JPWO2020160010A5

JPWO2020160010A5 -

Info

Publication number: JPWO2020160010A5
Application number: JP2021543157A
Authority: JP
Publication date: 2023-02-01

Claims

Formula (I)

(in the formula:
R and R ₁ are independently hydrogen, optionally substituted alkyl; optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl; or
R and R ₁ together with the nitrogen atom to which they are attached form an optionally substituted 3-7 membered heterocyclyl;
_R2 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl;
R3 is hydrogen _, optionally substituted alkyl, _R7C (O)-, _R7SO2- or _R7NHC (O)- _; or
R ₂ and R ₃ together with the atoms to which they are attached form an optionally substituted 3- to 7-membered heterocyclyl;
each _R4 is independently halogen, optionally substituted alkyl, CN, optionally substituted alkoxy, _NR12R13 or _hydroxy ;
_R5 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted cycloalkyl;
_R6 is _OR8 , _SR8 or _NR9R10 _;
_R7 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl;
R ₈ is hydrogen, optionally substituted alkyl; optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl can be;
_R9 is hydrogen, _OR11 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl; optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, _SO2 _- R8, _SO2NRaRb or _N ( _Ra _)Rb _;
R ₁₀ is hydrogen; optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl; optionally substituted aryl or optionally substituted heteroaryl Yes; or
R ₉ and R ₁₀ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl;
R _a and R _b are each independently hydrogen, optionally substituted alkyl; optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
R ₁₁ is hydrogen or optionally substituted alkyl;
R ₁₂ and R ₁₃ are each independently hydrogen, optionally substituted alkyl, R ₇ C(O)-, R ₇ SO ₂ - or R ₇ NHC(O)-; or
R ₁₂ and R ₁₃ together with the nitrogen atom to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, 2, 3 or 4)
or a pharmaceutically acceptable salt thereof.

R ₁ is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; preferably optionally substituted phenyl or optionally substituted 2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof , which is a 6-membered heteroaryl.

_3. The compound of claim 1 or 2, or a pharmaceutically acceptable compound thereof, wherein R is hydrogen, optionally substituted C1 _- C6 _- alkyl; optionally substituted C3-C8 _- cycloalkyl. salt .

R is hydrogen, methyl, ethyl, n-propyl, isopropyl, C3-C6 _- cycloalkyl, C3 _- C6 _- cycloalkylmethyl, 2-dimethylaminoethyl or ₃ -hydroxycyclobutyl. 3. A compound according to 3 or a pharmaceutically acceptable salt thereof .

R ₂ is hydrogen, optionally substituted C ₁ -C ₆ -alkyl, optionally substituted aryl-C ₁ -C ₆ -alkyl or optionally substituted heteroaryl-C ₁ -C ₆ -alkyl A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4.

6. A compound according to claim 5, wherein _R2 is hydrogen, C1- _C4 _- alkyl, halo _- C1- _C4 -alkyl, optionally substituted arylmethyl or optionally substituted heteroarylmethyl or a pharmaceutically acceptable salt thereof .

R ₂ is hydrogen, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, aryl optionally substituted with 1-5 halogens or optionally substituted with 1-5 halogens 7. A compound or a pharmaceutically acceptable salt thereof according to claim 6, which is aryl-C1 _- _C2 -alkyl.

8. The compound of claim 7, wherein _R2 is hydrogen, benzyl, optionally substituted phenyl-CF2-, optionally substituted heteroaryl _- _CF2- , _CF3 _, _CF3CH2- or isopropyl. or a pharmaceutically acceptable salt thereof .

R ₃ is hydrogen, C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylC(O)-, aryl-C ₁ -C ₄ -alkylC(O) -, aryl-C1 _- _C4 -alkylS(O) _2- , aryl _- C1- _C4 -alkylNHC(O)- or arylNHC(O)-. or a pharmaceutically acceptable salt thereof .

10. The claim of claim ₉ , wherein R3 is hydrogen, methyl, _CF3CH2- , acetyl, propionyl, phenethyl C(O)-, phenethyl SO2-, _benzylNHC (O)- or _phenylNHC (O)-. or a pharmaceutically acceptable salt thereof .

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein at _least one of _R2 and R3 is hydrogen.

