Solid forms of 6-chloro-3-[(1R)-1-[3,6-dimethyl-2-(2-methylindazol-5-YL)-4-OXO-chromen-8-YL]ethoxy]pyridine-2-carboxamide

Abstract

The present invention relates to solid forms of Compound A, methods of making, and use thereof for the treatment of disease.

Description

[0001] SOLID FORMS OF 6-CHLORO-3-[(lR)-l-[3,6-DIMETHYL-2-(2-

[0002] METHYLINDAZOL-5-YL)-4-OXO-CHROMEN-8-YL]ETHOXY]PYRIDINE-2-

[0003] CARBOXAMIDE

[0004] TECHNICAL FIELD

[0005] [1] The present invention relates to solid forms of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide, methods of making, and use thereof for the treatment of disease.

[0006] BACKGROUND

[0007] [2] The PIK3CA gene encoding the PI3K catalytic isoform pl 10a is the most frequently mutated gene in solid tumors and is also the most frequent site of genetic alteration within the PI3K pathway. PIK3CA mutations are most frequently found in endometrial, breast, and head and neck cancers. Approximately 40% of patients with HR+ / HER2- breast cancer harbor activating mutations in PIK3CA, which activates pl 10a and the P13K / AKT / mTOR signaling network. H1047R is the most common missense mutation in PIK3CA.

[0008] [3] Several PI3K-targeting agents have been tested in breast cancer patients. Approved and other investigational PI3Ka inhibitors in the clinic inhibit both wild-type (WT) and mutated PI3Ka with approximate equal potency. On-target WT PI3Ka mediated toxicity can include dose-limiting hyperglycemia as well as cutaneous and GI toxicity.

[0009] [4] There is a need for PI3Ka inhibitors with improved therapeutic indices for the treatment of diseases associated with mutant PI3K, including PIK3CA-mutant cancers. There is also a need for solid forms of PI3Ka inhibitors having advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties.

[0010] SUMMARY

[0011] [5] In one aspect, provided are solid forms including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid.

[0012] [6] In another aspect, provided are therapies including the solid forms for the treatment of disease, such as PIK3CA-mutated cancer. BRIEF DESCRIPTION OF THE FIGURES

[0013] [7] FIG. 1 is an XRPD pattern of a 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide dimalonic acid form.

[0014] [8] FIG. 2 is an XRPD pattern of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide Form A.

[0015] [9] FIG. 3 is an XRPD pattern of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide Form B.

[0016]

[0010] FIG. 4 is an XRPD pattern of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide Form C.

[0017]

[0011] FIG. 5 is an XRPD pattern of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide Form D.

[0018] DETAILED DESCRIPTION

[0019]

[0012] The compound 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide (“Compound A”), alternatively referred to as (R)-6-Chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-chromen-8- yl)ethoxy)picolinamide, is a potent and mutant-selective inhibitor of PI3Ka H1047R.

[0020] Compound A

[0021]

[0013] The present invention provides solid forms including Compound A. The solid forms may have one or more of advantageous physical stability, advantageous chemical stability, advantageous solubility, or advantageous pharmacokinetic properties.

[0022]

[0014] In one aspect, provided are solid forms including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid. In certain embodiments, the ratio of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to malonic acid is 1:2. In certain embodiments, the solid form is a crystalline solid form. In certain embodiments, the solid form is a cocrystalline solid form. In certain embodiments, the solid form is an anhydrous crystalline solid form. In certain embodiments, the solid form is an anhydrous non-solvated crystalline solid form. In certain embodiments, the solid form is crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide dimalonic acid. In certain embodiments, the solid form is cocrystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide dimalonic acid.

[0023]

[0015] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ± 0.2°, 7.1° ± 0.2°, 9.1° ± 0.2°, 9.9° ± 0.2°, 10.9° ± 0.2°, 11.3° ± 0.2°, 12.1° ± 0.2°, 12.8° ± 0.2°, 15.2° ± 0.2°, 16.8° ± 0.2°, 17.1° ± 0.2°, 19.9° ± 0.2°, 22.9° ± 0.2°, and 24.5° ± 0.2°.

[0024]

[0016] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yI)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ± 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0025]

[0017] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 6.4° ± 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0026]

[0018] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2-theta selected from 6.4° + 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0027]

[0019] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.8° ± 0.2° in combination with at least one peak selected from 6.4° ± 0.2°, 9.1° ± 0.2°, and 15.2° ± 0.2°.

[0028]

[0020] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.8° ± 0.2° in combination with at least two peaks selected from 6.4° ± 0.2°, 9.1° ± 0.2°, and 15.2° ± 0.2°.

[0029]

[0021] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yI)-4-oxo-chromen-8-yI]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.4° ± 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0030]

[0022] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyI-2- (2-methylindazol-5-yI)-4-oxo-chromen-8-yI]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.4° ± 0.2°, 7.1° ± 0.2°, 9.1° ± 0.2°, 9.9° ± 0.2°, 10.9° ± 0.2°, 11.3° ± 0.2°, 12.1° ± 0.2°, 12.8° ± 0.2°, 15.2° ± 0.2°, 16.8° ± 0.2°, 17.1° ± 0.2°, 19.9° ± 0.2°, 22.9° ± 0.2°, and 24.5° ± 0.2°.

[0031]

[0023] In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 1. In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern having at least one peak at diffraction angle 2-theta as shown in FIG. 1. In certain embodiments, the solid form including 6-Chloro- 3- [( 1R)- 1 - [3 ,6-dimethyI-2-(2-methylindazol-5-yI)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern having at least two peaks at diffraction angle 2-theta as shown in FIG. 1. In certain embodiments, the solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo- chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid is characterized by an X-ray powder diffraction pattern having at least three peaks at diffraction angle 2-theta as shown in FIG. 1. Therapeutic Uses

[0032]

[0024] Also provided herein are therapies including a solid form of the present disclosure for the treatment of patients with a disease, including PIK3CA-mutated cancer, such as PIK3CA- mutated advanced or metastatic breast cancer, or other solid tumors with a PIK3CA mutation. A solid form of the present disclosure may be used in monotherapy or in combination with one or more additional therapeutic agents. The therapies may provide new treatment options for patients, and may provide an enhanced and / or unexpected beneficial therapeutic effect in some patients over known therapies.

[0033]

[0025] The efficacy of a cancer treatment can be measured by various endpoints commonly used in evaluating cancer treatments, including but not limited to, tumor regression, tumor weight or size shrinkage, time to progression, overall survival, progression free survival, overall response rate, duration of response, best overall response, disease control rate, clinical benefit rate, time to response, and quality of life. Therapeutic agents may cause inhibition of metastatic spread without shrinkage of the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumoristatic effect. Novel approaches to determining efficacy of any particular mono- or combination therapy of the present invention can be optionally employed, including, for example, measurement of plasma or urinary markers of angiogenesis and / or cell cycle activity, tissue-based biomarkers for angiogenesis and / or cell cycle activity, and measurement of response through radiological imaging.

[0034]

[0026] In one aspect, provided is a method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0035]

[0027] In another aspect, provided is a method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0036]

[0028] In another aspect, provided is a method of treating a patient with a PIK3CA-mutated solid tumor, comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0037]

[0029] In another aspect, provided is a method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0038]

[0030] In another aspect, provided is a method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0039]

[0031] In another aspect, provided is a method of treating a patient with CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS), comprising administering to the patient an effective amount of a solid form of the present disclosure.

[0040]

[0032] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0041]

[0033] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of PIK3CA-mutated cancer.

[0042]

[0034] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of a PIK3CA-mutated solid tumor.

[0043]

[0035] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of PIK3CA-mutated breast cancer.

[0044]

[0036] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0045]

[0037] In another aspect, provided is a solid form of the present disclosure, for use in the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0046]

[0038] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0047]

[0039] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated cancer.

[0048]

[0040] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor.

[0049]

[0041] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated breast cancer.

[0050]

[0042] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0051]

[0043] In another aspect, provided is the use of a solid form of the present disclosure, in the manufacture of a medicament for the treatment of CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0052]

[0044] In certain embodiments, the PIK3CA-mutated cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, aids-related cancers, aids-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, cardiac (heart) tumors, atypical teratoid / rhabdoid tumor, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colorectal cancer, craniopharyngioma, cutaneous t-cell lymphoma, mycosis fungoides, Sezary syndrome, ductal carcinoma in situ (DCIS), embryonal tumors, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, hepatocellular cancer, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic cancer, metastatic squamous neck cancer, midline tract carcinoma with nut gene changes, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, chronic myeloproliferative neoplasm, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, childhood vascular tumors, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumors, transitional cell cancer of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, and Wilms tumor.

[0053]

[0045] In certain embodiments, the PIK3CA-mutated cancer is endometrial cancer, breast cancer, oesophageal squamous-cell cancer, cervical squamous-cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, glioblastoma, ovarian cancer, non-small-cell lung cancer, esophagogastric cancer, nerve-sheath tumor, head and neck squamous-cell carcinoma, melanoma, esophagogastric adenocarcinoma, soft-tissue sarcoma, prostate cancer, fibrolamellar carcinoma, hepatocellular carcinoma, diffuse glioma, colorectal cancer, pancreatic cancer, cholangiocarcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, renal non-clear-cell carcinoma, renal clear-cell carcinoma, germcell carcinoma, thymic tumor, pheochromocytoma, miscellaneous neuroepithelial tumor, thyroid cancer, leukemia, or encapsulated glioma.

