, difluprednate, enoxolone, fluazacort, fluchloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, flupredniden acetate, fluprednisolone, and flulane. This includes, but is not limited to, drenolide, fluticasone propionate, formocortal, halcinonide, halobetazole propionate, halomethasone, hydrocortisone, loteprednol etabonate, mazipredone, medrisone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, thixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and / or salts and derivatives thereof. In certain embodiments, the compounds of the present invention can also be used in combination with further pharmaceutically active agents for treating nausea. Examples of medications that can be used to treat nausea include dronabinol; granisetron; metoclopramide; ondansetron; and prochlorperazine; or their pharmaceutically acceptable salts.

[0124] The compounds of the present invention may also be used in combination with further pharmaceutically active compounds that disrupt or inhibit the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway. Other such combinations include PD-1 and PD-L1 antagonists. The compounds or pharmaceutical compositions of the present disclosure may also be used in combination with any 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 immunotherapeutic agents (e.g., monoclonal antibodies, immunomodulatory imides (IMiDs), anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAG1 and anti-OX40 agents, GITR agonists, CAR-T cells and BiTE).

[0125] 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), zaltumumab, nimotuzumab, and matuzumab. Small molecule antagonists of EGFR include gefitinib, erlotinib (Tarceva), and more recently, lapatinib (TykerB). For example, see Yan L, et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, Bio Techniques 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.

[0126] Non-limiting examples of small molecule EGFR inhibitors include any EGFR inhibitors described in the following patent publications, as well as all pharmaceutically acceptable salts and solvates thereof: European Patent Application Publication No. 520722, published December 30, 1992; European Patent Application Publication No. 566226, published October 20, 1993; International Publication No. 96 / 33980, published October 31, 1996; U.S. Patent No. 5,747,498, issued May 5, 1998; and October 3, 1996. International Publication No. 96 / 30347 published on [date]; Specification of European Patent Application Publication No. 787772 published on August 6, 1997; International Publication No. 97 / 30034 published on August 21, 1997; International Publication No. 97 / 30044 published on August 21, 1997; International Publication No. 97 / 38994 published on October 23, 1997; International Publication No. 97 / 49688 published on December 31, 1997; European Patent Application Publication No. 837063 published on April 22, 1998 Specifications; International Publication No. 98 / 02434 published on January 22, 1998; International Publication No. 97 / 38983 published on October 23, 1997; International Publication No. 95 / 19774 published on July 27, 1995; International Publication No. 95 / 19970 published on July 27, 1995; International Publication No. 97 / 13771 published on April 17, 1997; International Publication No. 98 / 02437 published on January 22, 1998; published on January 22, 1998 International Publication No. 98 / 02438; International Publication No. 97 / 32881, published on September 12, 1997; German Patent Application Publication No. 19629652, published on January 29, 1998; International Publication No. 98 / 33798, published on August 6, 1998; International Publication No. 97 / 32880, published on September 12, 1997; International Publication No. 97 / 32880, published on September 12, 1997; European Patent Application Publication No. 682027, published on November 15, 1995;International publication pamphlet No. 97 / 02266, published on January 23, 1997; International publication pamphlet No. 97 / 27199, published on July 31, 1997; International publication pamphlet No. 98 / 07726, published on February 26, 1998; International publication pamphlet No. 97 / 34895, published on September 25, 1997; International publication pamphlet No. 96 / 31510, published on October 10, 1996; International publication pamphlet No. 98 / 14449, published on April 9, 1998; International publication pamphlet No. 98 / 14450, published on April 9, 1998; International publication pamphlet No. 98 / 14451, published on April 9, 1998; International publication pamphlet No. 95 / 09847, published on April 13, 1995 T; International Publication No. 97 / 19065, published on 29 May 1997; International Publication No. 98 / 17662, published on 30 April 1998; U.S. Patent No. 5,789,427, issued on 4 August 1998; U.S. Patent No. 5,650,415, issued on 22 July 1997; U.S. Patent No. 5,656,643, issued on 12 August 1997; International Publication No. 99 / 35146, published on 15 July 1999; International Publication No. 99 / 35132, published on 15 July 1999; International Publication No. 99 / 07701, published on 18 February 1999; and International Publication No. 92 / 20642, published on 26 November 1992. Further non-exclusive examples of small molecule EGFR inhibitors include all EGFR inhibitors listed in Traxler, P., 1998, Exp. Opin. Ther. Patents 8(12):1599-1625.

[0127] Antibody-based EGFR inhibitors include all anti-EGFR antibodies or antibody fragments that can partially or completely block EGFR activation by their natural ligands. Non-exclusive examples of antibody-based EGFR inhibitors are 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. Therefore, EGFR inhibitors may be monoclonal antibodies such as Mab E7.6.3 (Yang, 1999, cited above), or Mab C225 (ATCC accession number HB-8508), or antibodies or antibody fragments having binding specificity thereto.

[0128] KRAS of the present invention G12CThe inhibitor can be used in combination with a MEK inhibitor. Specific MEK inhibitors that can be used in combination with the present invention include PD-325901, trametinib, pimacertib, MEK162 [also known as binimetinib], TAK-733, GDC-0973, and AZD8330. A specific MEK inhibitor that can be used in combination with a KRASG12C inhibitor in the present invention is trametinib (trade name: Mekinist®, marketed by Novartis Pharmaceuticals Corp.). Another specific MEK inhibitor is N-(((2R)-2,3-dihydroxypropyl)oxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide, also known as AMG1009089, 1009089, or PD-325901. Another specific MEK inhibitor that can be used in combination with the present invention is cobimetinib. MEK inhibitors include, but are not limited to, CI-1040, AZD6244, PD318088, PD98059, PD334581, RDEA119, ARRY-142886, and ARRY-438162.

[0129] PI3K inhibitors include woltmannin, 17-hydroxywoltmannin analog, 4-[2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)piperazine-1-yl]methyl]thieno[3,2-d]pyrimidine-4-yl]morpholine (also known as GDC 0941, described in International Publications 09 / 036,082 and 09 / 055,730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo[4,5-c]quinoline-1-yl]phenyl]propionitrile (also known as BEZ235 or NVP-BEZ235, described in International Publication 06 / 122806). (As listed in the fret), (S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (as listed in International Publication No. 2008 / 070740), LY294002(2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, Axon PI103 hydrochloride (available from Medchem), PI103 hydrochloride (3-[4-(4-morpholinylpyrido-[3',2':4,5]fl[3,2-d]pyrimidine-2-yl]phenol hydrochloride, available from Axon Medchem), PIK 75 (N'-[(1E)-(6-bromoimidazo[1,2-a]pyridine-3-yl)methylene]-N,2-dimethyl-5-nitrobenzene sulfon-hydrazide hydrochloride, available from Axon Medchem), PIK90 (N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-nicotinamide, Axon (Available from Medchem), GDC-0941 bismesylate (2-(1H-indazole-4-yl)-6-(4-methanesulfonyl-piperazine-1-ylmethyl)-4-morpholine-4-yl-thieno[3,This includes, but is not limited to, 2-d]pyrimidine bismesylate (available from Axon Medchem), AS-252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidin-2,4-dione (available from Axon Medchem), and TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidine-4-one (available from Axon Medchem), XL-765, and XL-147. Other PI3K inhibitors include demethoxypyridine, perifosin, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TG100-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0130] Examples of AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (inhibits Ak1 and Ak2) (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., International Publication No. 05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li (2004) J Nutr. 134 (12) Examples include, but are not limited to, Suppl), 3493S-3498S; perifosin (e.g., interfering with the membrane localization of Akt; Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13, 787-97); and trisirivine (TCN or API-2 or NCI identifier: NSC154020; Yang et al. (2004) Cancer Res. 64, 4394-9).

[0131] TOR inhibitors include, but are not limited to, AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus, and ATP-competitive TORC1 / TORC2 inhibitors (including PI-103, PP242, PP30, and Torin1). Other TOR inhibitors include FKBP12 enhancers; rapamycin and its derivatives (including: CCI-779 (temsirolimus), RAD001 (everolimus); International Publication No. 9409010) and AP23573; rapamycin and its derivatives disclosed in, for example, International Publication No. 98 / 02441 and International Publication No. 01 / 14387, e.g., AP23573, AP23464, or AP23841; 40-(2-hydroxyethyl) rapamycin Syn, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779), 40-epi-(tetrazolyl)-rapamycin (also known as ABT578), 32-deoxorapamycin, 16-pentinyloxy-32(S)-dihydrorapamycin, and other derivatives disclosed in International Publication No. 05005434); U.S. Patent No. 5,258,389, International Publication No. 94 / 090101 Brochures, 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, This includes derivatives disclosed in International Publication No. 94 / 02136, International Publication No. 95 / 16691, International Publication No. 96 / 41807, International Publication No. 96 / 41807 and U.S. Patent No. 5,256,790; phosphorus-containing rapamycin derivatives (e.g., International Publication No. 05016252); and 4H-1-benzopyran-4-one derivatives (e.g., U.S. Provisional Patent Application No. 60 / 528,340).

[0132] MCl-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the important anti-apoptotic members of the B cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 has been closely associated with tumor progression and resistance to not only traditional chemotherapy but also targeted therapies including BCL-2 inhibitors such as ABT-263.

[0133] KRAS G12C Inhibitors can also be used in combination with SHP2 inhibitors in the present invention. Examples of SHP2 inhibitors that can be used in the combination therapy of the present invention include, but are not limited to, SHP099 and RMC-4550 or RMC-4630 manufactured by Revolutions Medicines of Redwood City, CA.