5. The compound of any one of Claims ₁ to ₄ , or a pharmaceutically acceptable Salt to get .

saturated 4- to 6-membered heterocyclyl is unsubstituted or halogen, CN, hydroxyl, C1-C3-alkoxy, halo _- C1 _- C3 _- alkoxy, C1 _- C3 _- alkyl _, halo _- C1 13. The compound of claim 12, substituted with one or more substituents independently selected from -C3-alkyl _, spirocycloalkyl, spiroheterocyclyl or optionally substituted C1 _- C3 _- alkylidene or a pharmaceutically acceptable salt thereof .

The compound is of formula II

(In the formula,
m is 0, 1, 2 or 3;
Each R ₁₄ is independently hydroxyl, protected hydroxyl, cyano, amino, protected amino, halogen, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkylSO ₂ — , optionally substituted alkylC(O)- or optionally substituted alkylC(O)NH-; or
two adjacent R ₁₄ groups together with the carbon atom to which they are attached form an optionally substituted fused 3- to 7-membered carbocyclyl or heterocyclyl; or
two geminal R ₁₄ groups together with the carbon atom to which they are attached form an optionally substituted spiro 3- to 7-membered carbocyclyl or heterocyclyl; or
Two geminal R ₁₄ groups together form (R ₁₃ ) ₂ C=, where each R ₁₃ is independently halogen, C ₁ -C ₄ -alkyl or halo-C ₁ - is C ₄ -alkyl)
The compound according to claim 1, represented by or a pharmaceutically acceptable salt thereof.

said compound is of formula III

(In the formula,
X is O or C(R _a ) ₂ ;
Each R ₁₄ is independently hydroxyl, protected hydroxyl, cyano, amino, protected amino, halogen, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkylSO ₂ — , optionally substituted alkylC(O)- or optionally substituted alkylC(O)NH-; or
two adjacent R ₁₄ groups together with the carbon atom to which they are attached form an optionally substituted fused 3- to 7-membered carbocyclyl or heterocyclyl; or
two geminal R ₁₄ groups together with the carbon atom to which they are attached form an optionally substituted spiro 3- to 7-membered carbocyclyl or heterocyclyl; or
Two geminal R ₁₄ groups together form (R ₁₃ ) ₂ C=, where each R ₁₃ is independently halogen, C ₁ -C ₄ -alkyl or halo-C ₁ - is _C4 -alkyl;
each R _a is independently hydrogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, halogen, optionally substituted alkoxy or optionally substituted alkyl)
The compound according to claim 1, represented by or a pharmaceutically acceptable salt thereof .

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein n is 0-2.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each _R4 is halogen.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof , wherein n is 2 and each _R4 is chlorine.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, which is

but,

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, which is

said compound is of formula IV,

(where p is 0, 1 or 2)
The compound according to claim 14 or a pharmaceutically acceptable salt thereof, represented by.

p is 1 or 2 and each R ₁₄ is independently amino, protected amino, cyano, hydroxyl, fluorine, chlorine, C ₁ -C ₄ -alkoxy, halo-C ₁ -C ₄ -alkoxy, independently from the group consisting of C1- _C4 _- _alkylSO2 , C1- _C4 _- alkylC(O), C1- _C4 _- alkylC(O)NH- and hydroxyl, fluorine, chlorine and amino selected from the group consisting of C1- _C4 _- alkyl optionally substituted with one or more selected substituents; or
p is 2 and the two R ₁₄ groups together with the carbon atom to which they are attached form a spiroC ₃ -C ₆ -cycloalkyl or spiro-3- to 6-membered heterocycloalkyl; or
p is 2 and two R ₁₄ groups together form (R ₁₃ ) ₂ C=, where each R ₁₃ is independently hydrogen, fluorine, chlorine, methyl, CF ₃ or is CHF ₂ ,
22. A compound according to claim 21 or a pharmaceutically acceptable salt thereof .

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof , wherein p is 2.

22. The compound of claim 21, wherein _each R< ₁₄ > is independently hydroxyl, methyl, fluorine, chlorine, amino, _CH3SO2- , _CF3 , _CHF2 , _CH2F , cyano, acetoxy, or acetamido, or a pharmaceutically acceptable salt thereof .

two R ₁₄ groups together with the carbon atom to which they are attached form a spiro-cyclopropyl; or
22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein _two _R14 groups taken together form F2C=.

