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JP-7857285-B2 - Alpha protein kinase 1 inhibitor and method of use

JP7857285B2JP 7857285 B2JP7857285 B2JP 7857285B2JP-7857285-B2

Inventors

  • リュウ，ダンヤン
  • シュ，ティアン
  • シュ，コン
  • メルビン，ローレンス・エス，ジュニア
  • ウェイ，ション
  • リ，トンルエイ・レイモンド
  • ファン，ジェチン
  • パン，イェンファン
  • ダン，フアイシン
  • リヒテンシュタイン，ヘンリ

Assignees

  • シャンハイ・ヤオ・ユアン・バイオテクノロジー・カンパニー・リミテッド

Dates

Publication Date
20260512
Application Date
20210923
Priority Date
20200924

Claims (20)

  1. Compounds of formula XI, formula XI-B, or formula XI-C or a pharmaceutically acceptable salt thereof, in the formula, X is selected from -S-, -O-, and -NR a- , where, Ra is H, A is selected from azetidinyl, -N( R6 )-, -CH2 -N( R6 )-, and -CHR9 -N( R6 )-, where, R 6 is selected from H, -OH, optionally substituted C1 - C6 alkyl, optionally substituted C1 - C6 hydroxyalkyl, and C1 - C6 aminoalkyl, where, The R6 portion, which may be substituted, comprises 0 to 3 substituents independently selected from -OH and -NH2 . R9 is a C1 - C6 alkyl which may be substituted, where, The R9 portion, which may be substituted, contains 0 to 2 substituents that are -OH. R1 is selected from H, optionally substituted C1- C6 alkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 - C6 hydroxydeuterated alkyl, optionally substituted C1 - C6 haloalkyl, optionally substituted C1 - C6 aminoalkyl, optionally substituted C1 - C6 alkoxyl, optionally substituted saturated or unsaturated C3 - C6 cycloalkyl, optionally substituted monocyclic or bicyclic aryl, optionally substituted 5-10 membered heteroaryl containing 1-4 heteroatom ring vertices selected from N, O and S; optionally substituted saturated or unsaturated 3-7 membered heterocyclil containing 1-2 heteroatom ring vertices selected from N, O and S; and optionally substituted saturated or unsaturated 6-11 membered bicyclic heterocyclil containing 1-2 heteroatom ring vertices selected from N, O and S. The R1 portion may be substituted with -D, halo, -OH, -NH2 , =O, -CN, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 hydroxydeuterated alkyl, C1- C6 haloalkyl, C1 - C6 alkoxyl, C1 - C6 haloalkoxyl, -R7a, -X1, -R7a , CHR7aR8a , -OR7a , -O - X1 , -R7a , -X1 , -O- X1 , -R7a , -O- X1 , -C ( O)( R7a ), -C (O)( R7a ), -C(O)N( R7aR8a ), S(O) 2R7a , -S(O) 2N ( R7a comprising 0 to 4 substituents independently selected from R 8a ), -N(R 7a R 8a ), saturated or unsaturated C3 - C6 cycloalkyl, saturated or unsaturated 3-7 membered heterocyclils containing 1-2 heteroatomic ring vertices selected from N, O, and S, monocyclic or bicyclic aryls, 5-10 membered heteroaryls containing 1-4 heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated 7-8 membered bridged heterocyclils containing 1-2 heteroatomic ring vertices selected from N, O, and S, Each X1 is independently a C1-6 alkylene. Each R7a and R8a is independently selected from saturated or unsaturated 3-7 membered heterocyclils containing 1-2 heteroatom ring vertices selected from H, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1- C6 aminoalkyl, C1 - C6 alkoxyl, monocyclic or bicyclic aryl, N, O, and S, and the monocyclic or bicyclic aryl and the 3-7 membered heterocyclil group are substituted with 0-3 substituents selected from