[0134] Proteasome inhibitors include, but are not limited to, Kyprolis® (carfilzomib), Velcade® (bortezomib), and oprozomib.

[0135] Immunotherapies include, but are not limited to, anti-PD-1 drugs, anti-PDL-1 drugs, anti-CTLA-4 drugs, anti-LAG1 drugs, and anti-OX40 drugs.

[0136] Monoclonal antibodies include, but are not limited to, Darzalex® (daratumumab), Herceptin® (trastuzumab), Avastin® (bevacizumab), Rituxan® (rituximab), Lucentis® (ranibizumab), and Eylea® (aflibercept), etc.

[0137] Immunomodulatory drugs (IMiDs) are a class of immunomodulatory drugs (drugs that regulate the immune response) containing an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0138] Anti-PD-1 inhibitors, including but not limited to antibodies, include, but are not limited to, pembrolizumab (Keytruda®) and nivolumab (Opdivo®). Exemplary anti-PD-1 antibodies and their uses 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 / JP2006 / 309606 (International Publication 2006 / 121168 A1 brochure), each of which is expressly incorporated herein by reference. Contains: Yervoy® (ipilimumab) or tremelimumab (for CTLA-4), galiximab (for B7.1), BMS-936558 (for PD-1), MK-3475 (for PD-1), AMP224 (for B7DC), BMS-936559 (for B7-H1), MPDL3280A (for B7-H1), MEDI-570 (for ICOS), AMG557 (for B7H2), MGA271 (for B7H3), IMP321 (for LAG-3), BMS-663513 (for CD137), PF-05082566 (for CD137), CDX-1127 (for CD27), anti-OX40 (Providence Health Services), huMAbOX40L (to OX40L), atacicept (to TACI), CP-870893 (to CD40), lucatumumab (to CD40), dacetuzumab (to CD40), muromonab-CD3 (to CD3), ipilimumab (to CTLA-4). Immunotherapy also includes genetically modified T cells (e.g., CAR-T cells) and bispecific antibodies (e.g., BiTE).

[0139] GITR agonists include GITR fusion proteins as described in U.S. Patent No. 6,111,090 box.c, European Patent No. 090505B1, U.S. Patent No. 8,586,023, International Publication No. 2010 / 003118 and International Publication No. 2011 / 090754, or, for example, U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. 1866339, International Publication No. 2011 / 028683 and International Publication No. 2013 / 039954. This includes, but is not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the anti-GITR antibodies described in International Publication No. 2005 / 007190, International Publication No. 2007 / 133822, International Publication No. 2005 / 055808, International Publication No. 99 / 40196, International Publication No. 2001 / 03720, International Publication No. 99 / 20758, International Publication No. 2006 / 083289, International Publication No. 2005 / 115451, U.S. Patent No. 7,618,632, and International Publication No. 2011 / 051726.

[0140] The compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Therefore, in some embodiments, one or more of the compounds disclosed herein will be administered concurrently with the other agents described above. When used in combination therapy, the compounds described herein are administered concurrently or separately with a second agent. This concurrent administration may include concurrent administration of two agents in the same dosage form, concurrent administration of different dosage forms, and separate administrations. That is, both the compounds described herein and the agents described above can be combined into the same dosage form and administered concurrently. Alternatively, both the compounds disclosed herein and the agents described above can be administered concurrently, where both agents are in separate dosage forms. In another alternative, the compounds disclosed may be administered immediately before or after any of the agents described above. In some embodiments of the separate administration protocol, the compounds disclosed and any of the agents described above are administered with a gap of several minutes, several hours, or several days between them.

[0141] Since one aspect of the present invention is intended for the treatment of a disease / condition by a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions into a kit form. The kit comprises two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided foil packet. Further examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for the use of the separate components. The kit form is particularly advantageous when the separate components are administered in different forms of dosing (e.g., orally and parenterally), at different dosing intervals, or when the prescribing healthcare professional desires to set the dosages of the individual components of the combination.

[0142] All patents and other publications listed herein are incorporated herein by reference.

[0143] The following examples illustrate specific embodiments of the present invention. These examples are representative and do not limit the scope of the claims in any way. [Examples]

[0144] The following intermediate compounds of 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidine-2(1H)-one are representative examples of the present invention and should not be construed as limiting the scope of the present invention.

[0145] The synthesis of compound 9 and related intermediates is described in a U.S. provisional patent application filed on May 22, 2017. 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidine-2(1H)-one was prepared by the following method, which involves isolating the final product isomer by chiral chromatography. [ka]

[0146] Step 1: 2,6-Dichloro-5-fluoronicotinamide (Intermediate S). To a mixture of 2,6-dichloro-5-fluoronicotinic acid (4.0 g, 19.1 mmol, AstaTech Inc, Bristol, PA) in dichloromethane (48 mL), oxalyl chloride (2 M solution in DCM, 11.9 mL, 23.8 mmol), followed by a catalytic amount of DMF (0.05 mL), was added. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in 1,4-dioxane (48 mL) and cooled to 0°C. Ammonium hydroxide solution (28.0-30% NH3 base, 3.6 mL, 28.6 mmol) was slowly added by syringe. The resulting mixture was stirred at 0°C for 30 minutes and then concentrated. The residue was diluted with a 1:1 mixture of toluene / heptane, stirred for 5 minutes, and then filtered. The filtered solid was discarded, and the remaining mother liquor was partially concentrated to half its volume and filtered. The filtered solid was washed with heptane and dried overnight in a vacuum oven (45°C) to obtain 2,6-dichloro-5-fluoronicotinamide. 1 H NMR(400MHz,DMSO-d6)δ ppm 8.23(d,J=7.9Hz,1H)8.09(br s,1H)7.93(br s,1H).m / z(ESI,+ve ion):210.9(M+H).

[0147] Step 2: 2,6-Dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide. Oxalyl chloride (2M solution in DCM, 14.4 mL, 28.8 mmol) was slowly added by syringe to an ice-cold slurry of 2,6-dichloro-5-fluoronicotinamide (intermediate S, 5.0 g, 23.9 mmol) in THF (20 mL). The resulting mixture was heated at 75°C for 1 hour, after which heating was stopped and the reaction product was concentrated to half its volume. After cooling to 0°C, THF (20 mL) was added, and then a solution of 2-isopropyl-4-methylpyridine-3-amine (intermediate R, 3.59 g, 23.92 mmol) in THF (10 mL) was added dropwise by cannula. The resulting mixture was stirred at 0°C for 1 hour, then quenched with a 1:1 mixture of brine and saturated ammonium chloride solution. The mixture was extracted with dimethylammonium chloride (3×), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated to obtain 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide. This substance was used in the next step without further purification. m / z(ESI, +ve ions): 385.1(M+H)+.

[0148] Step 3: 7-Chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. KHMDS (1M THF solution, 50.2mL, 50.2 mmol) was slowly added by syringe to an ice-cold THF (40mL) solution of 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (9.2g, 24.0 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 40 minutes. The reaction product was quenched with saturated ammonium chloride aqueous solution and extracted with ELISA (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% 3:1 siRNA-EtOH / heptane) to obtain 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. 1 H NMR(400MHz,DMSO-d6)δ ppm 12.27(br s,1H),8.48-8.55(m,2H),7.29(d,J=4.8Hz,1H),2.87(quintet,J=6.6Hz,1H),1.99-2.06(m,3H),1.09(d,J=6.6Hz,3H),1.01(d,J=6.6Hz,3H).19F NMR(376MHz,DMSO-d6)δ:-126.90(s,1 F).m / z(ESI,+ve ion):349.1(M+H)+.

[0149] Step 4: 4,7-Dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one. To a solution of 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4.7 g, 13.5 mmol) and DIPEA (3.5 mL, 20.2 mmol) in acetonitrile (20 mL), phosphorus oxychloride (1.63 mL, 17.5 mmol) was added dropwise from a syringe. The resulting mixture was heated at 80°C for 1 hour, then cooled to room temperature and concentrated to obtain 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one. This substance was used in the next step without further purification. m / z(ESI, +ve ion): 367.1(M+H)+.

[0150] Step 5: (S)-tert-butyl4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate. To a 20 mL ice-cold acetonitrile solution of 4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2(1H)-one (13.5 mmol), DIPEA (7.1 mL, 40.3 mmol), followed by (S)-4-N-Boc-2-methylpiperazine (3.23 g, 16.1 mmol, Combi-Blocks, Inc., San Diego, CA, USA) was added. The resulting mixture was warmed to room temperature, stirred for 1 hour, and then diluted with cold saturated sodium bicarbonate aqueous solution (200 mL) and toluene (300 mL). The mixture was stirred for a further 5 minutes, the layers were separated, and the aqueous layer was extracted with further toluene (1×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-50% toluene / heptane) to obtain (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate. m / z (ESI, +ve ion): 531.2(M+H)+.

