# US 11,440,904 B2 · Substituted pyrimidines, pharmaceutical compositions and therapeutic methods thereof

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- Number: US 11,440,904 B2
- Document ID: US11440904B2
- Status: Granted
- Kind: B2
- Application number: 16/639,972
- Filed: 2018-08-27
- Published: 2020-06-18
- Granted: 2022-09-13
- Earliest claimed: 2017-08-28
- Applicants: Zhihong Chen
- Inventors: Zhihong Chen
- Web page: https://patentgrep.com/patent/US11440904B2

## CPC

- C07D 405/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 473/16: two nitrogen atoms
- C07D 487/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provide novel pyrimidine derivatives and analogs having inhibitory activities towards certain tyrosine kinases, e.g., Bruton's tyrosine kinase (Btk) and/or Focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), pharmaceutical compositions thereof, and methods of treatment, reduction or prevention of certain diseases or conditions mediated by such by tyrosine kinases, e.g., cancers, tumors, fibrosis, inflammatory diseases, autoimmune diseases, diabetes, or immunologically mediated diseases.

## Claims

### Claim 1

A compound having the structural formula of (I):
wherein,
X is NH(CH2)n, O or S, wherein n is 0 or 1;
A is a 5- to 7- membered, aliphatic or aromatic, cyclic or heterocyclic moiety;
R1 is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CN, OH, amino, carboxylic amide, sulfonamide and R1x, wherein R1x is selected from:
each of R2 and R3 is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, or R2 and R3 jointly form a 5- to 7-membered, aliphatic or aromatic, cyclic or heterocyclic moiety;
R4 and R5 jointly form a 12-membered aliphatic heterocyclic moiety,
or a pharmaceutically acceptable form thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 and R3 jointly form a 5-membered ring, having the structural formula (II):
wherein
B is phenyl;
Y1 is selected from CH, CH2, N, NH, O or S;
Y2 is selected from CH, CH2, N, NH, O or S;
Y3 is selected from CH, CH2, N, NH, O or S; and
the bond between Y1 and Y2 may be a double or single bond; the bond between Y2 and Y3 may be double or single bond; provided that
at least one Y1, Y2 and Y3 is CH or CH2; and
at least one of the bond between Y1 and Y2 and the bond between Y2 and Y3 is a single bond.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R4 and R5 are at meta-and para- positions, respectively, having the structural formula (IV):

### Claim 4 (depends on 1)

The compound of claim 1, having the structural formula of (V-a):

### Claim 5 (depends on 1)

The compound of claim 1, wherein R2 and R3 jointly form a 5-membered heterocyclic aryl moiety, having the structural formula of (VI-a):
wherein
Y1 is selected from CH, CH2, N, NH, O or S;
Y2 is selected from CH, CH2, N, NH, O or S;
Y3 is selected from CH, CH2, N, NH, O or S; and
the bond between Y1 and Y2 may be a double or single bond; the bond between Y2 and Y3 may be double or single bond; provided that
at least one Y1, Y2 and Y3 is CH or CH2; and
at least one of the bond between Y1 and Y2 and the bond between Y2 and Y3 is a single bond.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A is a 6-membered aliphatic cyclic or heterocyclic moiety, having the structural formula of (VIII):
wherein
Z is CH or N;
Y1 is selected from CH, CH2, N, NH, O or S;
Y2 is selected from CH, CH2, N, NH, O or S;
Y3 is selected from CH, CH2, N, NH, O or S; and
the bond between Y1 and Y2 may be a double or single bond; the bond between Y2 and Y3 may be double or single bond; provided that
at least one Y1, Y2 and Y3 is CH or CH2; and
at least one of the bond between Y1 and Y2 and the bond between Y2 and Y3 is a single bond.

### Claim 7

A compound selected from the group consisting of:

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1.