halo, -OH, -NH2 , =O, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, and saturated or unsaturated C3 - C6 cycloalkyl. In the substituents of the substituted R1 , the saturated or unsaturated C3 - C6 cycloalkyl, the saturated or unsaturated 3-7 membered heterocyclil, the monocyclic or bicyclic aryl, the 5-10 membered heteroaryl, and the saturated or unsaturated 7-8 membered cross-linked heterocyclil are each independently a saturated or unsaturated 3-7 membered heterocyclil containing one or two heteroatom ring vertices selected from halo, -OH , -NH2 , =O, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1-C6 alkoxyl, saturated or unsaturated C3-C6 cycloalkyl, N, O, and S , -CHR7bR8b , -OR7b , -C (O)N( R7bR8b ), -S(O) 2N ( R7bR8b ) and -N(R 7b R 8b ) are replaced by 0 to 3 parts selected from, Each R7b and R8b is independently selected from H and C1 - C6 alkyl, or R1 and R6 are bonded to form a 3-6 membered heterocycloalkyl. R5 is selected from H, deuterium, halo, C1 - C6 alkyl, C1 - C6 deuterated alkyl, and C1 - C6 haloalkyl. R2 and R3 are each independently selected from H, OH, C1 - C6 alkyl, C2- C6 alkynyl, C3 - C6 cycloalkyl and the monocyclic or bicyclic aryl, where C1 - C6 alkyl, C2 - C6 alkynyl, C3 - C6 cycloalkyl and the monocyclic or bicyclic aryl are each substituted with 0 to 3 moieties independently selected from halo, -OH, C1 - C6 alkyl, C1 - C6 hydroxyalkyl and C1 - C6 alkoxyl. However, R2 and R3 are not both H, or R2 and R3 are bonded to form a C3 - C6 cycloalkyl ring. Each R4 is independently selected from halo, -OH, -NH2 , C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, saturated or unsaturated C3 - C6 cycloalkyl, CHR7e R8e , and OR7e , where, Each R7e and R8e is independently selected from H, C1 - C6 alkyl, and C1 - C6 haloalkyl. The subscript p is 1, 2, or 3. D is CR 10 or N, E is CR 14 or N, F is either CR12 or N. G is CR 11 or N, However, if three or fewer of D, E, F, and G are N, R10 , R11 , R12 , and R14 , if present, are each independently selected from saturated or unsaturated 3-7 membered heterocyclines containing 1-2 heteroatom ring vertices selected from H, halo, -OH, C1 - C6 alkoxyl, -O- X1 - R7a , -C(O)N( R7aR8a ), and N, O , and S, where, Each X1 is independently a C1-6 alkylene. Each R7a and R8a is independently selected from H, C1 - C6 alkyl, and C1 - C6 alkoxyl. R 13 is a H, 3-7 membered heterocyclil containing 1-2 heteroatomic ring vertices selected from N, O, and S, or a saturated or unsaturated 7-8 membered bridged heterocyclil containing 1-2 heteroatomic ring vertices selected from N, O, and S. 3- to 7-membered heterocyclyls and 7- to 8-membered cross-linked heterocyclyls may be substituted with 0 to 2 moieties independently selected from -OH, C1 - C6 alkyl, C1 - C6 aminoalkyl, -NH2 , and C1 - C6 hydroxyalkyl. m is an integer from 1 to 6. R 18 is H. The aforementioned compound, or a pharmaceutically acceptable salt thereof.
  2. The compound according to claim 1, wherein X is -S-, X is -O-, or X is -NH-.
  3. The compound according to claim 1, wherein R 6 is selected from H, C1 - C6 alkyl, and C1 - C6 hydroxyalkyl.
  4. The compound according to claim 1, wherein R9 is selected from CH3 and CH2OH .
