Colony stimulating factor-1 receptor (CSF-1r) inhibitors

Small molecule CSF-1R inhibitors that cross the blood-brain barrier provide a novel approach to treat immune-mediated and neurological diseases by targeting the CSF-1R receptor, improving upon existing treatments.

JP2025094019APending Publication Date: 2025-06-24GENZYME CORP
View PDF 36 Cites 0 Cited by

Patent Information

Application Number
JP2025039893
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2015-07-20
Filing Date
2025-03-13
Publication Date
2025-06-24

AI Technical Summary

Technical Problem

Current treatments for immune-mediated diseases and neurological disorders such as multiple sclerosis, lupus nephritis, rheumatoid arthritis, ALS, and Huntington's disease lack effective agents that can cross the blood-brain barrier to target CSF-1R, a key receptor involved in these conditions.

Method used

Development of small molecule CSF-1R inhibitors that can cross the blood-brain barrier and inhibit the CSF-1R receptor, providing pharmaceutical formulations for treating these diseases.

Benefits of technology

The CSF-1R inhibitors effectively target and inhibit the CSF-1R receptor in the central nervous system, offering potential therapeutic benefits for immune-mediated and neurological diseases by addressing the limitations of existing treatments.

✦ Generated by Eureka AI based on patent content.

Smart Images

  • Figure 2025094019000073
    Figure 2025094019000073
  • Figure 2025094019000074
    Figure 2025094019000074
  • Figure 2025094019000075
    Figure 2025094019000075
Patent Text Reader

Abstract

To provide compounds useful as colony stimulating factor-1 receptor inhibitors ("CSF-1R inhibitors").SOLUTION: There are provided compounds containing the structure of formula I or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None
Need to check novelty before this filing date? Find Prior Art

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 194,619, filed on July 20, 2015, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to colony - stimulating factor - 1 receptor inhibitors ( "CSF - 1R inhibitors"). The CSF - 1R inhibitors of the present invention are small molecules that can cross the blood - brain barrier and reach the central nervous system (CNS). The present invention also relates to pharmaceutical formulations containing CSF - 1R inhibitors, as well as to the use of CSF - 1R inhibitors and pharmaceutical compositions containing CSF - 1R inhibitors for treating diseases. The present invention further relates to the use of CSF - 1R inhibitors and pharmaceutical compositions containing CSF - 1R inhibitors for treating immune - mediated diseases (including but not limited to multiple sclerosis, lupus nephritis, rheumatoid arthritis) and for treating neurological diseases (including but not limited to amyotrophic lateral sclerosis (ALS) and Huntington's disease). The CSF - 1R inhibitors of the present invention can be used to inhibit c - FMS, the cellular receptor for colony - stimulating factor - 1 (CSF - 1).

Summary of the Invention

Means for Solving the Problems

[0003] The present invention provides a compound of formula (I):

Chemical formula

[0004] X 8 and X 9 are each independently selected from N or C; T 1 、T 2 and T 3 are each independently selected from N or CR 10 where each R is independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 10 )aryl, (C2-C9)hetero aryl, (C2-C 14 )alkylnyl, (C1-C 10 )alkylamine, ((C1-C)alkyl)2amine, (C2-C 10 )alkynylamine, C(O)-, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl-, COOH-(C3-C 10 )cycloalkyl-, (C1-C 10 )alkoxy-, R 10 10 -(C1-C)alkyl-, R 10A -(C1-C 10 )alkyl, R 10A -(C3-C 10 )cycloalkyl, R 10A -(C2-C9)heterocycloalkyl, R 10A -(C6-C 14 )aryl, R 10A -(C2-C9)heteroaryl, R 10A -(C2-C 10 )alkylnyl, R 10A -(C1-C 10 )alkylamine, R 10A -((C1-C 10 )alkyl)2amine, R 10A -(C2-C10 ) alkynylamine, R 10A -C(O)-, R 10A -(C1~C 10 ) alkyl-C(O)O-, R 10A -(C1~C 10 ) alkoxy-, (C3~C 10 ) cycloalkyl-O-, (C2~C9) heterocycloalkyl-O-, (C6~C 14 ) ari -yl-O-, (C2~C9) heteroaryl-O-, R 10A -(C3~C 10 ) cycloalkyl-O-, R 10A -(C2~C9) heterocycloalkyl-O-, R 10A -(C6~C 14 ) ari -yl-O-, R 10A -(C2~C9) heteroaryl-O-, HO-, halo, cyano, H2N-, (CH3)HN-, (CH3)2N-, R 10A R 11 N-, R 10A R 11 N(O)C-, R 10A (R 11 C(O))N-, R 10A R 11 NC(O)O-, R 10A C(O)-, R 10A R 11 NC( O)R 10A N-, (C1~C 10 ) alkyl-OC(O)R 10A N-, (C3~C 10 ) cycloalkyl-OC(O)R 10A N-, (C2~C9) heterocycloalkyl-OC(O)R 10A N-, (C6~C 14 ) aryl-OC(O)R 10A N-, (C2~C9) heteroaryl-OC(O)R 10A N-, F3C-, F2HC-, CH3F2C-, FH2C-, CH3FHC-, ( CH3)2FC-; NC-, (C1~C 10 ) alkyl(O)P-, (C1~C 10)Alkyl-S-, (C1-C 10 )Alkyl-S-(C1-C 10 )Alkyl-, (C3-C 10 )Cyclo alkyl-S-, (C6-C 14 )Aryl-S-, (C2-C9) Heteroalkyl-S-, ( C2-C9) Heterocycloalkyl-S-, (C2-C9) Heteroaryl-S-, (C1- C 10 )Alkyl-S(O)-, (C3-C 10 )Cycloalkyl-S(O)-, (C6-C 14 )Aryl-S(O)-, (C2-C9) Heterocycloalkyl-S(O)-, (C2-C9) Heteroaryl-S(O)-, (C3-C 10 )Alkyl-S(O)2-, (C3-C 10 ) Cycloalkyl-S(O)2-, (C6-C 14 )Aryl-S(O)2-, (C2-C9) he terocycloalkyl-S(O)2-, (C2-C9) Heteroaryl-S(O)2-, R 10A R 11 NS(O)2-, (C1-C 10 )Alkyl-S(O)2R 10A N-, (C3-C 10 )Cyc loalkyl-S(O)2R 10A N-, (C6-C 14 )Aryl-S(O)2R 10A N-, (C2-C9) Heterocycloalkyl-SO2R 10A N-, and (C2-C9) Heteroaryl- S(O)2R 10A N- selected from the group consisting of; wherein, R 10A and R 11 are each independently, H, (C1-C 10 )Alkyl, (C3-C 10 )Cycloalkyl, (C2-C9) Heterocycloalkyl, (C6-C 14 )Aryl, (C2-C9) Heteroaryl, (C1-C10 ) alkylamine, ((C1-C 10 ) alkyl)2 amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, CO OH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) ari -yl-O-, (C2-C9) heteroaryl-O-, HO-, halo, (CH3)2N-, and H2N-; or R 10A and R 11 together form a 3- to 10-membered cycloalkyl, heterocyclo alkyl, aryl or heteroaryl ring, wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- and is optionally further substituted by 1 to 4 groups selected from halo, or H2N- ;

[0005] Y 1 is O, S, NR 12 or CR 12 R 13 and where R 12 is absent or R 12 and R 13 are each independently H, (C1- C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) a lkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl -O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO-, halo, and H2N-; R 1forms a carbonyl together with the carbon to which it is attached, and R 2 is absent, or R 1 and R 2 are each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl -O-, HO-, halo, and H2N-, or R 1 and R 2 are , together with the carbon to which they are attached, form a 3- to 10-membered ring; R 4 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)hetero ocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-, (C6-C 14)Selected from the group consisting of aryl - O -, (C2 - C9) heteroaryl - O -, HO -, halo, and H2N -, or R 4 and R 5 together with the carbon to which they are attached form a 3 - to 10 - membered ring; R 5 is absent, or is H, (C1 - C 10 )alkyl, (C3 - C 10 )cycloalkyl , (C2 - C9)heterocycloalkyl, (C6 - C 14 )aryl, (C2 - C9)heteroaryl, (C1 - C )alkylamine, ((C1 - C 10 )alkyl)2amine, (C1 - C3)alkynylamine, (C1 - C 10 )alkoxy -, (C1 - C 10 )alkoxy-(C1 - C 10 )alkyl -, (C3 - C 10 )cycloalkyl - O -, (C2 - C9)heterocycloalkyl - O -, (C6 - C 10 )aryl - O -, (C2 - C9)heteroaryl - O -, H O -, halo, and H2N -; 14