26. The compound of any of claims 1-25, or a pharmaceutically acceptable salt thereof , wherein R ₁ is optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

27. The compound of Claim 26, or a pharmaceutically acceptable compound thereof, wherein _R1 is phenyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or triazolyl, each of which is optionally substituted. salt .

1- wherein R ₁ is independently selected from C ₁ -C ₄ -alkyl, halo-C ₁ -C ₄ -alkyl, halogen, C ₁ -C ₄ -alkoxy and halo-C ₁ -C ₄ -alkoxy 28. The compound of claim 26 or 27, or a pharmaceutically acceptable salt thereof , substituted with 3 substituents.

29. The compound of Claim 28, or a pharmaceutically acceptable salt thereof , wherein the substituents are selected from methyl, methoxy, fluorine, chlorine, _CHF2 , _CF3 _, _CHF2O- and CF3O-.

R ₁ is a group as described below:

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof , selected from

_R1 is

(wherein X ₁ -X ₄ are each independently N or CR ₁₇ and R ₁₇ is hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen)
27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof , represented by:

R ₁ is a group represented by:

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof , selected from

_R1 is

(wherein one of Y ₁ , Y ₂ , Y ₃ and Y ₄ is O, S or NR ₁₆ and the rest are independently N or CR ₁₇ and R ₁₆ is hydrogen, optionally substituted alkyl, _R7C (O)-, _R7SO2- or _R7NHC (O) _; _R17 is hydrogen, optionally substituted alkyl, optionally substituted alkoxy or halogen; can be;
_R7 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl)
27. The compound according to claim 26 or a pharmaceutically acceptable salt thereof , represented by:

34. The compound of claim 33, wherein _Y3 is C _- _CF3 , _one of Y1, Y2 and _Y4 is O, S or _NR16 and the rest are independently N or _CR17 a pharmaceutically acceptable salt thereof .

R ₁ is a group represented by:

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof , selected from

the table below

or a pharmaceutically acceptable salt thereof.

37. A pharmaceutical composition comprising a compound according to any of claims 1-36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

In need of treatment of a disease or disorder mediated by cystic fibrosis transmembrane conductance regulator ( CFTR ) comprising a therapeutically effective amount of a compound according to any of claims 1-36 or a pharmaceutically acceptable salt thereof . A medicament for treating a CFTR-mediated disease or disorder in a subject.

said disease or disorder is cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation fibrinolytic deficiency, hereditary angioedema type 1, lipid handling deficiency, e.g. familial hypercholesterolemia, type 1 Chalbinemia , abetalipoproteinemia, lysosomal storage diseases, e.g. I-cell disease/pseudo-Haller, mucopolysaccharidosis, Sandhoff/Tay-Sachs, Crigler-Nadja type II, polyendocrine disease/hyperinsulinemia (hyperinsulemia), diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia , ACT deficiency, diabetes insipidus (DI), neurophysic DI, nephrogenic DI, Charcot-Marie-Tooth syndrome, Peliszeus-Merzbacher disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders such as Huntington's disease, spinocerebellar ataxia type I, spinal and medulla muscular atrophy, dentate nucleus red nucleus pallidus Louis somatopathy, and myotonic dystrophy, and spongiform encephalopathies such as hereditary Creutzfeldt-Jakob disease, Fabry disease, Streusler-Scheinker disease, secretory diarrhea, polycystic kidney disease, chronic obstructive pulmonary disease (COPD) ), dry eye disease or Sjögren's syndrome, congenital bilateral vas deferens (CBAVD), disseminated bronchiectasis, allergic pulmonary aspergillosis, chronic sinusitis, protein C deficiency, A-lipoproteinemia, Group consisting of moderate pulmonary disease, lipid handling deficiency, coagulation fibrinolysis, CFTR-associated metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, melanoma, glycanosis CDG type 1, ACT deficiency, and cholestatic liver disease 39. A medicament according to claim 38, selected from

A medicament for treating cystic fibrosis in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any of claims 1-36, or a pharmaceutically acceptable salt thereof . .

A medicament according to any of claims 38-40, further comprising a therapeutically effective amount of a compound which is a CFTR modulator, mucolytic or antibiotic.