KR-102962366-B1 - Compounds, compositions, and methods

Abstract

The present disclosure generally relates to LRRK2 inhibitors or their pharmaceutically acceptable salts, isotope enrichment analogs, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs or pharmaceutical compositions and methods of their preparation and use.

Inventors

• 드 빈센트 피달고, 쟈비어
• 에스트라다, 앤소니 에이.
• 펭, 지안웬 에이.
• 스위니, 자카리 케이.

Assignees

• 데날리 테라퓨틱스 인크.

Dates

Publication Date

20260511

Application Date

20200410

Priority Date

20190411

Claims (20)

1. A compound selected from the following, or a salt, stereoisomer, or mixture of stereoisomers that is permitted by the constraints thereof.
2. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
3. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
4. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
5. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
6. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
7. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
8. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
9. In paragraph 1, a compound having the following structure or a salt that is pharmaceutically permissible therewith.
10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
11. In claim 10, a pharmaceutical composition for use in the treatment of neurodegenerative diseases, cancer, or inflammatory diseases.
12. In paragraph 11, a pharmaceutical composition for use in the treatment of cancer.
13. A pharmaceutical composition according to claim 12, wherein the cancer is kidney cancer, breast cancer, prostate cancer, blood cancer, papillary carcinoma, lung cancer, acute myeloid leukemia, or multiple myeloma.
14. In claim 11, a pharmaceutical composition for use in the treatment of inflammatory diseases.
15. A pharmaceutical composition according to claim 14, wherein the inflammatory disease is leprosy, Crohn's disease, inflammatory bowel disease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoid arthritis, or ankylosing spondylitis.
16. A pharmaceutical composition in which the inflammatory disease of claim 14 is Crohn's disease.
17. In claim 11, a pharmaceutical composition for use in the treatment of neurodegenerative diseases.
18. A pharmaceutical composition in which the neurodegenerative disease of claim 17 is Parkinson's disease.
19. delete
20. delete

Description

Compounds, compositions, and methods Cross-reference regarding related applications This application claims priority under 35 U.S.C. §119 (e) to U.S. Provisional Application No. 62/832,775 filed April 11, 2019, the full text of which is incorporated herein by reference. field The present disclosure generally relates to novel heteroaryl-substituted pyrimidines and their use as therapeutic agents, e.g., inhibitors of LRRK2. Leucine-rich repeat kinase 2 (LRRK2) plays a crucial role in vesicle trafficking and immune function and is genetically associated with several human diseases. LRRK2 is a member of the ROCO protein family and shares five conserved domains with all other family members. Many missense mutations in the LRRK2 gene have been associated in family studies with autosomal dominant Parkinson's disease (Trinh and Farrar, Nature Reviews in Neurology, Vol. 9, 2013, 445-454; Paisan-Ruiz et al., J. Parkinson's Disease, Vol. 3, 2013, 85-103) and inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC) (Hui et al., Sci. Transl. Med., 2018, 10, 7795). G2019S, the most common pathogenic mutation, arises from the highly conserved kinase domain of LRRK2 (see [Gilks et al., Lancet, Vol 365, 2005, 415-416]). In vitro studies indicate that Parkinson's disease-associated mutations induce increased LRRK2 activity and decreased GTP hydrolysis rates (Guo et al., Experimental Cell Research, Vol. 313(16), 2007, 3658-3670). This evidence suggests that LRRK2 kinase and GTPase activities are important for the pathogenesis and that the LRRK2 kinase domain may regulate overall LRRK2 function (see [Cookson, Nat. Rev. Neurosci., Vol. 11, 2010, 791-797]). The LRRK2 N2081D mutation has been identified as a risk allele for Crohn's disease. This mutation is located in the same kinase domain as G2019S and is associated with increased kinase activity similar to that of G2019S mutants. The LRRK2 N2081D mutation is also found in some Parkinson's disease patients (Hui et al., Sci. Transl. Med., 2018, 10, 7795). Other studies have linked gastrointestinal inflammation as a precursor to brain inflammation and Parkinson's disease (Kishimoto, Y. et al., Neuromolecular Med. 2019, 21(3): 239-249); Grathwohl, S. et al., bioRxiv, Dec. 22, 2018 - 11:51). Although progress has been made in these areas, there remains a need for improved LRRK2 inhibitors useful for the treatment of various neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis, as well as peripheral disorders, such as inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Compounds useful as inhibitors of LRRK2 or their pharmaceutically acceptable salts, isotope enrichment analogs, tautomers, stereoisomers, mixtures of stereoisomers, or prodrugs are provided herein. The present disclosure also provides compositions comprising pharmaceutical compositions, kits comprising compounds, and methods for using (or administering) and preparing the compounds or their pharmaceutically acceptable salts, isotope enrichment analogs, tautomers, stereoisomers, mixtures of stereoisomers, or prodrugs. The present disclosure further provides compounds or compositions thereof for use in methods of treating diseases, disorders, or conditions mediated at least partially by LRRK2. Furthermore, the present disclosure provides the use of compounds or compositions thereof in the manufacture of medicines for the treatment of diseases, disorders, or conditions mediated at least partially by LRRK2. In certain embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof, an isotope enrichment analog, a tautomer, a stereoisomer, a mixture of stereoisomers, or a prodrug is provided. In another embodiment, a pharmaceutical composition is provided comprising a compound as described in any of the formulas described herein or a pharmaceutically acceptable salt thereof, an isotope enrichment analog, a tautomer, a stereoisomer, a mixture of stereoisomers, or a prodrug. In another embodiment, a method for treating a disease or condition mediated at least partially by LRRK2 is provided, comprising the step of administering to a subject requiring treatment for a disease or condition mediated at least partially by LRRK2 an effective amount of a pharmaceutical composition comprising a compound as described in any formula described herein or a pharmaceutically acceptable salt, isotope enrichment analog, tautomer, stereoisomer, mixture of stereoisomers or prodrug, and a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the compound is a compound of Table 1 or Table 2 or a pharmaceutically acceptable salt, isotope enrichment analog, tautomer, stereoisomer, mixture of stereoisomers, or prodrug. In another embodiment, a pharmaceutical composition is provided comprising a compound as presented in Table 1 or Table 2 or a pharmaceutically acceptab