[0006] R 6 is H, (C1 - C 10 )alkyl, (C3 - C 10 )cycloalkyl, (C2 - C9)hetero cycloalkyl, (C6 - C 14 )aryl, (C2 - C9)heteroaryl, (C2 - C 10 )alkynyl, (C1 - C 10 )alkylamine, ((C1 - C 10 )alkyl)2amine, (C2 - C 10 )alkynylamine, C(O)-, (C1 - C 10 )alkyl - C(O)O -, COOH-(C1 - C 10 )alkyl -, COOH-(C3 - C 10 ​​​)Cycloalkyl-, (C1-C 10 )Alkoxy-, R 14 -(C1-C 10 )Alkyl-, R 14 -(C3-C 10 )Cyclo alkyl, R 14 -(C2-C9) Heterocycloalkyl, R 14 -(C6-C 14 )Aryl, R 14 -(C2-C9) Heteroaryl, R 14 -(C2-C 10 )Alkynyl, R 14 -(C1-C 10 )Alkylamine, R 14 -((C1-C 10 )Alkyl)2amine, R 14 -(C2-C 10 )Alkynylamine, R 14 -C(O)-, R 14 -(C1-C 10 )Alkyl-C(O)O- , R 14 -(C1-C 10 )Alkoxy-, (C3-C 10 )Cycloalkyl-O-, (C2-C9) Heterocycloalkyl-O-, (C6-C 14 )Aryl-O-, (C2-C9) Hetero aryl-O-, R 14 -(C3-C 10 )Cycloalkyl-O-, R 14 -(C2-C9) Hetero cycloalkyl-O-, R 14 -(C6-C 14 )Aryl-O-, R 14 -(C2-C9) Hetero aryl-O-, HO-, Halo, Cyano, H2N-, (CH3)HN-, (CH3)2N-, R 14 R 15 N-, R 14 R 15 N(O)C-, R 14 (R 15 C(O))N-, R 14 R15 NC(O)O−, R 14 C(O)−, R 14 R 15 NC(O)R 14 N−, (C1 - C 10 ) alkyl - OC (O)R 14 N−, (C3 - C 10 ) cycloalkyl - OC(O)R 14 N−, (C2 - C9) he terocycloalkyl - OC(O)R 14 N−, (C6 - C 14 ) aryl - OC(O)R 14 N −, (C2 - C9) heteroaryl - OC(O)R 14 N−, F3C−, F2HC−, CH3F2C−, FH2C−, CH3FHC−, (CH3)2FC−; NC−, (C1 - C 10 ) alkyl (O)P−, (C1 - C 10 ) alkyl - S−, (C1 - C 10 ) alkyl - S - (C1 - C 10 ) alkyl -, (C3 - C 10 ) cycloalkyl - S−, (C6 - C 14 ) aryl - S−, (C2 - C9) heteroalkyl - S−, (C2 - C9) heterocycloalkyl - S−, (C2 - C9) heteroaryl - S−, (C1 - C 10 ) alkyl - S(O)−, (C3 - C 10 ) cyc loalkyl - S(O)−, (C6 - C 14 ) aryl - S(O)−, (C2 - C9) heterocy cloalkyl - S(O)−, (C2 - C9) heteroaryl - S(O)−, (C3 - C 10 ) alkyl - S(O)2−, (C3 - C 10 ) cycloalkyl - S(O)2−, (C6 - C 14 ) aryl - S(O)2−, (C2 - C9) heterocycloalkyl - S(O)2−, (C2 - C9) heteroaryl - S(O)2−, R 14 R 15NS(O)2-, (C1~C 10 )alkyl-S( O)2R 14 N-, (C3~C 10 )cycloalkyl-S(O)2R 14 N-, (C6~C 14 )aryl-S(O)2R 14 N-, (C2~C9)heterocycloalkyl-SO2R 14 N-, and (C2~C9)heteroaryl-S(O)2R 14 selected from the group consisting of N-; wherein R 14 and R 15 are each independently H, (C1~C 10 )alkyl, (C3~C 10 )cycloalkyl, (C2~C9)heterocycloalkyl, (C6~C 14 )aryl, (C2~C9)heteroaryl, (C1~C 10 )alkylamine, ((C1~C 10 )alkyl)2amine, (C1~C3)alkynylamine, (C1~C 10 )alkyl-C(O)O-, COO H-(C1~C 10 )alkyl, COOH-(C3~C 10 )cycloalkyl, (C1~C 10 ) alkoxy-, (C1~C 10 )alkoxy-(C1~C 10 )alkyl-, (C3~C 10 )cy cloalkyl-O-, (C2~C9)heterocycloalkyl-O-, (C6~C 14 )ary l-O-, (C2~C9)heteroaryl-O-, HO-, F2HC-O-, halo, (CH3)2N-, H2N-, F3C-C(O)-, F3C-, and F2HC-; selected; or R 14 and R 15 together form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; Here, each (C1~C 10 ) alkyl, (C6~C 14 ) aryl, (C2~C9) heteroaryl, (C3~C 10 ) cycloalkyl or (C2~C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1~C 10 ) alkyl, (C3~C 10 ) cycloalkyl, (C2~C9) heterocycloalkyl, (C6~C 14 ) aryl, (C2~C9) heteroaryl, (C1~C 10 ) alkylamine, ((C1~C 10 ) alkyl)2amine, (C1~C3) alkynylamine, (C1~C 10 ) alkyl-C(O)O-, COOH-(C1~C 10 ) alkyl, COOH-(C3~C 10 ) cycloalkyl, (C1~C 10 ) alkoxy-, (C1~C 10 ) alkoxy-(C1~C 10 ) alkyl-, (C3~C 10 ) cycloalkyl-O-, (C2~C9) heterocycloalkyl-O-, (C6~C 14 ) aryl-O-, (C2~C9) heteroaryl-O-, HO- , halo, or H2N-; ;

[0007] R 3 is N or CR 16 , where here R 16 is H, (C1~C 10 ) alkyl, (C3~C 10 ) cycloalkyl, (C2~ C9) heterocycloalkyl, (C6~C 14 ) aryl, (C2~C9) heteroaryl, (C1~C 10 ) alkylamine, ((C1~C 10 ) alkyl)2amine, (C1~C3) alk ynylamine, (C1~C 10) Alkyl-C(O)O-, COOH-(C1-C 10 ) Alkyl, COOH-(C3-C 10 ) Cycloalkyl, (C1-C 10 ) Alkoxy-, (C1-C 10 ) Alkoxy-(C1-C 10 ) Alkyl-, (C3-C 10 ) Cycloalkyl-O-, (C2 ~C9) Heterocycloalkyl-O-, (C6-C 14 ) Aryl-O-, (C2-C9) Heteroaryl-O-, HO-, halo, and H2N- and is selected from the group consisting of, or when m is 1, R 16 and R 4 together with the carbon to which they are attached form the formula ( II):

Chemical formula

[0008] The present invention also relates to formula (XIII):

Chemical formula

[0009] X 101 , X 102 , X 103 , X 104 and X 105 are each independently N, NR 107 or CR 107 selected from, where each R 107 is independently H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C ) aryl, (C2 - C9) heteroaryl, (C2 - C 14 ) alkylnyl, (C1 - C ) alkylamine, ((C1 - 10 C 10 ) alkyl)2amine, (C2 - C C 10 ) alkynylamine, C(O)-, (C1 - C 10 ) alkyl - C(O)O-, COOH - (C1 - C 10 ) alkyl -, COOH - (C3 - C 10 ) cycloalkyl -, (C1 - C 10 ) alkoxy -, R 10 -(C1 - C 108 ) alkyl - 10 , R 108 -(C3 - C 10 ) cycloalkyl, R 108 -(C2 - C9) heterocycloalkyl, , R 108 -(C6 - C 14 ) aryl, R 108 -(C2 - C9) heteroaryl, R 108 -(C2 - C 10 ) alkylnyl, R 108 -(C1 - C 10 ) alkylamine, R 108 -((C1 - C 10 ) alkyl)2amine, R108 -(C2 to C 10 ) alkynylamine, R 108 -C(O)-, R 108 -(C1 to C 10 ) alkyl-C(O)O-, R 108 -(C1 to C 10 ) alkoxy-, (C3 to C 10 ) cycloalkyl-O-, (C2 to C9) heterocycloalkyl-O-, (C6 to C 14 ) aryl-O-, (C2 to C9) heteroaryl-O-, R 108 -(C3 to C 10 ) cycloalkyl-O-, R 108 -(C2 to C9) heterocycloalkyl-O-, R 108 -(C6 to C 14 ) aryl-O-, R 108 -(C2 to C9) heteroaryl-O-, HO-, halo, cyano , H2N-, (CH3)HN-, (CH3)2N-, R 108 R 109 N-, R 108 R 109 N(O)C-, R 108 (R 109 C(O))N-, R 108 R 109 NC(O)O-, R 108 C(O)-, R 108 R 109 NC(O)R 108 N-, (C1 to C 10 ) alkyl-OC(O)R 108 N-, (C3 to C 10 ) cycloalkyl-OC(O)R 108 N-, (C2 to C9) heterocycloalkyl-OC(O)R 108 N-, (C6 to C 14 ) aryl-OC(O)R 108 N-, (C2 to C9) hetero aryl-OC(O)R 108 N-, F3C-, F2HC-, CH3F2C-, FH2C-, CH3 FHC-, (CH3)2FC-; NC-, (C1 to C10 ) Alkyl (O) P-, (C1-C 10 ) Alkyl - S-, (C1-C 10 ) Alkyl - S - (C1-C 10 ) Alkyl -, (C3-C 10 ) Cycloalkyl - S-, (C6-C 14 ) Aryl - S-, (C2-C9) Heteroalkyl - S-, (C2-C9) Heterocycloalkyl - S-, (C2-C9) Heteroaryl - S-, (C1-C 10 ) Alkyl - S (O)-, (C3-C 10 ) Cycloalkyl - S (O)-, (C6-C 14 ) Aryl - S (O)-, (C2-C9) Heterocycloalkyl - S (O)-, (C2-C9) Heteroaryl - S (O)-, (C3-C 10 ) Alkyl - S (O)2-, (C3-C 10 ) Cycloalkyl - S (O)2-, (C6-C 14 ) Aryl - S (O)2-, (C2 -C9) Heterocycloalkyl - S (O)2-, (C2-C9) Heteroaryl - S (O)2 -, R 108 R 109 NS (O)2-, (C1-C 10 ) Alkyl - S (O)2R 108 N-, (C3- C 10 ) Cycloalkyl - S (O)2R 108 N-, (C6-C 14 ) Aryl - S (O)2R 108 N-, (C2-C9) Heterocycloalkyl - SO2R 108 N-, and (C2-C9) Heteroaryl - S (O)2R 108 N- selected from the group consisting of; wherein, R 108 and R 109 are each independently H, (C1-C 10 ) Alkyl, (C3-C 10 ) Cycloalkyl, (C2-C9) Heterocycloalkyl, (C6-C 14 ) Aryl, ( (C2 - C9) heteroaryl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2 - amine, (C1 - C3) alkynylamine, (C1 - C 10 ) alkyl - C(O)O -, COOH - (C1 - C 10 ) alkyl, COOH - (C3 - C 10 ) cycloalkyl, (C1 - C 10 ) alkoxy -, (C1 - C 10 ) alkoxy - (C1 - C 10 ) alkyl -, (C3 - C 10 ) cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O -, (C6 - C 14 ) ary - l - O -, (C2 - C9) heteroaryl - O -, HO -, halo, (CH3)2N -, and H2N - selected from the group consisting of; or R 108 and R 109 together form a 3 - to 10 - membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; wherein each (C1 - C 10 ) alkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) cycloalkyl or (C2 - C9) heterocycloalkyl is (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2 - amine, (C1 - C3) alkynylamine, (C1 - C 10 ) alkyl - C(O)O -, COOH - (C1 - C 10 ) alkyl, COOH - (C3 - C 10 ) cycloalkyl, (C1 - C 10 ) alkoxy -, (C1 - C 10 ) alkoxy - (C1 - C10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl -O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO -, halo, or H2N- optionally further substituted by 1 to 4 groups selected therefrom; ;