[0151] Step 6: (3S)-tert-butyl4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate. A mixture of (S)-tert-butyl 4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate (4.3 g, 8.1 mmol), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (intermediate Q, 2.9 g, 10.5 mmol), potassium acetate (3.2 g, 32.4 mmol), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (661 mg, 0.81 mmol) in 1,4-dioxane (80 mL) was degassed with nitrogen for 1 minute. Deoxygenated water (14 mL) was added, and the resulting mixture was heated at 90°C for 1 hour. The reaction mixture was cooled to room temperature, quenched with a semi-saturated sodium bicarbonate aqueous solution, and extracted with ELISA (2×) and DCM (1×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-60% 3:1 ELISA-EtOH / heptane) to obtain (3S)-tert-butyl4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate. 1H NMR(400MHz,DMSO-d6)δ ppm 10.19(br s,1H),8.38(d,J=5.0Hz,1H),8.26(dd,J=12.5,9.2Hz,1H),7.23-7.28(m,1H),7.18(d,J=5.0Hz,1H),6.72(d,J=8.0Hz,1H),6.68(t,J=8.9Hz,1H),4.77-4.98(m,1H),4.24(br t,J=14.2Hz,1H),3.93-4.08(m,1H),3.84(br d,J=12.9Hz,1H),3.52-3.75(m,1H),3.07-3.28(m,1H),2.62-2.74(m,1H),1.86-1.93(m,3H),1.43-1.48(m,9H),1.35(dd,J=10.8,6.8Hz,3H),1.26-1.32(m,1H),1.07(dd,J=6.6,1.7Hz,3H),0.93(dd,J=6.6,2.1Hz,3H).19F NMR(376MHz,DMSO-d6)δ:-115.65(s,1 F),-128.62(s,1 F).m / z(ESI,+ve イオン):607.3(M+H).

[0152] Step 7: 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidine-2(1H)-one. Trifluoroacetate (25 mL, 324 mmol) was added to a solution of (3S)-tert-butyl4-(6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(2-isopropyl-4-methylpyridine-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl)-3-methylpiperazine-1-carboxylate (6.3 g, 10.4 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in DCM (30 mL), cooled to 0°C, and sequentially treated with DIPEA (7.3 mL, 41.7 mmol) and acryloyl chloride (0.849 mL, 10.4 mmol) solutions in DCM (3 mL; added dropwise by syringe). The reaction mixture was stirred at 0°C for 10 minutes, then quenched with a semi-saturated sodium bicarbonate aqueous solution and extracted with DCM (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent: 0-100% 3:1 HCl-EtOH / heptane) to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2-propenoyl)-1-piperazinyl)pyrido[2,3-d]pyrimidine-2(1H)-one. 1H NMR(400MHz,DMSO-d6)δ ppm 10.20(s,1H),8.39(d,J=4.8Hz,1H),8.24-8.34(m,1H),7.23-7.32(m,1H),7.19(d,J=5.0H z,1H),6.87(td,J=16.3,11.0Hz,1H),6.74(d,J=8.6Hz,1H),6.69(t,J=8.6Hz,1H),6.21(br d,J=16.2Hz,1H),5.74-5.80(m,1H),4.91(br s,1H),4.23-4.45(m,2H),3.97-4.21(m,1H),3.44-3.79(m,2H),3.11-3.31(m,1H),2.67-2. 77(m,1H),1.91(s,3H),1.35(d,J=6.8Hz,3H),1.08(d,J=6.6Hz,3H),0.94(d,J=6.8Hz,3H). 19 F NMR(376MHz,DMSO-d6)δ ppm -115.64(s,1 F),-128.63(s,1 F).m / z(ESI,+ve ion):561.2(M+H) + .

[0153] The present invention comprises the following steps, wherein the separation of rac-dione in steps 4 and 5 facilitates the successful separation of the atrop isomer. [ka]

[0154] Process description Process 1 [ka]

[0155] [Table 4]

[0156] To a solution of 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (compound 1) (25 kg; 119.1 mol) in dichloromethane (167 kg) and DMF (592 g), oxalyl chloride (18.9 kg; 148.9 mol) was added while maintaining the internal temperature at 15-20°C. Additional dichloromethane (33 kg) was added as a rinse, and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled, and then quenched with ammonium hydroxide (40.2 L; 595.5 mol) while maintaining the internal temperature at 0 ± 10°C. The resulting slurry was stirred for 90 minutes, and the product was recovered by filtration. The filtered solid was washed with DI water (3 × 87 L) and dried to obtain 2,6-dichloro-5-fluoronicotinamide (compound 2).

[0157] Process 2 [ka]

[0158] [Table 5]

[0159] In reactor A, oxalyl chloride (11.9 kg; 93.8 mol) was added to a solution of 2,6-dichloro-5-fluoronicotinamide (compound 2) (16.27 kg; 77.8 mol) in dichloromethane (359.5 kg) while maintaining a temperature of ≤25°C for 75 minutes. The resulting solution was then heated to 40°C ± 3°C and aged for 3 hours. Using vacuum, the solution was distilled to remove dichloromethane until the solution was below the stirrer. Then, dichloromethane (300 kg) was added, and the mixture was cooled to 0 ± 5°C. In a clean, dry reactor (reactor B), 2-isopropyl-4-methylpyridine-3-amine (ANILINE) (12.9 kg; 85.9 mol), followed by dichloromethane (102.6 kg), was added. The ANILINE solution was azeotropically dried by vacuum distillation, replacing it with further dichloromethane until the solution was dry (limit ≤0.05%) by KF analysis, while maintaining the internal temperature between 20 and 25°C. The volume of the solution was adjusted to approximately 23 L using dichloromethane. The dried ANILINE solution was then added to reactor A (while maintaining an internal temperature of 0 ± 5°C). The mixture was then heated to 23°C and aged for 1 hour. The solution was filtered into a clean reactor to obtain 2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridine-3-yl)carbamoyl)nicotinamide (compound 3) as a solution in DCM, which was used directly in the next step.

[0160] Process 3 [ka]

[0161] [Table 6]

[0162] While maintaining an internal temperature of 20-25°C, a dichloromethane solution of 2,6-dichloro-5-fluoro-N-{[4-methyl-2-(propan-2-yl)pyridine-3-yl]carbamoyl}pyridine-3-carboxamide (UREA (compound 3)) (15 kg; 38.9 mol) was converted to 2-MeTHF by vacuum distillation. The reactor volume was adjusted to 40 L, and then an additional 2-MeTHF (105.4 kg) was added. While maintaining a temperature of 5-10°C, sodium t-butoxide (9.4 kg; 97.8 mol) was added. The contents were warmed to 23°C and stirred for 3 hours. Then, the contents were cooled to 0-5°C, and ammonium chloride (23.0 kg; 430 mol) was added as a solution in 60 L of DI water. The mixture was warmed to 20°C, DI water (15 L) was added, and aging was carried out for a further 30 minutes. Stirring was stopped and the layers were separated. The aqueous layer was removed, and DI water (81.7 L) was added to the organic layer. A mixture of concentrated HCl (1.5 kg) and water (9 L) was prepared and then slowly added to the reactor until the pH was measured to be 4-5. The layers were separated, and the aqueous layer was back-extracted using 2-MeTHF (42.2 kg). The two organic layers were combined and washed with 10% citric acid solution (75 kg), followed by a mixture of water (81.7 L) and saturated NaCl (19.8 kg). The organic layers were then washed with saturated sodium bicarbonate (75 kg) to achieve the target pH of the aqueous solution ≥ 7.0 (washing was repeated if necessary). The organic layers were washed again with brine (54.7 kg) and then dried over magnesium sulfate (5 kg). The mixture was filtered to remove magnesium sulfate, and the filter bed was rinsed with 2-MeTHF (49.2 kg). The combined filtrate and washings were vacuum distilled to a volume of 40 L. The concentrated solution was heated to 55°C, and heptane (10-12 kg) was slowly added until the cloud point was reached. The solution was cooled to 23°C over 2 hours, and then heptane (27.3 kg) was added over 2 hours. The product slurry was aged at 20-25°C for 3 hours, then filtered and washed with a mixture of 2-MeTHF (2.8 kg) and heptane (9 kg). The product was dried using nitrogen and vacuum to obtain the solid 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridine-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (rac-DIONE (compound 4)).

[0163] Process 4 [ka]

[0164] [Table 7]

[0165] Under a nitrogen atmosphere, a stirred suspension of compound 4 (1.0 equivalent) in 2-methylterahydrofuran (7.0 L / kg) was added to a container along with (+)-2,3-dibenzoyl-D-tartaric acid (2.0 equivalents). Although 2-MeTHF is chiral, it is used as a racemic mixture. Different enantiomers of 2-MeTHF are randomly incorporated into the cocrystal. The resulting suspension was heated to 75°C and aged at 75°C until complete dissolution was observed (≤30 minutes). The resulting solution was polish-filtered into a second container at 75°C. To the polish-filtered solution, n-heptane (2.0 L / kg) was added at a rate that maintained the internal temperature above 65°C. The solution was then cooled to 60°C, crystal seeds (0.01 kg / kg) were added, and the mixture was aged for 30 minutes. The resulting suspension was cooled to 20°C over 4 hours, and then sampled for chiral purity analysis by HPLC. n-heptane (3.0 L / kg) was added to the suspension, and it was then aged under a nitrogen atmosphere at 20°C for 4 hours. The suspension was filtered, and the isolated solid was washed twice with (2:1) n-heptane:2-methyltetrahydrofuran (3.0 L / kg). This substance was dried under nitrogen and vacuum to obtain the M-dione:DBTA:Me-THF complex (compound 4a).

