3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propanenitrile

Abstract

The present disclosure provides salts, crystalline forms, and formulations of KRAS inhibitors and methods of their preparation and use.

Description

[0001] Related applications

[0002] This application relates to U.S. Provisional Application No. 63 / 588,914, filed October 9, 2023, and U.S. Provisional Application No. 63 / 698,286, filed September 24, 2024, the contents of each of the aforementioned U.S. Provisional Applications being incorporated herein by reference in their entirety. Background Technology

[0003] Ras proteins are part of a family of small GTPases activated by growth factors and various extracellular stimuli. The Ras family regulates intracellular signaling pathways responsible for cell growth, migration, survival, and differentiation. Activation of Ras proteins at the cell membrane leads to the binding of key effector factors and initiates a series of intracellular signaling pathways, including the RAF and PI3K kinase pathways. Somatic mutations in RAS can lead to uncontrolled cell growth and malignant transformation, while activation of RAS proteins is tightly regulated in normal cells (D. Simanshu, et al., Cell, 2017, 170(1), 17-33).

[0004] The Ras family consists of three members: KRAS, NRAS, and HRAS. RAS-mutated cancers account for approximately 25% of all human cancers. KRAS is the most common mutation subtype, accounting for 85% of all RAS mutations, while NRAS and HRAS mutations account for 12% and 3% of all Ras-mutated cancers, respectively (D. Simanshu, et al., Cell, 2017, 170(1), 17-33). KRAS mutations are prevalent in the three deadliest cancer types: pancreatic cancer (97%), colorectal cancer (44%), and lung cancer (30%) (AD Cox, et al., Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). Most RAS mutations occur at amino acid residues 12, 13, and 61. The frequency of specific mutations varies by RAS genotype, and while G12 and Q61 mutations are predominant in KRAS and NRAS, respectively, G12, G13, and Q61 mutations are most common in HRAS. Furthermore, the mutation spectrum of RAS subtypes varies by cancer type. For example, KRAS G12D mutations are predominant in pancreatic cancer (51%), followed by colorectal adenocarcinoma (45%) and lung cancer (17%), while KRAS G12V mutations are associated with pancreatic cancer (30%), followed by colorectal adenocarcinoma (27%) and lung adenocarcinoma (23%) (AD Cox, et al. Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). In contrast, KRAS G12C mutations are predominant in non-small cell lung cancer (NSCLC), accounting for 11% to 16% of lung adenocarcinomas and 2% to 5% of pancreatic and colorectal adenocarcinomas (AD Cox et al., Nat. Rev. Drug. Discov., 2014, 13(11), 828-51). Genomic studies across hundreds of cancer cell lines have shown that cell growth and survival of cancer cells carrying KRAS mutations are highly dependent on KRAS function (R. McDonald et al., Cell, 2017, 170(3), 577-92). A wealth of in vivo experimental evidence further supports the role of mutant KRAS as an oncogenic driver, with evidence suggesting that mutant KRAS is essential for early tumorigenesis and maintenance in animal models (AD Cox et al., Nat. Rev. Drug. Discov., 2014, 13(11), 828-51).

[0005] In summary, these findings indicate that KRAS mutations play a crucial role in human cancers. Therefore, developing inhibitors targeting KRAS (including mutated KRAS) will facilitate clinical treatment of diseases characterized by KRAS involvement, including those characterized by the involvement or presence of KRAS mutations. Summary of the Invention

[0006] This article provides the crystal forms, salts, and crystalline salt forms of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile having the following structures:

[0007] .

[0008] The compound referred to in this paper as "compound 1" is a KRAS inhibitor that can be used to treat various cancers and other diseases, especially KRAS with G12D mutations. Attached Figure Description

[0009] Figure 1 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form I) is shown.

[0010] Figure 2 The DSC thermogram of compound 1 hydrochloride dihydrate (crystal form I) is shown.

[0011] Figure 3 The TGA thermogram of compound 1 hydrochloride dihydrate (crystal form I) is shown.

[0012] Figure 4 The XRPD diffraction pattern of compound 1 dihydrochloride is shown.

[0013] Figure 5 The DSC thermogram of compound 1 dihydrochloride is shown.

[0014] Figure 6 The TGA thermogram of compound 1 dihydrochloride is shown.

[0015] Figure 7 The XRPD diffraction pattern of compound 1 fumarate is shown.

[0016] Figure 8 The DSC thermogram of compound 1 fumarate is shown.

[0017] Figure 9 The TGA thermogram of compound 1 fumarate is shown.

[0018] Figure 10 The XRPD diffraction pattern of compound 1 L-tartrate is shown.

[0019] Figure 11 The DSC thermogram of compound 1 L-tartrate is shown.

[0020] Figure 12 The TGA thermogram of compound 1 L-tartrate is shown.

[0021] Figure 13 The XRPD diffraction pattern of compound 1 adipate is shown.

[0022] Figure 14 The DSC thermogram of compound 1 adipate is shown.

[0023] Figure 15 The TGA thermogram of compound 1 adipate is shown.

[0024] Figure 16 The XRPD diffraction pattern of compound 1 phosphate is shown.

[0025] Figure 17 The DSC thermogram of compound 1 phosphate is shown.

[0026] Figure 18 The TGA thermogram of compound 1 phosphate is shown.

[0027] Figure 19 The XRPD diffraction pattern of the free base of compound 1 is shown.

[0028] Figure 20 The DSC thermogram of the free base of compound 1 is shown.

[0029] Figure 21 The TGA thermogram of the free base of compound 1 is shown.

[0030] Figure 22 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form II) is shown.

[0031] Figure 23 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form III) is shown.

[0032] Figure 24 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form IV) is shown.

[0033] Figure 25 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form V) is shown.

[0034] Figure 26The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form VI) is shown.

[0035] Figure 27 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form VII) is shown.

[0036] Figure 28 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form VIII) is shown.

[0037] Figure 29 The XRPD diffraction pattern of compound 1 hydrochloride dihydrate (crystal form IX) is shown.

[0038] Figure 30 An atomic displacement ellipsoid diagram of the hydrochloride dihydrate of compound 1 is shown. Detailed Implementation

[0039] When a compound is used for pharmaceutical purposes, its solid state can be important. The physical properties of a compound can change from one solid form to another, which can affect the suitability of that form for pharmaceutical use. For example, a particular crystalline solid compound can overcome the disadvantages of other solid forms of the compound, such as, for example, instability and / or reduced purity.

[0040] This article provides the solid crystal form and crystalline salt form of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile, i.e., compound 1. This compound can be used to treat various cancers.

[0041] Compound 1 is disclosed in PCT application PCT / US2022 / 078048 (WO2023064857A1) and U.S. Patent Application No. 18 / 046,303 (US20230144051A1), the entire contents of which are incorporated herein by reference.

[0042] The crystal form presented in this paper can be characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).

[0043] I. Definition

[0044] The following lists the definitions of various terms used to describe the crystal forms provided herein. These definitions apply to the terminology used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in specific instances.

[0045] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the compounds and their crystal forms pertain. Generally, the nomenclature used herein, as well as laboratory procedures for cell culture, molecular genetics, organic chemistry, and peptide chemistry, are well-known and commonly used in the art.

[0046] As used herein, the articles “a” and “a kind” refer to the grammatical object of the article, which is one or more kinds (i.e., at least one kind). For example, “element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0047] The terms “treat,” “treated,” “treating,” or “treatment” include the reduction or relief of at least one symptom associated with or caused by the treated state, condition, or disease. In some embodiments, treatment includes contacting an effective amount of the compound provided herein for androgen receptor-related conditions with KRAS.

[0048] As used herein, the terms “prevent” or “prevention” mean that if a symptom or disease does not occur, there is no development of a symptom or disease, or if a symptom or disease has already developed, there is no further development of a symptom or disease. The ability to prevent some or all of the symptoms associated with a symptom or disease is also considered.

[0049] As used herein, the terms "patient," "individual," or "subject" refer to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as sheep, cattle, pigs, dogs, cats, and rodents. In this embodiment, the patient, subject, or individual is a human.

[0050] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues to the extent of proper medical judgment without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0051] This disclosure also includes pharmaceutically acceptable salts of the compounds described herein. The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and so on. Pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both; typically, a non-aqueous medium, such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN). A list of suitable salts can be found at: AR Gennaro (editor), Remington's Pharmaceutical Sciences. 17th edition, (Mack Publishing Company, Easton, 1985), p. 1418; SM Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19; S. Gaisford, A. Adejare (eds.), Remington, The Science and Practice of Pharmacy, 23rd edition, (Elsevier, 2020), Chapter 17, pp. 307–14; SMBerge et al., J. Pharm. Sci., 1977, 66(1), 1–19; TS Wiedmann et al., Asian J. Pharm. Sci., 2016; 11, 722–34; D. Gupta et al., Molecules, 2018, 23(7), 1719; PHStahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002); and PHStahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use. 2nd edition (Wiley, 2011).

[0052] The terms "administering" or "administration," etc., refer to the provision of a therapeutic agent, such as the crystal form disclosed herein, to a subject in need of treatment. In this embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0053] As used herein, the term “about” will be understood by those skilled in the art and will vary to some extent depending on the context in which it is used. As used herein, when referring to measurable values ​​(such as quantity, duration, etc.), the term “about” means encompassing a variation of ±10% (inclusive) relative to a specified value, as such variation is suitable for the disclosed methods.

[0054] The following abbreviations may be used in this document: AcOH (acetic acid); Ac2O (acetic anhydride); aq. (aqueous); atm. (at various atmospheres); Boc (tert-butoxycarbonyl); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate); br (broad peak); Cbz (carboxybenzyl); calc. (calculated); d (doublet); dd (double doublet); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N'-diisopropyl azodicarbonate); D IEA (N,N-diisopropylethylamine); DIPEA (N,N-diisopropylethylamine); DIBAL (diisobutylaluminum hydride); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); DSC (differential scanning calorimetry); Et (ethyl); EtOAc (ethyl acetate); FCC (fast column chromatography); g (gram); h (hour); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz) J (coupling constant); L (liter); LCMS (liquid chromatography-mass spectrometry); LDA (lithium diisopropylaminodimethylamine); m (multiplexes); M (molar); mCPBA (3-chloroperbenzoic acid); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min (minute); mL (milliliter); mmol (millimole); MTBE (methyl tert-butyl ether); N (normal); NCS (N-chlorosuccinimide); NET3 (triethylamine); nM (nanomolar); NMP (N-methylpyrrolidone) NMR (Nuclear Magnetic Resonance Spectroscopy); OTf (Trifluoromethanesulfonate); Ph (Phenyl); pM (Picomol); PPT (Precipitation); RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography); rt (Room Temperature); s (Single Peak); t (Triplet); TBS (Tertiary Butyldimethylsilyl); tert (Tertiary); tt (Triplet); TFA (Trifluoroacetic Acid); THF (Tetrahydrofuran); TGA (Thermogravimetric Analysis); µg (Microgram); µL (Microliter); µM (Micromolar); wt% (Weight Percentage); XRPD (X-ray Powder Diffraction). The brine is a saturated aqueous solution of sodium chloride. In a vacuum, it is under vacuum conditions.

[0055] The compounds disclosed herein may exist as trans-isomers (i.e., conformationally diastereomers), which are stable at room temperature and can be separated by, for example, chromatography. For instance, the compounds provided herein may exist as trans-isomers in which the dichlorophenyl conformation relative to the remainder of the molecule is shown in partial formula (II-A) or formula (II-B) below. The compounds described herein or any examples should be understood to include all such trans-isomer forms of the compounds, including but not limited to trans-isomer forms represented by formula (II-A) or formula (II-B) below. The asymmetry of the trans-isomer is assigned as R. a or S a , as determined by conventional methods for characterizing asymmetric points.

[0056]

[0057] II. Salt and Crystal Form

[0058] 1. Characterization of crystal form

[0059] In some embodiments, the crystal forms described herein can be identified based on characteristic peaks in X-ray powder diffraction analysis. X-ray powder diffraction (XRPD) is a scientific technique for characterizing the structure of solid materials using X-rays, neutrons, or electron diffraction to examine powders, crystallites, or other solid materials. Descriptions of methods for obtaining certain XRPD diffraction patterns associated with the crystal forms provided herein can be found in the examples below. In one embodiment, the X-ray powder diffraction data provided herein is obtained using Cu Kα radiation.

[0060] Therefore, in one aspect, this article provides a compound which is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile or a pharmaceutically acceptable salt thereof, wherein the compound is crystalline.

[0061] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt. In another embodiment, the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, dihydrochloride, fumarate, L-tartrate, adipate, and phosphate.

[0062] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-((R a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile:

[0063] .

[0064] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-((S) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile:

[0065] .

[0066] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a solvate. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is a hydrate. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is a dihydrate.

[0067] Compound 1 hydrochloride dihydrate

[0068] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride dihydrate.

[0069] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form I.

[0070] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles (±0.2 degrees): 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.0.

[0071] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or at least four, five, six, seven, eight, nine or all) of the following peaks at angles (±0.2 degrees) expressed in 2θ: 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5 and 26.0.

[0072] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ: 5.7, 7.8, and 13.5.

[0073] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ: 5.7, 7.8, 13.5, and 17.2.

[0074] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks, expressed in 2θ angles, at an angle of ±0.2 degrees, of the following: 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.0. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks, expressed in 2θ angles, at an angle of ±0.2 degrees, of the following: 5.7, 7.8, 13.5, 17.2, 19.2, and 23.1.

[0075] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks, expressed in 2θ angles, at the following angles (±0.2 degrees): 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.0.

[0076] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 1 The description.

[0077] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) in 2θ, selected from the list in Table 1a (Crystal Form I).

[0078] Table 1a

[0079]

[0080] In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 2 The described DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with a peak at about 271°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with an onset at about 265°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 150°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 3 The depicted TGA thermogram.

[0081] In one embodiment, the compound or a pharmaceutically acceptable salt thereof comprises a monoclinic crystal. In another embodiment, the compound or a pharmaceutically acceptable salt thereof comprises a crystal having a space group of P21. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof comprises a crystal having unit cell parameters substantially as follows: a = 13.8490(4) Å, b = 8.0204(2) Å, c = 15.5461(4) Å, α = 90°, β = 100.617(3)°, γ = 90°, and / or V = 1697.21(8) Å. 3 In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof comprises a crystal having unit cell parameters substantially as shown in Table A.

[0082] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form II. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as a 2θ angle, at an angle (±0.2 degrees): 5.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.3.

[0083] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or at least four, five, six or all) of the following peaks at angles (±0.2 degrees) expressed in 2θ: 5.8, 7.6, 11.4, 12.5, 14.4, 17.9 and 25.3.

[0084] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ: 7.6, 12.5, and 17.9.

[0085] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ: 7.6, 12.5, 17.9, and 25.3.

[0086] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks, expressed in 2θ angles, at an angle of ±0.2 degrees, of the following: 55.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.3. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks, expressed in 2θ angles, at an angle of ±0.2 degrees, of the following: 5.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.3.

[0087] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 22 The description.

[0088] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) in 2θ, selected from the list in Table 1b (Crystal Form II).

[0089] Table 1b

[0090]

[0091] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form III. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in the figure. Figure 23 The description.

[0092] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form IV. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in the figure. Figure 24 The description.

[0093] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form V. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in the figure. Figure 25 The description.

[0094] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form VI. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in [example missing]. Figure 26 The description.

[0095] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form VII. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in [example missing]. Figure 27 The description.

[0096] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form VIII. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in the figure. Figure 28 The description.

[0097] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is crystal form IX. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern is substantially as shown in the figure. Figure 29 The description.

[0098] Compound 1 dihydrochloride

[0099] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile dihydrochloride.

[0100] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles (±0.2 degrees): 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1, and 23.9.

[0101] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven, eight, nine, ten, eleven or all) of the following peaks at angles (±0.2 degrees) expressed in 2θ: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1 and 23.9.

[0102] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at angles (±0.2 degrees) represented by 2θ: 5.6, 5.9, and 22.1. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least seven peaks at angles (±0.2 degrees) represented by 2θ: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1, and 23.9.

[0103] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.6, 5.9, 10.7, 13.2, 18.5, 22.1, and 23.9. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1, and 23.9.

[0104] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 4 The description.

[0105] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 2, expressed as a 2θ angle.

[0106] Table 2

[0107]

[0108] In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 5 The depicted DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with a peak at about 267°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with an onset at about 256°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 150°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 6 The depicted TGA thermogram.

[0109] Compound 1 fumarate

[0110] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile fumarate.

[0111] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles, at ±0.2 degrees: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.7.

[0112] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven, eight or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0 and 23.7.

[0113] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at angles (±0.2 degrees) represented by 2θ: 12.9, 17.7, and 23.7. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks at angles (±0.2 degrees) represented by 2θ: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.7.

[0114] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 12.9, 15.1, 17.7, 20.0, 22.0, and 23.7. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least nine peaks at the following angles (±0.2 degrees) expressed in 2θ: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.7.

[0115] In yet another embodiment, the compound according to claim 46 or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has peaks at the following angles (±0.2 degrees) expressed in 2θ: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0 and 23.7.

[0116] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 7 The description.

[0117] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 3, expressed as a 2θ angle.

[0118] Table 3

[0119]

[0120] In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 8 The depicted DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with a peak at about 200°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with an onset at about 199°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 150°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 9 The depicted TGA thermogram.

