Search

KR-102962548-B1 - Polyheterocyclic compounds as METTL3 inhibitors

KR102962548B1KR 102962548 B1KR102962548 B1KR 102962548B1KR-102962548-B1

Abstract

The present invention relates to a compound of formula (I) that acts as an inhibitor of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) enzyme activity: X, Y, and Z are each as defined herein. The present invention also relates to a method for preparing such compounds, a pharmaceutical composition comprising such compounds, and the use thereof in the treatment of proliferative disorders, such as cancer and autoimmune diseases, as well as other diseases or conditions involving METTL3 activity.

Inventors

  • 블랙애비, 웨슬리 피터
  • 하딕, 데이비드 제임스
  • 토마스, 엘리자베스 제인
  • 브룩필드, 프레드릭 아서
  • 셰퍼드, 존
  • 버버트, 크리스티안
  • 리길, 마크 피터

Assignees

  • 스톰 테라퓨틱스 리미티드

Dates

Publication Date
20260511
Application Date
20201201
Priority Date
20191202

Claims (20)

  1. As a compound of the chemical formula (I) presented below or a pharmaceutically acceptable salt thereof: In chemical formula (I): X is selected from the following: Q1 is selected from NH or N- CH3 ; R 1a is the group of the following chemical formula: In the chemical formula, p is an integer selected from 1 or 2; R 1c and R 1d are independently selected from the following: (i) hydrogen (including deuterium), (ii) C 1-3 alkyl, which is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, C 1-3 alkoxy, halo, C 1-3 haloalkoxy, -OC 3-4 cycloalkyl, or NH 2 ; -OC 3-6 cycloalkyl is optionally substituted with halo, cyano, or hydroxy, (iii) or R1c and R1d are connected together to form a 3-membered to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system with the carbon atom to which they are attached, each optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, C1-2 haloalkoxy, NR1ca R1da or -S(O) 0-2 R1ca R1da , wherein R1ca and R1da are H or C1-2 alkyl; R 1e and R 1f are each independently selected from the following: (i) Hydrogen (including deuterium); (ii) C 1-6 alkyl, which is optionally substituted with one or more substituents selected from cyano, hydroxy, C 1-2 alkoxy, halo, C 1-2 haloalkoxy, and NH 2 ; (iii) A group having the following chemical formula: In the chemical formula: q is 0, 1, 2, or 3; R 1g and R 1h are independently selected from the following: a) Hydrogen (including deuterium); b) C 1-6 alkyl, which is optionally substituted with one or more substituents selected from cyano, hydroxy, C 1-4 alkoxy, halo, C 1-4 haloalkoxy, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da , wherein R 1ca and R 1da are H or C 1-2 alkyl NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , and R 1ga and R 1ha are H or C 1-2 alkyl; -OC 3-6 cycloalkyl is optionally substituted with halo, cyano, or hydroxy; or c) or R 1g and R 1h are optionally linked together to form a 3-membered to 6-membered cycloalkyl or heterocyclic ring with the carbon atom to which it is attached, which is optionally substituted with one or more substituents selected from C 1-2 alkyl, C 1-2 haloalkyl, cyano, hydroxy, C 1-2 alkoxy, halo, C 1-2 haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , and R 1ga and R 1ha are H or C 1-2 alkyl; And T1 is selected from hydrogen, halo, C1-4 alkyl, C1-4 haloalkyl, cyano, hydroxy, NR1t R2t or -S(O) 0-2 R1t R2t ( R1t and R2t are H or C1-4 alkyl), C3-8 cycloalkyl, C2-3 alkenyl, C2-3 alkynyl, aryl, heterocyclil, monocyclic or dicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C3-8 cycloalkyl, bridged dicyclic C5-12 cycloalkyl, or bridged heterocyclic ring systems, which are each C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, C1-2 Optionally substituted with one or more substituents