JPWO2020249956A5

JPWO2020249956A5 -

Info

Publication number: JPWO2020249956A5
Application number: JP2021573749A
Authority: JP
Publication date: 2023-06-13

Claims

General formula (I), including all tautomers, all enantiomers and isotopic variants and salts and solvates thereof

[In the formula,
A is

and
one of X ¹ , X ² , X ³ is S and the other two of X ¹ , X ² and X ³ are CH;

represents a single or double bond such that ring A is aromatic;
each of X ⁴ and X ⁵ is independently CH or N;
^*1 indicates the point of attachment to ^Z1 , ^*2 indicates the point of attachment to ^Z2 ;
each of Z ¹ and Z ² is independently selected from ^* -C(O)NH- and ^* -NHC(O)-, ^* indicates the point of attachment to ring A ;
Y is -CH ₂ - or -CH(CH ₃ )- ;
R ⁴ is 6-14 membered aryl, 5-14 membered heteroaryl or 5-10 membered carbocyclic ring system, any of which are substituted with one or more substituents selected from You may also have:
halo, ^CN , nitro, ^R19 , ^OR19 , ^OR6 , ^SR6 , ^NR6R7 , C(O) ^R6 , C(O) ^R19 , C(O) ^OR6 , C(O)N( ^R6 )( ^R7 ), N( ^R7 )C(O) ^R6 ;
any is halo, CN, nitro, R ¹⁹ , OR ⁶ , SR ⁶ , NR ⁶ R ⁷ , C(O)R ⁶ C(O)OR ⁶ , C(O)N(R ⁶ )(R ⁷ ) and N(R ⁷ )C(O)R ⁶ optionally substituted with one or more substituents selected from C _1-6 alkyl or O(C _1-6 alkyl); and R ⁴ is oxo if not fully aromatic;
R ¹⁹ is a 5- or 6-membered aryl or heteroaryl ring system or a 3- to 7-membered carbocyclic or heterocyclic ring system, wherein these aryl, heteroaryl, carbocyclic or heterocyclic any of the systems with one or more substituents selected from halo, C _1-4 alkyl, C _1-4 haloalkyl, OH, O(C _1-4 alkyl), O(C _1-4 haloalkyl) optionally substituted;
R ⁶ is H, C _1-6 alkyl, C _1-6 haloalkyl, benzyl, 3-7 membered carbocyclyl or 3-7 membered heterocyclyl;
R ⁷ is H, C _1-6 alkyl or C _1-6 haloalkyl; or R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, have one or more additional heteroatoms and forms a 4- to 7-membered heterocyclic ring optionally substituted with one or more substituents selected from C _1-4 alkyl, oxo and halo;
compound .

general formula (Ia), (Ib) or (Ic)

2. The compound of claim 1, which is a compound of the formula wherein R ^<1> , R ^<2> , R ^<3> , R ^<4> , Z ^<1> , Z ^<2> and Y are as defined in claim 1.

general formula (Id), (Ie), (If) or (Ig)

A compound according to any one of claims 1 to 3, wherein Y is -CH ₂ -.

R ⁴ is phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl and benzocycloheptanyl, all of which are unsubstituted or substituted as defined in claim 1 or R ⁴ is pyridyl, quinolinyl, quinoxalinyl, all of which are unsubstituted or substituted as defined in claim 1 , indazolyl, indolyl, benzoxazolyl, dihydrobenzofuranyl, furyl and thienyl; or R ⁴ is either unsubstituted, or a carbocyclyl group selected from cyclohexyl and adamantyl, substituted as defined in claim 1 ;
5. A compound according to any one of claims 1-4 .

general formula (Ii),

[In the formula,
R ¹ , R ² , R ³ , A, Z ¹ and Z ² are as defined in claim 1;
R ¹⁰ is H, OH, halo, C _1-6 alkyl, —O(C _1-6 alkyl);
Each R ¹¹ is independently H, halo, OH, CN, C _1-6 alkyl, C _1-6 haloalkyl, —O(C _1-6 alkyl) or C(O)O—(C _1-6 alkyl); and n is 1 or 2; or
general formula (Iii) or (Iiii)

[In the formula,
R ¹ , R ² , R ³ , A, Z ¹ and Z ² are as defined in claim 1;
R ^11a is H, halo, C _1-4 alkyl, C _1-4 haloalkyl or C(O)O(C _1-4 alkyl);
R ^11b is H, halo, C _1-4 alkyl or C _1-4 haloalkyl; and R ^11c is H, halo, CN, C _1-4 alkyl or C _1-4 haloalkyl ]. 6. A compound according to any one of claims 1 to 5 , which is

general formula (Iai), (Ibi) or (Ici)

or a compound of general formula (Idi), (Iei), (Ifi) or (Igi)

or a compound of general formula (Iaii), (Ibii), or (Icii)

or a compound of general formula (Idii), (Ieii), (Ifii) or (Igii)

wherein R ^11a , R ^11b and R ^11c are as defined in claim 11 .

The compound is a compound of general formula (Iai), (Ibi), (Ici), (Idi), (Iei), (Ifi) or (Igi),
R ^11a is H, halo, C _1-4 alkyl or C(O)O(C _1-4 alkyl) and R ^11b is H; or both R ^11a and R ^11b are halo or a compound of general formula (Iaii), (Ibii), (Icii), (Idii), (Ieii), (Ifii) or (Igii),
R ^11a is H; and R ^11b is C _1-4 alkyl, C _1-4 alkyl substituted with OH, or C _1-4 haloalkyl; and R ^11c is H, halo, methyl or ethyl is
8. A compound according to claim 6 or claim 7 .