[0054]

[0046] In certain embodiments, the PIK3CA-mutated cancer is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, or head and neck cancer.

[0055]

[0047] In certain embodiments, the PIK3CA-mutated cancer is breast cancer, prostate cancer, or brain cancer. In certain embodiments, the PIK3CA-mutated cancer is breast cancer. In certain embodiments, the PIK3CA-mutated cancer is prostate cancer. In certain embodiments, the PIK3CA-mutated cancer is brain cancer.

[0056]

[0048] In certain embodiments, the PIK3CA -mutated cancer is a breast neoplasm, a thyroid neoplasm, an ovarian neoplasm, non-small-cell lung carcinoma, an endometrial neoplasm, or a pancreatic neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a breast neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a thyroid neoplasm. In certain embodiments, the PIK3CA-mutated cancer is an ovarian neoplasm. In certain embodiments, the PIK3CA-mutated cancer is non-small-cell lung carcinoma. In certain embodiments, the PIK3CA-mutated cancer is an endometrial neoplasm. In certain embodiments, the PIK3CA-mutated cancer is a pancreatic neoplasm.

[0057]

[0049] In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer. In certain embodiments, the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2- negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0058]

[0050] In certain embodiments, the PIK3CA-mutated solid tumor is a PIK3CA-mutated advanced solid tumor. In certain embodiments, the PIK3CA-mutated advanced solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is gynecological cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is head and neck cancer. In certain embodiments, the PIK3CA-mutated advanced solid tumor is triple negative breast cancer.

[0059] Pharmaceutical Compositions

[0060]

[0051] A solid form of the present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. A solid form of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0061]

[0052] A solid form of the present disclosure may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e. , at the site of desired action).

[0062]

[0053] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

[0063] Synthetic Methods

[0064]

[0054] Compound A can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compound A can be synthesized by following the steps outlined in General Schemes 1-5. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.

[0065] Scheme 1

[0066] (4) Compound A

[0067] 1551 Scheme 1 depicts an exemplary preparation of Compound A. Ketone (1) can be reduced to hydroxy compound (2) with a chiral catalyst such as the Noyori catalyst. Hydroxy compound (2) can undergo Mitsunobu reaction with hydroxypicolinonitrile (3) to provide heteroaryl ether (4). The nitrile of (4) can be converted to the amide (e.g., with Ghaffar- Parkins catalyst) to give Compound A.

[0068] Scheme 2

[0069] Compound A

[0070]

[0056] Scheme 2 depicts an alternative exemplary preparation of Compound A. Ketone (1) can be reduced to hydroxy compound (5) with a chiral catalyst such as the Noyori catalyst. Hydroxy compound (5) can undergo reaction with picolinamide (6) to give Compound A.

[0071] Scheme 3

[0072]

[0057] Scheme 3 depicts an exemplary preparation of ketone (1). Acid (7) can be converted to the acyl chloride (8) with, for example, oxaylyl chloride. Addition of aryl halide (9) to acyl chloride (8) can be performed in the presence of a base (e.g., lithium bis(trimethylsilyl)amide) to give diketone (10). Acidic conditions can be used to affect cyclization of diketone (10) to chromenone (11). Bromide (11) can be acylated via palladium catalysis to generate ketone (1). Exemplary palladium catalysis conditions may include bromide (11), tributyl(l -ethoxy ethenyl)stannane, and catalytic PdCh(Ph3)2 in 1,4-dioxane.

[0073]

[0058] Scheme 4 depicts an exemplary preparation of hydroxypicolinonitrile (3). Chloropyridine (12) can be iodinated (e.g., I2, Na2CO3, H2O) to provide iodopyridine (13). lodopyridine (13) can be converted to hydroxypicolinonitrile (3), for example, with copper cyanide in DMF.

[0074] Scheme 5

[0075]

[0059] Scheme 5 depicts an exemplary preparation of picolinamide (6). Acid (14) can be converted to the acyl chloride (15) with, for example, oxaylyl chloride. Acyl chloride (15) can be transformed into amide (6) with, for example, aqueous ammonia.

[0076] Definitions

[0077]

[0060] As used herein, the term “advanced" or "metastatic” means cancers that have spread to one or more parts of the body that were not the site of the original cancerous tissue.

[0078]

[0061] As used herein, the term “anhydrous crystalline solid form” refers to a crystalline solid form that does not have water associated in the crystal lattice. An anhydrous crystalline solid form may still contain residual water, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

[0079]

[0062] As used herein, the term “anhydrous non-solvated crystalline solid form” refers to a crystalline solid form that does not have water or organic solvent associated in the crystal lattice. An anhydrous non-solvated crystalline solid form may still contain residual water or organic solvent, which is not part of the crystal structure but may be adsorbed on the surface or absorbed in disordered regions of the crystal.

[0080]

[0063] As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in patients that is typically characterized by unregulated cell proliferation. Included in this definition are benign and malignant cancers.

[0081]

[0064] As used herein, the term “cocrystalline solid form” refers to a multi-component crystalline solid form including two compounds where the association of compounds is primarily through non-covalent and non-ionic chemical interactions such as hydrogen bonding. In the pharmaceutical arts, a cocrystal typically comprises a first compound which is an active pharmaceutical ingredient and a second compound which is referred to as a guest compound or coformer. A cocrystal may be distinguished from a crystalline salt form in that the first compound remains essentially uncharged or neutral. A cocrystal may be distinguished from a crystalline hydrate or solvate form in that the guest compound is not exclusively water or a solvent. A preferred coformer of the present disclosure is malonic acid.

[0082]

[0065] As used herein, the term “effective amount” refers to the amount or dose of a therapeutic agent, or a pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof, which provides an effective response in the patient under diagnosis or treatment.

[0083]

[0066] As used herein, the term “effective response” of a patient or a patient’s “responsiveness” to treatment with a therapeutic agent, or a pharmaceutically acceptable salt thereof, refers to the clinical or therapeutic benefit imparted to a patient upon administration of the therapeutic agent, or pharmaceutically acceptable salt thereof, optionally in combination with one or more additional agents, or a pharmaceutically acceptable salt thereof.

[0084]

[0067] As used herein, the term “in combination with” refers to the administration of a therapeutic agent, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, or a pharmaceutically acceptable salt thereof, either separately, simultaneously or sequentially in any order, such as for example, at repeated intervals as during a standard course of treatment for a single cycle or more than one cycle, such that one agent can be administered prior to, at the same time, or subsequent to the administration of the other agent, or any combination thereof.

[0085]

[0068] As used herein, the term “patient” refers to a mammal, preferably, a human.

[0086]

[0069] As used herein, the term “solid form” refers to a compound or composition in a solid physical state. Exemplary solid forms include crystalline solid forms and amorphous solid forms. Crystalline solid forms can be single-component or multi-component crystalline solid forms (e.g., salts, solvates, hydrates, or cocrystals).

[0087]

[0070] As used herein, the terms “treating”, “to treat”, or “treatment” refer to restraining, slowing, stopping, reducing, shrinking, maintaining stable disease, or reversing the progression or severity of an existing symptom, disorder, condition, or disease. Exemplary Aspects

[0088]

[0071] Various aspects of the invention are set forth in the following numbered clauses.

[0089]

[0072] Clause 1. A solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol- 5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid.

[0090]

[0073] Clause 2. The solid form of clause 1, wherein the ratio of 6-Chloro-3-[(lR)-l-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to malonic acid is 1:2.

[0091]

[0074] Clause 3. The solid form of clause 1 or clause 2, wherein the solid form is a crystalline solid form.

[0092]

[0075] Clause 4. The solid form of any one of clauses 1-3, wherein the solid form is a cocrystalline solid form.

[0093]

[0076] Clause 5. The solid form of any one of clauses 1-4, wherein the solid form is an anhydrous crystalline solid form.

[0094]

[0077] Clause 6. The solid form of any one of clauses 1-5, wherein the solid form is an anhydrous non-solvated crystalline solid form.

[0095]

[0078] Clause 7. A solid form that is crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide dimalonic acid.

[0096]

[0079] Clause 8. A solid form that is cocrystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide dimalonic acid.

[0097]

[0080] Clause 9. The solid form of any one of clauses 1-8, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ± 0.2°, 7.1° ± 0.2°, 9.1° ± 0.2°, 9.9° ± 0.2°, 10.9° ± 0.2°, 11.3° ± 0.2°, 12.1° ± 0.2°, 12.8° ± 0.2°, 15.2° ± 0.2°, 16.8° ± 0.2°, 17.1° ± 0.2°, 19.9° ± 0.2°, 22.9° ± 0.2°, and 24.5° ± 0.2°.

[0098]

[0081] Clause 10. The solid form of any one of clauses 1-9, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ± 0.2°, 9. 1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0099]

[0082] Clause 11. The solid form of any one of clauses 1-10, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 6.4° ± 0.2°, 9. 1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0100]

[0083] Clause 12. The solid form of any one of clauses 1-11, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2- theta selected from 6.4° ± 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0101]

[0084] Clause 13. The solid form of any one of clauses 1-12, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.8° ± 0.2° in combination with at least one peak selected from 6.4° + 0.2°, 9.1° ± 0.2°, and 15.2° ± 0.2°.