[0010] T 101 , T 102 and T 103 are each independently selected from N or CR 110 ; where each R is independently H, (C1-C 110 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 10 ) aryl, (C2-C9) he teroaryl, (C2-C 14 ) alkylnyl, (C1-C ) alkylamine, ((C1- 10 ) alkyl)2amine, (C2-C 10 ) alkynylamine, C(O)-, (C1-C C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl-, COOH-(C3-C 10 ) cycloalkyl-, (C1-C 10 ) alkyl-, COOH-(C3-C 10 ) cycloalkyl-, (C1-C 10 ) alkoxy-, R 110A -(C1-C 10 ) alkyl-, R 110A -(C3-C 10 ) cycloalkyl, R 110A -(C2-C9) heterocycloalkyl , R 110A -(C6-C 14 ) aryl, R 110A -(C2-C9) heteroaryl, R 110A -( C2-C 10)Alkylnyl, R 110A -(C1~C 10 )Alkylamine, R 110A -((C1~ C 10 )Alkyl)2amine, R 110A -(C2~C 10 )Alkynylamine, R 110A -C(O)-, R 110A -(C1~C 10 )Alkyl-C(O)O-, R 110A -(C1~C 10 )Alkoxy-, (C3~C 10 )Cycloalkyl-O-, (C2~C9)Heterocycloalkyl-O-, (C6~C 14 )Aryl-O-, (C2~C9)Heteroaryl-O-, R 110A -(C3~C 10 )Cycloalkyl-O-, R 110A -(C2~C9)Heterocycloalkyl-O-, R 110A -(C6~C 14 )Aryl-O-, R 110A -(C2~C9)Heteroaryl-O-, HO- , Halo, Cyano, H2N-, (CH3)HN-, (CH3)2N-, R 110A R 111 N-, R 110A R 111 N(O)C-, R 110A (R 111 C(O))N-, R 110A R 111 NC(O)O-, R 110A C(O)-, R 110A R 111 NC(O)R 110A N-, (C1~C 10 )Alkyl-OC(O)R 110A N-, (C3~C 10 )Cycloalkyl-OC(O)R 110A N-, (C2~C9)Hete rocycloalkyl-OC(O)R 110A N-, (C6~C 14 )Aryl-OC(O)R 110A N-, (C2-C9) heteroaryl-OC(O)R 110A N-, F3C-, F2HC-, CH 3F2C-, FH2C-, CH3FHC-, (CH3)2FC-; NC-, (C1-C 10 ) alkyl kil(O)P-, (C1-C 10 ) alkyl-S-, (C1-C 10 ) alkyl-S-(C1- C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-S-, (C6-C 14 ) aryl-S-, (C2-C9) heteroalkyl-S-, (C2-C9) heterocycloalkyl-S-, (C2-C9) heteroaryl-S-, (C1-C 10 ) alkyl-S(O)-, (C3-C 10 ) cycloalkyl-S(O)-, (C6-C 14 ) aryl-S(O)-, (C2-C9) hetero cycloalkyl-S(O)-, (C2-C9) heteroaryl-S(O)-, (C3-C 10 ) alkyl-S(O)2-, (C3-C 10 ) cycloalkyl-S(O)2-, (C6-C 14 ) aryl-S(O)2-, (C2-C9) heterocycloalkyl-S(O)2-, (C2-C9) heteroaryl-S(O)2-, R 110A R 111 NS(O)2-, (C1-C 10 ) alkyl-S(O)2R 110A N-, (C3-C 10 ) cycloalkyl-S(O)2R 110A N-, (C6-C 14 ) aryl-S(O)2R 110A N-, (C2-C9) heterocycloalkyl-SO2R 110A N-, and (C2-C9) heteroaryl-S(O)2R 110A selected from the group consisting of N- ; wherein R 110A and R 111 are each independently H, (C1-C10 ) alkyl, (C3~ C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) ari -yl-O-, (C2-C9) heteroaryl-O-, HO-, halo, (CH3)2N-, and H2N-; or R 110A and R 111 together form a 3- to 10-membered cycloalkyl, heterocyclic alkyl, aryl or heteroaryl ring; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl -O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO -, halo, or H2N- optionally further substituted by 1 to 4 groups selected from therein

[0011] Y 101 is O, S, NR 112 or CR 112 R 113 wherein wherein R 112 is absent or R 112 and R 113 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl -O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- selected from the group consisting of halo, and H2N-; R 101 together with the carbon to which it is attached forms a carbonyl, and R 102 is absent, or R 101 and R 102 are each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2 -C9)heterocycloalkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO-, halo, and H2N-, or R 101 and R 102 together with the carbon to which they are attached form a 3- to 10-membered ring; R 104 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)he terocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl- 、(C3-C 10Cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O -, ( C6 - C 14 ) aryl - O -, (C2 - C9) heteroaryl - O -, HO -, halo, and H2N - selected from the group consisting of, or R 104 and R 105 together with the carbon to which they are attached form a 3 - to 10 - membered ring; R is absent, or H, (C1 - C 105 ) alkyl, (C3 - C 10 ) cycloalkyl 10 ) cycloalkyl , (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) hetero aryl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2amine, (C1 - C3) alkynylamine, (C1 - C 10 ) alkoxy -, (C1 - C 10 ) alkoxy - (C1 - C 10 ) alkyl -, (C3 - C 10 ) cycloalkyl - O -, (C2 - C9) heterocyclo alkyl - O -, (C6 - C 14 ) aryl - O -, (C2 - C9) heteroaryl - O -, HO -, halo, and H2N - selected from the group consisting of;

[0012] R 106 is H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) he terocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C2 - C 10 ) alkylnyl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2amine , (C2 - C 10 ) alkynylamine, C(O)-, (C1 - C10 ) Alkyl-C(O)O-, COOH-(C1~C 10 ) Alkyl-, COOH-(C3~C 10 ) Cycloalkyl-, (C1~C 10 ) Alkoxy-, R 114 -(C1~C 10 ) Alkyl-, R 114 -(C3~C 10 ) Cy cloalkyl, R 114 -(C2~C9) Heterocycloalkyl, R 114 -(C6~C 14 ) Ari -yl, R 114 -(C2~C9) Heteroaryl, R 114 -(C2~C 10 ) Alkylnyl, R 114 -(C1~C 10 ) Alkylamine, R 114 -((C1~C 10 ) Alkyl)2amine, R 114 - (C2~C 10 ) Alkynylamine, R 114 -C(O)-, R 114 -(C1~C 10 ) Alkyl-C(O)O-, R 114 -(C1~C 10 ) Alkoxy-, (C3~C 10 ) Cycloalkyl-O -, (C2~C9) Heterocycloalkyl-O-, (C6~C 14 ) Aryl-O-, (C2~C9) Heteroaryl-O-, R 114 -(C3~C 10 ) Cycloalkyl-O-, R 114 -(C2~C9) Heterocycloalkyl-O-, R 114 -(C6~C 14 ) Aryl-O-, R 114 - (C2~C9) Heteroaryl-O-, HO-, Halo, Cyano, H2N-, (CH3)HN-, (CH3)2N-, R 114 R 115 N-, R 114 R 115 N(O)C-, R114 (R 115 C(O))N-、R 114 R 115 NC(O)O-、R 114 C(O)-、R 114 R 115 NC(O)R 114 N-、(C1~C 10 )alkyl-OC(O)R 114 N-、(C3~C 10 )cycloalkyl-OC( O)R 114 N-、(C2~C9)heterocycloalkyl-OC(O)R 114 N-、(C6~C 14 )aryl-OC(O)R 114 N-、(C2~C9)heteroaryl-OC(O)R 114 N -、F3C-、F2HC-、CH3F2C-、FH2C-、CH3FHC-、(CH3)2FC-;NC-、(C1~C 10 )alkyl(O)P-、(C1~C 10 )alkyl-S-、(C1~ C 10 )alkyl-S-(C1~C 10 )alkyl-、(C3~C 10 )cycloalkyl-S-、(C6~C 14 )aryl-S-、(C2~C9)heteroalkyl-S-、(C2~C9)hetero cycloalkyl-S-、(C2~C9)heteroaryl-S-、(C1~C 10 )alkyl -S(O)-、(C3~C 10 )cycloalkyl-S(O)-、(C6~C 14 )aryl-S(O)-、(C2~C9)heterocycloalkyl-S(O)-、(C2~C9)heteroaryl-S(O)-、(C3~C 10 )alkyl-S(O)2-、(C3~C 10 )cycloalkyl -S(O)2-、(C6~C 14 )aryl-S(O)2-、(C2~C9)heterocycloalkyl -S(O)2-、(C2~C9)heteroaryl-S(O)2-、R114 R 115 NS(O)2-, (C1~C 10 ) alkyl-S(O)2R 114 N-, (C3~C 10 ) cycloalkyl-S (O)2R 114 N-, (C6~C 14 ) aryl-S(O)2R 114 N-, (C2~C9) hetero cycloalkyl-SO2R 114 N-, and (C2~C9) heteroaryl-S(O)2R 114 N- selected from the group consisting of; wherein, R 114 and R 115 are each independently, H, (C1~C 10 ) alkyl, (C3~C 10 ) cycloalkyl, (C2~C9) heterocycloalkyl, (C6~C 14 ) aryl, ( C2~C9) heteroaryl, (C1~C 10 ) alkylamine, ((C1~C 10 ) alkyl)2amine, (C1~C3) alkynylamine, (C1~C 10 ) alkyl-C(O)O-, COOH-(C1~C 10 ) alkyl, COOH-(C3~C 10 ) cycloalkyl, (C1~C 10 ) alkoxy-, (C1~C 10 ) alkoxy-(C1~C 10 ) alkyl-, (C3~C 10 ) cycloalkyl-O-, (C2~C9) heterocycloalkyl-O-, (C6~C 14 ) ari -yl-O-, (C2~C9) heteroaryl-O-, HO-, F2HC-O-, halo, (C H3)2N-, H2N-, F3C-C(O)-, F3C-, and F2HC- selected from the group consisting of; or R 114 and R 115combines to form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl, COOH-(C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO- , halo, or H2N-; ;

[0013] R 103 is N or CR 116 ; wherein R 116 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10(C1-C3) alkyl)2 amine, (C1-C ethynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO-, halo, and H2N-, or when s is 1, R 116 and R 104 together with the carbon to which they are attached form formula (XIV): [Chemical formula] {wherein, the dotted line represents an optional double bond, t is 0, 1, 2, 3, 4 or 5; Z 101 is each independently H, halo, (C1-C 10 ) alkyl, (C2-C9) heteroalkyl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2 amine, (C2-C 10 ) alkynylamine, (C1-C 10 ) alkoxy-, or H2N-; Y 102 is O, S, NR 117 or CR 117 R 118 and here, R 117 is absent, or R 117 and R 118 are each independently H, (C1-C 10 ) alkyl, (C3-C 10)Cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 )aryl, (C2-C9) heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl, COOH-(C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9) heterocycloalkyl -O-, (C6-C 14 )aryl-O-, (C2-C9) heteroaryl-O-, HO -, halo, or H2N- selected from} to form a compound of] also relates to a compound containing the structure of.

[0014] The present invention further provides that X 1 is N; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 3 is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH also relates to a compound of formula (I) or formula (II).

[0015] The present invention further provides that X 1is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C or; X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 5 is C H; X 7 also relates to a compound according to formula (I) or formula (II) which is CH

[0016] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH also relates to a compound according to formula (I) or formula (II) which is CH

[0017] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C It also relates to the compound according to formula (I) or formula (II).

[0018] The present invention further provides that X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 7 is CH It also relates to the compound according to formula (I) or formula (II).

[0019] The present invention further provides that X 1 is N; X 2 is N; X 3 is N; X 4 is CR 7 is ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 4 is CR 7 ; X 5 is CH; X 7 is CR 7 ; of the formula (I) or or to a compound according to formula (II).