selected from haloalkoxy, C3-6 cycloalkyl, NR3tR4t or -S (O) 0-2R3tR4t , where R3t and R4t are H or C1-2 alkyl; (iv) or R1e and R1f are connected, together with the nitrogen atom to which they are attached, to form a monocyclic or bicyclic-heterocyclic ring, which is optionally substituted with one or more substituents selected from C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-4 alkoxy, halo, C1-4 haloalkoxy, NR1i R1j or -S(O) O-2 R1i R1j , where R1i and R1j are H or C1-4 alkyl and/or, or the monocyclic or bicyclic heterocyclic ring formed by R1e and R1f is optionally spiro-fused to a C3-6 cycloalkyl or heterocyclic ring, which is again C1-4 alkyl, C1-4 haloalkyl, C3-6 Optionally substituted with one or more substituents selected from cycloalkyl, cyano, hydroxy, C1-4 alkoxy, halo, C1-4 haloalkoxy, NR1i R1j or -S(O) 0-2 R1i R1j , where R1i and R1j are H or C1-4 alkyl; R 1b is selected from hydrogen, halo, or C 1-2 alkyl; R2a , R2b , and R2d are independently selected from hydrogen, cyano, halo, or C1-3 alkyl; Y is selected from the following: R 3a1 , R3b1 , R3c1 , R3d1 , R3e1 , R3f1 , R3g1 , R3h1 , R3i1 , R3j1 , R3k1, R3l1 , R3m1 , R3o1 , and R3p1 are independently selected from hydrogen and methyl; methyl is substituted with a hydroxyl substituent; R 3a2 , R 3b2 , R 3c2 , R 3d2 , R 3e2 , R 3f2 , R 3g2 , R 3h2 , R 3i2 , R 3j2 , R 3k2 , R 3l2 , R 3m2 , R 3o2, and R 3p2 is hydrogen or a halo; n is 1 or 2 and Z is selected from the following: A 1 is selected from CR 12 and N; A 2 is selected from CR 13 and N; A 5 is selected from CR 16 and N; A 6 is selected from CR 17 and N; A 7 is selected from CR 18 and N; A 8 is selected from CR 19 R 20 and NR 21 ; A 11 is selected from CR 28, R 29 , and NR 30 ; (i) R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R Z2 , R Z2a , R Z3a , R Zi1b , R Zi2e , R Z10, R Z12 , R Z13 , R Z14 , R Z15 , and R Z16 are independently selected from hydrogen, methyl, cyano, or halo; R Y5N and R Z2N are selected from methyl or hydrogen; (ii) R Z1 and R Z1a are selected from hydrogen, C 1-4 alkyl, cyano, halo, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl; (iii) R 12 , R 13 , R 16 , R 18 , R 19 , and R 20 are independently selected from hydrogen, halo, cyano, and methyl; (iv) R 17 is selected from hydrogen, halo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5-membered or 6-membered or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, heterocyclyl, -(OCH 2 CH 2 ) m -OCH 3 (where m is an integer from 1 to 6), NR q R r (where R q and R r are each independently hydrogen, C 1-4 alkyl, or R q and R r are connected together to form a 3-membered to 6-membered heterocyclic ring with the nitrogen atom to which they are attached); Any C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, 5-membered or 6-membered or heteroaryl, C3-6 cycloalkyl, -OC3-6 cycloalkyl, or heterocyclyl is optionally further substituted by one or more substituents selected from C1-2 alkyl, cyano, C1-2 haloalkyl, hydroxy, C1-2 alkoxy, halo, C1-2 haloalkoxy, NR1ea R1fa or -S(O) 0-2 R1ea R1fa , where R1ea and R1fa are H or C1-2 alkyl; (v) R 21 and R 30 are independently selected from hydrogen or methyl; (vi) R 28 and R 29 are compounds or pharmaceutically acceptable salts thereof selected from hydrogen, halo, methoxy, and methyl.
  2. In paragraph 1, X is selected from the following: Q 1 , R 1a , R 1b , R 2a , R 2b , and R 2d are compounds or pharmaceutically acceptable salts thereof as defined in claim 1.
  3. In paragraph 1 or 2, X is selected from the following: Q 1 , R 1a , R 1b , R 2a , R 2b , and R 2d are compounds or pharmaceutically acceptable salts thereof as defined in claim 1.