  5. R1 is selected from H and optionally substituted C1 - C6 alkyl groups. The optionally substituted C1 - C6 alkyl groups comprise 0 to 4 substituents independently selected from halo, -OH, -NH2 , =O, -CN, C1 - C6 hydroxyalkyl, C1 - C6 alkoxyl, C1 - C6 haloalkoxyl, saturated or unsaturated C3-C6 cycloalkyl , -CHR7aR8a, -OR7a, -C(O)(R7a ) , -C ( O ) N ( R7aR8a ), -S( O ) 2R7a , -S(O) 2N ( R7aR8a ) and -N (R7aR8a ) . Each R7a and R8a is independently selected from H, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, and C1 - C6 alkoxyl, Alternatively, R1 is a saturated or unsaturated C3 - C6 cycloalkyl group, which may be substituted. The C3 - C6 cycloalkyls, which may be substituted, contain 0 to 4 substituents independently selected from halo, -OH, -NH2 , =O, -CN, C1 - C6 hydroxyalkyls, C1 - C6 alkoxyls, and C1 - C6 haloalkoxyls. Alternatively, R1 is a 5-10 membered heteroaryl compound containing 1-4 heteroatom ring vertices selected from N, O, and S. 5-10 membered heteroaryls are substituted with 0-3 moieties selected from halo, -OH, -NH₂ , -CN, C₁ - C₆ alkyl, C₁ - C₆ hydroxyalkyl, C₁ - C₆ haloalkyl, C₁ - C₆ alkoxyl, 3-7 membered heterocyclils containing 1-2 heteroatom ring vertices selected from N, O and S , saturated or unsaturated C₃ - C₆ cycloalkyl , -CHRₙaR₁a , -ORₙa , -C(O)N( RₙaR₁a ), -S(O) ₂N ( RₙaR₁a ) and -N ( RₙaR₁a ). Each R7a and R8a is independently selected from H, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, and C1 - C6 alkoxyl, Alternatively, R1 is a monocyclic or bicyclic aryl substituted with 0 to 3 substituents selected from halo, 3- to 7-membered heterocyclils containing 1 to 2 heteroatomic ring vertices selected from N, O, and S, and 7- to 8-membered bridged heterocyclils containing 1 to 2 heteroatomic ring vertices selected from N, O, and S, where the 3- to 7-membered heterocyclil or 7- to 8-membered bridged heterocyclil is halo, -OH, -NH₂, =O, -CN, C₁ - C₆ alkyl, C₁ - C₆ hydroxyalkyl, C₁ - C₆ haloalkyl, C₁ - C₆ aminoalkyl, C₁ - C₆ alkoxyl, saturated or unsaturated C₃ - C₆ cycloalkyl, -CHRₙbR₁b , -ORₙb , -C (O)N( RₙbR₁b ), -S(O) ₂ It is replaced by 0 to 3 parts selected from N(R 7b R 8b ) and -N(R 7b R 8b ), Each R7b and R8b is independently selected from H and C1 - C6 alkyl groups. The compound according to claim 1.
  6. R1 is a C1 - C6 alkyl group substituted with 0-4 substituents independently selected from -OH, C1 - C6 hydroxyalkyl, C1 - C6 alkoxyl, -S(O) 2N ( R7aR8a ) and -N( R7aR8a ) . The compound according to claim 1, wherein each R7a and R8a is independently selected from H, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, and saturated or unsaturated C3-C6 cycloalkyl .
  7. R1 is a C1 -C6 alkyl group substituted with 0-2 substituents independently selected from -OH , C1 - C6 hydroxyalkyl, and -S(O) 2N ( R7aR8a ). The compound according to claim 1, wherein each R7a and R8a is independently selected from H and C1 - C6 alkyl groups.
  8. The compound according to claim 1, wherein R1 is a C1 - C6 hydroxyalkyl group which may be substituted.
  9. R1 is a pyridiyl substituted with 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing 1 to 2 heteroatom ring vertices selected from halo, -OH, -NH2 , -CN, C1 - C6 alkyl, N, O, and S. The compound according to claim 1, wherein the 3- to 7-membered heterocyclyl is substituted with 0 to 3 substituents selected from halo, -OH, -NH2 , -CN, C1 - C6 alkyl, and C1 - C6 haloalkyl.