[0020] The present invention further relates to X 1 being N; X 2 being N; X 3 being CR 7 ; X 4 being N ; X 5 being CR 7 ; X 6 being N; X 7 being CR 7 ; X 8 being C; X 9 being C and relates also to a compound according to formula (I) or formula (II).

[0021] The present invention further relates to X 1 being N; X 2 being N; X 3 being CR 7 ; X 4 being CR 7 ; X 5 being N; X 6 being N; X 7 being CR 7 ; X 8 being C; X 9 being C; or X 3 being CH; X 4 being CR 7 ; X 7 being CH, and relates also to a compound according to formula (I) or formula (II).

[0022] The present invention further relates to X 1 being N; X 2 being N; X 3 being N; X 4 being CR 7 ; X being N; X 5 being N; X 6 being N; X 7 being CR 7 ; X 8 being C; X 9 being C; or X 4is CR 7 ; X 7 is CH, and also relates to the compound according to formula (I) or formula (II).

[0023] The present invention further relates to a compound according to formula (I) or formula (II) where X 1 is N; X 2 is N; X 3 is CR 7 ; X 4 is N ; X 5 is N; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C, and also relates to the compound according to formula (I) or formula (II).

[0024] The present invention further relates to a compound according to formula (I) or formula (II) where X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 3 is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH and also relates to the compound according to formula (I) or formula (II).

[0025] The present invention further relates to a compound according to formula (I) or formula (II) where X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR​7 is; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is C or; X 2 is CH; X 3 is CH; X 4 is CR 7 is; X 5 is C H; X 7 is CH, also relates to the compound according to formula (I) or formula (II).

[0026] The present invention further relates to X 1 is C; X 2 is CR 7 is; X 3 is N; X 4 is CR 7 is; X 5 is CR 7 is; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 is; X 5 is CH; X 7 is CH is, also relates to the compound according to formula (I) or formula (II).

[0027] The present invention further relates to X 1 is C; X 2 is CR 7 is; X 3 is CR 7 is; X 4 is N; X 5 is CR 7 is; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is C It also relates to a compound according to formula (I) or formula (II).

[0028] The present invention further provides that X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 7 is CH It also relates to a compound according to formula (I) or formula (II).

[0029] The present invention further provides that X 1 is C; X 2 is N; X 3 is N; X 4 is CR 7 ; X is CR 5 ; X 7 is N; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C ; or X 4 is CR 7 ; X 5 is CH; X 7 is CR 7 It also relates to a compound according to formula (I) or formula (II).

[0030] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR​7 and; X 4 is N and; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is C also relates to a compound according to formula (I) or formula (II).

[0031] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 and; X 4 is CR 7 and; X 5 is N; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is C or; X 3 is CH; X 4 is CR 7 and; X 5 is N; X 7 is CH also relates to a compound according to formula (I) or formula (II).

[0032] The present invention further provides that X 1 is C; X 2 is N; X 3 is N; X 4 is CR 7 and ; X 5 is N; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is C or; X 4 is CR 7 and; X 7 is CH, also relates to a compound according to formula (I) or formula (II). ​

[0033] The present invention further relates to a compound according to formula (I) or formula (II), wherein X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is N ; X 5 is N; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C.

[0034] The present invention further relates to a compound according to formula (I) or formula (II), wherein X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is N; X 9 is C ; or X 3 is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH ; the present invention also relates to a compound according to formula (I) or formula (II).

[0035] The present invention further relates to a compound according to formula (I) or formula (II), wherein X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is N; X9 is C; or X 2 is CH; X 3 is CH; X 4 is CR 7 and; X 5 is C H; X 7 is CH, also relates to the compound according to formula (I) or formula (II).

[0036] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is N; X 4 is CR 7 and; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is N; X 9 is C or; X 2 is CH; X 4 is CR 7 and; X 5 is CH; X 7 is CH and, also relates to the compound according to formula (I) or formula (II).

[0037] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is CR 7 and; X 4 is N; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is N; X 9 is C and, also relates to the compound according to formula (I) or formula (II).

[0038] The present invention further relates to X 1is C; X 2 is N; X 3 is N; X 4 is CR 7 and; X X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is N; X 9 is C or; X 4 is CR 7 and; X 5 is CH; X 7 is CR 7 and, a compound according to formula (I) or formula (II). or formula (II).

[0039] The present invention further relates to X 1 is C; X 2 is N; X 3 is CR 7 and; X 4 is N and; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is N; X 9 is C or, a compound according to formula (I) or formula (II).

[0040] The present invention further relates to X 1 is C; X 2 is N; X 3 is CR 7 and; X 4 is CR 7 and; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is N or; X 3is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH also relates to a compound according to formula (I) or formula (II).

[0041] The present invention further relates to X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is N or; X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 5 is C H; X 7 is CH also relates to a compound according to formula (I) or formula (II).

[0042] The present invention further relates to X 1 is C; X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is N or; X 2 is CH; X 4 is CR 7 ; X 5 is CH; X 7 is CH Also relates to a compound according to formula (I) or formula (II).

[0043] X 1 is C; X 2 is CR 7 is; X 3 is CR 7 is; X 4 is N; X 5 is CR 7 is; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is N, formula (I) or a compound according to formula (II).

[0044] The present invention further relates to X 1 is C; X 2 is CR 7 is; X 3 is CR 7 is; X 4 is CR 7 is; X 5 is N; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is N or; X 2 is CH; X 3 is CH; X 4 is CR 7 is; X 7 is CH Also relates to a compound according to formula (I) or formula (II).

[0045] The present invention further relates to X 1 is C; X 2 is N; X 3 is CR 7 is; X 4 is N ; X 5 is CR 7 is; X 6 is N; X 7 is CR7 is; X 8 is C; X 9 is N also relates to a compound according to formula (I) or formula (II).

[0046] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 is; X 4 is CR 7 is; X 5 is N; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is N; or, X 3 is CH; X 4 is CR 7 is; X 7 is CH, also relates to a compound according to formula (I) or formula (II).

[0047] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 is; X 4 is N ; X 5 is N; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is N, also relates to a compound according to formula (I) or formula (II).

[0048] The present invention further provides that X 1 is C; X 2 is CR 7 is; X 3 is N; X 4 is N ; X 5 is CR 7 is; X 6 is N; X 7 is CR 7and X 8 is C; X 9 is N also relates to a compound according to formula (I) or formula (II).

[0049] The present invention further provides that X 1 is C; X 2 is CR 7 and X 3 is N; X 4 is CR 7 and X 5 is N; X 6 is N; X 7 is CR 7 and X 8 is C; X 9 is N; or X 2 is CH; X 4 is CR 7 and X 7 is CH, also relates to a compound according to formula (I) or formula (II).

[0050] The present invention further provides that X 1 is C; X 2 is CR 7 and X 3 is CR 7 and X 4 is N; X 5 is N; X 6 is N; X 7 is CR 7 and X 8 is C; X 9 is N, also relates to a compound according to formula (I) or formula (II).

[0051] The present invention further provides that X 1 is N; X 2 is CR 7 and X 3 is N; X 4 is N ; X 5 is CR 7 and X 6 is N; X 7 is CR 7 and X8 is C; X 9 is C also relates to a compound according to formula (I) or formula (II).

[0052] The present invention further relates to X 1 is N; X 2 is CR 7 is; X 3 is N; X 4 is CR 7 is; X 5 is N; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 is; X 7 is CH, also relates to a compound according to formula (I) or formula (II).

[0053] The present invention further relates to X 1 is N; X 2 is CR 7 is; X 3 is CR 7 is; X 4 is N; X 5 is N; X 6 is N; X 7 is CR 7 is; X 8 is C; X 9 is C, also relates to a compound according to formula (I) or formula (II).

[0054] The present invention further relates to X 1 is C; X 2 is CR 7 is; X 3 is N; X 4 is N ; X 5 is CR 7 is; X 6 is N; X 7 is CR 7 is; X 8is C; X 9 is C also relates to a compound according to formula (I) or formula (II).

[0055] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is N; X 4 is CR 7 and; X 5 is N; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 and; X 7 is CH, also relates to a compound according to formula (I) or formula (II).

[0056] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is CR 7 and; X 4 is N; X 5 is N; X 6 is N; X 7 is CR 7 and; X 8 is C; X 9 is C, also relates to a compound according to formula (I) or formula (II).

[0057] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is N; X 4 is N and; X 5 is CR 7 and; X 6 is N; X 7 is CR 7 and; X 8 is N; X9 is in C also relates to a compound according to formula (I) or formula (II).

[0058] The present invention further provides that X 1 is N; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 is C; or X 3 is CH; X 4 is CR 7 ; X 5 is CH, also relates to a compound according to formula (I) or formula (II).

[0059] The present invention further provides that X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 is C ; or X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 5 is CH ; also relates to a compound according to formula (I) or formula (II).

[0060] The present invention further provides that X 1 is N; X 2 is CR 7 ; X 3 is N; X 4is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 1 is CH; X 2 is CH; X 4 is CR 7 ; X 5 is CH relates also to a compound according to formula (I) or formula (II).

[0061] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 relates also to a compound according to formula (I) or formula (II).

[0062] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 2 is CH; X 3 is CH; X 4 is CR 7 relates also to a compound according to formula (I) or formula (II).

[0063] The present invention further relates to X1 is N; X 2 is N; X 3 is N; X 4 is CR 7 is ; X 5 is CR 7 is; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 4 is CR 7 is; X 5 is CH, also relates to the compound according to formula (I) or formula (II).

[0064] The present invention further relates to X 1 is N; X 2 is N; X 3 is CR 7 is; X 4 is N ; X 5 is CR 7 is; X 6 is N; X 7 is N; X 8 is C; X 9 is C, also relates to the compound according to formula (I) or formula (II).

[0065] The present invention further relates to X 1 is N; X 2 is N; X 3 is CR 7 is; X 4 is CR 7 is; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 3 is CH; X 4 is CR 7 is, also relates to the compound according to formula (I) or formula (II).

[0066] ​​ The present invention further relates to X 1 is N; X 2 is N; X 3 is N; X 4 is CR 7 and wherein; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C, and also relates to the compounds according to formula (I) or formula (II).

[0067] The present invention further relates to X 1 is N; X 2 is N; X 3 is CR 7 and; X 4 is N wherein; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C, and also relates to the compounds according to formula (I) or formula (II).

[0068] The present invention further relates to X 1 is N; X 2 is CR 7 and; X 3 is N; X 4 is N wherein; X 5 is CR 7 and; X 6 is N; X 7 is N; X 8 is C; X 9 is C, and also relates to the compounds according to formula (I) or formula (II).

[0069] The present invention further relates to X 1 is N; X 2 is CR 7 and; X 3 is N; X 4 is CR 7and; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; or, X 2 is CH; X 4 is CR 7 of the compound according to formula (I) or formula (II). The present invention further relates to a compound according to formula (I) or formula (II).