[0166] Process 5 [ka]

[0167] [Table 8]

[0168] In container A, a suspension of disodium hydrogen phosphate (21.1 kg, 2.0 equivalents) in DI water (296.8 L, 6.3 L / kg) was stirred until dissolution was observed (≥30 minutes). In container B, a suspension of M-dione:DBTA:Me-THF complex (composition 4a) [46.9 kg (corrected for M-dione to 25.9 kg, 1.0 equivalent)] in methyl tert-butyl ether (517.8 L, 11.0 L / kg) was stirred for 15-30 minutes. The solution obtained from container A was added to container B, and the mixture was then stirred for more than 3 hours. Stirring was stopped, and the two-phase mixture was left to stand for more than 30 minutes for separation. The lower aqueous phase was removed, and then back-extracted with methyl tert-butyl ether (77.7 L, 1.7 L / kg). The organic phases were combined in container B and dried with magnesium sulfate (24.8 kg, 0.529 kg / kg). The suspension obtained from container B was stirred for over 3 hours, and then filtered into container C. A methyl tert-butyl ether (46.9 L, 1.0 L / kg) rinse solution was added to container B, and then filtered into container C. The contents of container C were cooled to 10°C, and then distilled under vacuum while slowly heating to 35°C. Distillation was continued until 320-350 kg (6.8-7.5 kg / kg) of methyl tert-butyl ether was recovered. After cooling the contents of container C to 20°C, n-heptane (278.7 L, 5.9 L / kg) was added over 1 hour, and then vacuum distillation was carried out while slowly heating to 35°C. Distillation was continued until 190-200 kg (4.1-4.3 kg / kg) of a mixture of methyl tert-butyl ether and n-heptane was recovered. After cooling the contents of container C to 20°C, a second dose of n-heptane (278.7 L, 5.9 L / kg) was added over 1 hour, and then vacuum distillation was carried out while slowly heating to 35°C. Distillation was continued until 190-200 kg (4.1-4.3 kg / kg) of the methyl tert-butyl ether and n-heptane mixture was recovered. After cooling the contents of container C to 20°C, a third dose of n-heptane (195.9 L, 4.2 L / kg) was added over 1 hour, and then a sample was taken for solvent composition analysis by GC. The suspension in container C was stirred for more than 1 hour. The suspension was filtered and then washed with n-heptane (68.6 L, 1.5 L / kg) rinse solution from container C.The isolated solid was dried at 50°C, and the sample was submitted for storage suitability. Compound 5M of 7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-DIONE) was obtained.

[0169] In the first-generation process highlighted above, scaling was feasible with 200+ kg of rac-dione starting material (compound 5). In this process, adding a thermodynamically stable rac-dione crystalline form (which exhibits low solubility) would lead to batch failure. Based on our subsequent research, we found that increasing the DBTA equivalent and lowering the seed addition temperature by adjusting the heptane input schedule improved the robustness of the process. The improved method is resistant to the presence of thermodynamically stable rac-dione crystalline forms and facilitates successful atropisomer separation. Subsequent batches will incorporate the improved process for large-scale production.

[0170] Process 6 [ka]

[0171] [Table 9]

[0172] 7-Chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (M-DIONE) (3.7 kg; 9.8 mol) was combined with 10.5 kg of toluene in reactor (A) and distilled to remove water while maintaining the set point at 45°C until it became oily. Toluene (21 kg) was added to the residue and the mixture was stirred at 40-45°C for 30 minutes. The contents were cooled to 22°C, and then phosphoryl chloride (1.8 kg; 11.7 mol) was added. After cooling the mixture to 0-5°C, N,N-diisopropylethylamine (2.5 kg; 19.34 mol) was added while maintaining the temperature below 5°C. The solution was aged at 22°C for 3 hours. In a separate reactor (B), (s)-1-boc-3-methylpiperazine (2.21 kg; 10.8 mol) and N,N-diisopropylethylamine (1.26 kg; 9.75 mol) were combined in toluene (6 kg) and added to reactor (A) while maintaining a temperature <25°C. The reaction mixture was aged at 22°C for 15 minutes, and then quenched with sodium bicarbonate (973 g) in water (12.9 L) while maintaining a temperature <25°C. The mixture was stirred for 30 minutes, and then DCM (36.8 kg) was added while continuing to stir for 1 hour. The layers could be separated, and the lower organic layer was discharged into reactor (C). The aqueous layer in reactor (A) was back-extracted using DCM (18.4 kg), and the combined organic layer was washed with a saline solution (6.0 kg NaCl; 16.5 kg DI water). The organic layer was distilled under atmospheric pressure while maintaining an internal temperature of 45-55°C. The DCM was replaced during distillation to azeotropically dry the solution. After distillation, the solution volume was adjusted to 19 L using DCM. The solution was cooled to 30°C and filtered. Ethyl acetate (8.5 kg) was added to the filtrate, and then distillation was carried out under atmospheric pressure until 11-13 kg was recovered in the receiver. 30 g of the true product seed was added to the solution, and it was aged at 25-30°C for 1 hour. Then, under atmospheric pressure and an internal temperature of 45-55°C, further distillation was carried out until 8.2 kg of distillate was recovered. The slurry was cooled to 22°C, aged overnight, and then further cooled to 0-5°C. The product was recovered by filtration and washed twice with ethyl acetate (4.2 kg each).The cake was dried under nitrogen and vacuum to obtain tert-butyl(3S)-4-{7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl}-3-methylpiperazine-1-carboxylate (compound 6, PIPAZOLINE).

[0173] Process 7 [ka]

[0174] [Table 10]

[0175] Degassed dioxane (74.2 kg), tert-butyl(3S)-4-{7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl}-3-methylpiperazine-1-carboxylate (compound 6, pipezoline) (24.0 kg, 45.2 mol), potassium acetate (22.2 kg, 45.2 mol), and (dppf)PdCl2 (0.74 kg, 1.01 mol) were added to the reactor. The reactor was inactivated with nitrogen gas. Nitrogen gas was injected into the solution until the oxygen content was <500 mg / L. The reaction mixture was heated to 87.5°C. A solution of potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (12.6 kg, 54.3 mol) with an oxygen content of <500 mg / L in degassed dioxane (49.4 kg) and degassed water (14.4 kg) was transferred to the reaction mixture while maintaining an internal temperature of 82.5°C ± 7.5°C. The reaction mixture was adjusted to 87.5°C ± 1.5°C and stirred for 75 minutes ± 15 minutes. 1.0 M EDTA solution (47.3 kg), followed by water (40.1 kg), was added to the reactor while maintaining an internal temperature of 85°C ± 5°C. The reaction mixture was cooled to 20°C ± 3°C over >2 hours and stirred for >16 hours. The reaction mixture was filtered, and the crude solid was rinsed with water (3 × 120 kg). The solid was rinsed with a mixture of heptane (28.8 kg) and 2-propanol (33.1 kg), and then dried at <50°C for >10 hours. The crude solid and dichloromethane (240 kg) were added to a clean reactor. The contents were stirred at 20°C ± 5°C for >30 minutes. Si-thiol (144 kg) and dichloromethane (14.9 kg) were added to the reactor. The reaction mixture was stirred at 20°C ± 5°C for 18 hours. The reaction mixture was filtered and rinsed with dichloromethane (84 kg). The solution was distilled and the solvent was replaced with 2-propanol. The reaction mixture was heated to 60°C ± 3°C, and heptane (108 kg) was added while maintaining the reaction temperature at 60°C ± 3°C. The reaction mixture was stirred for 45 minutes, then cooled, and stirred at 20°C ± 5°C for 2.5 hours. The reaction mixture was filtered and rinsed with 50% v / v heptane / 2-propanol (61.9 kg).The isolated solid was dried at <50°C for 12 hours to obtain tert-butyl(3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl}-3-methylpiperazine-1-carboxylate (compound 7, BIARYL).

[0176] Process 8 [ka]

[0177] [Table 11]

[0178] To the reactor, tert-butyl(3S)-4-{6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-4-yl}-3-methylpiperazine-1-carboxylate (compound 7, BIARYL) (2.75 kg, 5.27 mol), DCM (13.7 L), and TFA (5.67 kg, 49.7 mol) were added. The reaction mixture was stirred at 20±5°C for 8 to 16 hours. To the second reactor, potassium carbonate (11.24 kg), water (54.8 L), and methanol (13.7 L) were added to produce a homogeneous solution. The reaction mixture was added to the potassium carbonate solution over 2 hours. The mixture was stirred for a further 12 hours at 20±5°C. The obtained slurry was filtered and rinsed with water (2 × 27.5 L). The wet cake was dried for 24 hours to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]pyrido[2,3-d]pyrimidine-2(1H)-one (compound 8, DESBOC).

[0179] Process 9 [ka]

[0180] [Table 12]

[0181] 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-4-[(2S)-2-methylpiperazin-1-yl]-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]pyrido[2,3-d]pyrimidine-2(1H)-one (compound 8, DESBOC) (156.25 g) was mixed with N-methylpyrrolidinone (625 mL) and stirred at ambient temperature. Acryloyl chloride (36.29 g; 401.0 mmol) was added to the resulting solution while maintaining an internal temperature of <30°C. The contents were stirred at 25°C for 2 hours. In a separate reactor, a solution of disodium phosphate (175.1 g; 1234 mmol) in DI aqueous solution (3.1 L) was prepared. The crude product solution was then transferred to the reactor containing the disodium phosphate solution at 25°C over >2 hours. During the addition process, the slurry was heated to 45°C, and after complete addition, it was aged at the same temperature for 2 hours. The mixture was cooled to 25°C and aged for 4 hours, after which the solid was recovered by vacuum filtration. The solid was washed twice with water (1.5 L each), and the product was dried under nitrogen and vacuum to obtain the product 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidine-2(1H)-one (crude compound 9). 4

[0182] Step 10 [ka]

[0183] [Table 13]

[0184] 6-Fluoro-7-(2-Fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidine-2(1H)-one (crude compound 9) (142.33 g; 253.9 mmol) was mixed with ethanol (996 mL) and water (270 mL). Acetic acid (21.8 ml; 380.8 mmol) was added, and the mixture was heated to 75°C to produce a solution, which was then filtered into a clean reactor. The solution was cooled to 45°C, and then water (1067 mL) was added while maintaining the internal temperature >40°C. The genuine compound 9 species was added to the solution, and the resulting mixture was aged for 30 minutes. Subsequently, water (1138 mL) was added over 2 hours. The mixture was cooled to 25°C and aged for 8 hours. The solid was then recovered by vacuum filtration and washed with a mixture of ethanol (355.8 mL) and water (711.6 mL). The solid was dried using vacuum and nitrogen to obtain 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-(1M)-1-[4-methyl-2-(propan-2-yl)pyridine-3-yl]-4-[(2S)-2-methyl-4-(prop-2-enoyl)piperazin-1-yl]pyrido[2,3-d]pyrimidine-2(1H)-one (compound 9).