[0121] Compound 1 L-tartrate

[0122] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile L-tartrate.

[0123] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles, at ±0.2 degrees: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.6.

[0124] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven, eight or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6 and 24.6.

[0125] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at angles (±0.2 degrees) represented by 2θ: 9.3, 18.6, and 24.6. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks at angles (±0.2 degrees) represented by 2θ: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.6.

[0126] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 9.3, 16.7, 18.6, 19.6, 22.3, and 24.6. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least nine peaks at the following angles (±0.2 degrees) expressed in 2θ: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.6.

[0127] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 10 The description.

[0128] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 4, expressed as a 2θ angle.

[0129] Table 4

[0130]

[0131] In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 11 The described DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by endothermic activity with a peak at about 208°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by endothermic activity with an initial peak at about 181°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 150°C. In still another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 12 The depicted TGA thermogram.

[0132] Compound 1 adipate

[0133] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile adipate.

[0134] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles, at an angle (±0.2 degrees): 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1, and 49.8.

[0135] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1 and 49.8.

[0136] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at angles (±0.2 degrees) represented by a 2θ angle: 6.3, 9.1, and 24.3. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks at angles (±0.2 degrees) represented by a 2θ angle: 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1, and 49.8.

[0137] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 6.3, 9.1, 18.2, 19.2, 34.1, and 49.8. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 6.3, 9.1, 18.2, 19.2, 34.1, and 49.8.

[0138] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 13 The description.

[0139] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 5, expressed as a 2θ angle.

[0140] Table 5

[0141]

[0142] In one embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 14 The described DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or its pharmaceutically acceptable salt has a DSC thermogram characterized by endothermic activity with at least one peak at about 154°C, 189°C, or 199°C. In another embodiment, the compound or its pharmaceutically acceptable salt has a DSC thermogram characterized by endothermic activity with an initial temperature of about 26°C. In another embodiment, the compound or its pharmaceutically acceptable salt has a DSC thermogram characterized by a dehydration event with an initial temperature of about 26°C. In another embodiment, the compound or its pharmaceutically acceptable salt has a substantially as described above. Figure 15 The depicted TGA thermogram.

[0143] Compound 1 phosphate

[0144] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile phosphate.

[0145] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles, at ±0.2 degrees: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.4.

[0146] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven, eight or all) of the following peaks at angles (±0.2 degrees) expressed in 2θ: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5 and 24.4.

[0147] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at angles (±0.2 degrees) represented by 2θ: 4.5, 13.5, and 13.7. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks at angles (±0.2 degrees) represented by 2θ: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.4.

[0148] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 4.5, 13.5, 13.7, 16.5, 21.5, and 24.4. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least nine peaks at the following angles (±0.2 degrees) expressed in 2θ: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.4.

[0149] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ angles: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5 and 24.4.

[0150] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 16 The description.

[0151] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 6, expressed as a 2θ angle.

[0152] Table 6

[0153]

[0154] In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 17 The depicted DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with a peak at about 227°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by exothermic activity with an onset at about 218°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 150°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 18 The depicted TGA thermogram.

[0155] Compound 1 free base

[0156] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile.

[0157] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that the XRPD diffraction pattern has at least one (or two) of the following peaks, expressed in 2θ angles, at ±0.2 degrees: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.7.

[0158] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in that its XRPD diffraction pattern has at least three (or four, five, six, seven, eight, nine or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8 and 22.7.

[0159] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.7, 7.1, and 8.3. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least six peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.7.

[0160] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.7, 7.1, 8.3, 13.0, 15.5, and 18.7. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having at least nine peaks at the following angles (±0.2 degrees) expressed in 2θ: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.7.

[0161] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized in an XRPD diffraction pattern having peaks at the following angles (±0.2 degrees), expressed in 2θ angles: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.7.

[0162] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern substantially as shown in the image. Figure 19 The description.

[0163] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is characterized by an XRPD diffraction pattern having a peak at an angle (±0.2 degrees) selected from the list in Table 7, expressed as a 2θ angle.

[0164] Table 7

[0165]

[0166] In one embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as follows Figure 20The described DSC thermogram is characterized by endothermic activity. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by endothermic activity with a peak at about 195°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by endothermic activity with an initial peak at about 176°C. In another embodiment, the compound or a pharmaceutically acceptable salt thereof has a DSC thermogram characterized by a dehydration event below about 100°C. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof has a substantially as described above. Figure 21 The depicted TGA thermogram.

[0167] III. Treatment Methods

[0168] Compound 1 of this disclosure can inhibit the activity of KRAS proteins, particularly KRAS proteins carrying the G12D mutation. Therefore, Compound 1 as described in this disclosure, its crystal form, its crystalline salts and their crystal forms, as well as formulations and dosage forms thereof (collectively, "the compositions of this disclosure") can be used to inhibit the activity of KRAS (including KRAS carrying the G12D mutation) in cells, individuals, or subjects requiring enzyme inhibition by administering an inhibitory amount of the compound to the cells, individuals, or subjects. Therefore, the compositions of this disclosure can be used to treat diseases involving KRAS (particularly KRAS carrying the G12D mutation), including cancer. Diseases involving KRAS include those associated with the expression or activity of KRAS, such as diseases in which abnormally proliferating cells (e.g., cancerous cells) express KRAS. Diseases involving KRAS carrying the G12D mutation include those associated with the expression or activity of KRAS carrying the G12D mutation, such as those in which (e.g., cancer) abnormally proliferating cells express or contain KRAS carrying the G12D mutation.

[0169] The types of cancers involving KRAS, particularly those carrying the G12D mutation, and that can be treated with the compositions disclosed herein include, but are not limited to: cancers (e.g., pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, gastric cancer, esophageal cancer, breast cancer, head and neck cancer, cervical skin cancer, thyroid cancer); hematopoietic malignancies (e.g., myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), chronic and juvenile myelomonocytic leukemia (CMML and JMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM)); and other tumors (e.g., glioblastoma and sarcoma). Furthermore, KRAS mutations have been found in acquired resistance to EGFR-resistant therapy (Knickelbein, K. et al. Genes & Cancer, (2015): 4-12). KRAS mutations have been found in immune and inflammatory disorders (Fernandez-Medarde, A. et al. Genes & Cancer, (2011): 344-358), such as Ras-associated lymphoproliferative disorder (RALD) or juvenile myelomonocytic leukemia (JMML) caused by somatic mutations in KRAS or NRAS.

[0170] The compositions disclosed herein can be used to treat various diseases associated with aberrant expression or activity of KRAS. Compounds that inhibit KRAS will help provide a means of preventing tumor growth or inducing tumor cell apoptosis or by inhibiting angiogenesis. Therefore, it is anticipated that the compositions disclosed herein will be shown to be useful for the treatment or prevention of proliferative conditions such as cancer. In particular, tumors with receptor tyrosine kinase activation mutants or upregulated receptor tyrosine kinases may be particularly sensitive to inhibitors.

[0171] In one aspect, this document provides a method for inhibiting KRAS activity, the method comprising contacting compound 1 with KRAS. In one embodiment, contact comprises administering the disclosed composition to a subject.

[0172] In one aspect, this document provides a method for inhibiting the KRAS protein carrying the G12D mutation, the method comprising contacting KRAS with compound 1. In one embodiment, contact comprises administering the composition of this disclosure to a subject.

[0173] Therefore, in one aspect, this document provides a method for treating a subject with cancer, the method comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof in the form of a composition of this disclosure. In one aspect, the cancer can be a cancer involving KRAS carrying a G12D mutation, such as cancer associated with the expression or activity of KRAS carrying a G12D mutation. Such cancers can include cancers in which (e.g., cancerous) abnormally proliferating cells express or contain KRAS carrying a G12D mutation.

[0174] In one embodiment, cancer is associated with the expression or activity of the KRAS protein. In another embodiment, cancer is associated with the expression or activity of the KRAS protein having a G12D mutation.

[0175] On the other hand, this document provides a method for treating cancer in a subject, the method comprising: identifying that the subject has a need for treatment of cancer and that the abnormally proliferating cells of the cancer contain KRAS with a G12D mutation; and administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt thereof in the form of a composition of this disclosure.

[0176] In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is pancreatic ductal carcinoma. In still another embodiment, the cancer is lung cancer. In yet another embodiment, the cancer is non-small cell lung cancer (NSCLC).

[0177] In another embodiment, the cancer is metastatic.

[0178] In yet another embodiment, the abnormally proliferating cells of the cancer contain KRAS with a G12D mutation.

[0179] On the other hand, this document provides a method for treating a disease or condition associated with KRAS activity, the method comprising administering a therapeutically effective amount of the composition of this disclosure to a subject in need.

[0180] In one embodiment, the disease or condition is an immune or inflammatory condition. In another embodiment, the immune or inflammatory condition is Ras-associated lymphoproliferative disorder or juvenile myelomonocytic leukemia caused by a KRAS somatic mutation.

[0181] In another aspect, this document provides a method for treating a disease or condition associated with abnormal activity of a KRAS protein carrying a G12D mutation, the method comprising administering a therapeutically effective amount of the composition of this disclosure to a subject in need.

[0182] On the other hand, this document provides a method for treating a disease or condition associated with abnormal activity of a KRAS protein carrying a G12V mutation, the method comprising administering a therapeutically effective amount of the composition of this disclosure to a subject in need.

[0183] On the other hand, this document also provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the composition disclosed herein.

[0184] In another aspect, this article also provides a method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of the composition disclosed herein, wherein the cancer is characterized by the presence or activity of a KRAS protein carrying a G12D mutation.

[0185] In another aspect, this document provides a method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition disclosed herein.

[0186] In one embodiment, the cancer is selected from carcinoma, hematologic malignancies, sarcomas, and glioblastoma. In another embodiment, the hematologic malignancies are selected from myeloproliferative neoplasms, myelodysplastic syndromes, chronic and juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, and multiple myeloma. In yet another embodiment, the cancer is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical cancer, skin cancer, and thyroid cancer.

[0187] In one aspect, this document provides a method for treating a subject in need of a disease or condition associated with KRAS interaction or the activity of a mutant thereof, the method comprising the step of administering to the subject a combination of the composition disclosed herein with another therapy or treatment agent as described herein.

[0188] In one embodiment, the cancer is selected from blood cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0189] In another embodiment, the lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma, squamous cell bronchial carcinoma, undifferentiated small cell bronchial carcinoma, undifferentiated large cell bronchial carcinoma, adenocarcinoma, bronchial carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, pavicellular carcinoma and non-pavicellular carcinoma, bronchial adenoma and pleural pulmonary blastoma.

[0190] In another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0191] In one embodiment, the gastrointestinal cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, exocrine pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic insulinoma, pancreatic glucagonoma, pancreatic gastrinoma, pancreatic carcinoid tumor, pancreatic vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal villous adenoma, large intestinal hamartoma, large intestinal leiomyoma, colorectal cancer, gallbladder cancer, and anal cancer.

[0192] In one embodiment, gastrointestinal cancer is colorectal cancer.

[0193] In another embodiment, the cancer is carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical skin cancer, and thyroid cancer.

[0194] In another embodiment, the cancer is a malignant tumor of the hematopoietic system. In one embodiment, the malignant tumor of the hematopoietic system is selected from multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasm.

[0195] In another embodiment, the cancer is a tumor. In yet another embodiment, the tumor is a glioblastoma or sarcoma.

[0196] In some embodiments, this disclosure provides a method for treating a subject with KRAS-mediated condition, the method comprising administering to the subject a composition of the disclosure or a pharmaceutically acceptable composition thereof.

[0197] In some embodiments, diseases and indications for which the compositions of this disclosure may be used to treat include, but are not limited to, blood cancers, sarcomas, lung cancer, gastrointestinal cancers, genitourinary cancers, liver cancer, bone cancer, nervous system cancers, gynecological cancers, and skin cancers.

[0198] Exemplary blood cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), 8p11 myeloproliferative syndrome, myelodyplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenström macroglobulinemia, pilocellular lymphoma, marginal zone lymphoma, chronic myeloid lymphoma, and Burkitt lymphoma.

[0199] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, rod cell sarcoma, fibroma, lipoma, hamartoma, lymphosarcoma, leiomyosarcoma, and teratoma.

[0200] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, chondromatous hamartoma, mesothelioma, cobblestone cell carcinoma and non-cobblestone cell carcinoma, bronchial adenoma, and pleural pulmonary blastoma.

[0201] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (exocrine pancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasodilator intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer, and anal cancer.

[0202] Exemplary urogenital cancers include: kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminomatous seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoidoma, lipoma), and urothelial carcinoma.

[0203] Exemplary liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0204] Exemplary bone cancers include, for example: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma, and giant cell tumor.

[0205] Exemplary neurological cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, glioma), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, neuroectodermal tumor), and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), neuroblastoma, Lhermitte-Duclos disease, and pineal tumors.

[0206] Exemplary gynecological cancers include breast cancer (ductal carcinoma, lobular carcinoma, breast sarcoma, triple-negative breast cancer, HER2-positive breast cancer, inflammatory breast cancer, papillary carcinoma), uterine cancer (endometrial cancer), cervical cancer (cervical cancer, pretumoral cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell tumor, Sertoli-stromal cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)) and fallopian tube cancer (carcinoma).

[0207] Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid.

[0208] Exemplary head and neck cancers include glioblastoma, melanoma, rod cell sarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal carcinoma, nasal cavity and paranasal carcinoma, thyroid cancer and parathyroid cancer, eye tumors, lip and oral cavity tumors, and squamous head and neck cancer.

[0209] The compositions disclosed herein can also be used to inhibit tumor metastasis.

[0210] In addition to carcinogenic tumors, the compositions disclosed herein can also be used to treat skeletal and chondrocyte disorders, including but not limited to achondroplasia, decreased cartilage production, dwarfism, lethal dysplasia (TD) (clinical types TD I and TD II), Apert syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson skin swirl syndrome, Pfeiffer syndrome, and craniosynostosis. In some embodiments, this disclosure provides a method for treating a subject suffering from a skeletal and chondrocyte disorder.

[0211] In one embodiment, the cancer is selected from blood cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0212] In another embodiment, the lung cancer is selected from non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma, squamous cell bronchial carcinoma, undifferentiated small cell bronchial carcinoma, undifferentiated large cell bronchial carcinoma, adenocarcinoma, bronchial carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, chondromatous hamartoma, mesothelioma, cobblestone cell carcinoma and non-cobblestone cell carcinoma, bronchial adenoma, and pleural pulmonary blastoma.

[0213] In another embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In yet another embodiment, the lung cancer is adenocarcinoma.

[0214] In one embodiment, the gastrointestinal cancer is selected from esophageal squamous cell carcinoma, esophageal adenocarcinoma, esophageal leiomyosarcoma, esophageal lymphoma, gastric cancer, gastric lymphoma, gastric leiomyosarcoma, exocrine pancreatic cancer, pancreatic ductal adenocarcinoma, pancreatic insulinoma, pancreatic glucagonoma, pancreatic gastrinoma, pancreatic carcinoid tumor, pancreatic vasoactive intestinal peptide tumor, small intestinal adenocarcinoma, small intestinal lymphoma, small intestinal carcinoid tumor, Kaposi's sarcoma, small intestinal leiomyoma, small intestinal hemangioma, small intestinal lipoma, small intestinal neurofibroma, small intestinal fibroma, large intestinal adenocarcinoma, large intestinal tubular adenoma, large intestinal villous adenoma, large intestinal hamartoma, large intestinal leiomyoma, colorectal cancer, gallbladder cancer, and anal cancer.

[0215] In one embodiment, gastrointestinal cancer is colorectal cancer.

[0216] In another embodiment, the cancer is carcinoma. In yet another embodiment, the carcinoma is selected from pancreatic cancer, colorectal cancer, lung cancer, bladder cancer, stomach cancer, esophageal cancer, breast cancer, head and neck cancer, cervical skin cancer, and thyroid cancer.

[0217] In another embodiment, the cancer is a malignant tumor of the hematopoietic system. In one embodiment, the malignant tumor of the hematopoietic system is selected from multiple myeloma, acute myeloid leukemia, and myeloproliferative neoplasm.

[0218] In another embodiment, the cancer is a tumor. In yet another embodiment, the tumor is a glioblastoma or sarcoma.

[0219] In one embodiment, the cancer is selected from the group consisting of: blood cancers, sarcomas, lung cancer, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0220] In one embodiment, the cancer is selected from the group consisting of: pancreatic cancer, cervical cancer, colon cancer, ovarian cancer, breast cancer, pancreatic cancer, carcinoma, and adenocarcinoma.

[0221] In another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is a solid tumor.

[0222] In one embodiment of the method described herein, the subject is a human being.

[0223] IV. Pharmaceutical Compositions

[0224] Compound 1, its crystal form, its crystalline salt, and its crystal form as described herein can be administered in a pharmaceutical composition comprising the crystal form disclosed herein and at least one pharmaceutically acceptable carrier or excipient.