[0102]

[0085] Clause 14. The solid form of any one of clauses 1-13, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.8° ± 0.2° in combination with at least two peaks selected from 6.4° + 0.2°, 9.1° ± 0.2°, and 15.2° + 0.2°.

[0103]

[0086] Clause 15. The solid form of any one of clauses 1-14, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.4° + 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

[0104]

[0087] Clause 16. The solid form of any one of clauses 1-15, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.4° ± 0.2°, 7.1° ± 0.2°, 9.1° ± 0.2°, 9.9° ± 0.2°, 10.9° ± 0.2°, 11.3° ± 0.2°, 12.1° ± 0.2°, 12.8° ± 0.2°, 15.2° ± 0.2°, 16.8° ± 0.2°, 17.1° ± 0.2°, 19.9° ± 0.2°, 22.9° ± 0.2°, and 24.5° ± 0.2°.

[0105]

[0088] Clause 17. The solid form of any one of clauses 1-16, having an X-ray powder diffraction pattern substantially as shown in FIG. 1.

[0106]

[0089] Clause 18. A pharmaceutical composition comprising the solid form of any one of clauses 1-17, and a pharmaceutically acceptable carrier.

[0107]

[0090] Clause 19. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a solid form of any one of clauses 1-16, or a pharmaceutical composition of clause 17.

[0108]

[0091] Clause 20. A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18.

[0109]

[0092] Clause 21. The method of clause 19 or clause 20, wherein the PI3K is PI3Ka.

[0110]

[0093] Clause 22. The method of any one of clauses 19-21, wherein the PI3K has a H1047R mutation.

[0111]

[0094] Clause 23. The method of any one of clauses 20-22, wherein the disease is a cancer.

[0112]

[0095] Clause 24. The method of clause 23, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0113]

[0096] Clause 25. The method of clause 23, wherein the cancer is breast cancer.

[0114]

[0097] Clause 26. The method of clause 23, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0115]

[0098] Clause 27. The method of any one of clauses 20-22, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0116]

[0099] Clause 28. A method of treating a patient with PIK3CA-mutated cancer, comprising administering to the patient an effective amount of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18.

[0117]

[0100] Clause 29. A method of treating a patient with a PIK3CA- mutated solid tumor, comprising administering to the patient an effective amount of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18.

[0118]

[0101] Clause 30. A method of treating a patient with PIK3CA-mutated breast cancer, comprising administering to the patient an effective amount of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18.

[0119]

[0102] Clause 31. A method of treating a patient with PIK3CA-mutated, advanced or metastatic breast cancer, comprising administering to the patient an effective amount of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18.

[0120]

[0103] Clause 32. The method of clause 28, wherein the PIK3CA-mutated cancer is PIK3CA H1047R-mutant cancer.

[0121]

[0104] Clause 33. The method of clause 29, wherein the PIK3CA-mutated solid tumor is a PIK3CA H1047R-mutant solid tumor.

[0122]

[0105] Clause 34. The method of clause 29, wherein the PIK3CA-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0123]

[0106] Clause 35. The method of clause 34, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0124]

[0107] Clause 36. The method of clause 34, wherein the PIK3CA-mutated solid tumor is head and neck cancer.

[0125]

[0108] Clause 37. The method of clause 34, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0126]

[0109] Clause 38. The method of clause 30, wherein the PIK3CA-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0127]

[0110] Clause 39. The method of clause 31, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R-mutant advanced or metastatic breast cancer.

[0128]

[0111] Clause 40. The method of clause 31, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated, advanced or metastatic breast cancer.

[0129]

[0112] Clause 41. The method of clause 31, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0130]

[0113] Clause 42. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in therapy.

[0131]

[0114] Clause 43. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

[0132]

[0115] Clause 44. The solid form, or pharmaceutical composition, for use according to clause 43, wherein the PI3K is PI3Ka.

[0133]

[0116] Clause 45. The solid form, or pharmaceutical composition, for use according to clause 43 or clause 44, wherein the PI3K has a H1047R mutation.

[0134]

[0117] Clause 46. The solid form, or pharmaceutical composition, for use according to any one of clauses 43-45, wherein the disease is a cancer.

[0135]

[0118] Clause 47. The solid form, or pharmaceutical composition, for use according to clause 46, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

[0136]

[0119] Clause 48. The solid form, or pharmaceutical composition, for use according to clause 46, wherein the cancer is breast cancer.

[0137]

[0120] Clause 49. The solid form, or pharmaceutical composition, for use according to clause 46, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

[0138]

[0121] Clause 50. The solid form, or pharmaceutical composition, for use according to any one of clauses 43-45, wherein the disease is CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis / skeletal, and spinal syndrome), or PIK3CA-related overgrowth syndrome (PROS).

[0139]

[0122] Clause 51. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in the treatment of PIK3CA-mutated cancer.

[0140]

[0123] Clause 52. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in the treatment of a PIK3CA-mutated solid tumor.

[0141]

[0124] Clause 53. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in the treatment of PIK3CA-mutated breast cancer.

[0142]

[0125] Clause 54. A solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, for use in the treatment of PIK3CA-mutated, advanced or metastatic breast cancer.

[0143]

[0126] Clause 55. The solid form or pharmaceutical composition for use according to clause

[0144] 51, wherein the PIK3CA-mutated cancer is PIK3CA H1047R-mutant cancer.

[0145]

[0127] Clause 56. The solid form or pharmaceutical composition for use according to clause

[0146] 52, wherein the PIK3CA-mutated solid tumor is a PIK3CA H1047R-mutant solid tumor.

[0147]

[0128] Clause 57. The solid form or pharmaceutical composition for use according to clause

[0148] 52, wherein the PIK3CA-mutated solid tumor is selected from gynecological cancer, head and neck cancer, and triple negative breast cancer.

[0149]

[0129] Clause 58. The solid form or pharmaceutical composition for use according to clause 57, wherein the PIK3CA-mutated solid tumor is gynecological cancer.

[0150]

[0130] Clause 59. The solid form or pharmaceutical composition for use according to clause 57, wherein the PTK3CA-mutated solid tumor is head and neck cancer.

[0151]

[0131] Clause 60. The solid form or pharmaceutical composition for use according to clause 57, wherein the PIK3CA-mutated solid tumor is triple negative breast cancer.

[0152]

[0132] Clause 61. The solid form or pharmaceutical composition for use according to clause

[0153] 53, wherein the PIK3CA-mutated breast cancer is PIK3CA H1047R-mutant breast cancer.

[0154]

[0133] Clause 62. The solid form or pharmaceutical composition for use according to clause

[0155] 54, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is PIK3CA H1047R- mutant advanced or metastatic breast cancer.

[0156]

[0134] Clause 63. The solid form or pharmaceutical composition for use according to clause 54, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptorpositive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA- mutated, advanced or metastatic breast cancer.

[0157]

[0135] Clause 64. The solid form or pharmaceutical composition for use according to clause 54, wherein the PIK3CA-mutated, advanced or metastatic breast cancer is estrogen receptorpositive (ER+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R-mutant, advanced or metastatic breast cancer.

[0158]

[0136] Clause 65. The use of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, in the manufacture of a medicament for the treatment of PIK3CA- mutated cancer.

[0159]

[0137] Clause 66. The use of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, in the manufacture of a medicament for the treatment of a PIK3CA-mutated solid tumor.

[0160]

[0138] Clause 67. The use of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, in the manufacture of a medicament for the treatment of PIK3CA- mutated breast cancer.

[0161]

[0139] Clause 68. The use of a solid form of any one of clauses 1-17, or a pharmaceutical composition of clause 18, in the manufacture of a medicament for the treatment of PIK3CA- mutated, advanced or metastatic breast cancer.

[0162]

[0140] Clause 69. A process for preparing a solid form of any one of clauses 1-17, comprising suspending 6-chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide and malonic acid in solvent, removing the solvent, and isolating the solid form.

[0163]

[0141] Clause 70. A product produced by a process comprising suspending 6-chloro-3-[(l R)- l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2- carboxamide and malonic acid in solvent, removing the solvent, and isolating the product.

[0164]

[0142] Clause 71. The process of clause 69 or product of clause 70, wherein the solvent is ethyl acetate.

[0165]

[0143] Clause 72. A solid form including 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide.

[0166]

[0144] Clause 73. A solid form that is anhydrous crystalline solid 6-Chloro-3-[(lR)-l-[3,6- dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide.

[0145] Clause 74. The solid form of clause 72 or clause 73, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.5° ± 0.2°, 7.9° ± 0.2°, 10.8° ± 0.2°, 11.6° ± 0.2°, 12.2° ± 0.2°, 13.4° ± 0.2°, 16.1° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 22.6° ± 0.2°, 23.8° ± 0.2°, 24.4° ± 0.2°, 26.2° ± 0.2°, 26.8° ± 0.2°, and 27.5° ± 0.2°.

[0167]

[0146] Clause 75. The solid form of any one of clauses 72-74, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 7.9° ± 0.2°, 12.2° ± 0.2°, 18.4° ± 0.2°, and 24.4° ± 0.2°.