  4. In paragraph 1 or 2, Q 1 is a compound or a pharmaceutically acceptable salt thereof which is NH.
  5. In paragraph 1 or 2, X is selected from the following: R 1a is a compound or a pharmaceutically acceptable salt thereof that is as defined in paragraph 1.
  6. In claim 1 or 2, R 1a is a group of the following chemical formula: In the chemical formula, p is an integer selected from 1 or 2; R 1c and R 1d are independently selected from the following: (i) hydrogen (including deuterium), or (ii) C 1-3 alkyl, which is optionally substituted with one or more substituents selected from cyano, oxo, hydroxy, C 1-2 alkoxy, halo, C 1-2 haloalkoxy and -OC 3-6 cycloalkyl; R 1e is selected from hydrogen (including deuterium) or C 1-2 alkyl, and: And R 1f is A group having the following chemical formula: In the chemical formula: q is 1 or 2, and; R 1g and R 1h are independently selected from the following: a) hydrogen (including deuterium); or b) C 1-2 alkyl, which is cyano, oxo, hydroxy, C 1-3 alkoxy, halo, or C 1-2 haloalkoxy; And T1 is selected from C1-4 alkyl, C1-4 haloalkyl, aryl, heterocyclil, monocyclic or dicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C3-8 cycloalkyl, bridged dicyclic C5-12 cycloalkyl, or bridged heterocyclic ring systems, each of which is optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, C1-2 haloalkoxy, or C3-6 cycloalkyl; Or R1e and R1f are connected, together with the nitrogen atom to which they are attached, to form a monocyclic or bicyclic-heterocyclic ring, which is optionally substituted and/or substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy, or the monocyclic or bicyclic heterocyclic ring formed by R1e and R1f is optionally spiro-fused to a C3-6 cycloalkyl or heterocyclic ring, which is again optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy; Any alkyl, alkoxy, or C3-6 cycloalkyl is additionally optionally substituted with one or more substituents selected from cyano, hydroxy, halo, NR 1k R 1l , or -S(O) 0-2 R 1k R 1l , where R 1k and R 1l are H or C1-4 alkyl, a compound or a pharmaceutically acceptable salt thereof.
  7. In claim 1 or 2, R 1a is a group of the following chemical formula: In the chemical formula, p is 1 and; R 1c and R 1d are independently selected from hydrogen (including deuterium) or C 1-2 alkyl; R 1e is selected from hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is a group having the following chemical formula: In the chemical formula: q is 1 or 2, and; R 1g and R 1h are independently selected from hydrogen (including deuterium) or C 1-2 alkyl; And T1 is selected from C3-4 cycloalkyl, heterocyclil, monocyclic or dicyclic heteroaryl, spirocyclic, carbocyclic or heterocyclic ring systems, bridged C3-8 cycloalkyl, bridged dicyclic C5-12 cycloalkyl, or bridged heterocyclic ring systems, each of which is optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, C1-2 haloalkoxy, or C3-6 cycloalkyl; Or R1e and R1f are connected, together with the nitrogen atom to which they are attached, to form a monocyclic or bicyclic-heterocyclic ring, which is optionally substituted and/or substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy, or the monocyclic or bicyclic heterocyclic ring formed by R1e and R1f is optionally spiro-fused to a C3-6 cycloalkyl or heterocyclic ring; This is further optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy, and any alkyl, alkoxy, or C3-6 cycloalkyl is additionally optionally substituted with one or more substituents selected from cyano, hydroxy, halo, NR 1k R 1l , or -S(O) 0-2 R 1k R 1l , where R 1k and R 1l are H or C1-4 alkyl, a compound or a pharmaceutically acceptable salt thereof.