[0225] Suitable pharmaceutical compositions can be formulated using methods known in the art, and their administration methods and dosages can be determined by a person skilled in the art. For parenteral administration, the compound can be dissolved in sterile water or saline or in a pharmaceutically acceptable medium for administering non-water-soluble compounds, such as those for vitamin K. For enteral administration, the compound can be administered in tablet, capsule, or dissolved in a liquid form. Tablets or capsules can be enteric-coated or in formulations for sustained release. Many suitable formulations are known, including the following that can be used topically to administer the compound: polymer or protein microparticles encapsulating the compound to be released; ointments; pastes; gels; hydrogels; or solutions. Sustained-release patches or implants can be used to provide release over a long period of time. Many techniques known to those skilled in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro. As described in the 20th edition, Lippencott Williams & Wilkins, (2000). Formulations for parenteral administration may contain, for example, excipients, polyalkylene glycols (such as polyethylene glycol), plant-derived oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolic acid copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compound. Other potentially useful parenteral delivery systems for regulating the compound include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-dodecyl ether, glycocholate, and deoxycholate, or oil solutions for administration as nasal drops or as gels.

[0226] In one aspect, this document provides a pharmaceutical composition comprising:

[0227] a) Compound 1 as described in this disclosure, its crystal form, its crystalline salts and their crystal forms, as well as their formulations and dosage forms;

[0228] b) Disintegrants;

[0229] c) Adhesive;

[0230] d) Anti-caking agents; and

[0231] e) Lubricant.

[0232] In one embodiment, the composition comprises two lubricants. In one embodiment, the composition further comprises f) an additive. In one embodiment, the composition further comprises f) a second lubricant.

[0233] In another embodiment, the crystalline form of a) is present at a dose between about 25 mg and 200 mg. In yet another embodiment, the crystalline form of a) is present at a dose of about 25 mg. In still another embodiment, the crystalline form of a) is present at a dose of about 100 mg. In one embodiment, the crystalline form of a) is present at a dose of about 200 mg.

[0234] In another embodiment, the disintegrant b) is sodium carboxymethyl starch.

[0235] In another embodiment, adhesive c) is MCC PH102. In yet another embodiment, adhesive c) is HPMC (Methocel E5 Premium LV Hydroxypropyl Methylcellulose).

[0236] In another embodiment, the anti-caking agent d) is colloidal silica.

[0237] In one embodiment, lubricant e) is sodium stearate fumarate.

[0238] In another embodiment, additive f) is magnesium stearate. In another embodiment, the second lubricant f) is magnesium stearate.

[0239] On the other hand, this document provides a pharmaceutical composition comprising:

[0240] a) The crystal form of the present invention;

[0241] b) Sodium carboxymethyl starch;

[0242] c) MCC PH102;

[0243] d) Colloidal silica;

[0244] e) Sodium stearate fumarate; and

[0245] f) Magnesium stearate.

[0246] In one embodiment, the pharmaceutical composition is a tablet.

[0247] IV. Preparation Method

[0248] This disclosure provides a method for preparing the salts of this disclosure.

[0249] Therefore, in one aspect, this article provides a method for preparing 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile hydrochloride A method for producing a dihydrate, comprising reacting 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile with an aqueous solution of hydrochloric acid.

[0250] In one embodiment, the reaction is carried out in a solvent containing an alcohol. In another embodiment, the reaction is carried out in a solvent containing a dialkyl ether. In yet another embodiment, the reaction is carried out in a solvent containing an alkyl ester. In still another embodiment, the reaction is carried out in a solvent containing an alcohol, a dialkyl ether, and an alkyl ester of an alkyl alkanoate.

[0251] In one embodiment, the alcohol is methanol. In another embodiment, the dialkyl ether is methyl tert-butyl ether. In yet another embodiment, the alkyl alkyl ester is ethyl acetate.

[0252] In yet another embodiment, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile and hydrochloric acid react in a substantially 1:1 molar ratio.

[0253] In another embodiment, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile is 3-((R a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile.

[0254] In another embodiment, 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile is 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile.

[0255] IV. Administration / Dosage / Preparation

[0256] On the other hand, this article provides a pharmaceutical composition comprising the crystal form provided herein and a pharmaceutically acceptable carrier.

[0257] The actual dose level of the active ingredient in the pharmaceutical composition discussed herein can be altered to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a specific subject, composition, and administration mode without toxicity to the subject.

[0258] In particular, the selected dose level will depend on a variety of factors, including the activity of the specific compound used, the timing of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds or materials used in combination with the crystal form, the age, sex, weight, condition, general health and prior medical history of the subject being treated, and similar factors well known in the medical field.

[0259] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can begin administering the pharmaceutical composition with the disclosed crystal form at a level lower than required to achieve the desired therapeutic effect, and gradually increase the dose until the desired effect is achieved.

[0260] In certain embodiments, it is particularly advantageous to formulate crystals in the form of dosage units to facilitate application and achieve dosage uniformity.

[0261] As used herein, “dosage unit form” refers to a physically discrete unit suitable as a unit dose for use in a subject to be treated; each unit contains a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect, along with the required pharmaceutical medium. The dosage unit form of the crystal form described herein is determined by and directly depends on: (a) the unique characteristics of the disclosed compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of mixing / formulating such disclosed compounds for treating the cancer of the subject.

[0262] As used herein, the term "free base equivalent" refers to the amount of active agent (e.g., compound 1) present in its pharmaceutically acceptable salt or in any other form. In other words, the term "free base equivalent" means the amount of free base of compound 1, or the equivalent of free base of compound 1 provided by a salt of said compound. The dosages provided herein refer to the free base equivalent of compound 1.

[0263] In one embodiment, the crystal form provided herein is formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the disclosed crystal form and a pharmaceutically acceptable carrier.

[0264] In one aspect, this document provides a dosage form comprising the compound 1 disclosed herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0265] In one embodiment, the dosage form is in tablet form. In another embodiment, the compound or a pharmaceutically acceptable salt thereof is present in an amount of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile in a dose of about 25 mg to about 200 mg per dosage form.

[0266] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is present in an amount of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile in a dose of about 25 mg per dosage form.

[0267] In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is present in an amount of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile in a dose providing about 100 mg per dosage form.

[0268] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is present in an amount of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinolin-8-yl)propionitrile in a dose of about 200 mg per dosage form.

[0269] In some embodiments, the dosage of the disclosed crystal form is from about 1 mg to about 1,000 mg. In some embodiments, the amount of compound 1 as described in this disclosure, its crystal form, its crystalline salt and crystal forms thereof, as well as formulations and dosage forms thereof, is included in the amount (calculated as an amount equivalent to the amount of free base of compound 1) providing a dosage of less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 20 mg or less than about 10 mg of compound 1. For example, the dosage is approximately 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or approximately 600 mg.

[0270] Routes of administration for any of the compositions disclosed herein include oral, intranasal, rectal, vaginal, parenteral, oral, sublingual, or topical application. The compounds used herein can be formulated for administration via any suitable route, such as oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lateral lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivallary), intranasal, intrarectal, intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, intrasheathal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, and topical application. In one embodiment, oral administration is preferred.

[0271] Suitable compositions and dosage forms include, for example, tablets, capsules, microcapsules, pills, capsule tablets, lozenges, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions, sugar tablets, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions that can be used in this disclosure are not limited to the specific formulations and compositions described herein.

[0272] For oral applications, tablets, sugar-coated pills, liquids, drops, suppositories or capsules, pouches, and soft capsules are particularly suitable. Compositions intended for oral use can be prepared according to any method known in the art, and such compositions may contain one or more pharmaceutical agents selected from the group consisting of inert, non-toxic pharmaceutical excipients suitable for the manufacture of tablets. Such excipients include, for example: inert diluents such as lactose; granulating and disintegrants such as corn starch; binders such as starch; and lubricants such as magnesium stearate. For aesthetic purposes or to delay the release of the active ingredient, tablets may be uncoated or may be coated using known techniques. Formulations for oral use may also be hard gelatin capsules in which the active ingredient is mixed with an inert diluent.

[0273] For parenteral administration, the disclosed compounds can be formulated for injection or infusion, such as intravenous, intramuscular, or subcutaneous injection or infusion, or for bolus or continuous infusion administration. Suspensions, solutions, or emulsions in oily or aqueous media can be used, optionally containing other formulations such as suspending agents, stabilizers, or dispersants.

[0274] Those skilled in the art will recognize or be able to determine, using no more than routine experiments, numerous equivalent forms of the specific procedures, embodiments, claims, and examples described herein. Such equivalent forms are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications to reaction conditions (including, but not limited to, reaction time, reaction size / volume, and experimental reagents (such as solvents, catalysts), pressure, atmospheric conditions (e.g., nitrogen atmosphere), and reducing / oxidizing agents) using alternatives recognized in the art and employing no more than routine experiments are all within the scope of this application.

[0275] It should be understood that whatever values ​​and ranges are provided herein, all values ​​and ranges encompassed by these values ​​and ranges are included within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the value ranges, are also contemplated in this application.

[0276] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings set forth in this disclosure.

[0277] Example

[0278] This disclosure is further illustrated by the following examples, which should not be construed as further limiting. Unless otherwise stated, the practice of this disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the scope of the art.

[0279] The KRAS inhibitors described herein, their synthesis, and their bioactivity against KRAS can be found in WO 2023 / 064857, which is incorporated herein by reference in its entirety.

[0280] Example 1: Synthesis of 3-(1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile (compound 1)

[0281]

[0282] Step 1. Methyl 2-amino-4-bromo-3-fluorobenzoate:

[0283]

[0284] Dimethyl sulfate (823 g, 6.53 mol) was added to a mixture of 2-amino-4-bromo-3-fluorobenzoic acid (1500 g, 6.22 mol) and potassium carbonate (945 g, 6.84 mol) in N,N-dicarboxamide or 1,4-dioxane (6 L) at 5 °C to 50 °C. After addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. Water (7.5 L) was gradually added to the reaction mixture to precipitate the product. After the addition of water, the mixture was stirred at room temperature for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (3 x 1.5 L). The solid was dried under vacuum overnight at about 50 °C to give the desired product (1530 g, 99% yield). Calculated value of LCMS C8H7BrFNO2: 246.96; Found value: 248 (M + H + ). 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J = 8.8, 1.7 Hz, 1H), 6.87 – 6.77 (m, 3H), 3.82 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -127.24

[0285] Step 2. Methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate:

[0286]

[0287] Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Pd-132) (8.12 g, 0.011 mol) was added to a mixture of methyl 2-amino-4-bromo-3-fluorobenzoate (1420 g, 5.72 mol), 2,3-dichlorophenylboronic acid (1226 g, 6.3 mol), and potassium fluoride (732 g, 12.6 mol) in acetonitrile (6 L) and water (1.5 L). The mixture was degassed, refilled with nitrogen, and heated to 70 °C for 1 hour to complete the reaction. Water (6 L) was added to the reaction mixture at 50 °C. The mixture was cooled to room temperature and stirred for 1 hour. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 2 L) containing 50% acetonitrile and water (2 x 2 L). The solids were dried under vacuum at about 50 °C overnight to give the desired product (1700 g, 94% yield). LCMS C 14 Calculated value of H9Cl2FNO2: 313.01; Measured value: 314 (M + H + ). 1 H NMR(400 MHz, DMSO-d6) δ 7.74 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (dd, J = 8.4, 1.4Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.9, 1.6 Hz, 1H), 6.70 (s(b), 2H), 6.51 (dd, J = 8.3, 6.6 Hz, 1H), 3.86 (s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -134.70

[0288] Step 3. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0289]

[0290] N-bromosuccinimide (684 g, 3.84 mol) was added to a solution of methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate (1150 g, 3.66 mol) in acetonitrile (5.75 L) at 50 °C to 66 °C. After the reaction was complete, the acetonitrile (3 L) was removed by rotary evaporation. Water (5.75 L) was added to the concentrated mixture and the mixture was stirred at room temperature for 2 to 3 hours. The solid was separated by filtration, and the wet filter cake was washed with water to give methyl 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate. LCMS C 14 Calculated value of H9BrFCl2NO2: 390.92; Measured value: 391 (M+H). 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 8.1,1.5 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (dd, J = 7.7, 1.5 Hz, 1H), 6.83(s(b), 2H), 3.87(s, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -128.19.

[0291] Step 4. 3-Amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid:

[0292]

[0293] The wet filter cake of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid was dissolved in THF (3 L) and methanol (1.5 L). Sodium hydroxide (1.5 M) aqueous solution (5 L) was added to the solution, and the mixture was stirred at approximately 50 °C for 2 hours to complete the saponification reaction. Hydrochloric acid (1.5 M) aqueous solution was gradually added to the mixture to adjust the pH to 3-4, and the mixture was stirred at room temperature for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (3 x 1.2 L). The solid was dried under vacuum overnight at approximately 50 °C to give the desired product (1354 g, 97.5% yield over two steps). LCMS C 13 Calculated value of H7BrCl2FNO2: 376.90; Measured value: 378 (M + H + ). 1H NMR (400 MHz, DMSO-d6)δ 7.85 (d, J = 1.7 Hz, 1H), 7.78 (dd, J = 8.1, 1.5 Hz, 1H), 7.52 (t, J = 7.9Hz, 1H), 7.39 (dd, J = 7.9, 1.5 Hz, 1H), 6.88. 19 F NMR (376 MHz, DMSO-d6) δ -128.95.

[0294] Step 5. 6-Bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione:

[0295]

[0296] Tetrahydrofuran (THF) (500 mL) containing triphosgene (500 g, 1.65 mol) was added to a solution of 3-amino-6-bromo-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylic acid (1254 g, 3.31 mol) in THF (4 L) at 60 °C, and the mixture was stirred for 1 hour to allow the reaction to complete. The mixture was cooled to 35 °C, and n-heptane (10 L) was slowly added to precipitate the product. The mixture was cooled to room temperature and stirred for 1 hour. The solid was separated by filtration and washed with n-heptane (2 x 1 L). The wet filter cake was dried overnight under vacuum at approximately 50 °C to give the desired product (1385 g, quantitative yield). LCMSC 14 Calculated value of H5BrCl2FNO3: 402.88; Measured value: 404 (M + H + ). 1 H NMR (400 MHz, DMSO-d6) δ12.24 (s, 1H), 8.10 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 8.1, 1.5 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.43 (dd, J = 7.7, 1.5 Hz, 1H). 19 F NMR (376 MHz, DMSO-d6)δ -123.98.

[0297] Step 6. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0298]

[0299] A mixture of 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (1078 g, 2.66 mol), ethyl acetoacetate (693 g, 5.32 mol), sodium acetate (393 g, 4.79 mol), and sodium chloride (933 g, 16 mol) in dimethyl sulfoxide (5 L) was heated to 50-60 °C for 5 hours. The temperature was increased to 100 °C and stirred for 1 hour to complete the reaction. The mixture was cooled to approximately 60 °C, and water (10 L) was gradually added to precipitate the product. The mixture was cooled to room temperature and stirred for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (2 x 2 L). The wet solid was dried overnight under vacuum at approximately 50 °C to give the desired product (1145 g, 91% yield). LCMSC 19 H 13 Calculated value of BrCl2FNO2: 470.94; Measured value: 472 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ12.05 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -124.80.

[0300] Step 6b. Ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0301] The title compound can alternatively be prepared by the following method. A solution of methyl 3-amino-2',3'-dichloro-2-fluoro-[1,1'-biphenyl]-4-carboxylate (100 g, 0.254 mol), ethyl acetoacetate (33.1 g, 0.51 mol), and p-toluenesulfonic acid (2.2 g, 0.013 mol) in xylene (1 L) was refluxed for 5 hours to remove water azeotropically. Sodium ethoxide (26 g, 0.381 mol) was added to the mixture, and the mixture was refluxed again for 5 hours. The mixture was cooled to room temperature and poured into dilute hydrochloric acid at pH = 6 to 7. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated, and the product was purified by silica gel column chromatography, eluting with ethyl acetate and heptane (0% to 30%) to give the desired product (65 g, 54%). LC-MSC 19 H 13 Calculated value of BrCl2FNO3: 470.91; Measured value: 472 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ12.05 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.58(t, J = 7.9 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 19 F NMR (376 MHz, DMSO-d6) δ -124.80.

[0302] Step 7. Ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0303]

[0304] A mixture of ethyl 6-bromo-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (246 g, 0.52 mol), acrylonitrile (69 g, 1.3 mol), trimethylamine (156 g, 1.56 mol), and bis(di-tert-butyl)-dimethylaminophenylphosphine palladium(II) dichloride (Pd-132) (14.7 g, 0.02 mol) in N,N-dimethylamide (1.5 L) was heated to 85 °C for 5 hours to complete the reaction. The mixture was cooled to 50 °C, and water (1 L) was gradually added. The mixture was cooled to room temperature, and 1 M hydrochloric acid was added to adjust the pH to pH 5 to 6. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 500 mL). The wet solids were dissolved in methanol (1 L) and dichloromethane (9 L). Sodium bisulfite (186 g, 1.8 mol) and water (4 L) were added to the solution. The mixture was stirred at room temperature for 1 hour, and the aqueous phase was separated and discarded. The organic phase was washed with water (2 x 2 L). Activated carbon (150 g) was added to the organic solution, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered through a diatomaceous earth bed, and the bed was washed with dichloromethane (2 L). The organic solution was concentrated to about 1 L, and heptane (3.5 L) was gradually added to precipitate the product. The solid was separated by filtration and washed with heptane (2 x 2 L). The wet solid was dried under vacuum at about 50 °C overnight to give the desired product (210 g). g, yield 90%). LCMSC 22 H 15 Calculated value of Cl2FNO3: 444.04; Measured value: 445 (M + H) + ). 1 ¹H-NMR (400 MHz, DMSO-d6) (cis and trans mixture): δ 12.05 (s, 1H), 8.64 (s, 0H), 8.39 (s, 1H), 7.86 (td, J = 7.7, 1.5 Hz, 1H), 7.63 – 7.53 (m, 1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.04 (d, J = 16.5 Hz, 1H), 6.88 (d, J = 11.9 Hz, 0H), 6.55 (d, J = 16.6 Hz, 1H), 5.91 (d, J = 12.0 Hz, 0H), 4.29 (q, J = 7.1 Hz, 2H). 2.47 (d, J = 5.0 Hz, 4H), 1.30 (td, J = 7.1, 3.2 Hz, 4H).

