JPWO2021216696A5

JPWO2021216696A5 -

Info

Publication number: JPWO2021216696A5
Application number: JP2022563376A
Authority: JP
Publication date: 2024-05-01

Claims

1. A pharmaceutical composition comprising a Bruton's tyrosine kinase (BTK) inhibitor and a pharma- tically acceptable carrier or excipient for use in treating a disease selected from acute respiratory distress syndrome, sepsis, sepsis-induced acute lung injury, diffuse alveolar damage, macrophage activation syndrome, secondary hemophagocytic lymphohistiocytosis, cytokine release syndrome, and systemic inflammatory response syndrome in a mammal in need of such treatment,
The pharmaceutical composition, wherein the BTK inhibitor is a compound of formula (I) or a pharma- ceutical acceptable salt thereof:

In the formula,
^Z2 is -N- or ^CR2 , where ^R2 is selected from hydrogen and alkyl;
^R3 and ^R4 are independently selected from hydrogen, methyl, chloro, fluoro, cyclopropyl, hydroxy, methoxy, cyano, trifluoromethyl, and trifluoromethoxy;
R ⁶ and R ⁷ are independently selected from hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, and cyano;
-Z-EWG- is -alkylene-NR'CO-, -alkylene-NR'SO ₂ -,

is selected from, where

are each independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo;
-alkylene-NR'CO-, -alkylene-NR'SO ₂ -,

a carbonyl or sulfonyl group in is bonded to -C(CN)=CHR ^c ;
R' is independently selected from hydrogen and alkyl;
R ^c is selected from alkyl, haloalkoxy, substituted alkyl, cycloalkyl, cycloalkylene-NR ^d R ^e , and cycloalkylene-alkylene-NR ^d R ^e ;
R ^d and R ^e are independently selected from hydrogen, alkyl, cycloalkyl, and 3- to 6-membered saturated monocyclic heterocyclyl, where heterocyclyl contains 1 or 2 heteroatoms independently selected from N, O, and S;
The heterocyclyl is substituted with 0, 1, or 2 substituents independently selected from hydroxy, alkyl, and fluoro.

The pharmaceutical composition of claim 1, wherein ^Z2 is -N-.

-Z-EWG- is

where

is independently substituted with 0, 1, or 2 substituents independently selected from alkyl, hydroxy, and halo;

The pharmaceutical composition of claim 1, wherein the carbonyl group in is bonded to -C(CN)=CHR ^c .

-Z-EWG- is

The pharmaceutical composition of claim 1 ,

The BTK inhibitor is (R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
2-((R)-3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-(3,4-dichlorophenoxy)-3-methoxyphenyl)-1H-pyrazolo-[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(4-(2,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-(phenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)
-3-cyclopropylacrylonitrile;
(R)-2-(3-(4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile; and (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile;
or a pharma- ceutically acceptable salt of any of the above compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

-Z-EWG- is

The pharmaceutical composition of claim 1 ,

The BTK inhibitor is 2-(2-((4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile;
(R)-2-(2-((4-amino-3-(4-(3-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(4-(2,6-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(4-(3,5-difluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(4-(2-fluorophenoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(S)-2-{2-[4-amino-5-(4-phenoxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-ylmethyl]-pyrrolidine-1-carbonyl}-3-cyclopropyl-acrylonitrile;
(S)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(S)-2-(2-((4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolidine-1-carbonyl)-4-(dimethylamino)-4-methylpent-2-enenitrile;
(S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(R)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
(S)-2-(2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-cyclopropylacrylonitrile;
2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;
2-((R)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(ethylamino)-4-methylpent-2-enenitrile;
2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(cyclopropylamino)-4-methylpent-2-enenitrile;
2-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-(2-methoxyethylamino)-4-methylpent-2-enenitrile;
(R)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-3-(1-aminocyclopropyl)acrylonitrile;
2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile;
2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-morpholino-pent-2-enenitrile;
2-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(1-piperidyl)pent-2-enenitrile;
2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(1-piperidyl)pent-2-enenitrile; and 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile;
or a pharma- ceutically acceptable salt of any of the above compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

The pharmaceutical composition of claim 1 , wherein R ^c is alkyl.

The pharmaceutical composition of claim 8, wherein R ^c is t-butyl.