[0070] The present invention further relates to X 1 is N; X 2 is CR 7 and; X 3 is CR 7 and; X 4 is N; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C also relates to the compound according to formula (I) or formula (II).

[0071] The present invention further relates to X 1 is C; X 2 is N; X 3 is CR 7 and; X 4 is CR 7 and; X 5 is CR 7 and; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; or, X 3 is CH; X 4 is CR 7 and; X 5 is CH also relates to the compound according to formula (I) or formula (II).

[0072] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is CR7 and; X 4 is CR 7 and; X 5 is CR 7 and; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 2 is CH; X 3 is CH; X 4 is CR 7 and; X 5 is CH also relates to a compound according to formula (I) or formula (II).

[0073] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is N; X 4 is CR 7 and; X 5 is CR 7 and; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 and; X 5 is CH also relates to a compound according to formula (I) or formula (II).

[0074] The present invention further relates to X 1 is C; X 2 is CR 7 and; X 3 is CR 7 and; X 4 is N; X 5 is CR 7 and; X 6 is N; X 7 is N; X 8 is C; X 9 is C also relates to a compound according to formula (I) or formula (II).

[0075] The present invention further provides that X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 2 is CH; X 3 is CH; X 4 is CR 7 ; and relates to compounds of formula (I) or formula (II).

[0076] The present invention further provides that X 1 is C; X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 4 is CR 7 ; X 5 is CH, and relates to compounds of formula (I) or formula (II).

[0077] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is N ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 ​also relates to a compound according to formula (I) or formula (II), which is C.

[0078] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 3 is CH; X 4 is CR 7 ; a compound according to formula (I) or formula (II). also relates to

[0079] The present invention further provides that X 1 is C; X 2 is N; X 3 is N; X 4 is CR 7 ; X is N; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C, also relates to a compound according to formula (I) or formula (II).

[0080] The present invention further provides that X 1 is C; X 2 is N; X 3 is CR 7 ; X 4 is N; X is N; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C, also relates to a compound according to formula (I) or formula (II).

[0081] The present invention further relates to X 1 is C; X 2 is CR 7 ; X 3 is N; X 4 is N ; X 5 is CR 7 ; X 6 is N; X 7 is N; X 8 is C; X 9 is C, and also relates to a compound according to formula (I) or formula (II).

[0082] The present invention further relates to X 1 is C; X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C or; X 2 is CH; X 4 is CR 7 ; and also relates to a compound according to formula (I) or formula (II). compound.

[0083] The present invention further relates to X 1 is C; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N; X 6 is N; X 7 is N; X 8 is C; X 9 is C and also relates to a compound according to formula (I) or formula (II).

[0084] The present invention further relates to R 7is, independently of each other, H, (C1~C 10 ) alkyl, (C3~C 10 ) cycloalkyl, (C2~C9) heterocycloalkyl, (C6~C 14 ) aryl, (C2~C9) heteroaryl, (C2~C 10 ) alkylnyl, (C1~C 10 ) alkylamine, ((C1~C 10 ) alkyl)2amine, (C2~C 10 ) alkynylamine, C(O)-, ( C1~C 10 ) alkyl-C(O)O-, COOH-(C1~C 10 ) alkyl-, COOH-(C3~C 10 ) cycloalkyl-, (C1~C 10 ) alkoxy-, R 8 (C1~C 10 ) alkyl-, R 8 (C3~C 10 ) cycloalkyl, R 8 (C2~C9) heterocycloalkyl, R 8 (C6~C 14 ) aryl, R 8 (C2~C9) heteroaryl, R 8 (C2~C 10 ) alkylnyl, R 8 (C1~C 10 ) alkylamine, R 8 ((C1~C 10 ) alkyl)2amine, R 8 (C2 ~C 10 ) alkynylamine, R 8 C(O)-, R 8 (C1~C 10 ) alkyl-C(O)O- 、R 8 (C1~C 10 ) alkoxy-, (C3~C 10 ) cycloalkyl-O-, (C2~C9) heterocycloalkyl-O-, (C6~C 14 ) aryl-O-, (C2~C9) heteroary -yl-O-, R8 (C3 to C 10 ) cycloalkyl - O -, R 8 (C2 to C9) heterocyclo alkyl - O -, R 8 (C6 to C 14 ) aryl - O -, R 8 (C2 to C9) heteroaryl - O -, HO -, halo, cyano, H2N -, (CH3)HN -, (CH3)2N -, R 8 R 9 N -, R 9 R 9 selected from N(O)C -, F3C -, F2HC -, CH3F2C -, FH2C -, CH3FHC -, or (CH3)2FC -; wherein R 8 and R 9 are each independently H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C1 to C 10 ) alkylamine, ((C1 to C 10 ) alkyl)2amine, (C1 to C3) alkynylamine, (C1 to C 10 ) alkyl - C(O)O -, COOH - (C1 to C 10 ) alkyl, COOH - (C3 to C 10 ) cycloalkyl, (C1 to C 10 ) a lkoxy -, (C1 to C 10 ) alkoxy - (C1 to C 10 ) alkyl -, (C3 to C 10 ) cyc loalkyl - O -, (C2 to C9) heterocycloalkyl - O -, (C6 to C 14 ) aryl - O -, (C2 to C9) heteroaryl - O -, HO -, halo, (CH3)2N -, and H2N -; or 8 and R 9combine to form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; and wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C2-C 10 )alkynylamine, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl, COOH-(C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1- C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocyclo alkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, H O-, halo, H2N-, (CH3)HN-, (CH3)2N-, F3C-, F2HC-, CH3 F2C-, FH2C-, CH3FHC-, or (CH3)2FC- and is optionally further substituted by 1 to 4 groups selected from, and also relates to a compound according to formula (I) or formula (II).

[0085] The present invention further provides that R 7 is each independently H, (C2-C9)heteroaryl, (C2-C 10 )alkynylamine, (C1-C 10 )alkoxy-, (C1-C10 ) alkyl-(C2 ~C9) heterocycloalkyl, (C2~C9) heterocycloalkyl-(C1~C 10 ) alkoxy-, (C1~C 10 ) alkoxy-(C2~C9) heterocycloalkyl-, (C2~C9) heteroalkyl-C(O)-, or F2HC-, where each (C1~C 10 ) alkyl, (C2~C9) heteroaryl or (C2~C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from (C1~C 10 ) alkyl, and relates also to a compound according to formula (I) or formula (II).

[0086] The present invention further relates to a compound according to formula (I) or formula (II) where R 7 is H.

[0087] The present invention further relates to a compound according to formula (I) or formula (II) where n is 1, 2 or 3.

[0088] The present invention further relates to a compound according to formula (I) or formula (II) where n is 1.

[0089] The present invention further relates to a compound according to formula (I) or formula (II) where R 1 and R 2 are each independently selected from H, (C1~C 10 ) alkyl, ( C1~C 10 ) alkylamine, (C1~C 10 ) alkoxy- or NH2, and relates also to a compound according to formula (I) or formula (II).

[0090] The present invention further relates to a compound according to formula (I) or formula (II) where R 1 is H.

[0091] The present invention further relates to a compound according to formula (I) or formula (II) where R2 also relates to a compound according to formula (I) or formula (II) wherein H .

[0092] The present invention further relates to a compound according to formula (I) or formula (II) wherein R 1 and R 2 are each H

[0093] The present invention further relates to a compound according to formula (I) wherein T 1 is CR 10 ; T 2 is CR 10 ; T 3 is CR 10 ; and R 3 is CR 16 .

[0094] The present invention further relates to a compound according to formula (I) wherein T 1 is CR 10 ; T 2 is CR 10 ; T 3 is CR 10 ; and R 3 is N

[0095] The present invention further relates to a compound according to formula (I) wherein T 1 is N; T 2 is CR 10 ; T 3 is CR 10 ; and R 3 is CR 16 .

[0096] The present invention further relates to a compound according to formula (I) wherein T 1 is N; T 2 is N; T 3 is CR 10 ; and R 3 is CR 16 .

[0097] The present invention further relates to a compound according to formula (I) wherein T 1 is N; T 2 is CR10 is; T 3 is N; R 3 is CR 16 also relates to the compound according to formula (I).

[0098] The present invention further relates to T 1 is CR 10 is; T 2 is N; T 3 is CR 10 is; R 3 is N also relates to the compound according to formula (I).

[0099] The present invention further relates to T 1 is CR 10 is; T 2 is CR 10 is; T 3 is N; R 3 is N also relates to the compound according to formula (I).

[0100] The present invention further relates to T 1 is CR 10 is; T 2 is N; T 3 is N; R 3 is N also relates to the compound according to formula (I).

[0101] The present invention further relates to T 1 is N; T 2 is N; T 3 is N; R 3 is CR 16 is also relates to the compound according to formula (I).

[0102] The present invention further relates to R 10 is H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl from the group consisting of (C1 - C 10 ) alkoxy and halo, also relates to the compound according to formula (I).

[0103] The present invention further relates to R​10 is also related to the compound of formula (I) selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo. The present invention also relates to the compound of formula (I).

[0104] The present invention further relates to R 16 which is selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and is also related to the compound of formula (I). The present invention also relates to the compound of formula (I).

[0105] The present invention further relates to R 16 which is selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and is also related to the compound of formula (I). The present invention also relates to the compound of formula (I).

[0106] The present invention further relates to R 10 and R 16 each independently selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and is also related to the compound of formula (I).

[0107] The present invention further relates to T 1 which is CR 10 wherein R 10 is H, (C1-C 10 ) alkyl or (C3-C 10 ) cycloalkyl; T 2 is CR 10 wherein R 10 is (C1-C 10 ) a lkyl, (C3-C 10)Cycloalkyl, (C1-C 10 )alkoxy and halo; T 3 is CH; R 3 is CH, also relates to the compound according to formula (I).

[0108] The present invention further relates to T 1 is CH; T 2 is CR 10 wherein R 10 is (C1-C 10 )a lkoxy); T 3 is CH, and R 3 is CH, also relates to the compound according to formula (I).

[0109] The present invention further relates to T 1 is CR 10 wherein R 10 is H, (C1-C 10 )alkyl or (C3-C 10 )cycloalkyl; T 2 is CR 10 wherein R 10 is (C1-C 10 )alk yl, (C1-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo; T 3 is CH, and R 3 is N, also relates to the compound according to formula (I).

[0110] The present invention further relates to T 1 is CH; T 2 is CR 10 wherein R 10 is (C1-C 10 )a lkoxy); T 3 is CH, and R 3 is N, also relates to the compound according to formula (I).

[0111] The present invention further relates to Y 1 is O, NR 18or CR 18 R 19 and the compound according to formula (I) is also related to.

[0112] The present invention further relates to the case where Y 1 is O in the compound according to formula (I).