[0168]

[0147] Clause 76. The solid form of any one of clauses 72-75, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 7.9° ± 0.2°, 12.2° ± 0.2°, 18.4° + 0.2°, and 24.4° ± 0.2°.

[0169]

[0148] Clause 77. The solid form of any one of clauses 72-76, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2-theta selected from 7.9° ± 0.2°, 12.2° ± 0.2°, 18.4° ± 0.2°, and 24.4° ± 0.2°.

[0170]

[0149] Clause 78. The solid form of any one of clauses 72-77, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 7.9° + 0.2° in combination with at least one peak selected from 12.2° + 0.2°, 18.4° + 0.2°, and 24.4° ± 0.2°.

[0171]

[0150] Clause 79. The solid form of any one of clauses 72-78, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 7.9° ± 0.2° in combination with at least two peaks selected from 12.2° ± 0.2°, 18.4° ± 0.2°, and 24.4° ± 0.2°.

[0172]

[0151] Clause 80. The solid form of any one of clauses 72-79, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 7.9° ± 0.2°, 12.2° ± 0.2°, 18.4° ± 0.2°, and 24.4° ± 0.2°.

[0173]

[0152] Clause 81. The solid form of any one of clauses 72-80, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.5° ± 0.2°, 7.9° ± 0.2°, 10.8° ± 0.2°, 11.6° ± 0.2°, 12.2° ± 0.2°, 13.4° ± 0.2°, 16.1° ± 0.2°, 17.9° ± 0.2°, 18.4° ± 0.2°, 22.6° ± 0.2°, 23.8° ± 0.2°, 24.4° ± 0.2°, 26.2° ± 0.2°, 26.8° ± 0.2°, and 27.5° ± 0.2°.

[0174]

[0153] Clause 82. The solid form of any one of clauses 72-81, having an X-ray powder diffraction pattern substantially as shown in FIG. 2.

[0154] Clause 83. The solid form of clause 72 or clause 73, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 8.4° ± 0.2°, 9.3° ± 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, 14.8° ± 0.2°, 15.6° ± 0.2°, 16.9° ± 0.2°, 19.9° ± 0.2°, 23.4° ± 0.2°, 24.2° ± 0.2°, and 25.1° ± 0.2°.

[0175]

[0155] Clause 84. The solid form of any one of clauses 72, 73, or 83, characterized by an X- ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 9.3° ± 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0176]

[0156] Clause 85. The solid form of any one of clauses 72, 73, or 83-84, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 9.3° + 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0177]

[0157] Clause 86. The solid form of any one of clauses 72, 73, or 83-85, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2-theta selected from 9.3° ± 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0178]

[0158] Clause 87. The solid form of any one of clauses 72, 73, or 83-86, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2- theta of 11.7° ± 0.2° in combination with at least one peak selected from 9.3° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0179]

[0159] Clause 88. The solid form of any one of clauses 72, 73, or 83-87, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2- theta of 11.7° ± 0.2° in combination with at least two peaks selected from 9.3° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0180]

[0160] Clause 89. The solid form of any one of clauses 72, 73, or 83-88, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2- theta of 9.3° ± 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, and 19.9° ± 0.2°.

[0181]

[0161] Clause 90. The solid form of any one of clauses 72, 73, or 83-89, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2- theta of 8.4° ± 0.2°, 9.3° ± 0.2°, 11.7° ± 0.2°, 14.0° ± 0.2°, 14.8° ± 0.2°, 15.6° ± 0.2°, 16.9° 0.2°, 19.9° ± 0.2°, 23.4° ± 0.2°, 24.2° 0.2°, and 25.1° ± 0.2°.

[0182]

[0162] Clause 91. The solid form of any one of clauses 72, 73, or 83-90, having an X-ray powder diffraction pattern substantially as shown in FIG. 3.

[0163] Clause 92. A solid form that is crystalline solid 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2- methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide mono-acetonitrile solvate.

[0183]

[0164] Clause 93. The solid form of clause 72 or clause 92, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 7.7° + 0.2°, 9.6° + 0.2°, 11.3° ± 0.2°, 12.0° ± 0.2°, 12.9° ± 0.2°, 15.7° ± 0.2°, 18.7° ± 0.2°, 20.5° ± 0.2°, and 23.3° ± 0.2°.

[0184]

[0165] Clause 94. The solid form of any one of clauses 72, 92, or 93, characterized by an X- ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 7.7° ± 0.2°, 12.0° + 0.2°, 12.9° + 0.2°, and 20.5° + 0.2°.

[0185]

[0166] Clause 95. The solid form of any one of clauses 72 or 92-94, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 7.7° ± 0.2°, 12.0° ± 0.2°, 12.9° ± 0.2°, and 20.5° ± 0.2°.

[0186]

[0167] Clause 96. The solid form of any one of clauses 72 or 92-95, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2-theta selected from 7.7° ± 0.2°, 12.0° ± 0.2°, 12.9° ± 0.2°, and 20.5° ± 0.2°.

[0187]

[0168] Clause 97. The solid form of any one of clauses 72 or 92-96, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.9° ± 0.2° in combination with at least one peak selected from 7.7° ± 0.2°, 12.0° ± 0.2°, and 20.5° ± 0.2°.

[0188]

[0169] Clause 98. The solid form of any one of clauses 72 or 92-97, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.9° ± 0.2° in combination with at least two peaks selected from 7.7° + 0.2°, 12.0° ± 0.2°, 12.9° ± 0.2°, and 20.5° ± 0.2°.

[0189]

[0170] Clause 99. The solid form of any one of clauses 72 or 92-98, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 7.7° ± 0.2°, 12.0° ± 0.2°, 12.9° ± 0.2°, and 20.5° ± 0.2°.

[0190]

[0171] Clause 100. The solid form of any one of clauses 72 or 92-99, characterized by an X- ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 7.7° + 0.2°, 9.6° + 0.2°, 11.3° ± 0.2°, 12.0° + 0.2°, 12.9° + 0.2°, 15.7° ± 0.2°, 18.7° ± 0.2°, 20.5° ± 0.2°, and 23.3° ± 0.2°.

[0191]

[0172] Clause 101. The solid form of any one of clauses 72 or 92-100, having an X-ray powder diffraction pattern substantially as shown in FIG. 4.

[0192]

[0173] Clause 102. A solid form that is crystalline solid 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide dihydrate.

[0193]

[0174] Clause 103. The solid form of clause 72 or clause 102, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 9.1° ± 0.2°, 10.7° ± 0.2°, 11.4° ± 0.2°, 12.5° ± 0.2°, 14.0° ± 0.2°, 15.5° ± 0.2°, 18.3° ± 0.2°, 19.4° ± 0.2°, 21.8° ± 0.2°, 22.5° ± 0.2°, 23.5° ± 0.2°, and 27.0° ± 0.2°.

[0194]

[0175] Clause 104. The solid form of any one of clauses 72, 102, or 103, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 9.1° ± 0.2°, 15.5° + 0.2°, 18.3° + 0.2°, and 22.5° + 0.2°.

[0195]

[0176] Clause 105. The solid form of any one of clauses 72 or 102-104, characterized by an X- ray powder diffraction pattern using CuKa radiation having at least two peaks at diffraction angle 2-theta selected from 9.1° ± 0.2°, 15.5° ± 0.2°, 18.3° ± 0.2°, and 22.5° ± 0.2°.

[0196]

[0177] Clause 106. The solid form of any one of clauses 72 or 102-105, characterized by an X- ray powder diffraction pattern using CuKa radiation having at least three peaks at diffraction angle 2-theta selected from 9.1° ± 0.2°, 15.5° ± 0.2°, 18.3° ± 0.2°, and 22.5° ± 0.2°.

[0197]

[0178] Clause 107. The solid form of any one of clauses 72 or 102-106, characterized by an X- ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 9.1° ± 0.2° in combination with at least one peak selected from 15.5° ± 0.2°, 18.3° ± 0.2°, and 22.5° ± 0.2°.

[0198]

[0179] Clause 108. The solid form of any one of clauses 72 or 102-107, characterized by an X- ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 9.1° ± 0.2° in combination with at least two peaks selected from 15.5° ± 0.2°, 18.3° ± 0.2°, and 22.5° ± 0.2°.

[0199]

[0180] Clause 109. The solid form of any one of clauses 72 or 102-108, characterized by an X- ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 9.1° ± 0.2°, 15.5° ± 0.2°, 18.3° ± 0.2°, and 22.5° ± 0.2°.

[0200]

[0181] Clause 110. The solid form of any one of clauses 72 or 102-109, characterized by an X- ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 9.1° ± 0.2°, 10.7° ± 0.2°, 11.4° ± 0.2°, 12.5° ± 0.2°, 14.0° ± 0.2°, 15.5° ± 0.2°, 18.3° ± 0.2°, 19.4° ± 0.2°, 21.8° ± 0.2°, 22.5° ± 0.2°, 23.5° ± 0.2°, and 27.0° ± 0.2°.

[0201]

[0182] Clause 111. The solid form of any one of clauses 72 or 102-110, having an X-ray powder diffraction pattern substantially as shown in FIG. 5.

