US 2023/0399319 A1 · Acylsulfamide Compound and Pharmaceutical Use Therefor

Abstract

An acylsulfamide compound, or a pharmaceutically acceptable salt thereof, having NLRP3 inflammasome inhibitory activity, a pharmaceutical composition comprising the same, and their medical use, etc., are provided. A compound of Formula [Ia]: or a pharmaceutically acceptable salt thereof, wherein a partial structure: is: Ring Cy is an optionally substituted heteroaryl or phenyl; RDy and REy are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-4 haloalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl, or alternatively, RDy and REy may combine together with the nitrogen atom to which they attach to form heterocycloalkyl, etc.

A compound of Formula [Ia]:

or a pharmaceutically acceptable salt thereof, wherein
a partial structure:
is:
Ring Cy is 5- to 6-membered heteroaryl comprising 1 to 3 nitrogen atoms, or phenyl, wherein the heteroaryl or the phenyl is substituted with RF at one of the atoms of α-position to a Cy ring-constituting atom attached to the NH group directly attached to the partial structure, and may be optionally substituted with the same or different 1 to 4 RGs;
RDy and REy are each independently
(1) hydrogen,
(2) C1-6 alkyl, wherein the alkyl may be optionally substituted with the same or different 1 to 3 Rd1s,
(3) C1-4 haloalkyl,
(4) C3-6 cycloalkyl, wherein the cycloalkyl may be optionally substituted with the same or different 1 to 3 halogen atoms,
(5) 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rd2s, or
(6) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heteroaryl may be optionally substituted with C1-6 alkyl or C1-4 haloalkyl, or alternatively,
RDy and REy may combine together with the nitrogen atom to which they attach to form
(a) 4- to 7-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rs1ys and/or may be fused with a 5- to 6-membered heteroaromatic ring comprising 1 to 3 nitrogen atoms wherein the heteroaromatic ring may be optionally substituted with the same or different 1 or 2 Rd3s,
(b) 7- to 11-membered spiro heterocycloalkyl comprising 1 to 3 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiro heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rd4s and/or may be optionally fused with a benzene ring,
(c) 6- to 10-membered fused heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the fused heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rd4s, or
(d) 5- to 9-membered bridged heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the bridged heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rd6s;
RF is
(1) halogen,
(2) C1-4 alkyl,
(3) C1-4 haloalkyl,
(4) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms, or
(5) C3-5 cycloalkyl,
RG is each independently a substituent selected from the group consisting of:
(1) halogen,
(2) C1-6 alkyl, wherein the alkyl may be optionally substituted with:
(a) C1-4 alkoxy,
(b) cyano,
(c) phenyl, or
(d) 5- to 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms,
(3) C1-4 haloalkyl,
(4) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms,
(5) cyano,
(6) CONRG1RG2, wherein RG1 and RG2 are each independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl,
(7) trialkylsilyl,
(8) pentafluorosulfanyl,
(9) C3-7 cycloalkyl, wherein the cycloalkyl may be optionally substituted with the same or different 1 to 3 Rs2s,
(10) C5-13 spiro cycloalkyl, wherein the spiro cycloalkyl may be optionally substituted with the same or different 1 to 3 Rs3s,
(11) 4- to 7-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rs4s,
(12) 7- to 11-membered Spiro heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the spiro heterocycloalkyl may be optionally substituted with the same or different 1 to 3 Rs5s,
(13) phenyl, wherein the phenyl may be optionally substituted with the same or different 1 to 3 Rs6s, and
(14) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heteroaryl may be optionally substituted with the same or different 1 to 3 Rs7s, or alternatively,
in the case where RF and RG or two RGs are substituted on neighboring atoms, then the RF and RG and/or the two RGs may combine together with the atoms to which they attach to form:
(a) a C5-6 cycloalkene ring, wherein the cycloalkene ring may be optionally substituted with the same or different 1 to 3 Rc1s,
(b) a 5- to 7-membered heterocycloalkene ring comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkene ring may be optionally substituted with the same or different 1 to 3 Rc2s,
(c) a benzene ring, wherein the benzene ring may be optionally substituted with the same or different 1 to 3 Rc3s, or
(d) a 5- to 7-membered heteroaromatic ring comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heteroaromatic ring may be optionally substituted with the same or different 1 to 3 Rc4s,
so that Ring Cy may form a bi- or tri-cyclic fused ring group;
Rc1 Rc2, Rc3 and Rc4 are each independently a substituent selected from the group consisting of:
(1) halogen,
(2) C1-6 alkyl,
(3) C1-4 haloalkyl, and
(4) oxo;
Rd1 is each independently a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxy,
(3) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms,
(4) cyano,
(5) COORe1, wherein Re1 is hydrogen or C1-6 alkyl,
(6) CONRe2Re3, wherein Re2 and Re3 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, or alternatively, Re2 and Re3 may combine together with the nitrogen atom to which they attach to form 5- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 or 2 halogen atoms,
(7) CORe4, wherein Re4 is C1-6 alkyl,
(8) SO2Re5, wherein Re5 is C1-6 alkyl,
(9) NRe6Re7, wherein Re6 is
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, and
Re7 is
(a) hydrogen,
(b) C1-6 alkyl,