[0113] The present invention further relates to the case where Y 1 is CR 18 R 19 in the compound according to formula (I).

[0114] The present invention further relates to the case where R 18 and R 19 are each H in the compound according to formula (I).

[0115] The present invention further relates to the case where Y 1 is NR 18 in the compound according to formula (I).

[0116] The present invention further relates to the case where m is 0, 1 or 2 in the compound according to formula (I).

[0117] The present invention further relates to the case where m is 1 in the compound according to formula (I).

[0118] The present invention further relates to the case where R 4 and R 5 are each independently selected from the group consisting of H, (C1-C 10 ) alkyl, hydroxy, halo and amino in the compound according to formula (I). is also related to.

[0119] The present invention further relates to the case where R 4 is H in the compound according to formula (I).

[0120] The present invention further relates to the case where R 5 is H in the compound according to formula (I).

[0121] The present invention further relates to the case where R4 and R 5 also relates to a compound according to formula (I), wherein each of them is H.

[0122] The present invention further provides that R 6 is selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl , (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) hetero aryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl-, COOH-(C3-C 10 ) cycloalkyl-, (C1-C 10 ) alkoxy-, R 14 -(C1-C 10 ) alkyl-, R 14 -(C3-C 10 ) cycloalkyl, R 14 -(C2-C9) heterocycloalkyl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl, R 14 -(C2-C 10 ) alkylnyl, R 14 -(C1-C 10 ) alkylamine, R 14 -((C1-C 10 ) alkyl)2amine, and R 14 -C(O)-; wherein each R 14 is independently selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10) selected from the group consisting of alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO , halo, or H2N- and is optionally further substituted by 1 to 4 groups selected therefrom, also relates to a compound according to formula (I).

[0123] The present invention further relates to R 6 which is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl l, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C​10 ) selected from the group consisting of alkylamines, wherein R 14 is, independently of one another, H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N- and relates also to a compound of formula (I).

[0124] The present invention further relates to a compound of formula (I) wherein R 16 and R 4 together with the carbon to which they are attached form a compound of formula ( II):

Chemical formula

[0125] The present invention further relates to a compound of formula 1 wherein T 10 is CR 2 ; T 10 is CR 3 ; T 10 is CR It also relates to the compounds according to (II).

[0126] The present invention further relates to R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and relates to the compounds according to formula (II) selected from the group consisting of compounds.

[0127] The present invention further relates to T 1 is CR 10 and CR 10 is H, (C1-C 10 ) alkyl or (C3-C 10 ) cycloalkyl; T 2 is CR 10 and R 10 is (C1-C 10 ) a lkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo; T 3 is CH, and relates to the compounds according to formula (II).

[0128] The present invention further relates to T 1 is CH; T 2 is CR 10 and R 10 is (C1-C 10 ) a lkoxy; T 3 is CH, and relates to the compounds according to formula (II).

[0129] The present invention further relates to T 1 is CH; T 2 is CR 10 and R 10 is halo; T 3 is CH, and relates to the compounds according to formula (II).

[0130] The present invention further relates to Y 1 and Y 2are each independently O, S, NR 18 or CR 18 R 19 and relates to compounds of formula (II) selected from

[0131] The present invention further relates to compounds of formula (II) wherein Y 1 is O.

[0132] The present invention further relates to compounds of formula (II) wherein Y 2 is O.

[0133] The present invention further relates to compounds of formula (II) wherein Y 1 is CR 18 R 19 and relates to compounds of formula (II).

[0134] The present invention further relates to compounds of formula (II) wherein R 18 and R 19 are each H.

[0135] The present invention further relates to compounds of formula (II) wherein Y 2 is CR 18 R 19 and relates to compounds of formula (II).

[0136] The present invention further relates to compounds of formula (II) wherein R 18 and R 19 are each H.

[0137] The present invention further relates to compounds of formula (II) wherein Y 1 is S.

[0138] The present invention further relates to compounds of formula (II) wherein Y 2 is S.

[0139] The present invention further relates to compounds of formula (II) wherein Y 1 is NR 18 and R 18 is H or (C1-C 10It also relates to a compound according to formula (II) which is alkyl.

[0140] The present invention further relates to a compound according to formula (II) wherein Y 2 is NR 18 and R 18 is H or (C1-C 10 ) alkyl.

[0141] The present invention further relates to a compound according to formula (II) wherein Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 and R is as defined above.

[0142] The present invention further relates to a compound according to formula (II) wherein Y 2 is O.

[0143] The present invention further relates to a compound according to formula (II) wherein p is 0, 1 or 2.

[0144] The present invention further relates to a compound according to formula (II) wherein p is 1.

[0145] The present invention further relates to a compound according to formula (II) wherein Z 1 is each independently selected from H, halo or (C1-C 10 ) alkyl.

[0146] The present invention further relates to a compound according to formula (II) wherein R 5 is selected from the group consisting of H, (C1-C 10 ) alkyl, HO-, halo and H2N- .

[0147] The present invention further relates to a compound according to formula (II) wherein R 5 is H or (C1-C 10 ) alkyl.

[0148] The present invention further relates to a compound according to formula (II) wherein R5 also relates to a compound according to formula (II) which is H.

[0149] The present invention further provides that R 6 is selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl , (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) hetero aryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl-, COOH-(C3-C 10 ) cycloalkyl-, (C1-C 10 ) alkoxy-, R 14 -(C1-C 10 ) alkyl-, R 14 -(C3-C 10 ) cycloalkyl, R 14 -(C2-C9) heterocycloalkyl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl, R 14 -(C2-C 10 ) alkylnyl, R 14 -(C1-C 10 ) alkylamine, R 14 -((C1-C 10 ) alkyl)2amine, and R 14 -C(O)-; wherein each R 14 is independently selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10) selected from the group consisting of alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroar yl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ([[]] C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- optionally further substituted by 1 to 4 groups selected from halo, or H2N- also relates to a compound according to formula (II).

[0150] The present invention further provides that R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalk yl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl, and R 14-(C1 to C 10 ) selected from the group consisting of alkylamines; wherein R 14 is, independently of one another, H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) he teroaryl, (C1 to C 10 ) alkylamine, (C1 to C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-, selected from the group consisting of; wherein each (C1 to C 10 ) alkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C3 to C 10 ) cycloalkyl or (C2 to C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, HO-, halo or H2N-, also relates to a compound according to formula (II).

[0151] The present invention further relates to R 6 is H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl l, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) hete roaryl, (C1 to C 10 ) alkylamine, ((C1 to C 10 ) alkyl)2amine, (C1 to C 10 ) alkyl-C(O)O-, COOH-(C1 to C 10 ) alkyl-, COOH-(C3 to C 10 ) cycloalkyl-, (C1 to C 10 ) alkoxy-, R14 -(C1 to C 10 ) alkyl-, R 14 -(C3 to C 10 ) cycloalkyl, R 14 -(C2 to C9) heterocycloalkyl, R 14 -(C6 to C 14 ) aryl, R 14 -(C2 to C9) heteroaryl, R 14 -(C2 to C 10 ) alkylnyl, R 14 -(C1 to C 10 ) alkylamine, R 14 -((C1 to C 10 ) alkyl)2amine, and R 14 -C(O)- selected from the group consisting of; wherein, R 14 is, each independently, H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) he teroaryl, (C1 to C 10 ) alkylamine, (C1 to C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC- selected from the group consisting of; wherein, each (C1 to C 10 ) alkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C3 to C 10 ) cycloalkyl or (C2 to C9) heterocycloalkyl is, ( C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C1 to C 10 ) alkylamine, ((C1 to C 10 ) alkyl)2amine, (C1 to C3) alkynylamine, (C1 to C 10 ) alkyl-C(O)O-, COOH-(C1 to C10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- and is optionally further substituted by 1 to 4 groups selected from halo, or H2N- also relates to a compound according to formula (II).

[0152] The present invention further provides that R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl aryl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine selected from the group consisting of; where R 14 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC- selected from the group consisting of; where each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1~C 10 ) alkyl, (C3~C 10 ) cycloalkyl, (C2~C9) heterocycloalkyl, (C6~C 14 ) aryl, (C2~C9) heteroaryl, HO-, halo or H2N-, and is further optionally substituted by 1 to 4 groups selected therefrom, also relates to a compound of formula (II).

[0153] The present invention further relates to formula (III):

Chemical formula

[0154] The present invention further relates to compounds according to formula (III) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 It also relates to compounds according to formula (III) wherein X

[0155] The present invention further relates to compounds according to formula (III) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 It also relates to compounds according to formula (III) wherein X

[0156] The present invention further relates to X2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; also relates to the compound according to formula (III).

[0157] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; also relates to the compound according to formula (III).

[0158] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; also relates to the compound according to formula (III).

[0159] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; also relates to the compound according to formula (III).

[0160] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; also relates to the compound according to formula (III).

[0161] The present invention further relates to X 2 is N; X 3 is CR 7 ; X4 is CR 7 ; X 5 is N, also relates to the compound according to formula (III).

[0162] The present invention further relates to a compound according to formula (III) wherein X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is N .

[0163] The present invention further relates to a compound according to formula (III) wherein X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N .

[0164] The present invention further relates to a compound according to formula (III) wherein X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 .

[0165] The present invention further relates to a compound according to formula (III) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N.

[0166] The present invention further relates to a compound according to formula (III) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N.

[0167] The present invention further relates to a compound according to formula (III) wherein n is 1.

[0168] The present invention further relates to a compound according to formula (III) wherein R 1 and R 2 are each H.

[0169] The present invention further relates to a compound according to formula (III) wherein R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo.

[0170] The present invention further relates to a compound according to formula (III) wherein T 1 is CR 10 and R 10 is H, (C1-C 10 )alkyl or (C3-C 10 )cycloalkyl; T 2 is CR 10 and R 10 is (C1-C 10 )alkyl, (C3-C )cycloalkyl, (C1-C 10 )alkoxy and halo; T 10 is CH; R 3 is CH or N. 3

[0171] The present invention further relates to a compound according to formula (III) wherein Y 1 is O.

[0172] The present invention further relates to a compound according to formula (III) wherein m is 1.

[0173] The present invention further relates to a compound according to formula (III) wherein R 4 and R 5 are each H.

[0174] The present invention further relates to R 6 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl yl, (C2-C9)heteroaryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 )alkylamine selected from the group consisting of; wherein R 14 is each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC- selected from the group consisting of; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is ( C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, HO-, halo or H2N- optionally further substituted by 1 to 4 groups selected from, also relates to a compound of formula (III).

