Substituted pyrrolo[2,3-d]pyrimidines as Bruton's Tyrosine Kinase inhibitors

Patent metadata

Field	Value
Publication number	US-11613543-B2
Application number	US-201916981059-A
Country	US
Kind code	B2
Filing date	Mar 22, 2019
Priority date	Mar 26, 2018
Publication date	Mar 28, 2023
Grant date	Mar 28, 2023

Abstract

The invention relates to compounds of the formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined in the specification; to intermediates in the preparation of the compounds, to pharmaceutical compositions comprising the compounds and to use of the compounds in the treatment of disease.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X 1 is formula (A) or formula (B):

X 1a is *—(CH 2 ) 1-3 — or *—CH 2 C(CH 3 ) 2 —;
X 1b is *—CH 2 O—, *—O—, or *—OCH 2 —;
X 2a is formula (C), formula (D), formula (E), formula (F), or formula (G):

X 2b is formula (E1) or formula (F1):

X 5 is CH or N;
X 6 is CH or N;
R 1 is H or F;
R 1a is H or F;
R 2 is H or F;
R 2a is H or F;
R 3 is H or CH 3 ;
R 4 is H or CH 2 OH;
R 5 is H or CH 2 OH;
R 6 is H or F;
R 7 is H, F, Cl, CH 3 , OCH 3 , or OCH 2 CH 3 ;
Z is absent or *—(CH 2 ) 2-3 NH—, wherein * is the point of attachment of Z to the N atom in formula (C);
Z 1 is *—(CH 2 ) 1-3 —, *—CH 2 CH 2 O—, *—CH 2 CH(CH 2 OH)O—, *—C(O)—, or *—O—, wherein * is the point of attachment of Z 1 to X 5 in formula (E) or formula (E1);
Z 2a is absent or **—(CH 2 ) 4 NH—, wherein ** is the point of attachment to N in formula (F);
Z 2b is **—(CH 2 ) 2 NH(CH 2 ) 3-4 —, wherein ** is the point of attachment to N in formula (F1);
Z 3 is absent or **—(CH 2 ) 4 NH—, wherein ** is the point of attachment to N in formula (F);
n is 0 or 1;
p is 0 or 1;
q is 0 or 1;
* is the point of attachment of X 1a or X 1b to the phenyl ring in formula (I); and
** is the point of attachment to X 1a or X 1b ;

with the provisos that:
(1) Z 2a and Z 3 are not both simultaneously absent;
(2) if Z 1 is *—CH 2 CH 2 O— or *—CH 2 CH(CH 2 OH)O— in formula (E) or formula (E1), then X 6 is not N; and
(3) if Z 1 is *—O— in formula (E) or formula (E1), then X 5 is not N and X 6 is not N.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X 1 is formula (A):

X 1a is *—(CH 2 ) 1-3 — or *—CH 2 C(CH 3 ) 2 —;
X 2a is formula (C), formula (E), or formula (F):

* is the point of attachment of X 1a to the phenyl ring in formula (I); and
** is the point of attachment to X 1a .

3. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
X 1 is:

and
* is the point of attachment to the phenyl ring in formula (I).

4. The compound according to claim 1 , wherein the compound is of formula (Ia):

or a pharmaceutically acceptable salt or stereoisomer thereof.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 6 is H.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is OCH 3 .

7. The compound according to claim 1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of:
rac-N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
(R)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
(S)—N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-7-(hydroxymethyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-ethoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylbenzoyl)piperidin-4-yl)oxy)piperidin-1-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(3-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)propyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(2-(9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-(((1-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperidin-4-yl)oxy)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((9-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((1-(3-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)propyl)piperidin-4-yl)oxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((4-(2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperazin-1-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropan-2-yl)benzamide,
N-(3-(6-(4-((4-(2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)ethyl)piperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-2-fluoro-4-(2-hydroxypropa

Assignees

• Novartis Ag

Inventors

• Arista Luca
• Hebach Christina
• Hollingworth Gregory John
• Holzer Philipp
• Imbach-Weese Patricia
• Lorber Julien
• Machauer Rainer
• Schmiedeberg Niko
• Vulpetti Anna
• Zoller Thomas

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/10

  Spiro-condensed systems · CPC title

• C07D239/22 Primary

  with hetero atoms directly attached to ring carbon atoms · CPC title