[0185] Process A1: Reaction Scheme and Input Table [ka]

[0186] [Table 14]

[0187] THF (6 vol) and diisopropylamine (1.4 equivalents) were added to reactor A. The resulting solution was cooled to -70°C, and n-BuLi (2.5 M in hexane, 1.5 equivalents) was slowly added. After the addition was complete, a solution of 3-fluoroanisole (1.0 equivalent) in THF (6 vol) was slowly added, and the mixture was held at -70°C for 5 minutes. B(EtO)3 (2.0 equivalents) was slowly added, and the mixture was held at -70°C for 10 minutes. The reaction mixture was quenched with 2N HCl. The quenched reaction mixture was extracted with MTBE (3 × 4 vol). The combined organic phase was concentrated to a total volume of 1.5 to 3. Heptane (7 to 9 vol) was added dropwise, and the mixture was cooled to 0 to 10°C and stirred for 3 hours. The mixture was filtered and rinsed with heptane (1.5 vol). The solid was dried under nitrogen at <30°C to obtain (2-fluoro-6-methoxyphenyl)boronic acid.

[0188] Process A2: Reaction Scheme and Input Table [ka]

[0189] [Table 15]

[0190] Dichloromethane (4 vols) and 2-fluoro-6-methoxy-4-methylphenylboronic acid (1 equivalent) were added to reactor A. The reaction mixture was cooled to -30°C and 1.5BBr3 (1.5 equivalents) was added dropwise. Once the addition was complete, the mixture was heated to 25°C and stirred for 2 hours. The reaction mixture was quenched in ice-cold (0-5°C) water (10 vols). MTBE (10 vols) was added, and the mixture was heated to 25°C and stirred for 1-2 hours, or until all solids were dissolved. The aqueous phase was separated and extracted with MTBE (3 vols). The combined organic extract was washed with water (3 vols) and then concentrated to a total volume of 1 vol. Heptane (10 vols) was added to the mixture and stirred for 2 hours. The resulting product was isolated by filtration and dried at <30°C to obtain (2-fluoro-6-hydroxyphenyl)boronic acid.

[0191] Process A3: Reaction Scheme and Input Table [ka]

[0192] [Table 16]

[0193] Process A3 In reactor A, potassium fluoride (21.0 kg; 20.87 mol) was added to water (28 L), and the contents were stirred for 30 minutes. In another reactor (reactor B), (2-fluoro-6-hydroxyphenyl)boronic acid (14.00 kg, 89.79 mol), followed by acetonitrile (206.1 kg) and citric acid (30.94 kg; 147.26 mol) were added at 25°C. The contents of reactor A were added to reactor B at 25°C, and the mixture was stirred at that temperature for 10 hours. The reaction mixture was filtered through a Celite bed (7.0 kg) and rinsed with acetonitrile (42 kg). Isopropanol (56 kg) was added to the filtrate, and then the mixture was distilled under vacuum at a temperature of <35°C, replacing the volume of distilled material back into the reactor with isopropanol. This process was repeated as needed to complete the solvent exchange from acetonitrile to isopropanol. The slurry was cooled to 15°C, aged for 1 hour, filtered, and washed with 28 kg of isopropanol. The cake was dried under vacuum and nitrogen, packaged, and compound A3 was obtained.

[0194] Resolution of M-dione compound 5 Chromatographic resolution of M-dione intermediates Numerous chiral chromatography techniques and methods were used to isolate the M-dione from compound 4. These techniques and stationary phases are well-known in the art and are outlined in Table 1. [ka]

[0195] [Table 17]

[0196] SFC, HPLC, and SMB technologies are well-known in the art, and Chiralpak® stationary phases are commercially available from sources such as Fisher Scientific and Daicel Corporation.

[0197] However, it is desirable to develop a more efficient method for isolating M-dione (compound 5).

[0198] Typical division This invention relates to the development of a viable typical resolution method for M / P-dione racemic mixtures (compound 4).

[0199] A total of 100 cocrystal screening experiments were performed, and three possible cocrystals of Zion were identified. Based on the maximum area ratio of M / P-Zion in the residual solid and the minimum area ratio in the supernatant, (+)-2,3-dibenzoyl-D-tartaric acid (DBTA) was selected as the chiral reagent for splitting.

[0200] Results from 100 cocrystal screening experiments and more than 20 solvent screenings revealed that 2-MeTHF / n-heptane provided better resolution results than other solvent systems. Based on the solubility results of M-dione cocrystals and P-dione cocrystals at different ratios of 2-MeTHF and n-heptane, 2-MeTHF / n-heptane (1.4:1, v / v) was selected as the optimal solvent composition for resolution.

[0201] To identify possible morphological transformations to dione racemates or M / P-dione during the crystallization process of chiral decomposition, the solubility of M-dione cocrystals, P-dione cocrystals, M+P-dione cocrystal mixtures (1:1, weight / weight), dione racemates, and DBTA was determined at different temperatures in 2-MeTHF / n-heptane (1.4:1, volume / volume). No morphological changes were observed for M-dione cocrystals and P-dione cocrystals at different temperatures for 7 days. However, after stirring the M+P-dione cocrystal mixture (1:1, weight / weight) at different temperatures for 7 days, dione racemate type C was obtained. Dione racemate type D (20 and 30°C) or dione racemate type C (40, 50, 60 and 65°C) were observed after stirring the dione racemates at the corresponding temperatures for 7 days. At all temperatures, the solubility of DBTA was observed to be approximately 100 mg / mL.

[0202] To further optimize the splitting process, a ternary phase diagram of the M / P-dione cocrystal was plotted based on equilibrium solubility results, but a eutectic point could not be obtained, presumably because the racemic C-type can crystallize when both M-dione and P-dione cocrystals are present. Another ternary phase diagram of M / P-dione was plotted based on equilibrium solubility results, but a eutectic point could not be obtained, presumably because the racemic C-type or D-type dione can crystallize when both M-dione and P-dione are present.

[0203] In summary, a chiral reagent (DBTA) and solvent system (2-MeTHF / n-heptane (1.4:1, volume / volume)) were identified for the resolution of dione racemates. A small-scale crystallization process using this resolution reagent and solvent system achieved a yield of 39% and an ee purity of 99% for M-dione. Furthermore, polymorphisms of the dione racemate were observed and investigated during the screening experiments.

[0204] 2. Screening experiment 2.1 Cocrystal Screening A total of 100 cocrystal screening experiments were performed using 20 types of acids and 5 types of solvent systems (the results are summarized in Table 2-1). Generally, before isolating XRPD, the dione racemic mixture and acid were mixed in a 1:1 molar ratio and stirred at RT for 3 days. Based on the XRPD results, three acids that could potentially form cocrystals of the dione racemic mixture were identified: (1S)-(-)-camfanic acid (Figure 2-2), (+)-2,3-dibenzoyl-D-tartaric acid (Figure 2-3), and D-(+)-malic acid (Figure 2-4). In addition, based on the XRPD results, four new free base crystal forms were obtained, which were designated as dione racemic mixture types B to E.

[0205] As shown in Table 2-2, the supernatants and residual solids of the three potential cocrystals were further tested by HPLC. The M-zion / P-zion ratio was measured and summarized in Table 2-2. The results showed that the DBTA cocrystal exhibited an M-zion / P-zion area ratio of 0.11 in the supernatant and 4.4 in the residual solid, suggesting that M-zion and P-zion exhibit good resolution after forming a cocrystal with DBTA. Therefore, DBTA was selected as the chiral reagent for further resolution optimization.

[0206] [Table 18]

[0207] [Table 19]

[0208] [Table 20]

[0209] 2.2 Solvent Screening To select a solvent best suited for further separation of M-dione and P-dione, area ratios of M / P-dione from HPLC were collected for over 20 solvent / solvent mixtures. As shown in Table 2-3, 2-MeTHF showed the best separation with an M-dione / P-dione area ratio of 0.7 in the supernatant and an M-dione / P-dione area ratio of 4.1 in the residual solid. However, 2-MeTHF / n-heptane (1:1, v / v) showed better separation results in cocrystal screening (Table 2-2), and therefore, 2-MeTHF / n-heptane was selected for further optimization. Area ratios of M / P-dione from HPLC were collected for different ratios of 2-MeTHF / n-heptane with different acid / base ratios. The results in Table 2-4 show that a high acid / FB ratio (2:1 or 1.5:1) in 2-MeTHF / n-heptane (8:1 or 4:1, v / v) is desirable for improving the M / P-dione ratio in the isolated solid.

[0210] Furthermore, the solubility of M- and P-cocrystals in different ratios of 2-MeTHF / n-heptane was measured at 5°C and 25°C, and the results are summarized in Table 2-5. The M-cocrystals were provided by the client, and the P-cocrystals were prepared in anti-poor and poor solvents (see Section 4.3 for experimental details). The solubility results in Table 2-5 showed that a volume ratio of 1.5:1 2-MeTHF / n-heptane could yield the best resolution at RT. More resolution experiments were conducted by the client, which showed that a volume ratio of 1.4:1 yielded the best resolution results. Therefore, a volume ratio of 1.4:1 2-MeTHF / n-heptane was selected as the solvent system for resolution.