[0175] The present invention further relates to n is 1; m is 1; R 1 and R 2 are each H; T 1 is CR 10 (wherein R 10 is H, (C1-C10 ) alkyl or (C3-C 10 ) cyclo alkyl); T 2 is CR 10 (wherein R 10 is (C1-C 10 ) alkyl, (C3 -C 10 ) cycloalkyl, (C1-C 10 ) alkoxy or halo); T 3 is CH; R 3 is CH or N; Y 1 is O; R 4 and R 5 are each H; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) hetero aryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine; wherein R 14 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C- and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1-C 10 ) alkyl, (C3-C10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, optionally further substituted by 1 to 4 groups selected therefrom, also relates to a compound according to formula (III).

[0176] The present invention further relates to a compound of formula (IV): [Chemical formula] [wherein, n is 1, 2 or 3; m is 0, 1 or 2; R 1 and R 2 are each independently H, (C1-C 10 ) alkyl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy- or NH2; T 1 is CR 10 ; T 2 is CR 10 ; T 3 is CR 10 ; R 3 is CR 16 or N; Y 1 is O, NR 18 or CR 18 R 19 ; R 4 and R 5 are each independently H, (C1-C 10 ) alkyl, hydroxy, halo and amino; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) hete rocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10) alkylamine, ((C1 - C 10 ) alkyl)2amine, (C1 - C 10 ) alkyl - C( O)O -, COOH - (C1 - C 10 ) alkyl -, COOH - (C3 - C 10 ) cycloalkyl -, (C1 - C 10 ) alkoxy -, R 14 - (C1 - C 10 ) alkyl -, R 14 - (C3 - C 10 ) cycloalkyl, R 14 - (C2 - C9) heterocycloalkyl, R 14 - (C6 - C 14 ) aryl, R 14 - (C2 - C9) heteroaryl, R 14 - (C2 - C 10 ) alkylnyl, R 14 - (C1 - C 10 ) alkylamine, R 14 - ((C1 - C 10 ) alkyl)2amine, and R 14 - C(O) - selected from the group consisting of; wherein, R 14 is, each independently, H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) he teroaryl, (C1 - C 10 ) alkylamine, (C1 - C 10 ) alkoxy -, HO -, F2HC - O -, F3C - C(O) -, F3C -, and F2HC - selected from the group consisting of; wherein, each (C1 - C 10 ) alkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) cycloalkyl or (C2 - C9) heterocycloalkyl is, ( C1 - C 10 ) alkyl, (C3 - C 10)Cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )Aryl, (C2-C9)heteroaryl, (C1-C 10 )Alkylamine, ((C1-C 10 )Alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )Alkyl-C(O)O-, COOH-(C1-C 10 )Alkyl, COOH-(C3-C 10 )Cycloalkyl, (C1-C 10 )Alkoxy-, (C1-C 10 )Alkoxy-(C1-C1 0)Alkyl-, (C3-C 10 )Cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-, (C6-C 14 )Aryl-O-, (C2-C9)heteroaryl-O-, HO- 、halo, or H2N- and is optionally further substituted by 1 to 4 groups selected from also relates to compounds thereof.

[0177] The present invention further relates to compounds of formula (IV) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; and X

[0178] The present invention further relates to compounds of formula (IV) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; and X

[0179] The present invention further relates to compounds of formula (IV) wherein X 2 is CR 7 ; and X​3 is N; X 4 is CR 7 ; X 5 is CR 7 also relates to the compound according to formula (IV).

[0180] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (IV).

[0181] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (IV).

[0182] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 also relates to the compound according to formula (IV).

[0183] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (IV).

[0184] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5also relates to the compound according to formula (IV), which is N.

[0185] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (IV).

[0186] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N also relates to the compound according to formula (IV).

[0187] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (IV).

[0188] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (IV).

[0189] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N also relates to the compound according to formula (IV).

[0190] The present invention further relates to the compound according to formula (IV), wherein n is 1.

[0191] The present invention further relates to a compound of formula (IV) in which R 1 and R 2 are each H.

[0192] The present invention further relates to a compound of formula (IV) in which R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo. The present invention further relates to a compound of formula (IV) in which T

[0193] is CR 1 and R 10 is H, (C1-C 10 )alkyl or (C3-C 10 )cycloalkyl; T 10 is CR 2 and R 10 is (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy or halo; T 3 is CH; and R 3 is CH or N.

[0194] The present invention further relates to a compound of formula (IV) in which Y 1 is O.

[0195] The present invention further relates to a compound of formula (IV) in which m is 1.

[0196] The present invention further relates to a compound of formula (IV) in which R 4 and R 5 are each H.

[0197] The present invention further relates to a compound of formula (IV) in which R 6 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C10 ) cycloalkyl , (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine selected from the group consisting of; wherein R 14 is each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC- selected from the group consisting of; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1-4 groups selected from (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N- and also relates to a compound according to formula (IV).

[0198] The present invention further provides that n is 1; m is 1; R 1 and R 2 are each H; T 1 is CR 10 (wherein R 10 is H, (C1-C 10 ) alkyl or (C3-C 10 ) cyclo alkyl) and; T 2is CR 10 (wherein R 10 is (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C1 - C 10 ) alkoxy or halo); T 3 is CH; R 3 is CH or N; Y 1 is O; R 4 and R 5 are each H; R 6 is H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) hetero aryl, R 14 -(C6 - C 14 ) aryl, R 14 -(C2 - C9) heteroaryl and R 14 -(C1 - C 10 ) alkylamine selected from the group consisting of; here, R 14 are each independently H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) he teroaryl, (C1 - C 10 ) alkylamine, (C1 - C 10 ) alkoxy-, HO-, F2HC - O-, F3C - C(O)-, F3C - and F2HC - selected from the group consisting of; here, each (C1 - C 10 ) alkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) cycloalkyl or (C2 - C9) heterocycloalkyl is (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl , (C6 - C 14Also relates to a compound according to formula (IV), optionally further substituted by 1 to 4 groups selected from aryl, (C2-C9) heteroaryl, HO-, halo or H2N-.

[0199] The present invention further relates to formula (V):

Chemical formula

[0200] The present invention further relates to compounds of formula (V) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 .

[0201] The present invention further relates to compounds of formula (V) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 .

[0202] The present invention further relates to compounds of formula (V) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X​5 is CR 7 also relates to the compound according to formula (V).

[0203] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (V).

[0204] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 also relates to the compound according to formula (V).

[0205] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (V).

[0206] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (V).

[0207] The present invention further relates to the compound according to formula (V) wherein n is 1.

[0208] The present invention further relates to R 1 and R 2 each being H, also relates to the compound according to formula (V).

[0209] The present invention further relates to R 10 is H, (C1 - C10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and relates to the compound of formula (V). It also relates to the compound of formula (V).

[0210] The present invention further relates to T 1 is CR 10 and R 10 is H, (C1-C 10 ) alkyl or (C3-C 10 ) cycloalkyl; T 2 is CR 10 and R 10 is (C1-C 10 ) alk yl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy or halo; T 3 is CH; R 3 is CH or N, and relates to the compound of formula (V).

[0211] The present invention further relates to Y 1 is O, and relates to the compound of formula (V).

[0212] The present invention further relates to m is 1, and relates to the compound of formula (V).

[0213] The present invention further relates to R 4 and R 5 are each H, and relates to the compound of formula (V).

[0214] The present invention further relates to R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl yl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14-(C1 to C 10 ) selected from the group consisting of alkylamines; wherein R 14 is, independently of one another, H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) he teroaryl, (C1 to C 10 ) alkylamine, (C1 to C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1 to C 10 ) alkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C3 to C 10 ) cycloalkyl or (C2 to C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl , (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, HO-, halo or H2N-, and relates also to a compound according to formula (V).

[0215] The present invention further relates to the case where n is 1; m is 1; R 1 and R 2 are each H; T 1 is CR 10 (wherein R 10 is H, (C1 to C 10 ) alkyl or (C3 to C 10 ) cyclo ) alkyl); T 2 is CR 10 (wherein R 10 is (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C1 to C 10 ) alkoxy or halo); T3 is CH; R 3 is CH or N; Y 1 is O; R 4 and R 5 are each H; R 6 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)hetero aryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9)heteroaryl and R 14 -(C1-C 10 )alkylamine selected from the group consisting of; wherein R 14 are each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C- and F2HC- selected from the group consisting of; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl 、(C6-C 14 )aryl, (C2-C9)heteroaryl, HO-, halo or H2N- also relates to the compound according to formula (V).

[0216] The present invention further relates to formula (VI)

Chemical formula

[0217] The present invention further relates to compounds according to formula (VI) wherein X 2 is N; X 3 is CR 7 and X 4 is CR 7 and X 5 is CR 7 and X

[0218] The present invention further relates to compounds according to formula (VI) wherein X 2 is CR 7 and X 3 is CR 7 and X 4 is CR 7 and X 5 is CR 7 and X

[0219] The present invention further relates to compounds according to formula (VI) wherein X 2 is CR 7 and X 3 is N; X 4 is CR 7 and X 5 is CR 7 and X

[0220] The present invention further relates to compounds according to formula (VI) wherein X 2 is CR 7 and X 3 is CR 7 and X4 is N; X 5 is CR 7 also relates to the compound according to formula (VI).

[0221] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (VI).

[0222] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (VI).

[0223] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (VI).

[0224] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N also relates to the compound according to formula (VI).

[0225] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (VI).

[0226] The present invention further relates to a compound of formula (VI) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N.

[0227] The present invention further relates to a compound of formula (VI) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N.

[0228] The present invention further relates to a compound of formula (VI) wherein n is 1.

[0229] The present invention further relates to a compound of formula (VI) wherein R 1 and R 2 are each H.

[0230] The present invention further relates to a compound of formula (VI) wherein R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo.

[0231] The present invention further relates to a compound of formula (VI) wherein T 1 is CR 10 and R 10 is H, (C1-C 10 )alkyl or (C3-C 10 )cycloalkyl; T 2 is CR 10 and R 10 is (C1-C 10 )alkyl, (C3-C )cycloalkyl, (C1-C 10 )alkoxy or halo; T 10 is CR 3 is CH; R 3 also relates to a compound of formula (VI) wherein R is CH or N.

[0232] The present invention further relates to a compound of formula (VI) wherein Y 1 is O.

[0233] The present invention further relates to a compound of formula (VI) wherein m is 1.

[0234] The present invention further relates to a compound of formula (VI) wherein R 4 and R 5 are each H.

[0235] The present invention further relates to a compound of formula (VI) wherein R 6 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heteroaryl, R -(C6-C 14 )aryl, R 14 -(C2-C9) 14 heteroaryl and R -(C1-C 14 )alkylamine; 10 wherein each R is independently selected from the group consisting of H, (C1-C Here, R 14 is each independently selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10)Cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 )aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, and also relates to a compound according to formula (VI).