[0305] Step 8. Ethyl 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate:

[0306]

[0307] A mixture of ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (155 g, 348 mmol), pyridine (450 mL), and 1,4-dioxane (450 mL) was heated to 50°C to 60°C to obtain a homogeneous solution. Sodium borohydride (65.8 g, 1741 mmol) was added partically to the solution at 50°C to 60°C. The resulting mixture was stirred at 50°C to 60°C for 22 hours to complete the reduction. After cooling to approximately 15°C, ethyl acetate (950 mL) was added to the reaction mixture. Concentrated hydrochloric acid was gradually added to the mixture to adjust the pH of the aqueous phase to 1 to 2. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (500 mL). The combined ethyl acetate phases were washed with 1N hydrochloric acid aqueous solution (500 mL), water (2 x 500 mL), and 10% brine (300 mL), and dried over sodium sulfate (75 g). The solution was concentrated, and the residue was purified by silica gel column chromatography (DCM containing 0% to 20% MeOH) to give the desired product (117.8 g, 76%). LC-MSC 22 H 17 Calculated value of Cl2FN2O3: 446.06; Measured value: 447 (M + H) + ). 1 H NMR (400 MHz, DMSO-d6) δ11.87 (s, 1H), 8.00 (s, 1H), 7.84 (dd, J = 7.9, 1.7 Hz, 1H), 7.71 – 7.48 (m,2H), 4.28 (q, J = 7.1 Hz, 2H), 2.79 (ddd, J = 11.7, 7.4, 3.7 Hz, 1H), 2.73 –2.59 (m, 3H), 2.46 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0308] Step 9. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0309]

[0310] Phosphorus oxychloride (62 g, 405 mmol) was added to a mixture of ethyl 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (60 g, 134 mmol), benzyltriethylammonium chloride (31 g, 135 mmol), and N,N-dimethylaniline (49.1 g, 405 mmol) in acetonitrile (300 mL) at below 20 °C. The mixture was heated to 60 °C for 1 hour to complete the reaction. The mixture was cooled to room temperature and collected in ice water (900 mL) at below 20 °C. The product was allowed to precipitate during water quenching. The mixture was stirred at room temperature for more than 5 hours. The solid was separated by filtration, and the wet filter cake was washed with water containing 10% acetonitrile (2 x 150 mL). The wet solid was dried overnight under vacuum at about 50 °C to give the desired product (57 g, 90% yield). LCMS C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5, 2.1 Hz,1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m, 1H), 2.85– 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0311] Step 10. Ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0312]

[0313] Phosphorus oxychloride (389.7 g, 4.04 mol) was added to a mixture of ethyl 6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-4-hydroxy-2-methylquinoline-3-carboxylate (600 g, 1.35 mol), benzyltriethylammonium chloride (307 g, 1.35 mol), and N,N-dimethylaniline (603 g, 4.04 mol) in acetonitrile (3 L). The mixture was heated to 60 °C for 1 hour to complete the reaction. The mixture was cooled to room temperature and collected in ice water (9 L) at a temperature below 20 °C. The product was allowed to precipitate during water quenching. The mixture was stirred at room temperature for more than 5 hours. The solid was separated by filtration, and the wet filter cake was washed with water containing 10% acetonitrile (2 x 1.5 L). The wet solid was dried overnight under vacuum at about 50 °C to give the desired product (563 g, 90% yield). LCMS C 22 H 14 Calculated value of Cl3FN2O2: 462.01; Measured value: 463 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) (mixture of cis and trans isomers) δ 8.72 (s,0.3H), 8.51 (s, 1H), 7.87 (ddd, J = 7.3, 5.6, 1.5 Hz, 1.3H), 7.64 – 7.46 (m,3H), 7.21 (d, J = 16.5 Hz, 1H), 7.05 (d, J = 11.9 Hz, 0.3H), 6.73 (d, J =16.5 Hz, 1H), 6.08 (d, J = 11.9 Hz, 0.3H), 4.53 (qd, J = 7.1, 2.0 Hz, 2H), 2.72 (d, J = 7.4 Hz, 4H), 1.41 (t, J = 7.1 Hz, 4H).

[0314] Step 11. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate:

[0315]

[0316] A mixture of ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (528 g, 1.14 mol) and PMHS (411 g, 6.83 mol) in toluene (1.8 L) was stirred at about 50 °C. In another 2 L flask, copper diacetoxyhydrate (4.1 g, 0.02 mol) and (9,9-dimethyl-9H-xanthon-4,5-diyl)bis(diphenylphosphine) (13.58 g, 0.023 mol) in toluene (300 ml) and tert-butanol (483 g, 6.52 mol) was stirred for 1 to 2 hours to form a solution. A copper acetate solution was slowly added to a solution of ethyl 4-chloro-6-(2-cyanovinyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate and PMHS in toluene at 50-60°C to complete the reduction. The reaction mixture was concentrated to approximately 2 L under vacuum distillation. Heptane (8 L) was added to the 2 L residue at approximately 50°C for 1 hour. The mixture was cooled to room temperature and stirred overnight. The solids were separated by filtration, and the wet filter cake was washed with heptane (2 x 1.2 L). The wet filter cake and silica gel (260 g) were stirred in dichloromethane (2.7 L) for 1 hour. The mixture was filtered through a silica gel bed (260 g), and the silica gel bed was washed with DCM (4 L) until the eluent was almost colorless. The dichloromethane was removed. Dichloromethane (140 mL) and methyl tert-butyl ether (260 mL) were added to the residue. The solids were separated by filtration, and the wet filter cake was washed with MTBE (2 x 1.2 L). The wet solids were dried overnight under vacuum at approximately 50 °C to give the desired product (476 g, 90% yield). LCMS C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5, 2.1 Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m, 1H), 2.85 – 2.72 (m, 3H), 2.69 (s,3H), 1.40 (t, J = 7.1 Hz, 3H).

[0317] Step 12. (R) a 4-Chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester:

[0318]

[0319] Racemic ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate was subjected to chiral separation (Chiralpak IB N, MTBE as eluent) to yield both (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate and (S)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate. LCMS C 22 H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd,J = 7.5, 2.1 Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 –2.86 (m, 1H), 2.85 – 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

[0320] Step 13. Ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate, by racemization:

[0321]

[0322] A mixture of (S)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (100 g) in sulfolane (200 mL) was heated to 185 °C for 2 hours to give racemic 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate. The mixture was cooled to 50 °C and acetonitrile (200 mL) was added. Water (700 mL) was added to the solution at 50 °C. The mixture was cooled to room temperature and stirred for 4 hours. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 200 mL). The wet solids were dried overnight under vacuum at about 50 °C to give the desired product (97 g, 97% yield). LCMS C 22H 16 Calculated value of Cl3FN2O2: 464.03; Measured value: 465 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.86 (dd, J = 7.5,2.1 Hz, 1H), 7.64 – 7.53 (m, 2H), 4.52 (q, J = 7.1 Hz, 2H), 2.97 – 2.86 (m,1H), 2.85 – 2.72 (m, 3H), 2.69 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H)

[0323] Step 14. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0324]

[0325] (R) a A mixture of ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (106.3 g, 228 mmol), (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester (58.8 g, 297 mmol), lithium chloride (19 g, 446 mmol), and diisopropylethylamine (99.5 g, 670 mmol) in dimethyl sulfoxide (400 mL) was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and then tert-butyl methyl ether (TBME) (1 L) and water (500 mL) were added. The organic phase was separated. The organic phase was washed with 0.1 N hydrochloric acid aqueous solution (500 mL), saturated sodium bicarbonate (500 mL), and water (500 mL). The solvent was removed under reduced pressure to obtain the desired product, which could be used in the next step without further purification. The analytical sample was purified by passing it through a silica gel column (containing 0% to 10% MeOH in DCM). LCMSC 32 H 33 Calculated value of Cl2FN4O4: 626.19; Measured value: 627 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ8.09 (s, 1H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.38 (dd, J = 7.7, 1.5 Hz, 1H), 7.14 (s, 1H), 4.49 – 4.37 (m, 2H), 4.31 (s, 1H), 3.71 (d, J = 4.1 Hz, 1H), 3.65 – 3.43 (m, 1H), 3.18 (d, J = 9.3 Hz, 1H), 3.02(s, 1H), 2.91 – 2.74 (m, 2H), 2.70 (dd, J = 13.6, 5.9 Hz, 2H), 2.55 (s, 3H), 1.81 – 1.60 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 – 1.06 (m, 4H), 0.92 (s, 9H).

[0326] Step 14a. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0327] The title compound can be prepared alternatively by the following method. A mixture of (R)-4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate (40 g, 85 mmol), lithium carbonate (19 g, 258 mmol), and (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl oxalate (29.4 g, 98 mmol) in DMSO (120 mL) was heated to 80 °C overnight. The reaction mixture was cooled to room temperature, and MTBE (300 mL) was added and filtered. The solids were washed with MTBE (100 mL). The combined filtrates were washed with water (2 × 320 mL). The organic phase was separated. The solvent was removed under reduced pressure to give the product, which could be used in the next step without further purification. The analytical sample was purified by silica gel column chromatography (DCM containing 0% to 10% MeOH). LCMS C 32 H 33 Calculated value of Cl2FN4O4: 626.19; Measured value: 627 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.82 (dd, J=8.1, 1.5 Hz,1H), 7.56 (t, J=7.8 Hz, 1H), 7.38 (dd, J=7.7, 1.5 Hz, 1H), 7.14 (s, 1H),4.49–4.37 (m, 2H), 4.31 (s, 1H), 3.71 (d, J==4.1 Hz, 1H), 3.65–3.43 (m, 1H), 3.18 (d, J==9.3 Hz, 1H), 3.02 (s, 1H), 2.91–2.74 (m, 2H), 2.70 (dd, J=13.6,5.9 Hz, 2H), 2.55 (s, 3H), 1.81–1.60 (m, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.34–1.06 (m, 4H), 0.92 (s, 6H).

[0328] Substitute transisomers (1R,4R,5S)-5-(((R) a )-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester is produced via a similar pathway from (S a 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester, rather than (R a It was prepared by a similar method starting with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0329] Step 15. (R) a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid:

[0330]

[0331] A 2 M aqueous solution of sodium hydroxide (134 mL, 268 mmol) was added to a solution of (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (140.0 g, 223 mmol) in acetonitrile (560 mL) and methanol (210 mL) at room temperature. The mixture was heated to 50 °C for 1 to 1.5 hours. The mixture was cooled to room temperature and acidified with 1 M aqueous hydrochloric acid to approximately pH 5. Acetonitrile and methanol were removed under vacuum. The product was extracted with ethyl acetate (1.7 L). The aqueous phase was separated and extracted with ethyl acetate (420 mL). The combined ethyl acetate phases were concentrated under vacuum to give the residue. 300 mL of tert-butyl methyl ether was added to the residue, and the mixture was stirred at room temperature for 2 hours. The solids were separated by filtration, and the wet filter cake was washed with TBME (2 x 100 mL). The solids were dried under vacuum at about 50 °C to give the desired product (135 g, quantitative), which could be used in the next step without further purification.

[0332] Step 15b. (R) a )-4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid:

[0333] The title compound can be prepared alternatively by the following method. Sodium trimethylsilanolate (338 g, 95%) was added to a solution of (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (1400 g, 2.231 mol) in tetrahydrofuran (14 L) and water (80 mL) at room temperature. The mixture was heated to 50 °C for 1 to 3 hours to complete the reaction. The mixture was cooled to room temperature and acidified with 1M hydrochloric acid aqueous solution to approximately pH 5. The tetrahydrofuran was removed under vacuum. The product was extracted with dichloromethane (6 L). The aqueous phase was separated and extracted with dichloromethane (6 L). The combined organic phases were concentrated under vacuum to give a DCM solution (6 L) containing the product. A concentrated dichloromethane solution was added to tert-butyl methyl ether (7 L) and then to the residue, and the mixture was stirred at room temperature for 2 hours. Then, n-heptane (7 L) was added to the mixture. The dichloromethane was removed under vacuum. The solid was separated by filtration, and the wet filter cake was washed with n-heptane (2 x 3 L). The solid was dried under vacuum at approximately 50 °C to obtain the desired product, which could be used in the next step without further purification.

[0334] Step 16. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0335]

[0336] N-iodosuccinimide (94 g, 396 mmol) was added to a mixture of 4-(((1R,4R,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-yl)amino)-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid (132 g, 220 mmol) and sodium phosphate (74.4 g, 440 mmol) in anhydrous acetonitrile (1614 ml), and the mixture was stirred for 1 hour. Water (1.6 L) was added to the mixture, and the resulting slurry was stirred at room temperature for 5 hours. The solids were separated by filtration, and the wet filter cake was re-slurryed in water (2.6 L) at room temperature for 5 hours. The solids were separated by filtration, and the wet filter cake was washed with water (2 x 250 mL). The solid was dried under vacuum at approximately 50°C to obtain the desired product (120 g, 80% yield). LCMS C 39 H28 Calculated value of Cl2FIN4O2: 680.06; Measured value: 681 (M + H + ). 1 H-NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.56(t, J = 7.8 Hz, 1H), 7.50 (dd, J = 7.7, 1.6 Hz, 1H), 5.49 (s, 1H), 4.28 (s,2H), 3.09 (s, 1H), 2.96 – 2.58 (m, 8H), 1.71 (s, 1H), 1.59 – 0.96 (m, 11H).

[0337] Step 17. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate:

[0338]

[0339] A mixture of cyclopropyl((1R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) methyl ketone (47.5 g, 260 mmol), (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (136.5 g, 200 mmol) and tetrabutylammonium acetate (242 g, 801 mmol) in DMF (1100 ml) was purged under nitrogen for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (2.75 g, 3 mmol) was added to the mixture. The mixture was purged under nitrogen for another 15 min, and then heated to 70 °C for 1 hour. The reaction mixture was cooled to room temperature and added to a semi-saturated aqueous solution of sodium bicarbonate (2200 mL). The solid was separated by filtration, and the wet filter cake was washed with water (600 mL). The solid was dried under vacuum at about 50 °C and purified by silica gel column chromatography (eluting with ethyl acetate containing 0% to 2% methanol) to give the desired product (142 g, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 12.4 Hz, 1H), 7.81 (dd, J =8.1, 1.6 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.3 Hz, 1H), 6.70 –6.44 (m, 1H), 5.68 – 5.13 (m, 1H), 4.54 – 4.18 (m, 2H), 4.00 – 3.80 (m, 1H), 3.51 (s, 1H), 3.19 (t, J = 9.0 Hz, 1H), 3.07 – 2.91 (m, 1H), 2.78 (d, J =10.7 Hz, 3H), 2.66 (d, J = 9.0 Hz, 3H), 2.57 (d, J = 11.7 Hz, 4H), 2.36 –2.08 (m, 2H), 1.88 (dd, J = 17.9, 10.5 Hz, 2H), 1.35 (d, J = 9.7 Hz, 2H),1.15 – 0.59 (m, 16H).

[0340] Step 17a. (1R,4R,5S)-5-(((R) a 6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate:

[0341] The title compound can be prepared alternatively by the following method: A mixture of cyclopropyl((1R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) ketone (17.7 kg, 101 mol), (1R,4R,5S)-5-((6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-3-iodo-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (64.7 kg, 95 mol), copper iodide (I) (0.42 kg, 2 mol), tris(4-fluorophenyl)phosphine (0.39 kg, 1 mol), and K2CO3 (36.4 kg, 191 mol) in DMSO (488.4 L) was purged with nitrogen gas below the liquid surface for 30 min. Palladium(II) acetate (60 g, 30 mmol) was added to the mixture. The mixture was purged with nitrogen under liquid surface for another 30 min, then heated to 50 °C for more than 10 h. The reaction mixture was cooled to room temperature, and EtOAc (906 L) was added, followed by water (1267 L) added slowly. The mixture was stirred at room temperature for 30 min and filtered through a diatomaceous earth bed. The diatomaceous earth bed was washed with EtOAc (33 L). The organic phase was separated from the aqueous phase, and the aqueous phase was back-extracted with EtOAc (195 L). The combined organic phases were washed with water (195 L). Water (130 L) and ammonium pyrrolidine dithiocarbamate (3.1 kg, 19 mol) were added to the EtOAc phase. The mixture was stirred at 50 °C for at least 4 h. The mixture was cooled to room temperature and filtered precisely. The aqueous phase was separated and discarded. The organic phase was washed with water (325 L). The organic phase was heated to 50 °C and passed through an activated carbon filter. The solution was concentrated under vacuum, and the solvent was exchanged for toluene to remove residual water, yielding the desired product in 98% solution yield. The toluene solution was then solvent-exchanged for NMP for the next step of indole cyclization without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.03(d, J=12.4 Hz, 1H), 7.81 (dd, J=8.1, 1.6 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 6.70–6.44 (m, 1H), 5.68–5.13 (m, 1H), 4.54–4.18 (m,2H), 4.00–3.80 (m, 1H), 3.51 (s, 1H), 3.19 (t, J=9.0 Hz, 1H), 3.07–2.91 (m,1H), 2.78 (d, J=10.7 Hz, 3H), 2.66 (d, J=9.0 Hz, 3H), 2.57 (d, J=11.7 Hz,4H), 2.36–2.08 (m, 2H), 1.88 (dd, J=17.9, 10.5 Hz, 2H), 1.35 (d, J=9.7 Hz,2H), 1.15–0.59 (m, 16H).