[0202] Examples

[0203]

[0183] Nuclear magnetic resonance (NMR) spectra are recorded at 400 MHz or 300 MHz as stated and at 300.3 K unless otherwise stated; the chemical shifts (5) are reported in parts per million (ppm). Spectra are recorded using a Bruker or Varian instrument with 8, 16 or 32 scans.

[0204]

[0184] LC-MS chromatograms and spectra are recorded using an Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instrument using a C-18 column such as a Luna-C18 2.0x30 mm or Xbridge Shield RPC18 2.1x50 mm. Injection volumes were 0.7 - 8.0 pl and the flow rates were typically 0.8 or 1.2 ml / min. Detection methods are diode array (DAD) or evaporative light scattering (ELSD) as well as positive ion electrospray ionization. MS range is 100 - 1000 Da. Solvents are gradients of water and acetonitrile both containing a modifier (typically 0.01 - 0.04 %) such as trifluoroacetic acid or ammonium carbonate.

[0205]

[0185] The XRPD patterns of crystalline solids are obtained on a Bruker D8 Endeavor X-ray powder diffractometer, equipped with a CuKa (1.5418A) source and a Linxeye detector, operating at 40 kV and 40 mA. The sample is scanned between 4 and 42 20°, with a step size of 0.009 26° and a scan rate of 0.5 seconds / step, and using 0.3° primary slit opening, and 3.9° PSD opening. The dry powder is packed on a quartz or silicon sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity. Crystal peak positions are determined in MDI- Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.774 29°. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.2 20° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.

[0206]

[0186] Differential scanning calorimetry (DSC) analysis is conducted using a TA Q2500 DSC run by (and data analyzed by) TA Trios Software v5.7.0.56. Samples are equilibrated at 25 °C in T-Zero crimped pans, then heated to 300 °C at 10 °C / min with a 50 mL / min nitrogen purge. The temperature and heat flow is calibrated against indium melting.

[0207]

[0187] Thermogravimetric analysis is collected using a TA Instruments Q5500 TGA run by (and data analyzed by) TA Trios 5.7.0.56. Samples (-3-10 mg) are heated from ambient temperature (approximately 25 °C) to 200-350 °C at a rate of 10 °C / min. N2 is the carrier (10 mL / min) and purge (50 mL / min) gas. Temperature is calibrated by Curie temperature determination with nickel and alumel standards. The weight calibration is performed with manufacturer- supplied standards.

[0208]

[0188] Dynamic vapor sorption (DVS) analysis is performed at 25 °C using a TA Instruments Discovery SA flow moisture balance run by (and data analyzed by) TA Trios 5.7.0.56. Sample size is -5-25 mg, drying 25 °C at 0%RH for 30 minutes, adsorption range 5% to 95% RH, desorption range 95% to 2.5% RH, and step interval 5%. The equilibrium criterion is <0.01% weight change in 5 minutes for a maximum of 30 minutes. Humidity verification calibration is performed with sodium bromide. The weight calibration is performed with manufacturer- supplied standard.

[0209]

[0189] Abbreviations:

[0210] ACN Acetonitrile

[0211] AcOH Acetic Acid

[0212] ADP Adenosine diphosphate

[0213] ATP Adenosine triphosphate

[0214] CDCI3 Chlorol'orm-d

[0215] DCM Dichloromethane

[0216] DMF N,N-dimethylformamide

[0217] DMSO Dimethylsulfoxide

[0218] DMSO-t / g Hexadeuterodimethylsulfoxide DSC Differential Scanning Calorimetry eq equivalents EtOAc Ethyl Acetate

[0219] EtOH Ethanol h hour(s)

[0220] !H NMR Proton nuclear magnetic resonance spectroscopy

[0221] IPA Isopropanol

[0222] Kg Kilograms

[0223] L Liters

[0224] LC-MS Liquid Chromatography - Mass Spectrometry

[0225] MeOH Methanol

[0226] MPa Megapascal

[0227] 2-MeTHF 2-Methyltetrahydrfuran min minute(s)

[0228] MS ES Mass Spectroscopy Electro Spray ppm parts per million rt room temperature

[0229] SFC Supercritical Fluid Chromatography

[0230] SGF Simulated Gastric Fluid

[0231] SIF Simulated Intestinal Fluid

[0232] THF Tetrahydrofuran

[0233] TGA Thermogravimetric Analysis

[0234] XRD X-ray Diffraction

[0235] XRPD X-ray Powder Diffraction

[0236] Example 1

[0237] (R)-6-Chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo-4H-chromen-8- yl)ethoxy)picolinamide (“Compound A”)

[0238]

[0190] Preparation 1: 6-Chloro-2-iodopyridin-3-ol

[0239]

[0191] 6-Chloropyridin-3-ol (1.0 kg, 7.72 mol) and water (10 L) were added to a 30 L reactor and stirred at 20 - 25 °C for 30 min. Sodium carbonate (1.64 kg, 15.44 mol) was slowly added giving a clear solution which was slowly treated with iodine (1.96 kg, 7.72 mol) at 10 - 15 °C. After addition was complete, the reaction was allowed to stir at rt for 17 h. The pH of the reaction was adjusted to 7 with 2M aqueous HC1 giving the title compound (1.75 kg, 89%) as an off-white solid that was removed by filtration and dried at 60 °C. ESI / MS (m / z): 256 (M+H).

[0240]

[0192] Preparation 1A: 6-Chloro-3-fluoropicolinoyl chloride

[0241] F^^ ci Y^QN l o

[0242]

[0193] A solution of 6-chloro-3-fluoropicolinic acid (250 g, 1.42 mol) and DMF (10.41 g, 142.4 mmol) in DCM (1.5 L) was cooled in an ice bath and treated dropwise with oxalyl chloride (361.5 g, 2.85 mol) maintaining the internal temperature below 10 °C. After addition was complete, allowed the reaction to warm to rt and stirred for 2 h. The reaction was concentrated under reduced pressure to give the title compound (253.24 g, 91%) as a yellow semi-solid. This intermediate was used without further purification or characterization.

[0243]

[0194] Preparation 2: 6-Chloro-3-hydroxypicolinonitrile

[0244]

[0195] 6-Chloro-2-iodopyridin-3-ol (1.0 kg, 3.92 mol) and DMF (3.0 L) were added to a 20 L reactor and stirred at 20 - 25 °C for 30 min. Copper(I) cyanide (439.7 g, 4.70 mol) was slowly added and the reaction stirred at 90 - 95 °C for 2 h. The reaction was cooled to below 10 °C and poured into ice water (10 L). The mixture was stirred for 30 min and filtered. The solids were washed with 2-methyltetrahydrofuran (2 X 2 L). The filtrate was extracted with fresh 2-methyltetrahydrofuran (3 X 5 L). The combined organic extracts were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure at 35 - 40 °C. The residue was triturated with water (5 L) at 0 - 5 °C for 1 hour to give the title compound (342.6 g, 57%) as a yellow solid on filtration. ESUMS (m / z): 153 (M-H).

[0245]

[0196] Preparation 2A: 6-Chloro-3-fluoropicolinamide

[0246]

[0197] A solution of aqueous ammonia (1.5 L) was cooled in an ice bath and treated portionwise with 6-chloro-3-fluoropicolinoyl chloride (250 g, 1.29 mol) maintaining the internal temperature below 15 °C. After addition was complete, allowed the reaction to warm to rt and stirred for 0.5 h. The suspension was filtered and the solids washed with water (2X) and dried at 50 °C for 12 h to give the title compound (218.3 g, 97%) as an off-white solid. ESI / MS (m / z) (3SC1 / 37C1): 175 / 177 (M+H).

[0247]

[0198] Preparation 3: 2-Bromo-4-methylphenyl propionate

[0248]

[0199] A solution of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) in EtOAc (3.5 L) at 0 °C was treated with pyridine (355.25 g, 4.49 mol). Propionyl chloride (380.91 g, 4.12 mol) was added dropwise keeping the temperature below 10 °C. The reaction was allowed to warm to 22 °C and stirred for 2 h. The reaction was diluted with water (1.4 L) and the organic layer separated. The organic layer was washed with saturated aqueous NaCl (2.0 L), dried over MgSCM, filtered, and concentrated under reduced pressure to afford the title compound as a light yellow liquid (872.00 g, 96% yield). ESI / MS (m / z) (79Br / 81Br): 265 / 267 (M+Na).

[0249]

[0200] Preparation 4: l-(3-Bromo-2-hydroxy-5-methylphenyl)propan-l-one

[0250]

[0201] A solution of trifluoromethanesulfonic acid (1.7 L) was treated with 2-bromo-4- methylphenyl propionate (870.0 g, 3.58 mol) at 0 - 15 °C and maintaining the internal temperature below 10 °C. The reaction was allowed to warm to 60 °C and stirred for 2 h. The reaction was cooled to 10 °C and poured into 8 kg of ice water. The mixture was stirred for 0.5 h and filtered. The solid was rinsed with water (1 L). The solid was slurried in water (3 L) for 30 min, filtered, and dried to give the title compound (865.0 g, 99%). ESI / MS (m / z) (79Br / 81Br): 241 / 243 (M-H).

