	US 12,227,475 B2
	Aza-heterocyclyl carboxamide and related compounds and their use in treating medical conditions
Michael Dominic Ryan, Littleton, MA (US); Thomas David Pallin, Essex (GB); Toby Jonathan Blench, Essex (GB); Toby Matthew Grover Mullins, Essex (GB); David Edward Clark, Essex (GB); Emanuela Gancia, Essex (GB); and Nadia Mamoona Ahmad, Essex (GB)
Filed by X-Biotix Therapeutics, Inc., Waltham, MA (US)
Filed on Apr. 27, 2022, as Appl. No. 17/730,565.
Claims priority of provisional application 63/180,197, filed on Apr. 27, 2021.
Prior Publication US 2023/0139502 A1, May 4, 2023
Int. Cl. C07D 207/16 (2006.01); A61P 31/04 (2006.01); C07D 207/14 (2006.01); C07D 207/48 (2006.01); C07D 401/14 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/14 (2006.01); C07D 417/14 (2006.01); C07D 498/08 (2006.01); C07F 9/6558 (2006.01)

CPC C07D 207/16 (2013.01) [A61P 31/04 (2018.01); C07D 207/14 (2013.01); C07D 207/48 (2013.01); C07D 401/14 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01); C07D 498/08 (2013.01); C07F 9/65583 (2013.01)]

21 Claims

1. A compound represented by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

A¹is 6-10 membered arylene or 5-10 membered heterocyclylene;

A²is a 4-10 membered aza heterocyelylene 4-6 membered saturated aza-heterocyclylene;

A³is one of the following:

a 4-10 membered aza-heterocyclyl optionally substituted with 1, 2, or 3 occurrences of R⁷; or

a 3-10 membered cycloalkyl substituted by (i) —N(R³)(R⁴) and (ii) 0, 1, 2, or 3 occurrences of R⁷;

X is —C(O)N(R³)—(C_0-6alkylene)-ψ or —(C_0-6alkylene)-N(R³)C(O)-ψ; wherein ψ is a bond to A²;

R^Ais one of the following:

3-6 membered carbocyclyl substituted with (i) 0, 1, or 2 occurrences of R⁶and (ii) 1 occurrence of Y₁; 3-6 membered heterocyclyl substituted with (i) 0, 1, or 2 occurrences of R⁶and (ii) 1 occurrence of Y¹; or

Y¹is —(C_0-6alkylene)-(3-10 membered heterocyclyl), —(C_0-6alkylene)-(3-10 membered carbocyclyl), —(C_0-6alkylene)-CO₂R³, —(C_0-6alkylene)-C(O)N(R³)(R⁴), —(C_0-6alkylene)-N(R³)C(O)R⁴, —(C_0-6alkylene)-N(R³)C(O)N(R³)(R⁴), —(C_0-6alkylene)-N(R³)S(O)₂R⁴, —(C_0-6alkylene)-S(O)₂N(R³)R⁴, C_1-6hydroxyalkyl, —(C_1-6alkylene)-N(R³)(R⁴), 3-7 membered heteroalkyl, —O—(C_1-6alkylene)-CO₂R³, or hydrogen;

R¹is —C(O)—R⁵, —CO₂—R⁵, —S(O)₂—R⁵, —C(O)N(R³)(R⁴), R⁵, or hydrogen;

R²is hydrogen, C_1-6alkyl, —(C_0-6alkylene)-(C_3-6cycloalkyl), —(C_1-6alkylene)-(C_1-6alkoxyl), or —(C_1-6alkylene)-CO₂R³;

R³and R⁴each represent independently for each occurrence hydrogen, C_1-6alkyl, C_1-6haloalkyl, or —(C_0-6alkylene)-(C_3-6cycloalkyl); or an occurrence of R³and R⁴attached to the same nitrogen atom are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring;

R⁵is —C_1-6alkyl, —C_1-6haloalkyl, —C_1-6hydroxyalkyl, —(C_0-6alkylene)-(3-7 membered heterocyclyl), —(C_0-6alkylene)-(3-7 membered saturated carbocyclyl), —(C_1-6alkylene)-N(R³)(R⁴), —(C_1-6alkylene)-(C_1-6alkoxyl), —(C_1-6alkylene)-CO₂R³, —(C_1-6alkylene)-SO₂R³, or —(C_1-6alkylene)-O—P(O)(OH)(R³);

R⁶represents independently for each occurrence halogen, hydroxyl, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxyl, —(C_1-6alkylene)-(C_1-6alkoxyl), or cyano; and

R⁷represents independently for each occurrence halogen, hydroxyl, cyano, C_1-6alkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxyl, —(C_1-6alkylene)-(C_1-6alkoxyl), —(C_0-6alkylene)-N(R³)(R⁴), —(C_0-6alkylene)-(C_3-7cycloalkyl), or —(C_0-6alkylene)-(4-10 membered heterocycloalkyl).

21. A compound in any one of Tables 1, 2, or 3-A, or a pharmaceutically acceptable salt thereof:

TABLE 1

Compound No.	Chemical Structure

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

TABLE 2

Compound
No.	Chemical Structure

9A

9B

9C

9D

9E

9F

9G

9H

9I

9J

9K

9L

9M

9N

9O

9P

9Q

9R

9S

9T

9U

9V

9W

9X

9Y

9Z

9AA

9AB

9AC

9AD

9AE

9AF

9AG

9AH

9AI

9AJ

9AM

9AN

9AO

9AP

9AQ

9AR

9AS

9AT

9AV

9AW

9AX

9AY

9AZ

9BA

9BB

9BC

9BD

9BE

9BF

9BG

TABLE 3-A

Title
Com-
pound
from
Example
No.	Chemical Structure

5

6

7

8