  8. In claim 1 or 2, R 1a is a group of the following chemical formula: In the chemical formula, R 1c and R 1d are independently selected from hydrogen (including deuterium) or C 1-2 alkyl; R 1e is selected from hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is a group having the following chemical formula: In the chemical formula: q is 1 and; R 1g and R 1h are independently selected from hydrogen (including deuterium) or C 1-2 alkyl; And T1 is selected from C3-4 cycloalkyl, heterocyclil, spirocyclic, carbocyclic or heterocyclic ring systems, bridged C3-8 cycloalkyl, bridged dicyclic C5-12 cycloalkyl, or bridged heterocyclic ring systems, each of which is optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, C1-2 haloalkoxy, or C3-6 cycloalkyl; A compound or a pharmaceutically acceptable salt thereof, wherein any alkyl or alkoxy is additionally optionally substituted with one or more substituents selected from cyano, hydroxy, or halo.
  9. In claim 1 or 2, R 1a is a group of the following chemical formula: In the chemical formula, p is 1 and; R 1c and R 1d are independently selected from hydrogen (including deuterium) or C 1-2 alkyl; A compound or a pharmaceutically acceptable salt thereof, wherein R1e and R1f are connected to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic-heterocyclic ring, which is optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, C3-6 cycloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy, and/or the monocyclic or bicyclic heterocyclic ring formed by R1e and R1f is optionally spiro-fused to a C3-6 cycloalkyl or heterocyclic ring, which is again optionally substituted with one or more substituents selected from C1-2 alkyl, C1-2 haloalkyl, cyano, hydroxy, C1-2 alkoxy, halo, or C1-2 haloalkoxy.
  10. In paragraph 1 or 2, R 1a is a compound or a pharmaceutically acceptable salt thereof selected from the following:
  11. In paragraph 1 or 2, R 1b is a compound or a pharmaceutically acceptable salt thereof selected from hydrogen or a halo.
  12. In claim 1 or 2, R 2a , R 2b , and R 2d are independently selected from hydrogen or halos, a compound or a pharmaceutically acceptable salt thereof.
  13. In paragraph 1 or 2, Y is a compound or a pharmaceutically acceptable salt thereof selected from the following:
  14. In paragraph 1 or 2, Y is a compound or a pharmaceutically acceptable salt thereof selected from the following:
  15. In paragraph 1 or 2, Z is selected from the following: A1 , A2 , A5 , A6, A7, R4 , R5, R6 , R8 , R9 , R10 , R11 , RY5N , RZ1 , RZ2 , RZ10 , RZ12 , RZ13, RZ14 , RZ15 , RZ16 , RZ2a , RZ3a , RZi1b , and RZi2e are compounds or pharmaceutically acceptable salts thereof that are as defined in claim 1 or 2.
  16. In paragraph 1, Z is as follows: R4 , R5 , and R6 are independently selected from hydrogen and halos; A1 is selected from CR12 and N, and R12 is selected from hydrogen, halo, cyano, and methyl; and A 2 is selected from CR 13 and N, and R 13 is selected from hydrogen, halo, cyano, and methyl, a compound or a pharmaceutically acceptable salt thereof.
  17. In paragraph 16, R4 , R5 , and R6 are hydrogen, compounds, or pharmaceutically acceptable salts thereof.
  18. In paragraph 16 or 17, R 12 is a compound or a pharmaceutically acceptable salt thereof selected from hydrogen and halos.
  19. In paragraph 16 or 17, R 13 is a compound or a pharmaceutically acceptable salt thereof selected from hydrogen and methyl.
  20. In paragraph 1 or 2, X is is; Y is is; and Z is is; R 1a , R 1b, R 2a , R 2b , R 2d , n, R 3a1 , R 3a2 , A 1 , A 2 , R 4 , R 5 , and R 6 are compounds or pharmaceutically acceptable salts thereof as defined in claim 1 or 2.