[0211] [Table 21]

[0212] [Table 22]

[0213] [Table 23]

[0214] 2.3 Solubility of Zeon DBTA cocrystals, Zeon racemic mixtures, and DBTA The 7-day equilibrium solubility of M-dione cocrystals, P-dione cocrystals, a mixture of M+P-dione cocrystals (1:1, w / w), and a dione racemic mixture in 2-MeTHF / n-heptane (1.4:1, v / v) was determined at different temperatures (20, 30, 40, 50, 60, 65, 75, and 80°C). After 5 days, discoloration suggesting decomposition was observed at 75 and 80°C, so solubility was not collected. No morphological changes were observed when M-cocrystals and P-cocrystals were stirred at different temperatures for 7 days (Figures 2-5 and 2-6). After stirring a mixture of M-dione cocrystals and a mixture of P-dione cocrystals (1:1, w / w) at different temperatures for 7 days, dione racemic mixture type C was obtained (Figure 2-7). After stirring the dion racemic mixture at different temperatures for 7 days, dion racemic mixture type D (20 and 30°C) and dion racemic mixture type C (40, 50, 60, and 65°C) were observed (Figures 2-8 and 2-9). The 5-day equilibrium solubility of DBTA in 2-MeTHF / n-heptane (1.4:1, v / v) was determined at various temperatures (20, 30, 40, 50, 60, and 65°C). A solubility of approximately 100 mg / mL was observed at all temperatures. No significant differences were observed with respect to temperature (Table 2-7).

[0215] [Table 24]

[0216] [Table 25]

[0217] 2.4 Ternary phase diagram 2.4.1 M / P-Zion Cocrystal M-dione cocrystals and P-dione cocrystals were weighed to the corresponding masses listed in Table 2-8 and stirred in 2-MeTHF / n-heptane (1.4:1, v / v) at RT for 72 hours. A ternary phase diagram of the M / P-dione cocrystal was drawn based on the 72-hour equilibrium solubility data, but no eutectic point was obtained (Figure 2-10).

[0218] [Table 26]

[0219] 2.4.2 M / P-Zeon M-dione and P-dione were weighed to their corresponding masses as listed in Table 2-9 and stirred in 2-MeTHF / n-heptane (1.4:1, v / v) at RT for 5 days. A ternary phase diagram was drawn based on the 5-day equilibrium solubility data in 1.0 mL of 2-MeTHF / n-heptane (1.4:1, v / v) at RT. M-dione type A, P-dione type A, and dione racemic types C and D were observed in the residual solid of the solubility sample. No eutectic points were obtained in the phase diagram (Figure 2-11).

[0220] [Table 27]

[0221] 3. Analysis of the solid state of crystalline morphology A total of five zion racemic crystal forms and two cocrystal forms were obtained. All of these forms were processed using XRPD, TGA, DSC, PLM, and 1 The analysis was performed using 1H NMR and summarized in Table 2-10. The solid-state analysis data suggested that dione racemic forms A and D were identified as 2-MeTHF solvates, form B as an acetone solvate, form C as an anhydride, and form E as an MTBE solvate.

[0222] Both the M-zion cocrystal type A and the P-zion cocrystal type A were found to be 2-MeTHF solvates. All analysis data are shown in Figures 3-1 to 3-22.

[0223] [Table 28]

[0224] 3.1.1 Competitive Slurry in Zeon Racemic Form In RT (Restoration Test), dion racemic mixtures B through E were successfully regenerated using dion racemic mixture A slurry in acetone, H2O / ACN (1:1, v / v), 2-MeTHF / n-heptane (1.4:1, v / v), and MTBE / n-heptane (1:1, v / v), respectively.

[0225] Approximately 5 mg of each dione racemic mixture (types A to E) was weighed into an HPLC vial. 0.3 mL of a saturated solution of the dione racemic mixture in 2-MeHTF / n-heptane (1.4:1, v / v) was added to the vial, and the mixture was then stirred at 20, 30, 40, 50, 60, and 65°C for 5 days.

[0226] Competitive slurry of 2-MeHTF / n-heptane (1.4:1, v / v) at the target temperature converts all free bases to dione racemic form C, suggesting that dione racemic form C is the most thermodynamically stable form of 2-MeHTF / n-heptane (1.4:1, v / v) between 20 and 65°C.

[0227] [Table 29]

[0228] 3.2 Preparation of P-dione cocrystals 3.2.1 Small scale 2 g of p-dione and 1 g of DBTA were dissolved in 18 ml of 2-MeTHF at 65°C to obtain a nearly clear solution. 18 ml of heptane was added to this solution over 1 hour. This solution was cooled to 20°C over 4 hours and aged overnight. The solution was evaporated at room temperature for about 1 hour using an air blower to obtain a yellowish oily paste. An additional 54 ml of heptane was added to this mixture while stirring for 2 hours. The suspension was filtered. The solid sample was designated 810465-16-A.

[0229] 3.2.2 Large scale 10 g of p-dione and 5 g of DBTA were dissolved in 100 ml of 2-MeTHF at 65°C. This solution was filtered through a 0.45 μm PTFE filter to obtain a clear solution. This clear solution was added dropwise to a 400 mL suspension of heptane containing approximately 1 g of seeds (810465-16-A) generated in the first experiment. This suspension was stirred at RT for 5 hours and then isolated. Approximately 10 g of p-dione cocrystals (810465-20-A) were produced in a yield of approximately 66%.

[0230] 4. Equipment and Methods 4.1 XRPD A PANalytical X-ray powder diffractometer was used in reflection mode for XRPD analysis. The XRPD parameters used are shown in Table 4-1.

[0231] [Table 30]

[0232] 4.2 TGA and DSC TGA data was collected using TA Instruments' TA Discovery 550, Q500, and Q5000TGA. DSC was performed using TA Instruments' Q500, Q5000, and Discovery 2500 DSC. The detailed parameters used are shown in Table 4-2.

[0233] [Table 31]

[0234] 4.3 HPLC Solubility was tested using an Agilent 1100 / 1260 HPLC. The detailed method is shown in Table 4-3.

[0235] [Table 32]

[0236] [Table 33]

[0237] 4.4 1 1H NMR 1 ¹H NMR spectra were collected using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0238] 4.5 PLM Polarized light microscope images were taken at room temperature using a Nikon DS-Fi2 upright microscope.

[0239] Further screening of compound 5 using 1,3-diphenyl-3-oxopropanesulfonic acid 11b. Because the pyridine moiety of compound 5 has low basicity and the number of "hits" for crystalline salt formation using standard screening settings is limited, it was chosen to screen racemic compound 4 with 1,3-diphenyl-3-oxopropanesulfonic acid 11b on a 0.06 mmol scale. [ka]

[0240] Gram-scale separation of racemic compound 5: 2.0 g of racemic compound 4 (5.7 mmol, 1.0 eq.) was added to 200 mL of EtOH:AcOH (90:10 vol: vol) in a 250 mL round-bottom flask. After the substance dissolved, 832 mg of sulfonic acid 11b (2.9 mmol, 0.5 eq.) was added to this solution. The clear solution was stirred at a stirring speed of 800 rpm for 15 hours. A white precipitate formed and was isolated from the mother liquor. The isolated salt was suspended in CH2Cl2 and treated with concentrated NaHCO3 aqueous solution using a separatory funnel. The organic layer was isolated and the basic aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined and dried over Na2SO3. The solvent was evaporated to obtain 415 mg of (M)-5 (96% ee) (see Figure 6-1).

[0241] The clear mother liquor was evaporated to dryness. The yellow oily substance was dissolved in CH2Cl2 and treated with concentrated NaHCO3 aqueous solution using a separatory funnel. The organic layer was isolated, and the basic aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined and dried over Na2SO3. The solvent was evaporated to obtain 1579 mg of 5 ((P)-atropisomer, 23% ee; Figure 6-2).

[0242] Polymorphic screening of M-zion DBTA cocrystals 5. Analysis of the crystal morphology of M-Zion DBTA cocrystals Polymorphic screening experiments for M-zion were performed under 100 conditions using slurry conversion, slow evaporation, slow cooling, poor solvent addition, vapor diffusion, temperature cycling, and wet grinding methods. A total of 17 crystalline forms (types A to Q) were obtained from the screening. The relationships between the forms are shown in Figure 4-1. Detailed analysis data are shown in Table 5-1, and the XRPD pattern overlay is shown in Figure 5-1. The results of the solid state analysis suggested that type G is a hydrate, while the other types are solvates.

[0243] 5.1 Equipment and Methods 5.1.1 XRPD XRPD on Si Zero Background Holder Panalytical X'Pert 3The procedure was performed using powder XRPD. The 2θ position was calibrated against a Panalytical Si reference standard disk. The parameters used are shown in Table 5-a.

[0244] [Table 34]

[0245] 5.1.2 TGA / DSC TGA data was acquired using a TA Discovery 550 TGA from TA Instrument. DSC was performed using a TA Q2000 DSC from TA Instrument. The DSC was calibrated with an indium reference standard, and the TGA was calibrated with a nickel reference standard. The detailed parameters used are shown in Table 5-b.

[0246] [Table 35]

[0247] 5.2 Polymorphic Screening The solubility of type A (3-05-A) was estimated by RT. Approximately 2 mg of solid was added to a 3 mL glass bottle. Then, the solvents listed in Table 5-c were added to the bottle in stages (50 / 50 / 200 / 700 μL) until the solid dissolved or the total volume reached 2 mL. The results are summarized in Table 5-c and served as a guideline for solvent selection in polymorph screening.