[0251]

[0202] Preparation 5: l-(3-Bromo-2-hydroxy-5-methylphenyl)-2-methyl-3-(2-methyl-2H- indazol-5-yl)propane- 1 ,3-dione

[0252]

[0203] A solution of l-(3-bromo-2-hydroxy-5-methylphenyl)propan-l-one (300.0 g, 1.23 mol) in THF (2.7 L) was cooled to -78 °C under nitrogen protection. LiHMDS (IM in THF, 4.32 mol) was added dropwise keeping the internal temperature below -70 °C. After 1 h, a solution of 2-methyl-2H-indazole-5-carbonyl chloride (288.21 g, 1.48 mol) in THF was added dropwise keeping the internal temperature below -78 °C. The reaction was stirred at -78 °C for 1 h and then allowed to warm to rt to stir for 12 h. The reaction was cooled to 0 - 10 °C and quenched dropwise with glacial acetic acid (1050 mL) and water (1050 mL). The reaction was concentrated under reduced pressure to give the title compound (503.26 g, 102%) as a yellow liquid. This compound was taken to the next synthetic step without further workup or purification.

[0253]

[0204] Preparation 6: 8-Bromo-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4- one

[0254]

[0205] A solution of l-(3-bromo-2-hydroxy-5-methylphenyl)-2-methyl-3-(2-methyl-2H- indazol-5-yl)propane-l, 3-dione (501.0 g, 1.25 mol) in acetic acid (1.5 L) was treated with concentrated hydrochloric acid (60 mL). The reaction was stirred at 100 °C for 2 h. The reaction was cooled to 20 °C, diluted with water (2505 mL), stirred for 30 min, and filtered. The solid was sequentially slurried in water (2 x 2505 mL), EtOAc (2004 mL), and ACN (1503 mL) to give the title compound (321.34 g, 67%) as a yellow solid.!H NMR (400 MHz, CDCh) 6 ppm 8.09 (s, 2H), 8.01(d, 1H), 7.96-7.84(d, 1H), 7.75(s, 1H), 7.68(d, 1H), 4.31(s, 3H), 2.48(s, 3H), 2.28(s, 3H).

[0255]

[0206] Preparation 7 : 8-acetyl-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4-one

[0256]

[0207] A solution of 8-bromo-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4-one (300.0 g, 782.80 mmol), tributyl(l-ethoxyethenyl)stannane (310.98 g, 861.08 mmol), and bis(triphenylphosphine)palladium(II) dichloride (21.98 g, 31.31 mmol) in 1,4-dioxane (1.5 L) was degassed with nitrogen for 30 min and stirred at 90 °C for 16 h. The reaction was cooled to 20 °C and treated with 2 M aqueous HC1 (500 mL). The resulting slurry was stirred at 20 °C for 30 min and filtered. The solid was dissolved in DCM / MeOH (10: 1) and washed with water (1.2 L). The organic layer was removed and stirred with saturated aqueous KF for 1 h. The slurry was filtered through diatomaceous earth and the filtrate dried over MgSC and concentrated under reduced pressure. The residue was slurried with DCM:petroleum ether (600 mL; 1:5) for 2 h and filtered to give the title compound (241.09 g, 89%) as a white solid. ESI / MS (m / z): 347 (M+H).

[0257]

[0208] Preparation 8: (S)-8-(l-hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one

[0258]

[0209] A solution of DBU (305.90 g, 2.01 mol) in chloroform (2.3 L) was treated slowly with formic acid (92.48 g, 2.01 mol) and 8-acetyl-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one (232.0 g, 669.79 mmol) below 30 °C followed by RuCl(p-cymene)[S,S-Ts- DPEN] (12.78 g, 20.09 mmol). The reaction was allowed to stir under nitrogen at 25 °C for 16 h. The reaction was quenched with 2M aquoues HC1 (1.2 L) below 30 °C, stirred for 15 min, and the layers separated. The organic layer was concentrated under reduced pressure and the residue slurried in ACN (300 mL) and filtered. The solid was slurried in ACN until the %ee was upgraded to >98% to give the title compound (203.16 g, 87%) as a light yellow solid. ESI / MS (m / z): 349 (M+H).

[0259]

[0210] Preparation 8A: (R)-8-(l-Hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-

[0260] 4H-chromen-4-one

[0261]

[0211] A 3 L 4-neck round bottom flask outfitted with an internal thermocouple, addition funnel, and nitrogen inlet was charged with 8-acetyl-3,6-dimethyl-2-(2-methyl-2H-indazol-5- yl)-4H-chromen-4-one (150 g, 433 mmol) and RuCl(p-cymene)[(R,R)-Ts-DPEN] (8.27 g, 12.99 mmol). Added chloroform (1.5 L) and stirred the mixture at 0 °C until fully suspended. When the temperature of the suspension was below 5 °C, DBU (197.8 g, 194 mL, 1.30 mol) was transferred to the addition funnel and added dropwise over 30 min maintaining the internal temperature below 30 °C. After addition was complete and the internal temperature was below 5 °C, added formic acid dropwise (59.80 g, 49 mL, 1.30 mol) via the addition funnel maintaining the internal temperature below 30 °C. When addition was complete, allowed the reaction to warm to rt and stir for 16 h under Nz. The complete reaction was treated with 2 M aqueous HC1 (750 mL) over 10 min and allowed to stir for 15 min. Stirring was stopped and the layers allowed to separate. The organic layer was transferred to a fresh vessel and concentrated under reduced pressure to 900 mL. Added 1.5 L of ACN and concentrated under reduced pressure to 900 mL (3X). Warmed the reaction to 60 °C and stirred for 1 h and then at rt overnight. The resulting solids were removed by filtration and the solids washed with ACN (2 x 300 mL). The solids were dried in a vacuum oven at 45 °C until constant weight was achieved to give the title compound (136.9 g, 91%).JH NMR (400 MHz, DMSO-d6) 5 ppm 1.41 (d, J=6.36 Hz, 3H), 2.10 (s, 3H), 2.43 (s, 3H), 4.23 (s, 3H), 5.28 (br d, J=5.87 Hz, 1H), 5.38 (br s, 1H), 7.56 (d, J=8.88 Hz, 1H), 7.70 - 7.74 (m, 1H), 7.76 (s, 1H), 7.77 (d, J=8.49 Hz, 1H), 8.14 (s, 1H), 8.53 (s, 1H).

[0262]

[0212] Preparation 9: (R)-6-Chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo- 4H-chromen-8-yl)ethoxy)picolinonitrile

[0263]

[0264]

[0213] A solution of (S)-8-(l-hydroxyethyl)-3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H- chromen-4-one (200.51 g, 575.53 mmol) in THF (1.6 L) was cooled to 0 °C and treated with triphenylphosphine (226.43 g, 863.29 mmol) and 6-chloro-3-hydroxypicolinonitrile (97.84 g, 633.08 mmol) under nitrogen. DIAD (217.63 g, 1.08 mol) was added dropwise keeping the internal temperature below 5 °C. The reaction was allowed to warm to 22 °C and stirred for 2 h. The reaction was concentrated under reduced pressure onto silica gel and eluted with 100% DCM. After concentrating under reduced pressure, the residue was slurried in MeOH (400 mL) and filtered to give the title compound (160.40 g, 57%) as a white solid. ESEMS (m / z): 485 (M+H).

[0265]

[0214] Compound A: (R)-6-chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H-indazol-5-yl)-4-oxo- 4H-chromen-8-yl)ethoxy)picolinamide

[0266]

[0215] Preparation A: A solution of (R)-6-chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H-indazol- 5-yl)-4-oxo-4H-chromen-8-yl)ethoxy)picolinonitrile (120.0 g, 247.46 mmol) and Ghaffar- Parkins catalyst (10.67 g, 24.75 mmol, CAS#: 173416-05-2) in EtOH (960 mL) was stirred at 80 °C for 16 h. The reaction was cooled to 25 °C and diluted with water (500 mL) and EtOAc (1 L). The organic layer was removed and the aqueous layer re-extracted with EtOAc (2 X 600 mL). The organic layers were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (118.69 g, 95%) as an off-white solid. ESI / MS (m / z): 503 (M+H).

[0267]

[0216] Preparation B: A 5L reactor outfitted with a Huber chiller, mechanical stirrer, temperature probe, condenser, and N2 inlet was charged with (R)-8-(l-hydroxyethyl)-3,6- dimethyl-2-(2-methyl-2H-indazol-5-yl)-4H-chromen-4-one (135 g, 387.5 mmol), 6-chloro-3- fluoropicolinamide L(87.93 g, 503.7 mmol), lithium tert-butoxide (49.63 g, 620 mmol), and THF (675 mL). The reaction was stirred at 40 °C overnight. The reaction was allowed to cool (jacket set to 20 °C) and when internal temperature was below 30 °C, added water (2L) and stirred at 55 °C for 1 h. The jacket was set to 20 °C and when the internal temperature was below 25 °C, the reaction was seeded with title compound (0.68 g, 0.5%) and allowed to stir at rt for 36 h. The resulting solids were removed by filtration and the solids washed with water (4 X 100 mL). The solid was dried at 45 °C until constant weight was achieved to give the title compound (167.4 g, 81%).]H NMR (400 MHz, DMSO-d6) 5 ppm 1.67 (d, J=6.36 Hz, 3H), 2.10 (s, 3H), 2.40 (s, 3H), 3.35 (s, 1H), 4.23 (s, 3H), 5.98-6.05 (m, 1H), 7.36 (d, .1=8.80 Hz, 1H), 7.51 (d, .1=9.05 Hz, 1H), 7.58 (d, J=9.05 Hz, 1H), 7.67 (br s, 1H), 7.71 - 7.77 (m, 1H), 7.82 (s, 1H), 7.88 (br s, 1H), 8.16 (s, 1H), 8.52 (s, 1H).