(c) C1-4 haloalkyl,
(d) CORe8, wherein Re8 is C1-6 alkyl, and the alkyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(i) halogen,
(ii) hydroxy,
(iii) C1-6 alkoxy, and
(iv) cyano, or
(e) SO2Re9, wherein Re9 is C1-6 alkyl or C1-4 haloalkyl,
(10) SO2NRf1, Rf2, wherein Rf1 and Rf2 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl,
(11) C3-6 cycloalkyl, wherein the cycloalkyl may be optionally substituted with hydroxy or C1-6 alkoxy,
(12) 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heterocycloalkyl may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen and oxo,
(13) phenyl, and
(14) 5- to 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heteroaryl may be optionally substituted with C1-6 alkyl or C1-4 haloalkyl;
Rd2 is each independently a substituent selected from the group consisting of:
(1) C1-6 alkyl,
(2) C1-4 haloalkyl,
(3) oxo, and
(4) CORg1, wherein Rg1 is C1-6 alkyl, and the alkyl may be optionally substituted with:
(a) hydroxy,
(b) C1-6 alkoxy, and
(c) cyano;
Rd3 is each independently a substituent selected from the group consisting of:
(1) C1-6 alkyl, and
(2) COORg2, wherein Rg2 is hydrogen or C1-6 alkyl;
Rd4, Rd5 and Rd6 are each independently a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxy,
(3) oxo,
(4) cyano,
(5) C1-6 alkyl,
(6) C1-4 haloalkyl,
(7) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms,
(8) NRg3Rg4, wherein Rg3 and Rg4 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, and
(9) 4- to 7-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(a) halogen,
(b) hydroxy,
(c) C1-6 alkyl,
(d) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms, and
(e) oxo;
Rs1y, Rs2, Rs3, Rs4, Rs5, Rs6, and Rs7 are each independently a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxy,
(3) C1-6 alkyl, wherein the alkyl may be optionally substituted with the same or different 1 to 3 R11ys,
(4) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms,
(5) cyano,
(6) ORt1, wherein Rt1 is C3-6 cycloalkyl,
(7) COR12,
(8) SO2R13,
(9) NRt2Rt3, wherein Rt2 is
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, and
Rt3 is
(a) hydrogen,
(b) C1-6 alkyl,
(c) C1-4 haloalkyl,
(d) COR14, or
(e) SO2R15,
(10) CONRt4Rt5, wherein Rt4 and Rt5 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, or alternatively, Rt4 and Rt5 may combine together with the nitrogen atom to which they attach to form 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 or 2 halogen or hydroxy,
(11) SO2NRt6Rt7, wherein Rt6 and Rt7 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl,
(12) COORt8, wherein Rt8 is hydrogen or C1-6 alkyl,
(13) oxo,
(14) C3-6 cycloalkyl,
(15) phenyl,
(16) 4- to 7-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 to 3 R16s, and
(17) 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms, wherein the heteroaryl may be optionally substituted with the same or different 1 to 3 R17s;
R11y is each independently a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxy,
(3) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(a) halogen,
(b) hydroxy,
(c) C1-6 alkoxy, and
(d) C3-6 cycloalkyl, wherein the cycloalkyl may be optionally substituted with the same or different 1 to 3 R1dys,
(4) cyano,
(5) NR21R22, wherein R21 is
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, and
R22 is
(a) hydrogen,
(b) C1-6 alkyl,
(c) C1-4 haloalkyl,
(d) COR1a, or
(e) SO2R1b,
(6) COR23, wherein R23 is C1-6 alkyl or C1-4 haloalkyl,
(7) SO2R24y, wherein R24y is C1-6 alkyl, wherein the alkyl may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(a) halogen, and
(b) C3-6 cycloalkyl,
(8) COOR25, wherein R25 is hydrogen or C1-6 alkyl,
(9) CONR26R27, wherein R26 and R27 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, or alternatively, R26 and R27 may combine together with the nitrogen atom to which they attach to form 5- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 or 2 halogen atoms,
(10) SO2NR28R29, wherein R28 and R29 are independently
(a) hydrogen,
(b) C1-6 alkyl, or
(c) C1-4 haloalkyl, or alternatively, R28 and R29 may combine together with the nitrogen atom to which they attach to form 4- to 7-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 or 2 halogen atoms,
(11) C3-6 cycloalkyl,
(12) 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heterocycloalkyl may be optionally substituted with the same or different 1 to 3 R1cs,
(13) phenyl,
(14) 5- to 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms, wherein the heteroaryl may be optionally substituted with the same or different 1 to 3 R1eys, and
(15) OR30y, wherein R30y is C3-6 cycloalkyl which may be optionally substituted with the same or different 1 to 3 R1fys;
R17 and R1ey are each independently a substituent selected from the group consisting of:
(1) halogen,
(2) C1-6 alkyl,
(3) C1-4 haloalkyl,
(4) C1-6 alkoxy,
(5) cyano,
(6) C3-6 cycloalkyl, and
(7) 4- to 6-membered heterocycloalkyl comprising an oxygen atom;
R12, R13, R14, R15, R1a, and R1b are each independently a substituent selected from the group consisting of:
(1) C1-6 alkyl,
(2) C1-4 haloalkyl,
(3) C3-6 cycloalkyl,
(4) 4- to 6-membered heterocycloalkyl comprising an oxygen atom,
(5) phenyl, and
(6) 5- to 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of nitrogen and oxygen atoms;
R16, R1c, R1dy, and R1fy are each independently a substituent selected from the group consisting of:
(1) halogen,
(2) hydroxy,
(3) C1-6 alkyl,
(4) C1-4 haloalkyl,
(5) C1-6 alkoxy, wherein the alkoxy may be optionally substituted with the same or different 1 to 3 halogen atoms, and
(6) oxo.

207 more elements

Acylsulfamide Compound and Pharmaceutical Use Therefor

Life of this patent

Acylsulfamide Compound and Pharmaceutical Use Therefor

Life of this patent

Abstract

Claims21