[0248] Polymorph screening experiments were conducted using various crystallization methods or solid-state transition methods. The methods used and the identified crystal types are summarized in Table 5-c.

[0249] [Table 36]

[0250] [Table 37]

[0251] 5.2.1 Slurry in RT Slurry experiments were performed in various solvent systems under RT (Restorative Consumption). Approximately 20 mg of type A (3-05-A) was suspended in 0.2 mL of solvent in a 3 mL glass bottle. The suspension was magnetically stirred under RT for 13 days, and the remaining solid was isolated for XRPD analysis. The results summarized in Table 5-e show that types A-D and J were obtained.

[0252] [Table 38]

[0253] 5.2.2 Slow evaporation Slow evaporation experiments were performed under 16 conditions. Briefly, 20 mg of type A (3-05-A) was dissolved in 0.2-0.8 mL of solvent in a 20 mL glass bottle. If dissolution was not achieved, the suspension was filtered using a PTFE membrane (pore size 0.2 μm), and the filtrate was used in the next step. Visually clear solutions were covered with Parafilm® having 5-10 pinholes and evaporated by RT. The solid was isolated for XRPD analysis. The results summarized in Table 5-f show that types A, C, D, J, K, L, N, and O were obtained.

[0254] [Table 39]

[0255] 5.2.3 Slow Cooling Slow cooling experiments were conducted in nine different solvent systems. Approximately 20 mg of type A (3-05-A) was suspended in 1 mL of solvent in a 3 mL glass bottle using RT (Restoration Time). The suspension was then heated to 50°C, equilibrated for 2 hours, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was slowly cooled to 5°C at a rate of 0.1°C / min. The results summarized in Table 5-g show that types C, G, J, L, and O were identified.

[0256] [Table 40]

[0257] 5.2.4 Addition of poor solvent A total of nine poor solvent addition experiments were conducted. Approximately 20 mg of the starting material (3-05-A) was dissolved in 0.2 to 1.4 mL of solvent to obtain a clear solution. The solution was magnetically stirred, and then 0.2 mL of poor solvent was added stepwise until a precipitate appeared or the total volume of poor solvent reached 15.0 mL. The resulting precipitate was isolated for XRPD analysis. The results in Table 5-h show that types A, C, H, and I were obtained.

[0258] [Table 41]

[0259] 5.2.5 Liquid vapor diffusion Five liquid vapor diffusion experiments were conducted. Approximately 20 mg of the starting material (3-05-A) was dissolved in a suitable solvent in a 3 mL bottle to obtain a clear solution. This solution was then placed in a 20 mL bottle with 3 mL of volatile solvent. The 20 mL bottle was sealed with a cap and kept at RT for a sufficient time for the organic vapor to interact with the solution. The precipitate was isolated for XRPD analysis. The results summarized in Table 5-i show that L-type, M-type, and Q-type precipitates were produced.

[0260] [Table 42]

[0261] 5.2.6 Solid vapor diffusion Solid vapor diffusion experiments were conducted using six different solvents. Approximately 10 mg of the starting material (3-05-A) was weighed into a 3 mL bottle and placed in a 20 mL vial with 2 mL of volatile solvent. The 20 mL vial was sealed with a cap and kept at RT for 7 days, allowing the solvent vapor to interact with the sample. The solid was tested by XRPD, and the results summarized in Table 5-j show that types A and M were produced.

[0262] [Table 43]

[0263] 5.2.7 Temperature Cycle Temperature cycling experiments were performed in seven different solvent systems. Approximately 20 mg of the starting material (3-05-A) was suspended in 1 mL of solvent in a 3 mL glass bottle using RT (Restoration Time). The suspension was then heated to 50°C, equilibrated for 1 hour, and filtered using a PTFE membrane (pore size 0.20 μm). The filtrate was slowly cooled to 5°C at a rate of 0.2°C / min, and then heated to 50°C at a rate of 1°C / min. This cycle was repeated once more, and then cooled to 5°C at a rate of 0.2°C / min. The samples were stored at 5°C until the solid was isolated and analyzed using XRPD. The results summarized in Table 5-k show that types A, G, and O were confirmed.

[0264] [Table 44]

[0265] 5.2.8 Slurry at 5℃ Slurry experiments were conducted at 5°C in various solvent systems. Approximately 20 mg of the starting material (3-05-A) was suspended in 0.2 mL of solvent in a 3 mL glass bottle. The suspension was magnetically stirred at 5°C for 7 days, and the remaining solid was isolated for XRPD analysis. The results summarized in Table 5-l show that types A, C to E, and J were obtained.

[0266] [Table 45]

[0267] 5.2.9 Wet grinding Wet grinding experiments were conducted under five conditions. Briefly, 10 mg of type A (3-05-A) was placed in a mortar and ground in approximately 20 μL of solvent for 5 minutes. The solid was isolated for XRPD analysis. The results summarized in Table 5-m show that type A was obtained.

[0268] [Table 46]

[0269] [Table 47]

[0270] [Table 48]

[0271] 5.3 Type A Type A (3-05-A) was provided by the client. The XRPD results shown in Figure 5-4 suggested crystalline properties. As shown by the TGA and DSC data in Figure 5-5, the weight loss was 7.3% up to 125°C, with two endothermic reactions observed at 109.4°C and 120.0°C (peaks). As shown in Figure 5-6, 1 The presence of 2-MeTHF was confirmed by 1H NMR spectroscopy. Based on these results, type A was considered to be a 2-MeTHF solvate.

[0272] 5.4 Type B A type B sample (3-07-A1) was obtained by RT using a type A slurry in MTBE. The XRPD pattern shown in Figure 5-7 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-10, a 7.2% weight loss up to 125°C and endothermic activity at 115.7°C (peak) were observed. As shown in Figure 5-9, 1 The presence of MTBE was confirmed by 1H NMR spectroscopy. Based on these results, type B was considered to be an MTBE solvate.

[0273] 5.5 C type The C-type sample (3-08-A5) was obtained by slow evaporation in ethyl acetate using RT. The XRPD pattern shown in Figure 5-10 suggested crystallinity. The TGA and DSC data shown in Figure 5-11 showed an 8.0% weight loss up to 125°C and two endothermic reactions at 92.7°C and 116.4°C (peaks). As shown in Figure 5-12, 1 The presence of toluene was confirmed by the 1H NMR spectrum. Based on these results, the C-type was considered to be a toluene solvate.

[0274] 5.6 D type Type D (3-07-A12) was obtained by RT using a slurry of type A in IPAc. The XRPD results shown in Figure 5-13 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-14, a 7.5% weight loss up to 130°C was observed, along with endothermic reactions at 75.4°C, 110.5°C, 148.0°C, and 116.6°C (peak), and exothermic reactions at 265.9°C. As shown in Figure 5-15, 1 The presence of IPAc was confirmed by 1H NMR spectroscopy. Based on these results, type D was considered to be an IPAc solvate.

[0275] 5.7 E type Type E (3-07-A15) was obtained by RT from a slurry of type A in anisole. The XRPD results shown in Figure 5-16 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-17, an 8.6% weight loss up to 125°C and two endothermic reactions were observed at 103.8°C and 119.0°C (peaks). As shown in Figure 5-18, 1 The presence of IPAc was confirmed by 1H NMR spectroscopy. Based on these results, the E-type was considered to be an anisole solvate.

[0276] 5.8 F type Type F (3-07-A19) was obtained by RT from a slurry of type A in IPAc / H2O (volume:volume 1:9). The XRPD results shown in Figure 5-19 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-20, a weight loss of 6.2% up to 130°C and two endothermic reactions were observed at 86.5°C and 107.9°C (peaks). As shown in Figure 5-18, 1 The presence of IPAc was confirmed by 1H NMR spectroscopy. Based on these results, the F-type was considered to be an IPAc solvate.

[0277] 5.9 G type G-type (3-07-A26) was obtained by RT from a slurry of A-type in MeOH / H2O (aw=0.8). The XRPD results shown in Figure 5-22 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-23, a 6.4% weight loss up to 100°C and endothermic reactions were observed at 86.0°C, 127.2°C, and 133.1°C (peaks). As shown in Figure 5-24, the solution... 1 Neither MeOH nor MeTHF signals were observed in the 1H NMR spectrum. Based on these results, the G-type was considered to be a hydrate.

[0278] 5.10 H type H-type (3-10-A1) was obtained by adding a poor solvent using acetone / H2O. The XRPD results shown in Figure 5-25 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-26, a 3.6% weight loss up to 130°C and endothermic activity at 107.6°C (peak) were observed. As shown in Figure 5-27, 1 The presence of acetone was confirmed by the 1H NMR spectrum. Based on these results, the H-type was considered to be acetone solvate.

[0279] 5.11 Type I Type I (3-10-A3) was obtained by adding a poor solvent using DMSO / H2O. The XRPD results shown in Figure 5-28 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-29, a 7.3% weight loss up to 150°C and endothermic activity at 128.9°C (peak) were observed. As shown in Figure 5-30, 1 The presence of DMSO was confirmed by 1H NMR spectroscopy. Based on these results, type I was considered to be the DMSO solvate.

[0280] 5.12 J type J-type (3-08-A2) was obtained by slow evaporation in THF. The XRPD results shown in Figure 5-31 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-32, a 7.3% weight loss up to 125°C and endothermic reaction at 115.7°C (peak) were observed. As shown in Figure 5-33, 1 The presence of THF was confirmed by 1H NMR spectroscopy. Based on these results, the J-type was considered to be a THF solvate.