[0268] Example 2

[0269] Crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methyIindazoI-5-yl)-4-oxo-chromen- 8-yl]cthoxy]pyridine-2-carboxamide dimalonic acid form (“crystalline Compound A dimalonic acid form”)

[0270]

[0217] Preparation of crystalline Compound A dimalonic acid form was performed by suspending 6-chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen-8- yl]ethoxy]pyridine-2-carboxamide (2.0g) and 3.0 mol equivalents of malonic acid (1.3g) in ethyl acetate (20 mL). The mixture was magnetically stirred (500 rpm) at 55 °C for approximately 2h 30min then cooled down to RT. The solid product was isolated and dried on Whatman paper under vacuum for about 50 minutes to yield crystalline Compound A dimalonic acid form (2.3g, 70.2% yield).

[0271] XRPD

[0218] A prepared sample of the crystalline dimalonic acid form was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having a peak at 12.8° in combination with one or more of the peaks selected from the group consisting of 6.4°, 9.1°, and 15.2°; with a tolerance for the diffraction angles of 0.2 degrees.

[0272] Table 1. XRPD peaks

[0273] Single Crystal Structure Analysis

[0274]

[0219] A suitable single crystal was analyzed by single-crystal X-ray diffractometry. The structure of crystalline Compound A dimalonic acid form was determined to be an anhydrous crystal form, composed of two Compound A molecules and four malonic acid molecules in the asymmetric unit. The hydrogen bonding of the complex suggests a 2:1 malonic acid compound cocrystal.

[0275] Example 3

[0276] Solubility Studies

[0277]

[0220] Aqueous solubility was measured across a range of pH conditions (pH 1-7.5) and in simulated gastric and intestinal fluids. A small amount of material, typically 1-3 mg, was weighed into vials and weights recorded. Media was added to obtain a concentration of 2 mg / mL. Media includes water, 0.01N HC1 (~pH 2), 0.1N HC1 (~pH 1), pH 4.5 (USP) buffer, pH 6.0 (USP) buffer, pH 7.5 (USP) buffer, simulated gastric fluid (SGF), simulated intestinal fluid-fasted (SIF-fasted), and simulated intestinal fluid-fed (SIF-fed). The vials were tightly capped and agitated by rotating at least 180 degrees to ensure all material contacts the media. Samples agitated overnight for approximately 24 hours at ambient, room temperature conditions (23 ± 3°C). Samples were filtered through a 0.22 pm PVDF centrifugal filter. The pH of the filtrate was recorded and then analyzed by HPLC (High Performance Liquid Chromatography) to determine free base drug concentration.

[0278] Table 2. Solubility Studies

[0279]

[0221] Solubility of the dimalonic acid crystal was higher in all aqueous media (pH 1-7.5) relative to the crystalline free base. In addition, solubility of the dimalonic acid crystal was higher in simulated intestinal fluids (SIF-fasted and SIF-fed) relative to the free base. Example 4

[0280] Crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen- 8-yl]ethoxy]pyridine-2-carboxamide Form A (“crystalline Compound A Form A”)

[0281]

[0222] Crystalline Compound A Form A was produced by suspending amorphous Compound A (709 mg) in ethanol and stirring (750 rpm) the mixture overnight at ambient temperature. The solid product was isolated using Whatman paper under vacuum and dried under nitrogen stream for about 30 minutes to yield Form A.

[0282] XRPD

[0283]

[0223] A prepared sample of the crystalline Form A was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 3 below, and in particular having a peak at 7.9° in combination with one or more of the peaks selected from the group consisting of 12.2°, 18.4°, and 24.4°; with a tolerance for the diffraction angles of 0.2 degrees.

[0284] Table 3. XRPD peaks

[0285] Thermal Analysis

[0286]

[0224] Form A is anhydrous based on minimal weight loss detected on heating to 200 °C. DSC analysis showed a sharp endothermic peak at 198 °C attributed to Form A melting. Single Crystal Structure Analysis

[0287]

[0225] A suitable single crystal was analyzed by single-crystal X-ray diffractometry. The structure of Form A was determined to be an anhydrous crystal form, composed of two Compound A molecules in the asymmetric unit.

[0288] Alternative Preparation

[0289]

[0226] Crystalline Form A: A 5 L jacketed reactor outfitted with overhead stirring, temperature probe, Huber unistat 410 dynamic temperature control system, distillation head, and nitrogen inlet was charged with (R)-6-chloro-3-(l-(3,6-dimethyl-2-(2-methyl-2H- indazol-5-yl)-4-oxo-4H-chromen-8-yl)ethoxy)picolinamide (hydrate form, 200 g, 374.98 mmol) and THF (3.0 L). The mixture was stirred at rt for 15 min and filtered through GF / F filter paper. The filtrate was added back to the reactor and the jacket set to 55 °C. Removed solvent by distillation until volume reduced from 3.0 L to 800 mL. Added MeOH (200 mL) and re-warmed the mixture to 55 °C. Added heptane (600 mL) over no more than 15 min and then added Form A seed crystals (1.0 g) and stirred the mixture at 55 °C for 3.5 h. Added heptane (1.0 L) over 1 h and aged the mixture at 55 °C for 1 h before slowly ramping down the temperature of the mixture to rt over 4 h. Once the slurry was at rt, allowed to age for 16 h. Filtered the slurry over PPE cloth and washed the cake with 600 mL of a mixture of THF in heptane (1:2). The cake was then washed with heptane (2 X 1.0 L) and then dried at 45 °C until constant weight was achieved to give the title compound (163.17 g, 86%).JH NMR (400 MHz, CDCI O 8 ppm 1.83 (d, J=6.36 Hz, 3H), 2.20 (s, 3H), 2.43 (s, 3H), 4.29 (s, 3H), 5.96 (d, J=6.48 Hz, 1H), 7.17 (d, J=1.96 Hz, 2H), 7.41 (br s, 1H), 7.48 (d, J=9.07 Hz, 1H), 7.72 (s, 1H), 7.83 (d, J=8.93 Hz, 1H), 7.92 (s, 1H), 7.99 (s, 1H), 8.10 (s, 1H).

[0290] Example 5

[0291] Crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen- 8-yl]ethoxy]pyridine-2-carboxamide Form B (“crystalline Compound A Form B”)

[0292]

[0227] Preparation of Compound A Form B was performed by dissolving amorphous Compound A (752 mg) in 3:1 methanol- water mixture. Sample was stirred (750rpm) at ambient temperature for almost 3 hours and white solids precipitated. Suspension was filtered under vacuum through Whatman paper and dried in nitrogen stream for about 10 minutes to give solids consistent with Form B. XRPD

[0293]

[0228] A prepared sample of the crystalline Form B was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 4 below, and in particular having a peak at 11.7° in combination with one or more of the peaks selected from the group consisting of 9.3°, 14.0°, and 19.9°; with a tolerance for the diffraction angles of 0.2 degrees.

[0294] Table 4. XRPD peaks

[0295] Thermal Analysis

[0296]

[0229] Form B is likely anhydrous based on minimal weight loss detected on heating to 200 °C. An endothermic event at 190 °C is likely attributed to Form B melting.

[0297] Example 6

[0298] Crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methyIindazol-5-yl)-4-oxo-chromen- 8-yl]ethoxy]pyridine-2-carboxamide Form A (“crystalline Compound A Form C”)

[0299]

[0230] Compound A Form C was prepared by combining acetonitrile (1 mL) and amorphous Compound A (~53 mg). The mixture was stirred (750 rpm) at ambient temperature for about 4 hours. The suspension was centrifuged for 5 minutes to give solids consistent with Form C.

[0300] XRPD

[0301]

[0231] A prepared sample of the crystalline Form C was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 5 below, and in particular having a peak at 12.9° in combination with one or more of the peaks selected from the group consisting of 7.7°, 12.0°, and 20.5°; with a tolerance for the diffraction angles of 0.2 degrees.

[0302] Table 5. XRPD peaks

[0303] Thermal Analysis

[0304]

[0232] On heating at a rate of 10 °C / min, Form C DSC shows a broad endotherm at 109 °C, likely attributed to desolvation. On TGA, the mass loss observed on heating from ambient to approximately 50 °C is consistent with 0.54 molar equivalent of ACN. This result also suggests that the sample desolvates on drying.

[0305] Single Crystal Structure Analysis

[0306]

[0233] A Form C single crystal was analyzed by single-crystal X-ray diffractometry. The structure of Form C was determined to be a mono-acetonitrile solvate, composed of one Compound A molecule and one acetonitrile molecule in the asymmetric unit.

[0307] Example 7

[0308] Crystalline 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5-yl)-4-oxo-chromen- 8-yl]ethoxy]pyridine-2-carboxamide Form A (“crystalline Compound A Form D”)

[0309]

[0234] Compound A Form D was produced by combining water (5 mL) and amorphous Compound A (500 mg) and stirring at 750 rpm and 60 °C for a few minutes. The slurry was cooled to ambient temperature and stirred overnight at 750 rpm. The solid product was isolated on Whatman paper under vacuum and dried under nitrogen stream for about 2h30min to yield Form D.

