US-12617775-B2 - Processes of making CSF-1R inhibitors and methods of use thereof

Abstract

The present disclosure relates to processes of making a compound represented by Formula (I) and methods of use thereof.

Inventors

• Elena Kostik
• Ann Gelormini
• Michael D. Kaufman

Assignees

• DECIPHERA PHARMACEUTICALS, LLC

Dates

Publication Date

20260505

Application Date

20250814

Claims (8)

1. 1 . A dihydrate form of the compound of Formula (II): prepared by a process comprising: reacting a compound of Formula (IX): with a compound of Formula (XII): in the presence of a first catalyst to produce a compound of Formula (IV): reacting the compound of Formula (IV) with a compound represented by: in the presence of a second catalyst, to produce a compound of Formula (III): and reacting the compound of Formula (III) with isopropylamine, thereby preparing the compound of Formula (II).
2. 2 . A pharmaceutical composition, comprising the dihydrate form of claim 1 and a pharmaceutically acceptable excipient.
3. 3 . The dihydrate form of claim 1 , wherein the first catalyst is a palladium catalyst.
4. 4 . The dihydrate form of claim 1 , wherein the first catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(OAc) 2 /SPhos, Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ·DCM, XPhos Pd G2, and Pd 2 (dba) 3 .
5. 5 . The dihydrate form of claim 1 , wherein the first catalyst is Pd(PPh 3 ) 4 .
6. 6 . The dihydrate form of claim 1 , wherein the second catalyst is a palladium catalyst.
7. 7 . The dihydrate form of claim 1 , wherein the second catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(OAc) 2 /SPhos, Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ·DCM, XPhos Pd G2, and Pd 2 (dba) 3 .
8. 8 . The dihydrate form of claim 1 , wherein the second catalyst is Pd(PPh 3 ) 4 .

Description

CROSS-REFERENCE This application is a continuation of International Application No. PCT/US2025/027041 filed Apr. 30, 2025, which claims priority to U.S. Provisional Application No. 63/641,022 filed May 1, 2024, the contents of which are incorporated herein by reference. The present disclosure relates to processes of making a compound represented by Formula (I) or (II) and methods of use thereof. BACKGROUND Colony-stimulating factor 1 receptor (CSF-1R) and its ligand, colony stimulating factor 1 (CSF-1) together form a lineage dependency for normal macrophage development and differentiation from monocytes. As such, tumor-associated macrophages (TAMs) are dependent on CSF-1R (also known as FMS) kinase activity for proliferation, and maintenance of their differentiated state and immunosuppressive phenotype. The role of TAMs in promoting an invasive and immunosuppressive tumor microenvironment is well established. TAMs mediate tumor growth, angiogenesis, invasiveness, metastasis, and immunosuppression through the secretion of and response to a variety of cytokines or other soluble factors. TAMs are educated by tumors to enable escape from immune surveillance by dampening a cytotoxic T cell immune response, thereby shielding the tumor from T cell eradication. For example, TAMs express PD-L1, a known immunosuppressive checkpoint that induces T cell anergy. Several inhibitors targeting CSF-1R have advanced into the clinic as direct antitumor therapies and potential immunotherapies. Many of these drugs also inhibit the closely related Type III receptor tyrosine kinases KIT, PDGFRα/β and FLT3, which may limit their utility due to off-target toxicity. Antibodies targeting CSF-1R are much more specific yet result in >10,000-fold increases in plasma levels of CSF-1, the ligand for CSF-1R, due to blockade of CSF-1 clearance, among other drawbacks. Tenosynovial giant cell tumor (TGCT) is a proliferative and inflammatory disease that includes entities formerly known as pigmented villonodular synovitis (PVNS), and giant cell tumor of the tendon sheath (GCTTS), intraarticular or extraarticular. It is a rare neoplasm of the joint or tendon sheath, with destructive proliferation of synovial like mononuclear cells, admixed with multinucleate giant cells, foam cells, siderophages and inflammatory cells. There are two types of TGCT: the local or nodular form (where the tumor involves the tendons that support the joint, or in one area of the joint) and the diffuse form (where the entire lining of the joint is involved). Treatment is surgical excision of the tumor. However, it is often difficult to perform a marginal excision for the diffuse form of TGCT resulting in a high recurrence rate. It can be characterized by overexpression of CSF-1. Thus, there is a need for selective small-molecule CSF-1R inhibitors that are useful in the treatment of disorders associated with the proliferation of TAMs including solid tumors of various cancers and treatment of mesenchymal tumors including TGCT and diffuse-type tenosynovial giant cell tumor (DTGCT). Certain impurities may be incompatible with other substances in a composition when formulated into pharmaceutical compositions comprising the active pharmaceutical ingredient and a pharmaceutically acceptable carrier; reduce shelf life of the composition; cause difficulties during formulation and use of the composition; cause physical and chemical instabilities of the compositions; lower therapeutic effects of the composition; show adverse biological effects such as genotoxicity; or change the odor, color, or taste of the composition. Therefore, there is a need for a highly pure active pharmaceutical ingredient. Provided herein, in some embodiments, are processes of making a compound represented by Formula (I) that is highly pure and methods of use thereof. SUMMARY Described herein, in part, are processes of making a compound represented by Formula (I): and methods of use thereof. In some embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutically acceptable carrier. Provided herein, in part, are methods of treating diseases and conditions including, but not limited to a tenosynovial giant cell tumor (TGCT) including diffuse-type tenosynovial giant cell tumor (DTGCT) and localized tenosynovial giant cell tumor. Provided herein, in part, are methods of treating diseases and conditions including, but not limited to graft versus host disease (GVHD) including chronic graft versus host disease (cGVHD) and acute graft versus host disease (aGVHD). Provided herein, in part, are methods of treating diseases and conditions including, but not limited to a neurodegenerative diseases or conditions including Parkinson's disease (PD), Alzheimer's Disease (AD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), mild cognitive impairment, and Huntington's Disease (HD). Provided herein, in part, are methods of treating diseases and c