The BTK inhibitor is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-
10. The pharmaceutical composition of claim 9, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers of (IA)-4,4-dimethylpent-2-enenitrile (compound (IA)), and/or a pharma- ceutically acceptable salt of any of the above compounds.

The pharmaceutical composition according to claim 9, wherein the compound is a substantially pure (E) or (Z) isomer of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (compound (IA)), and/or a pharma- ceutically acceptable salt thereof.

The pharmaceutical composition according to claim 11, wherein at least about 85% (w/w) of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile or at least about 85% (w/w) of a pharma- ceutical acceptable salt of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile is the (E) isomer.

The pharmaceutical composition of claim 6, wherein R ^c is substituted alkyl.

R ^c is -C(CH ₃ ) ₂ -(4-R ⁸ -piperazin-1-yl);
R ⁸ is selected from hydrogen, alkyl, alkoxyalkyl, haloalkyl, alkylsulfonyl, alkoxycarbonyl, acyl, and oxetan-3-yl;
The piperazinyl ring is further optionally substituted independently with one or two alkyl groups.
The pharmaceutical composition of claim 13.

The BTK inhibitor is 2-[[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]-piperidin-1-yl]carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile;
2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(piperazin-1-yl)pent-2-enenitrile;
2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]-pyrimidin-1-yl]piperidine-1-carbonyl]-4-(4-ethylpiperazin-1-yl)-4-methyl-pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-isopropylpiperazin-1-yl)-4-methylpent-2-enenitrile; (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(tert-butyl)piperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-(4-(2-methoxyethyl)piperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)pent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pent-2-enenitrile;
2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pent-2-enenitrile;
2-((R)-3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-methylpent-2-enenitrile;
(R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile;
(R)-4-(4-acetylpiperazin-1-yl)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4-methylpent-2-enenitrile; and (R)-methyl-4-(5-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)piperazine-1-carboxylate;
or a pharma- ceutically acceptable salt of any of the above compounds, wherein the compound is selected from the (E)-isomer, the (Z)-isomer, and a mixture of the (E)- and (Z)-isomers.

The pharmaceutical composition of claim 14, wherein R ⁸ is oxetan-3-yl.

The pharmaceutical composition according to claim 16, wherein the BTK inhibitor is selected from the group consisting of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (compound (IB)); and/or the (E) isomer, (Z) isomer, and mixtures of (E) and (Z) isomers of any pharma- ceutical acceptable salt of the above compound.

The pharmaceutical composition of claim 16, wherein the BTK inhibitor is a substantially pure (E) or (Z) isomer of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile (compound (IB)), or a pharma- ceutical acceptable salt thereof.

19. The pharmaceutical composition of claim 18, wherein at least about 85% (w/w) of the 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile or at least about 85% (w/w) of a pharma- ceutically acceptable salt of the 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile is the (E) isomer.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in place of corticosteroid therapy.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with corticosteroid therapy.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with a non-corticosteroid immunosuppressant and/or an anti-inflammatory agent.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with corticosteroid maintenance therapy.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the mammal is a human.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with an active pharmaceutical ingredient selected from interferon α, interferon γ, cyclophosphamide, tacrolimus, mycophenolate mofetil, methotrexate, dapsone, sulfasalazine, azathioprine, anti-CD20 agents, anti-TNα agents, anti-IL6 agents against a ligand or its receptor, anti-IL17 agents against a ligand or its receptor, anti-IL1 agents against a ligand or its receptor, anti-IL2 agents against a ligand or its receptor, anti-CD2 agents, anti-CD3 agents, anti-CD80/86 agents, anti-sphingosine-1-phosphate receptor agents, anti-C5 agents, anti-mTOR agents, anti-calcineurin agents, anti-BAFF/BlyS agents, leflunomide, and teriflunomide.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with rituximab, ofatumumab, obinutuzumab, or veltuzumab, or a biosimilar of any of the above.

The pharmaceutical composition according to any one of claims 1 to 19, wherein the pharmaceutical composition is administered in combination with at least one antiviral agent.

28. The pharmaceutical composition of claim 27, wherein the antiviral agent comprises at least one agent selected from an entry inhibitor, an uncoating inhibitor, a reverse transcriptase inhibitor, an integrase inhibitor, a transcription inhibitor, and a protease inhibitor.

The pharmaceutical composition of claim 27, wherein the antiviral agent comprises remdesivir.