[0342] Substitute transisomers (1R, 4R, 5S)-5-(((S) a )-6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester is obtained via a similar pathway by performing steps 14 to 17 from (S a 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester, rather than (R a It was prepared by a method starting with ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0343] Step 18. (1R,4R,5S)-5-((R) a 8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]tert-butyl hexane-2-carboxylate:

[0344]

[0345] A mixture of (1R,4R,5S)-5-((6-(2-cyanoethyl)-3-(((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)ethynyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-4-yl)amino)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (141.0 g, 159 mmol) and cesium carbonate (78 g, 238 mmol) in dimethyl sulfoxide (1 L) or N-methyl-2-pyrrolidone was heated to 80-85°C for 1.5 hours. The reaction was cooled to room temperature and water (2 L) was gradually added. The product gradually precipitated from the solution. The resulting slurry was stirred at room temperature for 1 hour. The solid was separated by filtration, and the wet filter cake was washed with water (2 x 300 mL). The wet solid was dried under vacuum. The solid was purified by rapid chromatography using dichloromethane containing 60% to 100% ethyl acetate. The solvent was removed, and the solid in heptane (840 mL) was crystallized from ethyl acetate (420 mL) and tert-butyl methyl ether (420 mL) and heptane (9840 mL) to give the desired product (122 g, 87% yield). LCMS C 40 H 40 Calculated value of Cl2FN5O3: 727.25; Measured value: 728 (M + H) + ). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.81 (dt, J = 8.0, 2.1 Hz, 1H), 7.55 (td, J = 7.8, 5.0 Hz, 1H), 7.45 – 7.29 (m, 1H), 6.26 (s, 1H), 5.81 –5.49 (m, 1H), 5.34 – 5.13 (m, 1H), 5.00 (dd, J = 14.3, 6.8 Hz, 1H), 4.19 –3.97 (m, 1H), 3.63 (dt, J = 6.8, 3.1 Hz, 1H), 3.40 (d, J = 9.4 Hz, 1H), 3.27– 3.09 (m, 1H), 2.95 (dt, J = 14.2, 7.6 Hz, 1H), 2.89 – 2.73 (m, 3H), 2.70 (d, J = 2.7 Hz, 4H), 2.34 – 2.20 (m, 1H), 2.21 – 1.97 (m, 2H), 1.73 (dp, J =15.0, 4.8 Hz, 1H), 1.66 – 1.34 (m, 2H), 1.21 – 1.03 (m, 1H), 1.02 – 0.79 (m,4H), 0.78 – 0.22 (m, 11H).

[0346] Step 19. 3-((R) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile:

[0347]

[0348] At room temperature, (1R,4R,5S)-5-((R) aA solution of tert-butyl hexane-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (167.7 g, 230.1 mmol) in dichloromethane (1.35 L) was mixed with trimethyliodosilane (69 g, 345 mmol) and stirred for 1 h. Sodium bicarbonate aqueous solution (500 mL) was added to quench the reaction. The organic phase was separated and washed with water. The solvent was evaporated by rotary evaporator, and the residue was passed through a silica gel bed (dichloromethane containing 1% to 20% methanol). The solvent was exchanged for ethyl acetate and tert-butyl methyl ether to give the crystalline product (136 g, 94% yield). LCMS C 35 H 32 Calculated value of Cl2FN5O: 627.20; Measured value: 628 (M + H) + ). 1 H-NMR (400 MHz, DMSO-d6) δ 1 H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J = 13.6Hz, 1H), 7.89 – 7.73 (m, 1H), 7.64 – 7.33 (m, 2H), 6.69 – 6.14 (m, 1H), 5.76– 5.43 (m, 1H), 4.97 (d, J = 4.9 Hz, 1H), 4.31 (dd, J = 17.0, 6.0 Hz, 1H), 4.18 – 3.94 (m, 1H), 3.58 – 3.45 (m, 1H), 2.94 (dt, 2H, J = 12.4, 6.1 Hz),2.89 – 2.56 (m, 8H), 2.44 – 2.19 (m, 2H), 2.07 (d, J = 12.9 Hz, 1H), 1.96 –1.54 (m, 3H), 1.30 – 1.13 (m, 1H), 1.06 – 0.20 (m, 6H).

[0349] Substitute for the transisomer 3-((S) a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile is produced via a similar pathway by performing steps 14 to 19 from (S a 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylic acid ethyl ester, rather than (R a It was prepared by the method of ethyl 4-chloro-6-(2-cyanoethyl)-7-(2,3-dichlorophenyl)-8-fluoro-2-methylquinoline-3-carboxylate.

[0350] Example 2. 3-((R) a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile monohydrochloride dihydrate

[0351]

[0352] At 30℃ to 50℃, towards 3-((R) a A solution of 53.8 g (85 mmol) of free base of propionitrile (53.8 g, 85 mmol) dissolved in methanol (110 mL), ethyl acetate (50 mL), water (11 mL), and tert-butyl methyl ether (TBME) (110 mL) was added to the solution of TBME. Seeds were added to the mixture, and the solution gradually became cloudy. TBME (440 mL) was slowly added to the mixture over 1 hour at approximately 40 °C. The mixture was cooled to approximately 15 °C and stirred for 2 hours. The solids were separated by filtration, and the wet filter cake was washed with TBME (2 x 110 mL) containing 5% methanol and 20% ethyl acetate. The wet solids were slurried in ethyl acetate (270 mL) and dried under vacuum at about 50 °C to give the desired product (53.7 g, 90% yield). LCMSC 35 H 32Calculated value of Cl2FN5O: 627.20; Measured value: 628 (M + H) + ). 1 H NMR (500 MHz, DMSO-d6) δ8.15 (s, 1H), 7.83 (dd, J = 8.1, 1.6 Hz, 1H); 7.57 (dd, J = 7.9, 7.9,1H); 7.45 (dd, J = 7.7, 1.6 Hz, 1H); 6.44 (s, 1H); 5.65 (s, 1H); 5.51 (d, J =10.6Hz, 1H); 4.14 (td, J = 6.4, 2.6 Hz, 1H); 3.84-3.90 (m, 1H); 3.30-3.37 (m,1H); 3.43-3.50 (m, 1H); 2.86-2.95 (m, 1H); 2.83-2.92 (m.1H); 2.79 1.69 -1.83 (m, 1H); 1.65 (d, J = 13.0,2.6 Hz, 1H); 9.1Hz, 1H); 0.91-1.00 (m, 2H); 0.82-0.88 (m, 2H); 0.72-0.80 (m, 1H); 0.63-0.69 (m, 1H). 13C NMR (125 MHz, DMSO-d6) δ 171.6; 145.8; 132.8; 135.1; 132.8; 131.9; 131.5; 131.4; 129.2; 101.6; 120.7; 57.9; 56.5; 44.5; 42.5; 30.5; 38.3; 32.8; 22.1; 17.5; 17.1; 13.2; 13.0; 7.70; 7.80. 19F NMR (376 MHz, DMSO-d6) δ -122.1 (s).

[0353] Substitute for the transisomer 3-((S) a)-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile monohydrochloride dihydrate is obtained via a similar pathway by performing steps 15 to 21 from 3-((S a )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile instead of 3-((R a It was prepared by a method starting with )-1-((1R,4R,5S)-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile.

[0354] Example 3. Synthesis of cyclopropyl((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexan-2-yl) ketone (step 17a in Example 1)

[0355] Step 1. (R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl ester:

[0356]

[0357] A solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-ethyl ester (241 g, 0.938 mol) in anhydrous toluene (1.6 L) was added dropwise over 1 h at -50 °C to -40 °C with tetrahydrofuran (1.01 L, 1.01 mol) containing 1 M triethyl borohydride. After the addition, the mixture was stirred at approximately -50 °C for 1 h. DIPEA (726 mL, 4.17 mol) was added dropwise to the mixture over 1 h. 4-Dimethylaminopyridine (1.49 g, 12.2 mmol, 0.013 equivalent) was added to the mixture, followed by the dropwise addition of trifluoroacetic anhydride (156.5 mL, 1.126 mol) over 1.5 h. After the addition, the mixture was stirred at approximately -50 °C for 1 h, and then slowly warmed to room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0°C and slowly diluted with water (2.41 L), while maintaining the temperature below 10°C during addition. The organic layer was separated and washed with water (2.41 L) and saturated brine (720 mL). The organic layer was dried over sodium sulfate (120 g). The solution was concentrated under reduced pressure to give the desired product (230 g, quantitative) as a yellow oil. GCMS C 12 H 19 Calculated value of NO4: 241.1; Measured value: 214.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 6.70-6.48 (m, 1H), 4.99-4.86(m, 1H), 4.70-4.52 (m, 1H), 4.30-4.11 (m, 2H), 3.15-2.98 (m, 1H), 2.73-2.57(m, 1H), 1.53-1.38 (m, 9H), 1.34-1.21 (m, 4H).

[0358] Step 2. (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester

[0359]

[0360] A solution of (R)-2,3-dihydro-1H-pyrrole-1,2-dicarboxylic acid 1-(tert-butyl)-2-ethyl ester (230 g, 0.938 mol) in toluene (2.3 L) was added to the mixture over 1 h at -30 °C to -25 °C. Chloroiodomethane (273 mL, 3.752 mol) was added dropwise to the mixture over 2 h at approximately -30 °C to -20 °C, and the mixture was stirred for 16 h. Semi-saturated sodium bicarbonate (2.3 L) was added to the mixture, and the mixture was warmed to room temperature. The mixture was filtered through diatomaceous earth to remove white solids, and the filter bed was washed with toluene (1.5 L). The organic layer was separated from the filtrate and washed with water (2 × 1.15 L) and saturated brine (1.15 L). The toluene solution was concentrated under reduced pressure to give a 6:1 mixture (231 g) of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester and (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester, as determined by GC-MS analysis.

[0361] An aqueous solution of methylamine (40%, 344 g) was added to the crude mixture product obtained above (226 g), and the mixture was stirred at room temperature for 16 h. Water (340 mL) and methyl tert-butyl ether (340 mL) were added to the mixture. The organic layer was separated and washed with water (340 mL) and saturated brine (230 mL). The solution was concentrated under reduced pressure to give a yellow oil containing 2% (1S,3R,5S)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester (177 g, calculated yield 73%), as determined by GCMS analysis. GCMS C 13 H 21 Calculated value of NO4: 255.1; Measured value: 255.1 (M + ). 1 H-NMR (400MHz, CDCl3) δ 4.56-4.39 (m, 1H), 4.18-4.01 (m, 2H), 3.51-3.36 (m, 1H), 2.60-2.42 (m, 1H), 2.00-1.92 (m, 1H), 1.45-1.32 (m, 9H), 1.23-1.15 (m, 4H), 0.87-0.79 (m, 1H), 0.70-0.56 (m, 1H).

[0362] Step 3. (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0363]

[0364] A solution of (1R,3R,5R)-2-azabicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-(tert-butyl)3-ethyl ester (177 g, 0.694 mol) in tetrahydrofuran (1.56 L) was added to tetrahydrofuran containing 1M lithium aluminum hydride (777 mL, 0.777 mol, 1.12 equivalents). After the addition, the mixture was stirred at 3 °C for 2 h. Water (27 mL) was added dropwise to the mixture to quench the reaction. Sodium hydroxide solution (15%, 27 mL) and water (80 mL) were added dropwise to the mixture sequentially. The mixture was stirred at room temperature for 1 h. DCM (2.35 L) was added to the mixture. The suspension was filtered through a diatomaceous earth (100 g) bed and washed with DCM (300 mL). The filtrate was concentrated under reduced pressure and dried in a vacuum oven at 40 °C for 18 h to obtain a yellow oil containing 2% isomers of (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (133 g, 90% yield), as determined by GC-MS analysis. 11 H 19 Calculated value of NO3: 213.1; Measured value: 213.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 4.83 (brs, 1H), 4.34 (brs, 1H), 2.45 (ddd, 1H), 1.55-1.43 (m, 12H), 0.80 (q, 1H), 0.40 (brs, 1H).

[0365] Step 4. (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0366]

[0367] DMSO (42.7 mL, 0.603 mol) was added dropwise to DCM (535 mL) containing oxaloyl chloride (26.4 mL, 0.301 mol) over 30 min at -78 °C, while maintaining the temperature below -60 °C during the addition. After stirring at -78 °C for 30 min, DCM (535 mL) containing (1R,3R,5R)-3-(hydroxymethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (53.5 g, 0.251 mol) was added dropwise to the solution over 40 min at -78 °C. After stirring at -78 °C for 30 min, NEt3 (104.9 mL, 0.753 mol) was added dropwise to the solution over 40 min at -78 °C. After stirring at -78 °C for 1 h, the reaction mixture was warmed to 0 °C and stirred for 30 min. Water (888 mL) was added to the mixture and stirred for 20 min. The aqueous layer was separated and extracted with DCM (2 × 888 mL). The combined organic layers were washed successively with 1 M HCl (888 mL), water (888 mL), and saturated brine (888 mL). The organic layers were concentrated under reduced pressure to give (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester (44 g, 83% yield), a yellow oil. GCMSC 11 H 17 Calculated value of NO3: 213.1; Measured value: 213.2 (M + ). 1 H-NMR (400 MHz, CDCl3) δ 9.54-9.31(m, 1H), 4.64-4.39 (m, 1H), 3.68-3.45 (m, 1H), 2.68-2.33 (m, 1H), 2.24-2.10(m, 1H), 1.53-1.41 (m, 10H), 0.88-0.71 (m, 1H), 0.39-0.28 (m, 1H).

[0368] Step 5. (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

[0369]

[0370] K₂CO₃ (28.8 g, 0.209 mol, 2 equivalents) was added to a solution of (1R,3R,5R)-3-formyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (22 g, 0.104 mol) in methanol (352 mL) at 0 to 5 °C. Dimethyl (18.3 mL, 0.110 mol) phosphonate was added dropwise to the mixture at 0 to 5 °C for 30 min, while maintaining the temperature < 5 °C during the addition. After stirring at 0 to 5 °C for 15 min, the reaction mixture was warmed to room temperature and stirred for 2 h. Water (372 mL) and EtOAc (930 mL) were added to the mixture, and the mixture was stirred for 15 min. The aqueous layer was separated and extracted with EtOAc (372 mL). The combined organic layers were washed with water (560 mL) and saturated brine (560 mL). The organic solution was concentrated under reduced pressure and purified by silica gel elution with a gradient of heptane containing 0% to 10% EtOAc to give a 7:1 mixture (82 g, calculated yield 74%) of (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate and (1R,3S,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate, as a pale yellow oil. GCMS C 12 H 17 Calculated value of NO2: 207.1; Measured value: 207.0 (M + ). 1 H-NMR (400MHz, CDCl3) δ 4.78-4.54 (m, 1H), 3.60-3.46 (m, 1H), 2.52-2.40 (m, 1H), 2.30-2.22 (m, 1H), 2.18-2.08 (m, 1H), 1.50-1.48 (m, 9H), 1.16-1.05 (m, 1H), 0.91-0.80 (m, 1H), 0.78-0.66 (m, 1H).

[0371] Step 6. Cyclopropyl((1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-yl) methyl ketone

[0372]

[0373] A mixture of (1R,3R,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester and (1R,3S,5R)-3-ethynyl-2-azabicyclo[3.1.0]hexane-2-carboxylate tert-butyl ester (82 g, 0.39 mol) and dioxane containing 4M HCl (297 mL, 1.19 mol, 3 equivalents) was stirred at room temperature for 4 h. The reaction mixture was diluted with THF (1.23 L) and cooled to 0 °C. NEt3 (275.8 mL, 1.98 mol) was added dropwise to the reaction mixture over 1.5 h at 0 °C while maintaining the temperature <10 °C. Cyclopropaneformyl chloride (45.4 g, 0.43 mol) was added to the reaction mixture at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. 1M HCl (410 mL, 5 volumes) and DCM (820 mL) were added. The aqueous layer was separated and extracted with DCM (2 × 820 mL). The combined organic layers were washed with water (820 mL) and saturated brine (820 mL). The organic layers were concentrated under reduced pressure to give a crude residue (60 g). Diatomaceous earth (120 g) was added to the crude residue, and the mixture was dried under reduced pressure to give a dry loaded powder (186 g). The dried loaded powder was purified on a silica gel column (1.5 kg) and eluted with a gradient of heptane containing 15% to 40% EtOAc. The desired fraction was concentrated under reduced pressure and dried under vacuum at 30 °C for 18 h to give the title compound (40.8 g, 59% yield) as a brown oil. GCMS C 12 H 17 Calculated value of NO2: 175.1; Measured value: 175.0 (M + ). 1 H-NMR (400 MHz, DMSOd6) δ 5.14 (dt, 0.45H), 4.81 (dt, 0.55H), 3.82 (t, 0.55H), 3.71 (t, 0.45H), 3.42 (d, 0.45H), 3.15 (d,0.55H), 2.57 (ddd, 0.45H), 2.44 (ddd, 0.55H), 2.09 (dd, 0.45H), 2.04 (ddd,0.55H), 1.97 (dd, 0.55H), 1.86-1.69 (m, 1H), 1.62 (dddd, 0.45H), 1.01 (td,0.55H), 0.90 (td, 0.45H), 0.87-0.68 (m, 5H).

