NZ798969B2

NZ798969B2 - Benzoazepine analogs as inhibiting agents for bruton's tyrosine kinase

Info

Publication number: NZ798969B2
Application number: NZ798969A
Authority: NZ
Inventors: Brian T Hopkins; Joseph P Lyssikatos; Bin; Isaac Marx; Daniel B Patience; Matthew Peterson; Robin Prince; Fengmei Zheng
Original assignee: Biogen Ma Inc
Filing date: 2018-04-13
Publication date: 2026-02-03

Abstract

Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods for their production and compounds of formula (I) for use in treating a disease responsive to the inhibition of Bruton's tyrosine.

Claims

What is claimed is:

1. A compound of Formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein: Ring A is 5-membered monocyclic heteroaryl ning 3 heteroatoms ndently selected from N, O and S, wherein said 5-membered clic heteroaryl is optionally substituted with one or more R1; R1 in each occurrence is ndently selected from C1-6alkyl and 3- to 5- membered carbocyclyl, n said C1-6alkyl and 3- to 5-membered carbocyclyl are optionally substituted with one or more R10; R10 in each occurrence is independently selected from halo, -CN, C1-6alkyl, and 3- to 5-membered carbocyclyl; R2 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, -CN, -C(O)R2a, - C(O)2R2a, -C(O)N(R2a)2, -S(O)2R2a, and -S(O)2N(R2a)2, wherein said kyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one or more R20; R2a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, 4- to 6-membered monocyclic yclyl, and 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 4- to 6-membered monocyclic yclyl, and 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and ndently substituted with one or more R20; R20 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, 4- to 6-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halo, -CN, 20a, -C(O)2R20a, -C(O)N(R20a)2, a)2, - N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, a)S(O)2R20a, -OR20a, - OC(O)R20a, -OC(O)N(R20a)2, -SR20a, -S(O)R20a, -S(O)2R20a, -S(O)N(R20a)2, and - S(O)2N(R20a)2; R20a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2- 6alkynyl, 4- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R4 is ed from H and kyl, wherein said C1-6alkyl is optionally substituted with one or more halo; R5 is selected from H and C1-6alkyl wherein said C1-6alkyl is optionally substituted with one or more halo; R6 is selected from H and kyl, n said C1-6alkyl is optionally substituted with one or more halo; or R5 and R6, together with the atoms to which they are attached, form a ring containing one or two heteroatoms selected from O, N, and S, wherein the ring is optionally substituted with one or more R50; and R50 is a C1-6alkyl; ed that the compound of formula(I) is not represented by , or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II’): (II’) or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or 2, or a pharmaceutically able salt thereof, wherein ring A is selected from 1,2,3-oxadiazole, 1,3,4-oxadiazole, 1,2,4-oxadizole, 1,2,3- thiadiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazole, 1,2,3-triazole, and 1,2,4-triazole, each of which is optionally substituted with one or two R1.

4. The compound of claim 1 or 2, or a ceutically acceptable salt thereof, wherein ring A is ented by one of the following formula: ; ; ; ; ; or .

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R1 in each occurrence is independently C1-6alkyl or C3-5cycloalkyl; wherein said C1-6alkyl and C3-5cycloalkyl are optionally substituted with one to three R10; and R10 in each occurrence is independently selected from halo, -CN and C1-6alkyl.

6. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1 in each occurrence is ndently selected from –C(CH3)3, - CH(CH3)2, -C(CH3)2CHF2, -C(CH3)2CF3, -C(CH3)2CH2F, -C(CH3)2CN, 1- cyclopropyl, cyclobutyl, and 3,3-difluorocyclobutyl.