N-tert-butyl-5-[[2-(5-chloro-2- hydroxy-phenyl )acetyl]amino]thiophene-2-carboxamide (compound 1);
N-tert-butyl-5-[[2-(5-chloro-2-hydroxy-phenyl)acetyl]amino]thiophene-3-carboxamide (compound 1.2);
N-tert-butyl-4-[[2-(5-chloro-2- hydroxy-phenyl )acetyl]amino]thiophene-2-carboxamide (compound 1.3);
N-[(5-chloro-2- hydroxy-phenyl )methyl]-3-(2,2-dimethylpropanoylamino)benzamide (compound 2);
N-[(5-chloro-2- hydroxy-phenyl )methyl]-4-(2,2-dimethylpropanoylamino)pyridine-2-carboxamide (compound 3);
N2-tert-butyl-N4-[(2-hydroxyphenyl)methyl]pyridine-2,4-dicarboxamide (compound 4);
N1-tert-butyl-N3-[(2-hydroxyphenyl)methyl]benzene-1,3-dicarboxamide (compound 5);
N-[3-[[2-(5-Chloro-2- hydroxy-phenyl )acetyl]amino]phenyl]-2,2-dimethyl-propanamide (compound 6);
N-[4-[[2-(5-Chloro-2- hydroxy-phenyl )acetyl]amino]-2-pyridyl]-2,2-dimethyl-propanamide (compound 7);
N-[4-[[2-(5-Chloro-2- hydroxy-phenyl )acetyl]amino]-2-pyridyl]cyclohexanecarboxamide (compound 7.1);
5-[[2-(4-tert-butyl-2-fluoro-5- hydroxy-phenyl )acetyl]amino]-N-(1-cyano-1-methyl-ethyl)thiophene-2-carboxamide (compound 8);
5-[[2-[2-fluoro-5-hydroxy-4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]acetyl]amino]-N-[1-(trifluoromethyl)cyclopropyl] a compound selected from thiophene-2-carboxamide (compound 9); and salts and solvates thereof.

10. A compound according to any one of claims 1 to 9 for use in medicine.

10. A compound according to any one of claims 1-9 for use in the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A.

10. Use of a compound according to any one of claims 1-9 in the manufacture of a medicament for the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A.

10. A method for the treatment or prevention of diseases and conditions affected by the modulation of TMEM16A comprising administering an effective amount of a compound according to any one of claims 1 to 9 to a patient in need of such treatment. A method comprising administering to

13. Any of claims 10-12 , wherein the diseases and conditions affected by modulation of TMEM16A are selected from respiratory diseases and conditions, dry mouth (xerostomia), intestinal hypermotility, cholestasis and ocular conditions. A compound, use or method for use according to claim 1.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9 and a pharmaceutically acceptable excipient.

10. A process for the preparation of a compound according to any one of claims 1 to 9 , comprising
A. Z ¹ is ^* -C(O)NH-, Z ² is ^* -NHC(O)-, and A is

For compounds of general formula (I) where:
general formula (II)

wherein X ¹ , X ² , X ³ , Y and R ⁴ are as defined in claim 1.
general formula (III)

a compound of the formula [wherein R ¹ , R ² and R ³ are as defined in general formula (I)];
B. reacting in the presence of a coupling reagent and under basic conditions; For compounds of general formula (I) wherein Z ¹ is ^* -NHC(O)- and Z ² is ^* -C(O)NH-:
general formula (X)

[wherein R ¹ , R ² , R ³ and A are as defined in claim 1], the compound of general formula (XI)
H ₂ N-Y-R ⁴ (XI)
a compound of the formula wherein Y and ^R4 are as defined in claim 1;
B. reacting with a coupling agent under basic conditions; For compounds of general formula (I) wherein Z ¹ is ^* -NHC(O)- and Z ² is ^* -C(O)NH-:
A compound of general formula (XV) as defined above,
general formula (XVI)

a compound of the formula wherein A, Y and ^R4 are as defined in claim 1;
D. reacting under basic conditions; For compounds of general formula (I) wherein Z ¹ is ^* -C(O)NH- and Z ² is ^* -C(O)NH-:
General formula (XX)

[wherein A, Y and ^R4 are as defined in claim 1] with compounds of general formula (III) as defined above;
E. reacting in the presence of a coupling agent under basic conditions; For compounds of general formula (I) wherein Z ¹ is ^* -C(O)NH- and Z ² is ^* -C(O)NH-:
General formula (XXV)

[wherein R ¹ , R ² , R ³ and A are as defined in claim 1] with compounds of general formula (XI) as defined above;
F. reacting in the presence of a coupling agent under basic conditions; For compounds of general formula (I) where Z ¹ is ^* -NHC(O)- and Z ² is ^* -NHC(O)-:
General formula (XXX)

wherein A, Y and R ⁴ are as defined in claim 1 and R ³² is halo
general formula (XXXI)

a compound of the formula wherein R ¹ , R ² and R ³ are as defined in claim 1;
G. reacting in the presence of a phosphorus ligand, a palladium catalyst and a base; ^The ^general ^formula ⁽ _{_} ^_ For the compounds of I):
General formula (XXXV)

wherein R ¹ , R ² , R ³ and A are as defined in claim 1.
The structure below:

or 5-chloro-3H-benzofuran-2-one with H. A compound of general formula (I) as defined in claim 1, wherein any of R ³ ; R ¹ , R ² and R ³ ; or R ⁴ comprises a phenyl group substituted by alkoxy, of general formula (I) as defined in claim 1, wherein ^any of R3; ^R1 , ^R2 and ^R3 ; or ^R4 comprises a phenyl group substituted with OH by treatment with boron tribromide. A method comprising converting to a compound.

Compounds of general formula (II), (X), (XVI), (XX), (XXV), (XXX) or (XXXV) as defined in claim 16 .