  10. R1 is a monocyclic or bicyclic aryl substituted with 0 to 3 moieties selected from halo, -OH, -NH2 , =O, -CN, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, C1 - C6 haloalkyl, C1 - C6 aminoalkyl, C1 - C6 alkoxyl, and 3-7 membered heterocyclines containing 1-2 heteroatom ring vertices selected from N, O, and S. The aforementioned 3- to 7-membered heterocyclyl is substituted with 0 to 3 moieties selected from halo, -OH, -NH₂ , =O, -CN, C₁ - C₆ alkyl, C₁ - C₆ hydroxyalkyl, C₁ - C₆ haloalkyl, C₁ - C₆ aminoalkyl, C₁ - C₆ alkoxyl , saturated or unsaturated C₃ - C₆ cycloalkyl, -CHRₙbR₁b , -ORₙb , -C(O) N ( RₙbR₁b ), -S(O) ₂N ( RₙbR₁b ), and -N ( RₙbR₁b ), where, The compound according to claim 1, wherein each R7b and R8b is independently selected from H and C1 - C6 alkyl.
  11. R1 is a monocyclic or bicyclic aryl molecule substituted with a halo and 0 to 3 moieties selected from a 3 to 7-membered heterocycline containing 1 to 2 heteroatom ring vertices selected from N, O, and S. The compound according to claim 1, wherein the 3- to 7-membered heterocyclyl is further substituted with 0 to 3 moieties selected from -OH, -NH2 , =O, -CN and -C1 to C6 alkyl groups.
  12. The compound according to claim 1, wherein D, E, F, and G are CR10 , CR14 , CR12 , and CR11 , respectively.
  13. The compound according to claim 1, wherein F and G are CR12 and CR11 , respectively, E is N or CR14 , and D is N or CR10 .
  14. R12 and R14 are H, R10 and R11 are independently selected from halo, -OH, C1 - C6 alkyl, and -C(O)N( R7a R8a ), where, Each R7a and R8a is independently selected from H, C1 - C6 alkyl, and C1 - C6 alkoxyl. R 13 is selected from 3-7 membered heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, and saturated or unsaturated 7-8 membered bridged heterocyclines containing 1-2 heteroatomic ring vertices selected from N, O, and S, where, The compound according to claim 1, wherein the 3- to 7-membered heterocyclyl and the 7- to 8-membered crosslinked heterocyclyl may be substituted with 0 to 2 moieties independently selected from -OH, -NH2 , C1 - C6 alkyl, C1 -C6 hydroxyalkyl, and C1- C6 aminoalkyl.
  15. A compound according to claim 1 having formula XI-B-1 or XI-B-2, or a pharmaceutically acceptable salt thereof, in the formula, R 15 is selected from -OH, C1 - C6 alkyl, C1 - C6 hydroxyalkyl, and C1 - C6 aminoalkyl. R16 and R17 are each independently selected from the halo. A compound, or a pharmaceutically acceptable salt thereof.
  16. The compound according to claim 1, having formula XI-B-1-a-I or formula IB-2-a-I, A compound or a pharmaceutically acceptable salt thereof, wherein R4 is a halo.
  17. The compound according to claim 1, having formula XI-B-1-a-II or formula XI-B-2-a-II, or a pharmaceutically acceptable salt thereof.
  18. The compound according to claim 1, having formula XI-B-1-a-III or formula XI-B-2-a-III, or a pharmaceutically acceptable salt thereof.
  19. The compound according to claim 1, having formula XI-B-1-a-IV or formula IB-2-a-IV, or a pharmaceutically acceptable salt thereof.
  20. The compound according to claim 1, having formula XI-C-1 .