7. The nd of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, C1-6alkyl, C4-6cycloalkyl, saturated 4- to 6-membered monocyclic heterocyclyl, -C(O)R2a, -C(O)2R2a, and -S(O)2R2a, wherein said C1-6alkyl, C4- 6cycloalkyl, and saturated 4- to 6-membered monocyclic heterocyclyl are optionally substituted with one to three R20; R2a in each occurrence is independently selected from H, kyl, kyl, and saturated 4- to 6-membered monocyclic heterocyclyl, wherein said C1-6alkyl, 4- to 6- membered clic carbocyclyl, and saturated 4- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R20; R20 in each occurrence is independently ed from C1-6alkyl, cloalkyl, ted 4- to 6-membered clic heterocyclyl, halo, -CN, -N(R20a)2, and -OR20a; and R20a in each occurrence is independently H or C1-6alkyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, C1-6alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -C(O)R2a, -C(O)2R2a, and -S(O)2R2a, wherein said kyl, cyclobutyl, cyclopentyl and cyclohexyl, yl, tetrahydrofuranyl, and tetrahydropyranyl are optionally substituted with one to three R20; R2a is C1-6alkyl optionally substituted with one R20; R20 in each occurrence is independently selected from C1-3alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halo, -N(R20a)2, and -OR20a; and R20a in each occurrence is independently H or methyl.

9. The nd of claim 8, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from -H, -SO2CH3, -C(=O)OC(CH3)3, -C(=O)CH2N(CH3)2, -CH3, - CH2CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH(CH3)OH, - CH2C(CH3)2OH, 2CH2OH, -CH2CHF2, -CH2CF3, , , , , and .

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R4 is H or C1-3alkyl optionally substituted with one to three .

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R5 is H or C1-3alkyl optionally substituted with one to three fluoro.

12. The nd of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R6 is H or kyl optionally substituted with one to three fluoro.

13. The compound of any one of claims 1-12, or a ceutically acceptable salt thereof, n R5 and R6 together with the atoms to which they are attached, form a 5- to 6-membered saturated heterocyclic ring containing one or two heteroatoms selected from O, N, and S, wherein the ring is optionally substituted with one R50; and R50 is a C1- 3alkyl.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: (IIA);or (IIA’); or a pharmaceutically able salt thereof, wherein: ring A is represented by one of the ing formula: ; ; or ; R1 is C1-6alkyl; R2 is C1-6alkyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein said C1-6alkyl is optionally substituted with one to three R20; R20 for each occurrence is independently halo or –OR20a; R20a is H or C1-3alkyl; R5 is H or C1-3alkyl.

15. The compound of claim 14, or a pharmaceutically able salt f, wherein R1 is tert-butyl; R2 is , , -CH2CHF2, -CH2CF3, -CH2CH2OH, -CH2CH2OCH3, or - CH2C(CH3)OH; and R5 is methyl or isopropyl.

16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. Use of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a er responsive to inhibition of Bruton’s tyrosine kinase in a human subject, wherein the disorder is an autoimmune disorder or multiple sis.

18. A compound selected from: , , , and or a pharmaceutically acceptable salt, stereoisomer, or a mixture of isomers thereof.

19. The compound of claim 18, wherein the compound is:

20. The compound of claim 18, wherein the compound is:

21. The compound of claim 18, wherein the compound is:

22. The compound of claim 18, wherein the compound is: 193193 Form 33 27 1.54060 25 WL= 88’? 19 Tonheta/Theta) 17 (Coupled 15 2Theta 006 008 001 009 009 0017 008 OOZ 00L 0 s1un03 SUBSTITUTE SHEET (RULE 26) (61M) M0|:l JEGH v .®_u_ Foo.<-mo-mo Foo.<-mo-mo 0mm Fm Fm rm Fm UmQ Gav 0&6: 933mm 8. Ooodmw om? 00? mm om mm ow mp (%) :Iu?leM EE>> SUBSTITUTE SHEET (RULE 26) 8 2: Enos: .®_n_ .®_n_ m8 SUBSTITUTE SHEET (RULE 26) Zl9 mm Show mm QVV R 88m. mm ids mm v 898 L‘ L01 a .®_u_ 66Z z.___:____:_::_::_ 2 Emct?m?oé €9Z :2 ___: t :__: :7: m; .8338 6LZ « 325 SUBSTITUTE SHEET (RULE 26) (61M) M0|:l leeH 358355 omm <._. m<-N m<-N Tmo Tmo Fm Fm oom Regs: Fm Fm UmQ 0mm 000.com oatma 9,28 oom GOV m... m.®_u_ om? oow om on om oxm SUBSTITUTE SHEET (RULE 26) 2: 23.3: :_ mm? 7g 09 L om? 0.|r.9/_.0.L900.77 LuLL mm? i: 99 ow? }. .77 LL mvr <© mo mm? .®_n_ .®_n_ om? SUBSTITUTE SHEET (RULE 26)