[0281] 5.13 K type The K-type (3-08-A14) was obtained by slow evaporation in acetone. The XRPD results shown in Figure 5-34 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-35, a 5.7% weight loss up to 150°C was observed, along with endothermic reactions at 96.7°C, 119.8°C, and 147.4°C (peaks), and exothermic reactions at 157.4°C (peak). As shown in Figure 5-36, 1 The presence of acetone was confirmed by the 1H NMR spectrum. Based on these results, the K-type was considered to be an acetone solvate.

[0282] 5.14 L type The L-type (3-11-A4) was obtained by liquid vapor diffusion in 2-MeTHF / n-heptane. The XRPD results shown in Figure 5-37 suggested that the crystal had a favorable orientation. As shown by the TGA and DSC data in Figure 5-38, a 7.9% weight loss up to 130°C and endothermic activity at 126.2°C (peak) were observed. As shown in Figure 5-39,1 The presence of acetone was confirmed by the 1H NMR spectrum, but no signal for n-heptane was observed. Based on these results, the L-form was considered to be a 2-MeTHF solvate.

[0283] 5.15 M type Type M (3-11-A2) was obtained by liquid vapor diffusion in ethyl acetate / IPA. The XRPD results shown in Figure 5-40 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-41, a 3.7% weight loss up to 150°C and endothermic activity at 122.6°C (peak) were observed. As shown in Figure 5-42, 1 The presence of IPA was confirmed by the 1H NMR spectrum, but no pharmaceutically acceptable signal for pharmaceutically acceptable phosphate was observed. Based on these results, the M-type was considered to be an IPA solvate.

[0284] 5.16 N type N-type (3-08-A8) was obtained by slow evaporation in EtOH. The XRPD results shown in Figure 5-43 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-44, a 4.1% weight loss up to 150°C and endothermic reactions were observed at 85.4°C, 126.5°C, and 150.9°C (peak). As shown in Figure 5-45, 1 The presence of EtOH was confirmed by 1H NMR spectroscopy. Based on these results, the N-type was considered to be the EtOH solvate.

[0285] 5.17 O type Type O (3-08-A11) was obtained by slow evaporation in MIBK. The XRPD results shown in Figure 5-46 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-47, a 2.0% weight loss up to 130°C and endothermic reactions were observed at 106.2°C and 151.2°C (peaks). As shown in Figure 5-48, 1 The presence of MIBK was confirmed by 1H NMR spectroscopy. Based on these results, type O was considered to be an MIBK solvate.

[0286] 5.18 P type The P-type (3-07-A14) was obtained by slow evaporation in DMF. The XRPD results shown in Figure 5-49 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-50, a weight loss of 8.3% up to 130 °C and an endotherm at 89.9 °C (peak) were confirmed. As shown in Figure 5-51, 1 the presence of DMF was confirmed by the 1H NMR spectrum. Based on these results, the P-type was considered to be a DMF solvate.

[0287] 5.19 Q-type The Q-type (3-11-A1) was obtained by liquid-vapor diffusion in MIBK / n-heptane. The XRPD results shown in Figure 5-52 suggested crystallinity. As shown by the TGA and DSC data in Figure 5-53, a weight loss of 6.0% up to 120 °C and endotherms at 92.9 °C, 148.9 °C and 170.0 °C (peak) were observed. As shown in Figure 5-54, 1 the presence of MIBK was confirmed by the 1H NMR spectrum, but no signal for n-heptane was observed. Based on these results, the Q-type was considered to be a MIBK solvate.

[0288] 6. Crystal data and experiments of Composition 4a Experiment. Single colorless plate crystals of (Composition 4a) were used as received. Suitable crystals (0.28×0.18×0.09) mm 3 were selected and mounted on a nylon loop of a Bruker APEX-II CCD diffractometer using paratone oil. During data collection, the crystal was kept at T = 173(2) K. The structure was analyzed using the XT (Sheldrick, 2015) structure analysis program with the Intrinsic Phasing solution method using Olex2 (Dolomanov et al., 2009). The model was refined using the version of XL using the least squares method (Sheldrick, 2008).

[0289] Crystal data. C 65 H 72 C l2 F2N8O15 , Mr = 1314.20, triclinic system, P1 (No.1), a = 11.5683(10) Å, b = 11.6705(10) Å, c = 13.9593(12) Å, α = 68.1780(10)°, β = 69.4150(10)°, γ = 87.7760(10)°, V = 1628.7(2) Å 3 , T = 173(2) K, Z = 1, Z’ = 1, μ(MoK α ) = 0.178, measured reflections 26758, unique 11949 (R int = 0.0528), all of which were used in all calculations. The final wR2 was 0.2465 (all data), and R1 was 0.0835 (I > 2(I)).p

[0290]

Table 49

[0291]

Table 50

[0292]

Table 51

[0293]

Table 52

[0294]

Table 53

[0295]

Table 54

[0296]

Table 55

[0297] Table 56

[0298] Table 57

[0299] Table 58

[0300] Table 59

[0301] Table 60

[0302] Table 61

[0303] Table 62

[0304] Table 63

[0305] Table 64

[0306] Table 65

[0307] Table 66

[0308] [Table 67]

[0309] [Table 68]

[0310] [Table 69]

[0311] [Table 70]

[0312] The foregoing is merely illustrative of the present invention and is not intended to limit the invention to the disclosed uses. Modifications and alterations that are commonplace to those skilled in the art are intended to fall within the scope and nature of the invention as defined in the appended claims. All references, patents, applications and publications mentioned herein are incorporated herein by reference in their entirety as they are described herein.

Claims

1. A composition, comprising formula 4: 【Chemistry 1】 Compounds of formula B: 【Chemistry 2】 A composition containing the compound.

2. The compound of formula 4 is formula 5M: 【Transformation 3】 The composition according to claim 1, which is a compound of the above.

3. The compound of formula 4 is formula 5P: 【Chemistry 4】 The composition according to claim 1, which is a compound of the above.

4. The compound of formula B is formula B1: 【Transformation 5】 A composition according to any one of claims 1 to 3, wherein the compound is [the compound].

5. The compound of formula B is formula B2: 【Transformation 6】 A composition according to any one of claims 1 to 3, wherein the compound is [the compound].

6. The composition according to any one of claims 1 to 3, comprising the compound of formula 4 and the compound of formula B in a ratio of 2:

1.

7. The aforementioned composition has the formula: 【Transformation 7】 The composition according to any one of claims 1 to 3, further comprising 2-methyltetrahydrofuran having

8. The composition according to any one of claims 1 to 3, wherein the ratio of 2-methyltetrahydrofuran to the compound of formula B is 2:

1.

9. The aforementioned composition has the formula: 【Transformation 8】 The composition according to claim 1, having the following characteristics.

10. The aforementioned composition has the formula: 【Chemistry 9】 The composition according to claim 9, having the following characteristics.

11. The aforementioned composition has the formula: 【Chemistry 10】 The composition according to claim 9, having the following characteristics.

12. The aforementioned composition has the formula: 【Chemistry 11】 The composition according to claim 9, having the following characteristics.

13. The aforementioned composition has the formula: 【Chemistry 12】 The composition according to claim 9, having the following characteristics.

14. The composition according to any one of claims 1 to 13, wherein the composition is in a crystalline state.

15. A method for producing the composition of formula 4a, wherein the chemical structure is as follows: 【Chemistry 13】 Compound 4 having the formula: 【Chemistry 14】 When reacted with compound B1 having the structure 【Chemistry 15】 A method comprising forming a composition of formula 4a having the above.

16. The following chemical structure: 【Chemistry 16】 A method for obtaining a compound of formula 5M having the following characteristics: a) The following chemical structure: 【Chemistry 17】 Compound 4 having the formula: [Chemistry 18] When reacted with compound B1 having the structure: 【Chemistry 19】 Forming a composition of formula 4a having the above as a crystal; b) Isolating composition 4a; c) Treating the isolated composition 4a with a base to produce the compound of formula 5M. A method that includes this.

17. The aforementioned base is Na ２ HPO ４ The method according to claim 16.

18. The aforementioned base is NaHCO ３ The method according to claim 16.

19. A composition, comprising formula 4: 【Chemistry 20】 Compounds of formula 11: 【Chemistry 21】 A composition containing the compound.

20. The compound of formula 4 is formula 5M: 【Chemistry 22】 The composition of claim 19, which is a compound of the above.

21. The compound of formula 4 is formula 5P: 【Chemistry 23】 The composition of claim 19, which is a compound of the above.

22. The compound of formula 11 is formula 11a: 【Chemistry 24】 A composition according to any one of claims 19 to 21, wherein the compound is [the compound].

23. The compound of formula 11 is formula 11b: 【Chemistry 25】 A composition according to any one of claims 19 to 21, wherein the compound is [the compound].

24. The aforementioned composition has the formula: 【Chemistry 26】 The composition according to claim 19, having the following characteristics.

25. The aforementioned composition has the formula: 【Chemistry 27】 The composition according to claim 19, having the following characteristics.

26. The aforementioned composition has the formula: 【Chemistry 28】 The composition according to claim 19, having the following characteristics.

27. The aforementioned composition has the formula: 【Chemistry 29】 The composition according to claim 19, having the following characteristics.

28. The composition according to any one of claims 19 to 27, comprising the compound of formula 4 and the compound of formula 11 in a 1:1 ratio.

29. Using the compound of formula 5M mentioned above, formula: 【Transformation 30】 The method according to claim 16, which produces a compound having

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