Description

This invention relates to compounds that are inhibitors of α-protein kinase 1 (ALPK1), as well as related compositions and methods. Alpha-kinases show little sequence similarity to conventional protein kinases. A total of six alpha-kinase members have been identified. These include alpha-protein kinase 1 (ALPK1), ALPK2, ALPK3, elongation factor-2 kinase (eEF2K), and transient receptor potential cation channels M6 and M7 (TRPM6 and TRPM7). See Ryazano et al., Curr Biol 9:R43-45 (1999), and Ryazano et al., Proc Natl Acad Sci USA 94:4884-4889 (1997). ALPK1 is an intracellular serine-threonine protein kinase that plays a crucial role in activating the innate immune response to bacteria via TRAF-interacting proteins through forkhead-associated domain (TIFA)-dependent pro-inflammatory nuclear factor-kappa-B (NFκB) signaling. See Zimmermann et al. Cell Rep. 20:2384–2395 (2017); Milivojevic et al., PLOS Pathog. 13:E1006224–E1006224 (2017); and Zhou et al., Nature 561:122–126 (2018). Inappropriate activation of ALPK1 signaling is associated with diseases and disorders related to excessive or inappropriate inflammation. For example, ALPK1 is involved in uric acid monosodium monohydrate (MSU)-induced inflammation and gout. Lee et al., Sci. Rep. 6:25740-25740 (2016). Elevated ALPK1 expression is also associated with lymph node metastasis and tumor growth in oral squamous cell carcinoma. Chen et al., Am J Pathol 189:190-199 (2019). Furthermore, gene mutations in ALPK1 are associated with sweat adenoma, spiral carcinoma, "retinal dystrophy, optic edema, splenomegaly, anhidrosis and migraine" ("ROSAH") syndrome, and "periodic fever, aphthous stomatitis, pharyngitis and adenitis" ("PFAPA") syndrome. For example, see Rashid et al., Nature Communications (2019); Williams et al., Genetics in Medicine 21:2103–2115 (2019); and Sangiorigi et al., Eur. J. Human Genetics (2019). This disclosure provides compounds of formula I described herein, as well as lower embodiments of formula I, and related compositions and methods, which are inhibitors of ALPK1 kinase activity. In some embodiments, compounds of formula I are provided herein. Equation I (wherein A, p, R1 , R2 , R3 , R4 , and R5 are as defined herein.) In some embodiments, the compound of formula I is represented by formula IA. Formula IA (wherein p, R1 , R2 , R3 , R4 , R5 , R6 , and R9 are as defined herein.) In some embodiments, the compound of formula I is represented by formula IA-1. Formula IA-1 (wherein p, R1 , R2 , R3 , R4 , R5 , R6 , and R9 are as defined herein). In some embodiments, the compound of formula I is represented by formula IB. Formula IB (wherein p, R2 , R3 , R4 , R5 , R13 , D, E, F, and G are as defined herein.) In some embodiments, the compound of formula I is represented by formula IB-1. Formula IB-1 (wherein p, R2 , R3 , R4 , R5 , R15 , R16 , and R17 are as defined herein.) In some embodiments, the compound of formula I is represented by formula IC. Formula IC (wherein p, m, R2 , R3 , R4 , R5 , and R18 are as defined herein.) In some embodiments, compounds of formula XI are provided herein. Formula XI (wherein X, A, p, R1 , R2 , R3 , R4 , and R5 are as defined herein). In some embodiments, the compound of formula I is represented by formula XI-A. Formula XI-A (wherein X, p, R1 , R2 , R3 , R4 , R5 , R6 , and R9 are as defined herein). In some embodiments, the compound of formula I is represented by formula XI-A-1. Formula XI-A-1 (wherein X, p, R1 , R2 , R3 , R4 , R5 , R6 , and R9 are as defined herein). In some embodiments, the compound of formula I is represented by formula XI-A-1-a. Formula XI-A-1-a (wherein p, R1 , R2 , R3 , R4 , R5 , R6 , and R9 are as defined herein). In some embodiments, the compound of formula I is represented by formula XI-B. Formula XI-B (wherein X, p, R2 , R3 , R4 , R5 , R13 , D, E, F, and G are as defined herein.) In some embodiments, the compound of formula I is represented by formula XI-B-1. Formula XI-B-1 (wherein X, p, R2 , R3 , R4 , R5 , R15 , R16 , and R17 are as defined herein). In some embodiments, the compound of formula I is represented by formula XI-B-1-a. Formula XI-B-1-a (wherein p, R2 , R3 , R4 , R5 , R15 , R16 , and R17 are as defined herein.) In some embodiments, the compound of formula I is represented by formula XI-C. Formula XI-C (wherein X, p, m, R2 , R3 , R4 , R5 , and R18 are as defined herein). In some embodiments, the compound of formula XI is represented by formula XI-C-1. Formula XI-C-1 (wherein p, m, R2 , R3 , R4 , R5 , and R18 are as defined herein.) In embodiments, this disclosure provides pharmaceutical compositions comprising compounds of formulas I, IA, IB, IC, XI, XI-A, XI-B, or XI-C as described herein, or their subordinate embodiments. In embodiments, this disclosure provides a method for inhibiting ALPK1 kinase activity in target cells or tissues requiring a therapeutic approach that inhibits ALPK1 kinase activity in those cells or tissues, comprising administering a compou