[0374] Example 4. Synthesis of (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate (step 14a in Example 1)

[0375] Step 1. (E)-4-methoxybut-3-en-2-one:

[0376]

[0377] A mixture of 350 g (1.0 equivalent) of 4,4-dimethoxy-2-butanone and sodium acetate (11 g, 0.05 equivalent) was heated to 145 °C to 150 °C under a nitrogen atmosphere, with the resulting methanol purged during heating. When the reaction was complete, the mixture was cooled to 70 °C to 80 °C. The product was distilled under vacuum to give the desired product (130 g, 50% yield). ¹H NMR (CD₂Cl₂ / CHDOD, 400 MHz): δ 7.60 (d, ¹H, J=12.8 Hz), 5.53 (d, ¹H, J=12.8 Hz), 3.81 (s, ³H), 2.17 (s, ³H). 13C NMR (CD2Cl2 / CD3OD, 100.6 MHz): δ 27.1, 58.0, 107.0, 165.2, 199.6.

[0378] Step 2. (E)-4-(allylamino)but-3-en-2-one:

[0379]

[0380] A mixture of (E)-4-methoxybut-3-en-2-one (150 g) and NEt3 (182 g) in DCM (450 mL) was added and stirred under nitrogen at 10-15 °C. An aqueous solution of allylamine hydrochloride (60%, 234 g) was slowly added to the mixture at 10-15 °C. After the addition, the mixture was stirred for 30 min. When the reaction was complete, water (150 g) was added to the reaction mixture. The organic phase was separated, and the aqueous phase was extracted with DCM (300 mL). The combined organic phases were washed with brine (150 mL) and concentrated under vacuum to give a crude product (175 g, 93% yield) as a yellow oil. 1HNMR (500MHz, CDCl3): δ 9.75 (bs, 1H); 6.58 (dd, 1H, J=16.8, 2); 5.78-5.86 (m,1H); 5.19 (d, 1H, J=16.8)); 5,14 (d, 1H, J=10, 1)); 5.00 (d, 1H, J=10, 1); 3.74-3.77 (m, 2H); 2.03, (s, 3H). 13C NMR (125 Hz, CDCl3): 197.5; 153.2; 165.3; 117.6; 94.9; 51.1; 29.2.

[0381] Step 3. (E)-Allyl (3-oxobut-1-en-1-yl)carbamate tert-butyl ester:

[0382]

[0383] Will (A mixture of E)-4-(allylamino)but-3-en-2-one (130 g), trimethylamine (105 g), and N,N-dimethylaminopyridine (13 g) in toluene (390 mL) was heated to 50°C to 55°C. (Boc)₂O (259 g) was added in parts while maintaining the reaction temperature between 50°C and 55°C. The reaction mixture was stirred at 50°C to 55°C for 2 h to complete the reaction. The mixture was cooled to 10°C to 15°C, and 3 M HCl aqueous solution was added to the mixture until the pH was 5 to 6. The organic phase was separated, and the aqueous phase was extracted with toluene (260 mL). The combined organic phases were washed with water (260 mL). Activated carbon (1 g) was added. The mixture was stirred at 50°C to 55°C for 1 h, and then cooled to 20°C to 30°C. The mixture was filtered through a diatomaceous earth bed, and the diatomaceous earth bed was washed with toluene. The filtrate was concentrated to the residue, which was then co-evaporated with MeCN to give a yellow oily residue (189 g, 80% yield). ¹H NMR (500 MHz, CDCl₃): δ 8.11 (d, ¹H, J=15); 5.68–5.73 (m, ¹H); 5.49 (d, ¹H, J=15); 5.14 (d, ¹H, J=18); 5.09 (d, ¹H, J=10); 4.13 (t, 2H); 2.20 (s, 3H); 1.50 (s, 9H). 13C NMR (125 MHz, CDCl3): 198.6; 153.0; 143.2; 131.8; 117.8; 109.5; 84.0; 47.0; 28.3; 28.1.

[0384] Step 4. 5-Acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester:

[0385]

[0386] A solution of (E)-allyl(3-oxobut-1-en-1-yl)carbamate tert-butyl (270 g) in MeCN (3240 mL) was placed in a UV reactor. When the reaction was complete, the yellow oily residue (a mixture of major and minor isomers) was used for the next step without further purification. The sample was purified by column chromatography to obtain analytical data. ¹H NMR (500 MHz, CDCl₃) δ 4.62–6.78 (bd, ¹H); 3.40 (bt, ¹H); 3.16 (bs, ¹H); 3.06 (bs, ¹H); 2.69 (s, ¹H); 1.97 (s, ³H); 1.70–1.73 (m, ¹H); 1.46 (s, ⁹H).

[0387] Step 5. (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate:

[0388]

[0389] A mixture of 150 g of 5-acetyl-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester (MeCN) in 1500 mL was added to a 30% sodium hydroxide solution (173.5 g) in 1500 mL at 30-40 °C. The mixture was stirred at 30-40 °C for 30 min to complete the reaction. The mixture was cooled to 10-15 °C, and 6 M HCl aqueous solution was added to adjust the pH to 8-9. The mixture was concentrated under vacuum at 50-55 °C to remove MeCN, and methanol (90 mL) was added to the residue. The mixture was cooled to 10-15 °C, and 6 M HCl was added to adjust the pH to 2-3 (the solid precipitated during pH adjustment), and stirred for another 2-3 h. The solid was separated and washed with water (300 mL). The wet solid was dried under vacuum at 50-55 °C.

[0390] Recrystallization: The mixture of solids in toluene (1500 mL) was heated to 60-70°C to form a solution. (R)-(+)-1-phenylethylamine (80.7 g) was added at 40-70°C. The solution was cooled to 30-35°C for 90 min (the solid gradually precipitated) and stirred for 1 h. The suspension was cooled to 20-25°C for 90 min and stirred for 2 h. The solids were separated and washed with toluene (40 mL). The mixture of filter cake and toluene (1200 mL) was heated to 100-105°C to form a solution. The mixture was cooled to 75-85°C for 90 min (the solid precipitated) and stirred for 1 h. The mixture was cooled to 20-25°C for 2 h and stirred for 2 h. The solids were separated and washed with toluene (40 mL). The recrystallization process was repeated once more.

[0391] Free base: Add 30% NaOH aqueous solution to a mixture of wet filter cake in toluene (225 mL) and water (225 mL) at 10°C to 15°C until the pH is 9 to 10. Stir the mixture for 30 min and separate the organic phase. Add 6 M HCl aqueous solution to the aqueous phase at 10°C to 15°C until the pH is 2 to 3 (solids expected). Then cool the mixture to 3°C to 8°C and stir for 1 h. Separate the solids and wash with water (40 mL). Dry the wet filter cake under vacuum at 50°C to 55°C to give the desired (1R,4S,5S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (25 g, 18% yield).

[0392] (Boc)₂O (310 g) was added to a mixture of acid (245 g), pyridine (86 g), and ammonium carbonate (111 g) in MeCN (3700 mL) at 15°C to 25°C. The mixture was stirred for 5 h to complete the reaction. The solid was separated and washed with MeCN (250 mL). The filtrate and wash were combined and concentrated under vacuum at 40°C to 45°C, followed by azeotropic reaction with heptane. EtOAc (130 mL) and n-heptane (650 mL) were added to the residue at 40°C to 45°C. The mixture was cooled to 10°C to 15°C (solid precipitate) and stirred for 2 h. The solid was separated and washed with n-heptane (250 mL). The wet filter cake was dried under vacuum at 50°C to 55°C to quantitatively obtain the desired product (1R,4S,5S)-5-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate tert-butyl ester.

[0393] (1R,4S,5S)-5-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (214 g) was added to a cooled 15% NaOH aqueous solution (800 mL) at 10°C to 15°C. Sodium hypochlorite (91.2 g) was added at 10°C to 20°C, and the mixture was stirred for 2 h. The mixture was heated to 40°C to 45°C for 4 h to complete the reaction. The reaction mixture was cooled to 15°C to 20°C, and citric acid was added to adjust the pH to 5 to 6. The mixture was alkalized to pH 14 by adding sodium hydroxide. The alkalized mixture was extracted with 2-methyltetrahydrofuran (2 × 1000 mL). The combined organic phases were concentrated under vacuum, and the residue was azeotropically reacted with MeCN. The residue was dissolved in (140 mL), and activated carbon (2 g) was added. The mixture was stirred at 25°C to 30°C for 2 h. The mixture was filtered, and the filter bed was rinsed with MeCN (85 mL). The combined filtrate and rinsing solution were added to a solution of oxalic acid (120 g) in MeCN (850 mL) at 40-45°C. The solution was cooled to 3-7°C and stirred for 1 hour. The solid was separated and rinsed with MeCN (110 mL). The wet filter cake was dried under vacuum at 40-50°C to give the desired (1R,4R,5S)-5-amino-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl oxalate (248 g, 91% yield) as a white solid. HPLC-MS C 10 H 18 Calculated value of N₂O₂: 198.14; Measured value (M+H): 199.1 1 H NMR (500 MHz, DMSO-d6): δ8.44 (s, 3H); 3.34, (m, 1H); 4.24, dt, 1H, J=6.9,1.7 Hz); 3.20-3.31 (m, 2H); 2.84, (dt, 1H, J=6.5, 3.0); 1.65-1.71 (m, 1H); 1.42 (s, 9H); 1.19 (d, 1H, J=8.1). 13 C NMR (125 Hz, DMSO-d6): δ 165.0; 155.8; 79.5; 61.5; 50.6; 44.9; 40.8; 33.8; 28.6.

[0394] Example 5. Characterization Parameters

[0395] X-ray powder diffraction (XRPD)

[0396] X-ray powder diffraction (XRPD) was obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD). The general experimental procedure for XRPD is as follows: (1) X-ray radiation from copper at 1.5418 Å and LYNXEYE TM (1) Detector; (2) X-ray power at 40 kV and 25 mA; and (3) Dispersing sample powder on a zero-background sample holder. The general measurement conditions for XRPD are: starting angle of 3 degrees; stopping angle of 30 degrees; sampling of 0.015 degrees; and scanning speed of 2 degrees / min.

[0397] Differential scanning calorimetry (DSC)

[0398] DSC was obtained from a Discovery DSC2500 differential scanning calorimeter with an autosampler from TA Instruments. The DSC instrument conditions were as follows: 20°C to 300°C, 10°C / min; Tzero aluminum sample tray and lid; and nitrogen flow rate of 50 mL / min.

[0399] Thermogravimetric analysis (TGA)

[0400] TGA was obtained from a Discovery TGA5500 thermogravimetric analyzer with an automated sampler. Typical experimental conditions for TGA were: temperature ramp from 25°C to 300°C at 10°C / min; nitrogen purge flow rate of 25 mL / min; and a platinum sample holder.

[0401] Example 6. Screening of polymorphs of compound 1 hydrochloride

[0402] Solubility measurement

[0403] The solubility of compound 1HCl (prepared according to Example 4) was measured according to the solubility procedures at 25°C in Table 8 and at 50°C in Table 9. The results are summarized in Table 10.

[0404] Table 8

[0405]

[0406] Table 9

[0407]

[0408] Table 10

[0409]

[0410] *Assessment was conducted visually.

[0411] #The mixture is emulsified during stirring.

[0412] At 25 °C, compound 1 HCl exhibits excellent solubility (> 50 mg / mL) in MeOH, n-butanol, dimethylformamide (DMF), 2-methoxyethanol, and DMSO. It is slightly soluble (1 mg / mL < solubility < 15 mg / mL) in acetonitrile, chloroform, dichloromethane, 1,4-dioxane, acetone, methyl ethyl acetone, methyl isobutyl ketone, EtOH, n-propanol, isopropanol, and MTBE / MeOH / EtOAc / water (volume ratio 66:20:10:4). It has poor solubility (< 1 mg / mL) in toluene, tert-butyl methyl ether (MTBE), EtOAc, isopropyl acetate, isobutyl acetate, ethyl formate, tetrahydrofuran (THF), 2-methylTHF, and MeOH / water / EtOAc (volume ratio 3:0.3:96.7). It is completely insoluble in heptane.

[0413] At 50 °C, compound 1 HCl exhibits excellent solubility (> 50 mg / mL) in MeOH, n-propanol, isopropanol, n-butanol, dimethylformamide (DMF), 2-methoxyethanol, and DMSO. It has relatively good solubility (15 mg / mL < solubility < 50 mg / mL) in chloroform, acetone, EtOH, and MTBE / MeOH / EtOAc / water (volume ratio 66:20:10:4). It is slightly soluble (1 mg / mL < solubility < 15 mg / mL) in acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran (THF), methyl ethyl ketone, and methyl isobutyl ketone. It exhibits poor solubility (< 1 mg / mL) in toluene, tert-butyl methyl ether (MTBE), ethyl formate, EtOAc, isopropyl acetate, isobutyl acetate, 2-methylTHF, and MeOH / water / EtOAc (volume ratio 3:0.3:96.7). It is completely insoluble in heptane.

[0414] Phase equilibrium at 25 ± 1℃ and 50 ± 1℃

[0415] Phase equilibrium studies were conducted to provide information on the dominant crystalline forms for phase identification. Based on its solubility in various solvent systems (Table 10), compound 1 HCl was equilibrated in representative solvent groups at 25 ± 1 °C (Table 11) and 50 ± 1 °C (Table 12). Compound 1 HCl was added to the solvents listed in Tables 11 and 12 until a turbid solution was obtained, and then approximately 20 mg of compound 1 HCl was added to the turbid solution. The mixtures were stirred at 25 ± 1 °C for 48 h and 50 ± 1 °C for 24 h, respectively. The solids were filtered, dried under vacuum, and analyzed by XRPD to obtain the results in Tables 11 and 12. Five potential new crystalline forms (crystalline forms II to VI) were obtained.

[0416] Compound 1, an HCl solid obtained after phase equilibrium at 25 °C in n-BuOH, ethyl formate, n-propanol, methyl ethyl ketone (MEK), 2-methyltetrahydrofuran (2-methylTHF), and THF, exhibited different XRPD patterns compared to the starting materials. These new crystal forms were designated as crystal forms II to VI.

[0417] The solid 1HCl obtained after phase equilibrium in ethyl formate, MEK, 2-methylTHF and THF at 50 °C has crystal forms III, V, V and VI, respectively.

[0418] Table 11

[0419]

[0420] Table 12

[0421]

[0422] Evaporation at 25℃ and 50℃

[0423] Evaporation studies were conducted to identify the dominant crystal form during uncontrolled precipitation. XRPD was used to study the solid-state morphology of the evaporated samples at 25 ± 1 °C and 50 ± 1 °C. The results are presented in Tables 13 (25 ± 1 °C) and 14 (50 ± 1 °C).

[0424] Compared with the XRPD patterns of the initial material crystal form I and crystal forms II to VI obtained after phase equilibrium, compound 1 HCl solid obtained by evaporation at 25 °C in a mixture of IPA, methyl ethyl ketone (MEK), and 66% MTBE, 20% MeOH, 10% EtOAc, and 4% water exhibits a different XRPD pattern. This new crystal form is named crystal form VII.

[0425] The compound 1 HCl solid obtained by evaporation at 50 °C in a mixture of DCM, 1,4-dioxane, MIBK, MEK, ethyl formate, THF, and 3% MeOH and 0.3% water in EtOAc has crystal form VII.

[0426] Table 13

[0427]

[0428] Table 14

[0429]

[0430] Antisolvent addition

[0431] Saturated and near-saturated solutions of compound 1 HCl (crystal form I) were prepared at room temperature in the solvents listed in Table 15. Antisolvents were added dropwise to induce precipitation. The results are presented in Table 15, and crystal form VIII was obtained upon addition of 2-methylTHF to the DMF solution.

[0432] Table 15

[0433]

[0434] Add in reverse

[0435] Saturated and near-saturated solutions of compound 1 HCl (crystal form I) were prepared at 25 °C in the solvents listed in Table 16 and added dropwise to a large volume of miscible antisolvent. The results are presented in Table 16. In the reverse addition experiments (Table 16), crystal form VII was identified from DMF-MTBE, DMF-EtOAc, and DMF-Me-THF. Crystal form V was identified from MeOH-MeTHF.

[0436] Table 16

[0437]

[0438] Sudden cooling of saturated solutions

[0439] Saturated or near-saturated solutions of compound 1 HCl prepared at 25 °C were quenched to approximately -20 °C to -30 °C to induce precipitation of a higher-energy form. Representative solvents were selected based on solubility data measured at 25 °C and 50 °C. Crystal form IX solid was observed in DMF, and the results are listed in Table 17.