[0310] XRPD

[0311]

[0235] A prepared sample of the crystalline Form D was characterized by an XRPD pattern using CuKa radiation as having diffraction peaks (2-theta values) as described in Table 6 below, and in particular having a peak at 9.10in combination with one or more of the peaks selected from the group consisting of 15.5°, 18.3°, and 22.5°; with a tolerance for the diffraction angles of 0.2 degrees.

[0312] Table 6. XRPD peaks

[0313] Thermal Analysis

[0314]

[0236] On heating at a rate of 10 °C / min, Form D DSC shows two endothermic events 64 °C and 118 °C. On TGA, the mass loss observed on heating from ambient to approximately 80 °C is consistent with 1.4 molar equivalent of water. This result also suggests that the sample dehydrates on drying.

[0315] Single Crystal Structure Analysis

[0316]

[0237] A suitable single crystal was analyzed by single-crystal X-ray diffractometry. The structure of Form D was determined to be a di-hydrate crystal form, composed of one Compound A molecule and two water molecules in the asymmetric unit. Example 8

[0317] PI3K-Alpha kinase (PIK3CA) activity in vitro cell based assay

[0318]

[0238] PI3K- Alpha kinase (PI3Ka) activity: wild-type PI3Ka, H1047R mutant PI3Ka, and E545K mutant PI3Ka in vitro cell based assays and determination of ICso values for inhibitors.

[0319]

[0239] The MDA-MB-453 (ATCC-HTB-131) cell line (PI3Ka H1047R) and MCF-7 (ATCC- HTB-22) cell line (PI3Ka E545K), MDA-MB-361 (ATCC-HTB-27) cell line (PI3Ka E545K), and SKBR3 (ATCC-HTB-30) cell line (wild type PI3Ka) were obtained from the American Type Culture Collection (Manassas, VA). MDA-MB-453 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), IX non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and IX Anti-Anti (Gibco 15240). MCF-7 cells were maintained in Minimum Essential Media (MEM) (Gibco 11095) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), IX non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360), IX Anti-Anti (Gibco 15240) and 10 pg / mL human insulin (Sigma I 9278). MDA-MB-361 cells were maintained in Dulbecco’s Modified Eagle Media (DMEM, Gibco 12430) supplemented with 20% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), IX non-essential amino acids (NEAA, Gibco 11140), 1 mM sodium pyruvate (Gibco 11360) and IX Anti-Anti (Gibco 15240). SKBR3 cells were maintained in McCoy’s 5A (Gibco 16600) supplemented with 10% Fetal Bovine Serum, heat inactivated (FBS HI, Gibco 10082), and IX Anti-Anti (Gibco 15240). Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air.

[0320]

[0240] For compound testing in 0% FBS, MDA-MB-453, MCF-7 and SKBR3 cells were seeded at a density of 1.5xl04, l.OxlO4, and l.OxlO4cells, respectively, per well in white 384- well plates in 20 pl of Minimum Essential Media (MEM) assay media with IX NEAA, 1 mM sodium pyruvate, and 1 pg / mL human insulin (Sigma 19278) (Assay Medium); while MDA- MB-361 cells were seeded at a density of 1.5xl04per well in white 384-well plates in 20 pl Assay Medium without insulin. After plating, cells were allowed to attach overnight. Compounds dissolved in 10 mM stock solutions in DMSO were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte). A 5X intermediate compound dilution plate in MEM with IX NEAA and 1 mM sodium pyruvate (150 pM starting compound concentration in 1.5% DMSO) was then prepared. Five pl of the intermediate serially diluted compounds were added to the cell plate to final concentrations ranging from 30 mM to 0.0015 mM in 0.3% DMSO. 0.3% DMSO alone was used to establish the maximum (MAX) signal and GDC-0032 at a final concentration of 1 pM was used as a reference compound for the minimum (MIN) signal. After 3 hours treatment, the medium was removed, and the cells were lysed in 10 pL of IX SureFire Lysis buffer with shaking for 10 minutes at room temperature. The Acceptor Mix (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Acceptor Beads) was prepared by diluting Activation buffer 25-fold in combined Reaction Buffer 1 and Reaction Buffer 2. The Acceptor beads were diluted 50-fold in the combined Reaction Buffers. Five pL of Acceptor Mix was added to each well, the plate was sealed and covered with foil and incubated for 1 hour at room temperature. The Donor Mix (dilution buffer + SureFire Ultra Donor Beads) was prepared by diluting Donor Beads 50-fold in dilution buffer. Five pL of the Donor Mix was added to each well and the plate sealed and covered with foil and incubated for 1-2 hours at room temperature in the dark. The plates were read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings.

[0321]

[0241] Compounds were tested in duplicate and the % inhibition at each compound concentration was used to generate two dose response curves. One IC50 was generated using average % inhibition at each compound concentration. The data were processed using the Genedata-Screener tool. Relative IC5o values were determined using luminescence units by calculating percent inhibition with respect to the in-plate “MIN” (GDC-0032 reference control) and “MAX” (DMSO) controls. The data was analyzed using a 4-parameter nonlinear logistic equation (four-parameter logistic concentration-response curve):

[0322] Y = bottom + [(top - bottom) / l+(X / ICso)slope], where

[0323] Y = % inhibition,

[0324] X = concentration of inhibitor, bottom = minimum value of y attained by curve- fit, top = maximum value of y attained by curve- fit and slope = steepness of curve at the IC5o- % Inhibition = [(signal at X - median Min) / (median Max - median Min)] x 100

[0325] IC5o: concentration of compound that reduces a given response (ligand binding, enzyme response) by 50%.

[0326] Relative IC50: concentration giving half the compound’s maximum response.

[0327]

[0242] Compound selectivity was calculated by dividing IC50 in SKBR3 by IC50 in cell lines harboring mutant PI3Ka (MDA-MB-453: H1047R; MCF-7 and MDA-MB-361: E545K).

[0328]

[0243] Compound A exhibited an IC5o value of 27.3 nM for the PI3Ka H1047R mutant.

[0329]

[0244] Compound A exhibited 19.2 x fold-selectivity for PI3K-Alpha kinase H1047R mutant versus wild-type.

[0330]

[0245] Compound A exhibited an IC50value of 194.4 nM for the MDA-MB-361 PI3Ka E545K mutant.

Claims

WE CLAIM:

1. A solid form comprising 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2-(2-methylindazol-5- yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide and malonic acid.

2. The solid form of claim 1, wherein the ratio of 6-Chloro-3-[(lR)-l-[3,6-dimethyl-2- (2-methylindazol-5-yl)-4-oxo-chromen-8-yl]ethoxy]pyridine-2-carboxamide to malonic acid is 1:2.

3. The solid form of claim 1 or claim 2, wherein the solid form is a crystalline solid.

4. The solid form of any one of claims 1-3, wherein the solid form is an anhydrous crystalline solid form.

5. The solid form of any one of claims 1-4, characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at diffraction angle 2-theta selected from 6.4° ± 0.2°, 7.1° ± 0.2°, 9.1° ± 0.2°, 9.9° ± 0.2°, 10.9° ± 0.2°, 11.3° ± 0.2°, 12.1° ± 0.2°, 12.8° ± 0.2°, 15.2° ± 0.2°, 16.8° ± 0.2°, 17.1° ± 0.2°, 19.9° ± 0.2°, 22.9° ± 0.2°, and 24.5° ± 0.2°.

6. The solid form of any one of claims 1-5, characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at diffraction angle 2-theta of 12.8° ± 0.2° in combination with at least one peak selected from 6.4° + 0.2°, 9.1° ± 0.2°, and 15.2° ± 0.2°.

7. The solid form of any one of claims 1-6, characterized by an X-ray powder diffraction pattern using CuKa radiation having peaks at diffraction angle 2-theta of 6.4° ± 0.2°, 9.1° ± 0.2°, 12.8° ± 0.2°, and 15.2° ± 0.2°.

8. A pharmaceutical composition comprising the solid form of any one of claims 1-7,and a pharmaceutically acceptable carrier.

9. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a solid form of any one of claims 1-7, or a pharmaceutical composition of claim 8.

10. A method of treating a patient with a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a solid form of any one of claims 1-7, or a pharmaceutical composition of claim 8.

11. The method of claim 9 or claim 10, wherein the PI3K is PI3Ka.

12. The method of any one of claims 9-11, wherein the PI3K has a H1047R mutation.

13. The method of any one of claims 10-12, wherein the disease is a cancer.

14. The method of claim 13, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

15. The method of claim 13, wherein the cancer is breast cancer.

16. The method of claim 13, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

17. A solid form of any one of claims 1-7, or a pharmaceutical composition of claim8, for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).

18. The solid form for use according to claim 17, wherein the PI3K is PI3Ka.

19. The solid form for use according to claim 17 or 18, wherein the PI3K has a H1047R mutation.

20. The solid form for use according to any one of claims 17-19, wherein the disease is a cancer.

21. The solid form for use according to claim 20, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer, or prostate cancer.

22. The solid form for use according to claim 20, wherein the cancer is breast cancer.

23. The solid form for use according to claim 20, wherein the cancer is hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer.

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