Description

Polyheterocyclic compounds as METTL3 inhibitors The present invention relates to a specific compound that acts as an inhibitor of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) activity. The present invention also relates to a method for preparing such a compound, a pharmaceutical composition comprising such a compound, and its use in the treatment of proliferative disorders, such as cancer, autoimmune, neurological, infectious and inflammatory diseases, as well as other diseases or conditions involving METTL3 activity. N6 -methyladenosine (m6A) is the most common and abundant covalent modification of messenger RNA, regulated by the 'writer', 'eraser', and 'reader' of this mark (Meyer & Jaffrey 2014; Niu Y et al., 2013; Yue et al., 2015). Approximately 0.1% to 0.5% of all mRNA adenosines are modified by m6A (Li Y et al., 2015). In vitro data have shown that m6A influences fundamental aspects of mRNA biology, primarily mRNA expression, splicing, stability, localization, and translation (Meyer et al., 2015; Sledz & Jinek 2016). M6A variants are tissue-specific, and there is significant variability in their incidence profiles in non-disease tissues (e.g., brain, heart, kidney) and diseased tissues and cells (lung, kidney, breast, and leukemia cancer cells) (Meyer et al. 2012). m6A variants and their erasers and lighters, such as FTO, ALKBH5, methyltransferase-like 3 (METTL3) and METTL14, are associated with major diseases, such as solid organ cancer, leukemia, type 2 diabetes, neuropsychiatric behavioral disorders, and depressive disorders (Chandola et al. 2015; Koranda et al. 2018). RNA methyltransferase, METTL3, is not the sole enzyme but is a major enzyme that catalyzes m6A modification of RNA. It exists as a heterotrimeric complex with METTL14 (Liu et al. 2014, Wang et al. 2016) and Wilm's Tumor Associated Protein (WTAP) (Ping et al. 2014). Catalytically active residues present in METTL3 transfer a methyl group from the cofactor S-adenosylmethionine to the substrate RNA, and METTL14 facilitates the binding of the substrate RNA. WTAP localizes the complex to specific nuclear regions and also localizes the RNA substrate to the complex (Wang X et al. 2016). METTL3 has been reported to play a role in many modes of cancer development (Fry et al. 2018). Genetic knockdown of METTL3 in lung cancer cell lines (A549, H1299, and H1792) and HeLa cells reduces the growth, survival, and invasion of human lung cancer cells (Lin S et al. 2016). METTL3 is significantly upregulated in human bladder cancer (Cheng et al. 2019). Knockdown of METTL3 significantly reduced bladder cancer cell proliferation, invasion, and survival in vitro, and tumorigenicity in vivo. AF4/FMR2 family member 4 (AFF4), two key regulators of the NF-κB pathway (IKBKB and RELA), and MYC were additionally identified as direct targets of METTL3-mediated m6A modification. In renal carcinoma cell lines (CAK-1, CAK-2, and ACHN), genetic knockdown reduced cell proliferation through the phosphatidinyl inositol 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) signaling pathway (Li X et al. 2017). Recently, Barbieri et al. (2017) defined a set of RNA-modifying enzymes required for AML leukemia and identified a key leukemia pathway involving METTL3 RNA methyltransferase. In this pathway, METTL3 is stably recruited by the CCAAT-box-binding transcription factor CEBPZ to the promoters of a specific set of active genes, leading to m6A methylation and increased translation of each mRNA. One important target is SP1 , an oncogene in some cancers that regulates c-MYC expression. Consistent with these findings, METTL3 has been reported to be capable of co-transcriptionally methylating its targets. The pathway described by Barbieri et al. is important for AML leukemia because three of its components are required for AML cell growth: (i) m6A RNA methyltransferase METTL3; (ii) transcription factor CEBPZ, which targets this enzyme as a promoter; and (iii) SP1, whose translation depends on m6A modification by METTL3. Furthermore, observations by Barbieri et al. define the enzymatic activity of METTL3 as a novel candidate target for the treatment of AML. In a separate, independent study, METTL3 was reported to play an essential role in controlling the myeloid differentiation of normal mammalian hematopoietic and leukemic cells (Vu et al. 2017). Forced expression of wild-type METTL3, rather than mutant METTL3 (with defective catalytic activity), significantly promotes cell proliferation and inhibits cell differentiation in human umbilical cord blood-derived CD34+ hematopoietic stem/progenitor cells (HSPCs). Genetic knockdown of METTL3 has the opposite effect. METTL3 is highly expressed in AML compared to normal HSPCs or other types of cancer. In human AML cell lines, knockdown of METTL3 significantly induces cell differentiation and apoptosis, and inhibits leukemic progression in mice xenografted with MOLM-13 AML cells. The biological function of METTL3 appe