[0440] Table 17

[0441]

[0442] Characterization of the new crystal form

[0443] A total of nine polymorphs of the crystalline compound 1HCl were identified using standard polymorph screening methods, including the original polymorph (polymorph I) and eight new polymorphs (polymorphs II to IX). Polymorph I is the most stable form of compound 1HCl and is a dihydrate. Figures 22 to 29 XRPD diffraction patterns for crystal forms II to IX.

[0444] Crystal form II was obtained through phase equilibrium (at 25 °C, in n-BuOH), evaporation (at 50 °C, in n-BuOH), and quenching (in n-BuOH) experiments (Tables 11, 17, and 17); crystal form III was obtained through phase equilibrium in ethyl formate (at 25 °C and 50 °C) (Tables 11 and 12); crystal form IV was obtained through phase equilibrium (at 25 °C, in n-propanol) experiments (Table 11); crystal form V was obtained through phase equilibrium (at 25 °C and 50 °C, in MEK and 2-methylTHF, Tables 11 and 12), antisolvent addition (addition of 2-methyl to a MeOH solution of compound 1 HCl, Table 15), and corresponding reverse addition (Table 16); crystal form VI was obtained through phase equilibrium in THF (at 25 °C and 50 °C) (Tables 11 and 12); and crystal form V was obtained through phase equilibrium in MEK (at 25 °C and 50 °C), in IPA, and in 66% MTBE and 20% MeOH. Crystal form VII was obtained by evaporation in a mixture of 10% EtOAc and 4% water (at 25°C) in DCM, 1,4-dioxane, MIBK, ethyl formate, THF, and 3% MeOH and 0.3% water in EtOAc (at 50°C); crystal form VIII was obtained by antisolvent addition (adding 2-methylTHF to a DMF solution of compound 1 HCl) and reverse addition (adding a DMF solution of compound 1 HCl to 2-methylTHF, EtOAc, and MTBE); crystal form IX was obtained by quenching in DMF (Table 17).

[0445] Example 7. Salt sieving

[0446] Compound 1 hydrochloride dihydrate

[0447] The monoHCl salt of compound 1 was prepared according to Example 2 and is a dihydrate.

[0448] XRPD analysis confirmed that the single HCl salt crystal form I is a crystalline solid. The XRPD spectrum is shown in... Figure 1 The peak data is provided in Table 1.

[0449] DSC thermogram illustration is from Figure 2It first dehydrates at below 150°C, followed by an exothermic melting / decomposition event at an initial temperature of approximately 265°C and a peak temperature of approximately 271°C.

[0450] TGA thermal spectrum illustration from Figure 3 At temperatures below 100°C, approximately 4.6% weight loss was observed due to water loss. Between 150°C and 300°C, approximately 11.4% weight loss was due to decomposition.

[0451] Compound 1 dihydrochloride

[0452] Preparation of compound 1 dihydrochloride.

[0453] At room temperature, a stirred solution of (1R,4R,5S)-5-(8-(2-cyanoethyl)-2-((1R,3R,5R)-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-1-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (0.500 g, 0.678 mmol) in methanol (1.000 mL) (2 volumes) and EtOAc (2 mL, 4 volumes) was added to water (0.283 mL, 3.39 mmol) containing 12 M hydrochloric acid (5 equivalents of water containing 37% HCl). The reaction mixture was heated to 50 °C for 1 h. Then, additional EtOAc (8 mL, 16 volumes) was added to precipitate more dihydrochloride. The resulting slurry was heated to 50 °C for 15 min, then cooled to room temperature and stirred for 1 h. The solid was collected by vacuum filtration and washed with EtOAc. It was dried overnight under normal vacuum at room temperature to give the product dihydrochloride as a pale yellow solid (0.470 g, purity 98.09% as determined by HPLC at 254 nm, containing 4.63% water as determined by KF, yield 92%). LCMS: 628.1, 630.1 (M+H). The hydrochloride ratio was 1.95 by chloride titration.

[0454] XRPD analysis confirmed that the dihydrochloride is a crystalline solid. The XRPD spectrum is shown in... Figure 4 The peak data is provided in Table 2.

[0455] DSC thermogram illustration is from Figure 5 It first dehydrates at below 150°C, followed by an exothermic melting / decomposition event at an initial temperature of approximately 256°C and a peak temperature of approximately 267°C.

[0456] TGA thermal spectrum illustration from Figure 6In the middle temperature range, a weight loss of approximately 4.5% due to water loss was observed below 150°C. The compound decomposes above 150°C, with a weight loss of approximately 16.6% up to 300°C.

[0457] Compound 1 fumarate

[0458] Preparation of compound 1 fumarate.

[0459] Dissolve 76.56 mg of free base in 1 mL of acetone in a 4 mL clear glass vial with stirring. Add 17.43 mg of fumaric acid (1.23 equivalents) to the solution and mix thoroughly. Evaporate the solution to dryness overnight at room temperature without capping. Add 1 mL of EtOAc to the resulting oily / solution and heat to 60°C with stirring for 1 hour. h until solids appear. Slurry the suspension at room temperature for 20 min. Collect the fumarate solids by filtration, wash with EtOAc, and vacuum dry at 50 °C for 1 minute. h. The salt ratio between free base and fumaric acid was determined to be 1.0 by NMR analysis. The water content was determined to be 5.17 by KF analysis.

[0460] XRPD analysis confirmed that the fumarate is a crystalline solid. The XRPD spectrum is shown in... Figure 7 The peak data is provided in Table 3.

[0461] DSC thermogram illustration is from Figure 8 It first dehydrates at below 150°C, and then melts / decomposes at an initial temperature of about 199°C and a peak temperature of about 200°C.

[0462] TGA thermal spectrum illustration from Figure 9 In the middle temperature range, a weight loss of approximately 4.4% due to water loss was observed below 100°C. The fumarate is likely a dihydrate. The compound decomposes above 150°C, with a weight loss of approximately 10.0% up to 300°C.

[0463] Compound 1 L-tartrate

[0464] Preparation of compound 1 L-tartrate.

[0465] Dissolve 76.81 mg of free base in 1 mL of methanol in a 4 mL clear glass vial with stirring. Add 23.83 mg of L-tartaric acid (1.3 equivalents) to the solution and mix thoroughly. Evaporate the solution to approximately 0.5 mL at room temperature without capping. Then add 1 mL of EtOAc and heat to 50 °C with stirring for 1 hour. The suspension was stirred at room temperature for 2 h until a solid appeared. The L-tartrate solid was collected by filtration, washed with EtOAc, and vacuum dried at 50 °C for 1 h. h. NMR analysis determined the salt ratio between the free base and L-tartaric acid to be 1.2.

[0466] XRPD analysis confirmed that L-tartrate is a crystalline solid. The XRPD spectrum is shown in... Figure 10 The peak data is provided in Table 4.

[0467] DSC thermogram illustration is from Figure 11 It first dehydrates at below 150°C, and then melts / decomposes at an initial temperature of about 181°C and a peak temperature of about 208°C.

[0468] TGA thermal spectrum illustration from Figure 12 In the middle temperature range, a weight loss of approximately 4.0% was observed, primarily due to water loss. The compound decomposes above 100°C, with a weight loss of approximately 17.5% up to 300°C.

[0469] Compound 1 adipate

[0470] Preparation of compound 1 adipate.

[0471] Dissolve 80.15 mg of free base in 0.5 mL of acetone in a 4 mL clear glass vial with stirring. Add 22.89 g of acetone to the solution. mg of adipic acid (1.23 equivalents) was added and heated to 60°C to dissolve. The solution was evaporated overnight at room temperature without a cap to form an oil. 1 mL of EtOAc was added to the resulting oil, and the mixture was heated to 60°C to dissolve. The solution was evaporated at room temperature without a cap until an oil appeared. It was then heated to 60°C until a solid appeared, while 1 mL of EtOAc was added. The suspension was stirred at room temperature for 30 min. The adipic acid salt was collected by filtration, washed with EtOAc, and dried under vacuum at 50°C for 30 min. The salt ratio between the free base and adipic acid was determined to be 1.3 by NMR analysis.

[0472] XRPD analysis confirmed that adipic acid salt is a crystalline solid. The XRPD spectrum is shown in... Figure 13 The peak data is provided in Table 5.

[0473] DSC thermogram illustration is from Figure 14 The DSC thermogram shows that the initial dehydration occurred at an initial temperature of approximately 26 °C, with a peak temperature of 88.9 °C. Subsequently, due to the melting / decomposition of the compound, multiple endothermic events occurred at peak temperatures of approximately 154 °C, 189 °C, and 199 °C.

[0474] TGA thermal spectrum illustration from Figure 15 In the middle range, a weight loss of 0.87% was observed below 100°C. A second weight loss of approximately 15% was observed between 150°C and 300°C due to compound decomposition.

[0475] Compound 1 phosphate

[0476] Preparation of phosphate of compound 1.

[0477] 74.40 mg of free base was dissolved in 0.4 mL of acetone in a 4 mL clear glass vial with stirring. 9.0 µL of 85% phosphoric acid (1.1 equivalents) was added to this solution with stirring to form a viscous solid. Then 2 mL of EtOAc was added, and the mixture was heated to 60 °C for 1 h to obtain a good slurry. The suspension was stirred at room temperature for 30 minutes. The phosphate was collected by filtration, washed with EtOAc, and dried under vacuum at 50 °C for 30 min. NMR analysis determined the salt ratio between the free base and phosphate to be 1.8.

[0478] XRPD analysis confirmed that the phosphate was a crystalline solid. The XRPD spectrum is shown in... Figure 16 The peak data is provided in Table 6.

[0479] DSC thermogram illustration is from Figure 17 It may first undergo dehydration / desolvation at below 150°C, followed by an exothermic melting / decomposition event at an onset temperature of approximately 218°C and a peak temperature of approximately 227°C.

[0480] TGA thermal spectrum illustration from Figure 18 In the middle range, a weight loss of 5.4% was observed below 150°C. A second weight loss of approximately 11.7% was observed between 150°C and 300°C due to compound decomposition.

[0481] Compound 1 free base

[0482] The free base of crystalline compound 1 was characterized by XRPD, DSC, and TGA. The XRPD spectrum is shown in... Figure 19 The XRPD data is provided in Table 7, which confirms that the free alkali is a crystalline solid.

[0483] DSC thermogram illustration is from Figure 20 The DSC thermograms show that the free base may first dehydrate at below 100°C, followed by melting / decomposition at an initial temperature of approximately 176°C and a peak temperature of approximately 195°C.

[0484] TGA thermal spectrum illustration from Figure 21In the medium temperature range, a weight loss of approximately 1.2% was observed below 150°C. The compound begins to decompose above 200°C, reaching a weight of approximately 4.8% at 300°C.

[0485] Example 8. Single crystal determination of compound 1 hydrochloride dihydrate

[0486] A suitable single crystal of compound 1 hydrochloride dihydrate was selected and analyzed by single-crystal X-ray diffraction. The standard uncertainty in this report is indicated by crystallographic brackets, for example, 0.123(4) is equivalent to 0.123 ± 0.004. The crystal system is monoclinic and the space group is P21. The cell parameters and calculated volume are: a = 13.8490(4) Å, b = 8.0204(2) Å, c = 15.5461(4) Å, α = 90°, β = 100.617(3)°, γ = 90°, V = 1697.21(8) Å. 3 The chemical formula weight is 701.04 g·mol⁻¹. −1 Where Z=2, the calculated density is 1.372 g·cm³. −3 Further details regarding the crystal data and crystallographic data collection parameters are summarized in Table A. As indicated by the fitting residual R-value of 0.0426 (4.26%), the quality of the obtained structures is high. R-factors in the range of 2% to 6% are considered the most reliable for the determined structures.

[0487] The atomic shift ellipsoid diagram of compound 1 HCl dihydrate is shown from Figure 30 middle. Figure 30 The asymmetric unit shown contains a compound 1 cation, a chloride anion, and two water molecules.

[0488] The absolute structure of a crystal can be determined by analyzing its anomalous X-ray scattering. Anomalous scattering is assessed by the intensity difference between Friedel pairs. For a large θ... maxThe measured reflectance data showed a Friedel coverage of 52.9%. The refined parameter x, called the Flack parameter (HDFlack, et al., Acta Cryst., 1999, A55, 908–15; HDFlack, et al., G., J. Appl. Cryst., 2000, 33, 1143–48; HDFlack, Acta Cryst., 1983, A39, 876–881; S. Parsons, et al., Acta Cryst., 2013, B69, 249–259.), encodes the relative abundance of the two components in the inverted twin. The structure contains the positively refined model with a 1−x fraction and its inverted x fraction. To obtain a low standard uncertainty, the Flack parameter should be close to 0 if the resolved structure is correct and close to 1 if the inverted model is correct. Figure 30 The measured Flack parameter of the structure of compound 1 HCl dihydrate shown is 0.028 (19), which indicates a strong reversal distinguishing ability.

[0489] Additional information about the absolute structure can be assessed by applying Bayesian statistics to the Bijvoet difference. This analysis provides a range of probabilities for different assumptions about the absolute structure. This analysis yields the Hooft y parameter, which is interpreted in the same way as the Flack x parameter. Furthermore, this analysis yields three probabilities: the absolute structure is correct, incorrect, or racemic twinned. For the current dataset, the (Flack equivalent) Hooft y parameter is 0.001(14), the probability of a correct structure is 1.000, and both the probabilities of an incorrect structure or racemic twinned structure are less than 10−200.

[0490] therefore, Figure 30 The absolute configuration of the model is correct. This structure contains six chiral centers located at C22, C23, C26, C27, C29, and C31, bonded with S, R, R, R, and R configurations, respectively (see [reference]). Figure 30 The biphenyl ring exhibits an M(R) isomerism. a Configuration. All chirality is consistent with the configuration presented as shown throughout this disclosure.

[0491] Table A. Crystal data and data collection parameters

[0492]

[0493] Example 9. Compound 1 hydrochloride dihydrate tablet formulation

[0494] For simplicity, the hydrochloride dihydrate of compound 1 is referred to as "Cmpd 1 HCl" in this example.

[0495] Use the components and amounts listed in Table 18 to prepare tablet formulations.

[0496] Table 18. Formulations of 25mg, 100mg, and 200mg tablets (common blends):

[0497]

[0498] Tablet weights and dimensions are listed in Tables 19 and 19A.

[0499] Table 19. Tablet weight and size:

[0500]

[0501] *The dosage of compound 1 is provided as a free base equivalent.

[0502] The manufacturing steps for synthesizing the tablets in Table 19 are as follows:

[0503] - Pass Cmpd 1 HCl through a Comill sieve equipped with a 039R screen at 750 RPM.

[0504] - Allow HPMC, mannitol, and MCC PH101 to pass through Comill sequentially.

[0505] - Blend all particulate materials in a 20L box mixer at 15 RPM for 10 minutes.

[0506] - Load the pre-granulated blend into a suitable wet granulator and perform wet granulation (impeller speed: 150 RPM / shredder speed: 1800 RPM / water pump rate: 75 g / min with atomized air).

[0507] - Pass the wet particles through a Comill screen equipped with a 125R screen at 750 RPM.

[0508] -Dry wet particles in a fluidized bed dryer (target LOD < 2.5%).

[0509] - Pass the dried granules through a Comill screen equipped with a 032R sieve at 2200 RPM.

[0510] - Load half of the dried granules into a 10L box mixer.

[0511] - Combine MCC PH102, silica, and sodium carboxymethyl starch together, pass through a Comill mixer equipped with a 032R sieve at 750 RPM, and then add to a 20L box mixer.

[0512] - Load the remaining half of the dried granules into a 20L box mixer. Mix at 15 RPM for 20 minutes.

[0513] - Pass sodium stearate through a 40-mesh sieve.

[0514] - Take a portion of the blend from a 10L box mixer; the blend should be twice the amount of sodium stearate. Mix it with the sodium stearate in a plastic bag for 30 seconds.

[0515] - Load the stearyl fumarate mixture into a 20L box mixer. Mix at 15 RPM for 5 minutes.

[0516] - Pass magnesium stearate through a 40-mesh sieve

[0517] - Take a portion of the blend from a 20L box mixer; the blend should be twice the amount of magnesium stearate. Mix it with the magnesium stearate in a plastic bag for 30 seconds.

[0518] - Load the magnesium stearate mixture into a 20L box mixer. Mix at 15 RPM for 5 minutes.

[0519] - Use a tablet press to compress an appropriate amount of the blend into tablets to provide a dose of compound 1.

[0520] Table 19A. Tablet weight and size:

[0521]

[0522] *The dosage of compound 1 is provided as a free base equivalent.

[0523] The manufacturing steps for the tablets used in the synthesis of Table 19A are as follows:

[0524] - Pass Cmpd 1 HCl through a Flexsift sieve equipped with a 039R screen at 1000 RPM.

[0525] - Pass HPMC, mannitol, and MCC PH101 sequentially through Flexsift

[0526] - Blend all particulate materials in a 20L box mixer at 15 RPM for 10 minutes.

[0527] - Load the pre-granulated blend into a suitable wet granulator and perform wet granulation (impeller speed: 150 RPM / shredder speed: 1800 RPM / water pump rate: 75 g / min with atomized air).

[0528] - Pass the wet particles through a Comill screen equipped with a 125R screen at 750 RPM.

[0529] -Dry wet particles in a fluidized bed dryer (target LOD < 2.5%).

[0530] - Pass the dried granules through a Comill screen equipped with a 032R sieve at 2200 RPM.

[0531] - Load half of the dried granules into a 10L box mixer.

[0532] - Combine MCC PH102, silica, and sodium carboxymethyl starch together and pass through a Flexsift equipped with a 039R screen at 1000 RPM, then add to a 20L box mixer.

[0533] - Load the remaining half of the dried granules into a 20L box mixer. Mix at 15 RPM for 20 minutes.

[0534] - Pass sodium stearate through a Flexsift equipped with a 039R sieve at 1000 RPM.

[0535] - Load sodium stearate fumarate into a 20L box mixer. Mix at 15 RPM for 5 minutes.

[0536] - Pass magnesium stearate through a Flexsift sieve equipped with a 039R screen at 1000 RPM.

[0537] - Load magnesium stearate into a 20L box mixer. Mix at 15 RPM for 5 minutes.

[0538] - Use a tablet press to compress an appropriate amount of the blend into tablets to provide a dose of compound 1.

[0539] Support stability data are provided in Tables 20 to 23.

[0540] Table 20. Cmpd 1 HCl, 25 mg IR tablets, at 25°C / 60% RH

[0541]

[0542] NT: Not tested

[0543] Table 21. Cmpd 1, 25 mg IR tablets, at 40°C / 75% RH

[0544]

[0545] NT: Not tested

[0546] Table 22. Cmpd 1, 100 mg IR tablets, at 25°C / 60% RH

[0547]

[0548] NT: Not tested

[0549] Table 23. Cmpd 1, 100 mg IR tablets, at 40°C / 75% RH

[0550]

[0551] NT: Not tested

[0552] Table 24 lists the ingredients used in alternative tablet formulations. The preparation procedures and dosages for tablets are similar to those described above.

[0553] Table 24

[0554]

[0555] In addition to those described herein, various modifications to this disclosure will become clear to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Every reference cited in this application, including but not limited to all patents, patent applications, and publications, is incorporated herein by reference in its entirety.

Claims

1. A compound 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile or a pharmaceutically acceptable salt thereof, wherein the compound is crystalline.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of: hydrochloride, dihydrochloride, fumarate, L-tartrate, adipate, and phosphate.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the compound is a solvate.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein it is a hydrate.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile hydrochloride.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is a solvate.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 6 or 7, wherein it is a hydrate.

9. The compound according to any one of claims 6 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile hydrochloride dihydrate.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form I.

11. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as a 2θ angle, at an angle (±0.2 degrees): 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.

0.

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or at least four, five, six, seven, eight, nine, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5 and 26.

0.

13. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.8, and 13.

5.

14. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 55.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.

0.

15. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.8, 13.5, 17.2, 19.2, and 23.

1.

16. The compound according to any one of claims 6 to 10, or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.8, 13.5, 17.2, 19.2, 20.5, 22.8, 23.1, 23.5, and 26.

0.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 1.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, having a DSC thermogram characterized by exothermic activity with a peak at about 271°C.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, having a DSC thermogram characterized by exothermic initiation at about 265°C.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, having a DSC thermogram substantially as depicted in Figure 2.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, having a TGA thermogram substantially as depicted in FIG3.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, comprising a monoclinic crystal.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9 and 21, wherein the space group is [space group number missing]. P 21 crystals.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9 and 21, comprising a crystal having essentially the following cell parameters: a = 13.8490(4) Å, b = 8.0204(2) Å, c = 15.5461(4) Å, α = 90°, β = 100.617(3)°, γ = 90°, and / or V = 1697.21(8) Å 3 .

25. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9 and 21, comprising a crystal having unit cell parameters substantially as shown in Table A.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form II.

27. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as a 2θ angle, at an angle (±0.2 degrees): 5.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.

3.

28. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or at least four, five, six, or all) of the following peaks at the following angles (±0.2 degrees), expressed in terms of 2θ angle: 5.8, 7.6, 11.4, 12.5, 14.4, 17.9 and 25.

3.

29. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 7.6, 12.5 and 17.

9.

30. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 55.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.

3.

31. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.8, 7.6, 11.4, 12.5, 14.4, 17.9, and 25.

3.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 25 to 30, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 22.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form III.

34. The compound according to claim 32 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 23.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form IV.

36. The compound according to claim 34 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 24.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form V.

38. The compound according to claim 36 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 25.

39. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form VI.

40. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 26.

41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form VII.

42. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 27.

43. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 6 to 9, wherein it is crystal form VIII.

44. The compound according to claim 42 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 28.

45. The compound according to any one of claims 6 to 9, or a pharmaceutically acceptable salt thereof, wherein it is crystal form IX.

46. ​​The compound according to claim 44 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 29.

47. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile dihydrochloride.

48. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1, and 23.

9.

49. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, eight, nine, ten, eleven, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1 and 23.

9.

50. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.6, 5.9 and 22.

1.

51. The compound according to claim 46 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least seven peaks, expressed as 2θ, at the following angles (±0.2 degrees): 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1, and 23.

9.

52. The compound according to claim 50 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.6, 5.9, 10.7, 13.2, 18.5, 22.1 and 23.

9.

53. The compound according to claim 48 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.6, 5.9, 10.7, 12.0, 12.8, 13.2, 15.6, 15.9, 18.5, 20.1, 22.1 and 23.

9.

54. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 46 to 52, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 4.

55. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 46 to 53, having a DSC thermogram characterized by exothermic activity with a peak at about 267°C.

56. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 46 to 54, having a DSC thermogram characterized by exothermic initiation at about 256°C.

57. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 46 to 55, having a DSC thermogram substantially as depicted in FIG5.

58. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 46 to 56, having a TGA thermogram substantially as depicted in FIG6.

59. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile fumarate.

60. The compound according to claim 58 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as a 2θ angle, at an angle (±0.2 degrees): 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.

7.

61. The compound according to claim 58 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, eight, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0 and 23.

7.

62. The compound according to claim 60 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 12.9, 17.7, and 23.

7.

63. The compound according to claim 58 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six peaks, expressed as 2θ, at the following angles (±0.2 degrees): 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.

7.

64. The compound according to claim 62 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 12.9, 15.1, 17.7, 20.0, 22.0 and 23.

7.

65. The compound according to claim 58 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least nine peaks, expressed as 2θ, at the following angles (±0.2 degrees): 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0, and 23.

7.

66. The compound according to claim 64 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 12.9, 15.1, 17.3, 17.7, 19.8, 20.0, 20.8, 22.0 and 23.

7.

67. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 58 to 65, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 7.

68. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 58 to 66, having a DSC thermogram characterized by exothermic activity with a peak at about 200°C.

69. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 58 to 67, having a DSC thermogram characterized by exothermic initiation at about 199°C.

70. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 58 to 68, having a DSC thermogram characterized by being substantially endothermic as depicted in FIG8.

71. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 58 to 69, having a TGA thermogram substantially as depicted in FIG9.

72. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile L-tartrate.

73. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.

6.

74. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, eight, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6 and 24.

6.

75. The compound according to claim 73 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 9.3, 18.6, and 24.

6.

76. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six peaks, expressed as 2θ, at the following angles (±0.2 degrees): 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.

6.

77. The compound according to claim 75 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 9.3, 16.7, 18.6, 19.6, 22.3, and 24.

6.

78. The compound according to claim 71 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least nine peaks, expressed as 2θ, at the following angles (±0.2 degrees): 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.

6.

79. The compound according to claim 77 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 9.3, 16.7, 18.6, 19.1, 19.4, 19.6, 22.3, 22.6, and 24.

6.

80. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 71 to 78, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 10.

81. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 71 to 79, having a DSC thermogram characterized by endothermic activity with a peak at about 208°C.

82. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 71 to 79, having a DSC thermogram characterized by an initial endothermic reaction at about 181°C.

83. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 71 to 80, having a DSC thermogram characterized substantially by endothermic properties as depicted in FIG11.

84. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 71 to 82, having a TGA thermogram substantially as depicted in FIG12.

85. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile adipate.

86. The compound according to claim 84 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1, and 49.

8.

87. The compound according to claim 84 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, or all) of the following peaks at the following angles (±0.2 degrees), expressed in terms of 2θ angle: 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1 and 49.

8.

88. The compound according to claim 86 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 6.3, 9.1 and 24.

3.

89. The compound according to claim 84 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least six peaks, expressed in 2θ angles, at the following angles (±0.2 degrees): 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1 and 49.

8.

90. The compound according to claim 88 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 6.3, 9.1, 18.2, 19.2, 34.1 and 49.

8.

91. The compound according to claim 84 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 6.3, 9.1, 10.1, 18.2, 19.2, 24.3, 34.1 and 49.

8.

92. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 84 to 90, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 13.

93. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 84 to 91, having a DSC thermogram characterized by endothermic activity at at least one peak at about 154°C, 189°C or 199°C.

94. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 84 to 92, having a DSC thermogram characterized by an initial endothermic response at about 26°C.

95. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 84 to 93, having a DSC thermogram characterized substantially by endothermic properties as depicted in FIG14.

96. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 84 to 94, having a TGA thermogram substantially as depicted in FIG15.

97. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile phosphate.

98. The compound according to claim 96 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as 2θ angles, at ±0.2 degrees: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.

4.

99. The compound according to claim 96 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, eight, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5 and 24.

4.

100. The compound according to claim 98 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 4.5, 13.5 and 13.

7.

101. The compound according to claim 96 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six peaks, expressed as 2θ, at the following angles (±0.2 degrees): 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.

4.

102. The compound according to claim 100 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 4.5, 13.5, 13.7, 16.5, 21.5 and 24.

4.

103. The compound according to claim 96 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least nine peaks, expressed as 2θ, at the following angles (±0.2 degrees): 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5, and 24.

4.

104. The compound according to claim 102 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 4.5, 13.5, 13.7, 16.5, 16.9, 18.1, 21.5, 23.5 and 24.

4.

105. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 96 to 103, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 16.

106. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 96 to 104, having a DSC thermogram characterized by exothermic activity with a peak at about 227°C.

107. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 96 to 105, having a DSC thermogram characterized by exothermic initiation at about 218°C.

108. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 96 to 106, having a DSC thermogram characterized substantially by endothermic properties as depicted in FIG17.

109. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 96 to 107, having a TGA thermogram substantially as depicted in FIG18.

110. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile.

111. The compound according to claim 109 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least one (or two) of the following peaks, expressed as a 2θ angle, at an angle (±0.2 degrees): 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.

7.

112. The compound according to claim 109 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows at least three (or four, five, six, seven, eight, nine, or all) of the following peaks at angles (±0.2 degrees) represented by a 2θ angle: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8 and 22.

7.

113. The compound according to claim 111 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.1 and 8.

3.

114. The compound according to claim 109 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least six peaks, expressed as 2θ, at the following angles (±0.2 degrees): 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.

7.

115. The compound according to claim 113 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.1, 8.3, 13.0, 15.5 and 18.

7.

116. The compound according to claim 109 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern has at least nine peaks, expressed as 2θ, at the following angles (±0.2 degrees): 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8, and 22.

7.

117. The compound according to claim 115 or a pharmaceutically acceptable salt thereof, characterized in that... The XRPD diffraction pattern shows peaks at the following angles (±0.2 degrees), expressed as 2θ: 5.7, 7.1, 8.3, 13.0, 13.5, 14.3, 15.5, 18.7, 20.8 and 22.

7.

118. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 109 to 116, characterized in that... The XRPD diffraction pattern is basically depicted in Figure 19.

119. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 109 to 117, having a DSC thermogram characterized by endothermic activity with a peak at about 195°C.

120. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 109 to 118, having a DSC thermogram characterized by an initial endothermic reaction at about 176°C.

121. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 109 to 119, having a DSC thermogram characterized substantially by endothermic properties as depicted in FIG20.

122. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and 109 to 120, having a TGA thermogram substantially as depicted in FIG21.

123. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 121, wherein the 3-(1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1H-pyrrolo[3,2-c]quinoline-8-yl)propionitrile is 3-(( R a )-1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile.

124. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 121, wherein the 3-(1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile is 3-(( S a )-1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile.

125. A pharmaceutical composition comprising: a) The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 123; b) Disintegrants; c) Adhesive; d) Anti-caking agents; and e) Lubricant.

126. The pharmaceutical composition of claim 124, wherein the composition further comprises f) Additives or secondary lubricants.

127. The pharmaceutical composition according to claim 124 or 125, wherein the disintegrant b) is sodium carboxymethyl starch.

128. The pharmaceutical composition according to any one of claims 124 to 126, wherein the binder c) is HPMC (Methocel E5 Premium LV hydroxypropyl methylcellulose) or MCC PH102.

129. The pharmaceutical composition according to any one of claims 124 to 127, wherein the anti-caking agent d) is colloidal silica.

130. The pharmaceutical composition according to any one of claims 124 to 128, wherein the lubricant e) is sodium stearate fumarate.

131. The pharmaceutical composition according to any one of claims 124 to 129, wherein the second lubricant or additive f) is magnesium stearate.

132. A pharmaceutical composition comprising: a) The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 123; b) Sodium carboxymethyl starch; c) MCC PH102; d) Colloidal silica; e) Sodium stearate fumarate; and f) Magnesium stearate.

133. A dosage form comprising a compound according to any one of claims 1 to 123 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 124 to 131.

134. The dosage form according to claim 132, wherein the dosage form is in the form of a tablet.

135. The dosage form according to claim 132 or 133, wherein the compound or a pharmaceutically acceptable salt thereof is provided in a dose of about 25 mg to about 200 mg per dosage form in a 3-(1-((1)) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c The amount of quinoline-8-yl)propionitrile is present.

136. The dosage form according to any one of claims 132 to 134, wherein the compound or a pharmaceutically acceptable salt thereof is provided in a dose of about 25 mg per dosage form in a 3-(1-((1)) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c The amount of quinoline-8-yl)propionitrile is present.

137. The dosage form according to any one of claims 132 to 134, wherein the compound or a pharmaceutically acceptable salt thereof is a 3-(1-((1)) solution providing a dose of about 100 mg per dosage form. R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c The amount of quinoline-8-yl)propionitrile present.

138. The dosage form according to any one of claims 132 to 136, wherein the compound or a pharmaceutically acceptable salt thereof is a 3-(1-((1)) solution providing a dose of about 200 mg per dosage form. R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c The amount of quinoline-8-yl)propionitrile present.

139. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 123, a pharmaceutical composition according to any one of claims 124 to 131, or a dosage form according to any one of claims 132 to 136.

140. The method of claim 138, wherein the cancer is associated with the expression or activity of the KRAS protein.

141. The method of claim 138 or 139, wherein the cancer is associated with the expression or activity of a KRAS protein having a G12D mutation.

142. A method for treating cancer in a subject, the method comprising: The subject was identified as having a need for cancer treatment, and the abnormally proliferating cells of the cancer contained KRAS with a G12D mutation; And administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 123, the pharmaceutical composition according to any one of claims 124 to 131, or the dosage form according to any one of claims 132 to 136.

143. The method of claim 141, wherein the cancer is colorectal cancer.

144. The method of claim 141, wherein the cancer is pancreatic cancer.

145. The method of claim 141, wherein the cancer is pancreatic ductal carcinoma.

146. The method of claim 141, wherein the cancer is lung cancer.

147. The method of claim 141, wherein the cancer is non-small cell lung cancer (NCSLC).

148. The method according to any one of claims 138 to 146, wherein the cancer is metastatic.

149. The method according to any one of claims 138 to 147, wherein the abnormally proliferating cells of the cancer comprise KRAS with a G12D mutation.

150. A method for preparing 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c A method for preparing quinoline-8-yl)propionitrile hydrochloride dihydrate, the method comprising preparing 3-(1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile reacts with aqueous hydrochloric acid.

151. The method of claim 149, wherein the reaction is carried out in a solvent containing an alcohol.

152. The method of claim 150, wherein the reaction is carried out in a solvent containing a dialkyl ether.

153. The method of claim 149, wherein the reaction is carried out in a solvent containing an alkyl ester.

154. The method of claim 149, wherein the reaction is carried out in a solvent comprising an alcohol, a dialkyl ether, and an alkyl ester of a alkyl alkanoate.

155. The method according to claim 149 or 150, wherein the alcohol is methanol.

156. The method according to claim 151 or 153, wherein the dialkyl ether is a methyl tert-butyl ether.

157. The method according to claim 152 or 153, wherein the alkyl alkanoate is ethyl acetate.

158. The method according to any one of claims 149 to 156, wherein the 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile and hydrochloric acid react in a molar ratio of approximately 1:

1.

159. The method according to any one of claims 149 to 157, wherein the 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile is 3-(( R a )-1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile.

160. The method according to any one of claims 149 to 157, wherein the 3-(1-((1) R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile is 3-(( S a )-1-((1 R 4 R 5 S )-2-azabicyclo[2.1.1]hexane-5-yl)-2-((1 R ,3 R 5 R )-2-(cyclopropanecarbonyl)-2-azabicyclo[3.1.0]hexane-3-yl)-7-(2,3-dichlorophenyl)-6-fluoro-4-methyl-1 H -pyrrolo[3,2- c Quinoline-8-yl)propionitrile.

Images