[0236] The present invention further provides that n is 1; m is 1; R 1 and R 2 are each H; T 1 is CR 10 (wherein R 10 is H, (C1-C 10 )alkyl or (C3-C 10 )cyclo alkyl); T 2 is CR 10 (wherein R 10 is (C1-C 10 )alkyl, (C3 -C 10 )cycloalkyl, (C1-C 10 )alkoxy or halo); T 3 is CH; R 3 is CH or N; Y 1 is O; R 4 and R 5 are each H; R 6 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9) hete roaryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 )alkylamine, and is selected from the group consisting of; wherein R 14 are each independently H, (C1-C 10) Alkyl, (C3 - C 10 ) Cyclo alkyl, (C2 - C9) Heterocycloalkyl, (C6 - C 14 ) Aryl, (C2 - C9) Het eroaryl, (C1 - C 10 ) Alkylamine, (C1 - C 10 ) Alkoxy-, HO-, F2HC - O-, F3C - C(O)-, F3C - and F2HC - selected from the group consisting of; wherein each (C1 - C 10 ) Alkyl, (C6 - C 14 ) Aryl, (C2 - C9) Heteroaryl, (C3 - C 10 ) Cycloalkyl or (C2 - C9) Heterocycloalkyl is optionally further substituted by 1 - 4 groups selected from (C1 - C 10 ) Alkyl, (C3 - C 10 ) Cycloalkyl, (C2 - C9) Heterocycloalkyl , (C6 - C 14 ) Aryl, (C2 - C9) Heteroaryl, HO-, Halo or H2N-, also relates to a compound of formula (VI).

[0237] The present invention further relates to formula (VII)

Chemical formula

[0238] The present invention further provides that X 2 is N; X​3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; also relates to the compound according to formula (VII).

[0239] The present invention further relates to a compound according to formula (VII) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; also relates to the compound according to formula (VII).

[0240] The present invention further relates to a compound according to formula (VII) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; also relates to the compound according to formula (VII).

[0241] The present invention further relates to a compound according to formula (VII) wherein X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; also relates to the compound according to formula (VII).

[0242] The present invention further relates to a compound according to formula (VII) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; also relates to the compound according to formula (VII).

[0243] The present invention further relates to a compound according to formula (VII) wherein X 2 is N; X3 is N; X 4 is CR 7 ; X 5 is CR 7 also relates to the compound according to formula (VII).

[0244] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; X

[0245] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (VII).

[0246] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is N also relates to the compound according to formula (VII).

[0247] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N also relates to the compound according to formula (VII).

[0248] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (VII).

[0249] The present invention further relates to a compound according to formula (VII) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N.

[0250] The present invention further relates to a compound according to formula (VII) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N.

[0251] The present invention further relates to a compound according to formula (VII) wherein n is 1.

[0252] The present invention further relates to a compound according to formula (VII) wherein R 1 and R 2 are each H.

[0253] The present invention further relates to a compound according to formula (VII) wherein each R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo.

[0254] The present invention further relates to a compound according to formula (VII) wherein each R 10 is H.

[0255] The present invention further relates to a compound according to formula (VII) wherein Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 .

[0256] The present invention further relates to a compound according to formula (VII) wherein Y 2also relates to the compound according to formula (VII), which is O.

[0257] The present invention further relates to the compound according to formula (VII), wherein p is 1.

[0258] The present invention further relates to R 5 which is H or (C1-C 10 ) alkyl, and also relates to the compound according to formula (VII).

[0259] The present invention further relates to R 5 which is H, and also relates to the compound according to formula (VII).

[0260] The present invention further relates to R 6 which is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl a (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine, and is selected from the group consisting of; wherein R 14 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-, and are selected from the group consisting of; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1-C 10) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, optionally further substituted by 1 to 4 groups selected therefrom, also relates to a compound according to formula (VII).

[0261] The present invention further provides that n is 1; p is 1; R 1 and R 2 are each H; R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) al koxy and halo; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1-C 10 ) alkyl; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine; wherein R 14 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; Here, each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, and also relates to a compound according to formula (VII).

[0262] The present invention further relates to a compound according to formula (VII) wherein R 5 is H and Y 2 is O.

[0263] The present invention further relates to formula (VIII):

Chemical formula

[0264] The present invention further provides that X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR​7 It also relates to the compound according to formula (VIII).

[0265] The present invention further provides that X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 It also relates to the compound according to formula (VIII).

[0266] The present invention further provides that X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 It also relates to the compound according to formula (VIII).

[0267] The present invention further provides that X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 It also relates to the compound according to formula (VIII).

[0268] The present invention further provides that X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N. It also relates to the compound according to formula (VIII).

[0269] The present invention further provides that X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7Also relates to the compound according to formula (VIII).

[0270] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; Also relates to the compound according to formula (VIII).

[0271] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N; Also relates to the compound according to formula (VIII).

[0272] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is N ; Also relates to the compound according to formula (VIII).

[0273] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N ; Also relates to the compound according to formula (VIII).

[0274] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 ; Also relates to the compound according to formula (VIII).

[0275] The present invention further relates to X 2 is CR 7 ; X 3 is N; X4 is CR 7 ; X 5 is N, and also relates to the compound according to formula (VIII).

[0276] The present invention further relates to the compound according to formula (VIII) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N, and also relates to the compound according to formula (VIII).

[0277] The present invention further relates to the compound according to formula (VIII) wherein n is 1.

[0278] The present invention further relates to the compound according to formula (VIII) wherein R 1 and R 2 are each H.

[0279] The present invention further relates to the compound according to formula (VIII) wherein each R 10 is selected from the group consisting of H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo.

[0280] The present invention further relates to the compound according to formula (VIII) wherein each R 10 is H.

[0281] The present invention further relates to the compound according to formula (VIII) wherein Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19

[0282] The present invention further relates to the compound according to formula (VIII) wherein Y 2 is O.

[0283] ​​The present invention further relates to a compound of formula (VIII) wherein p is 1.

[0284] The present invention further relates to a compound of formula (VIII) wherein R 5 is H or (C1-C 10 ) alkyl.

[0285] The present invention further relates to a compound of formula (VIII) wherein R 5 is H.

[0286] The present invention further relates to a compound of formula (VIII) wherein R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R -(C6-C 14 ) aryl, R 14 -(C2-C9) 14 heteroaryl and R -(C1-C 14 ) alkylamine, selected from the group consisting of; 10 wherein R is, independently of each other, H, (C1-C 14 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 10 ) aryl, (C2-C9) he 14 teroaryl, (C1-C ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-, selected from the group consisting of; 10 wherein each (C1-C ) alkyl, (C6-C 10 ) aryl, (C2-C9) heteroaryl, (C3-C 14 ) cycloalkyl or (C2-C9) heterocycloalkyl is (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl 10 , (C6-C ​14 ) It also relates to a compound according to formula (VIII), optionally further substituted by 1 to 4 groups selected from aryl, (C2-C9) heteroaryl, HO-, halo or H2N-.

[0287] The present invention further provides that n is 1; p is 1; R 1 and R 2 are each H; R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alk oxy and halo; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1-C 10 ) alkyl; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine; wherein R 14 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C14 ) Aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) cycloalkyl or (C2 - C9) heterocycloalkyl is optionally further substituted by 1 - 4 groups selected from (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl , (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, HO-, halo or H2N-, and also relates to the compound according to formula (VIII).

[0288] The present invention further relates to the case where R 5 is H and Y 2 is O, and also relates to the compound according to formula (VIII).

[0289] The present invention further relates to formula (IX):

Chemical formula

[0290] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 and also relates to compounds of formula (IX).

[0291] ​ The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; and also relates to a compound according to formula (IX).

[0292] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; and also relates to a compound according to formula (IX).

[0293] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; and also relates to a compound according to formula (IX).

[0294] The present invention further relates to X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; and also relates to a compound according to formula (IX).

[0295] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; and also relates to a compound according to formula (IX).

[0296] The present invention further relates to X 2 is CR 7 ; X 3is N; X 4 is N; X 5 is CR 7 It also relates to the compound according to formula (IX).

[0297] The present invention further relates to the compound according to formula (IX) wherein n is 1.

[0298] The present invention further relates to R 1 and R 2 It also relates to the compound according to formula (IX) wherein each is H.

[0299] The present invention further relates to each R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy and halo, and it also relates to the compound according to formula (IX) selected from the group consisting of .

[0300] The present invention further relates to each R 10 is H, and it also relates to the compound according to formula (IX).

[0301] The present invention further relates to Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 and it also relates to the compound according to formula (IX).

[0302] The present invention further relates to Y 2 is O, and it also relates to the compound according to formula (IX).

[0303] The present invention further relates to the compound according to formula (IX) wherein p is 1.

[0304] The present invention further relates to R 5 is H or (C1-C 10 ) alkyl, and it also relates to the compound according to formula (IX).

[0305] The present invention further relates to a compound of formula (IX) wherein R 5 is H.

[0306] The present invention further relates to a compound of formula (IX) wherein R 6 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl , (C2-C9)heteroaryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 )alkylamine; wherein each R 14 is independently selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cyclo alkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is optionally further substituted by 1-4 groups selected from (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl , (C6-C 14 )aryl, (C2-C9)heteroaryl, HO-, halo or H2N-, and relates to a compound of formula (IX).

[0307] The present invention further relates to a compound of formula (IX) wherein n is 1; p is 1; R 1 and R2 is each H; R 10 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alk oxy and halo, selected from the group consisting of; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1-C 10 )alkyl; R 6 is H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heteroaryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9)heteroaryl and R 14 -(C1-C 10 )alkylamine, selected from the group consisting of; wherein R 14 is each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-, selected from the group consisting of; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl , (C6-C 14It also relates to a compound of formula (IX) optionally further substituted by 1 to 4 groups selected from aryl, (C2-C9) heteroaryl, HO-, halo or H2N-.

[0308] The present invention further relates to R 5 being H and Y 2 being O, and also relates to a compound of formula (IX).

[0309] The present invention further relates to formula (X)

Chemical formula

[0310] The present invention further relates to compounds of formula (X) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 .

[0311] The present invention further relates to compounds of formula (X) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR​7 Also relates to the compound according to formula (X), which is:

[0312] The present invention further relates to X 2 being CR 7 ; X 3 being N; X 4 being CR 7 ; X 5 being CR 7 Also relates to the compound according to formula (X), which is:

[0313] The present invention further relates to X 2 being CR 7 ; X 3 being CR 7 ; X 4 being N; X 5 being CR 7 Also relates to the compound according to formula (X), which is:

[0314] The present invention further relates to X 2 being CR 7 ; X 3 being CR 7 ; X 4 being CR 7 ; X 5 being N. Also relates to the compound according to formula (X), which is:

[0315] The present invention further relates to X 2 being N; X 3 being CR 7 ; X 4 being N; X 5 being CR 7 Also relates to the compound according to formula (X), which is:

[0316] The present invention further relates to X 2 being N; X 3 being CR 7 ; X 4 being CR 7 ; X 5 being N and. Also relates to the compound according to formula (X), which is:

[0317] The present invention further relates to a compound of formula (X) wherein X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N .

[0318] The present invention further relates to a compound of formula (X) wherein X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 .

[0319] The present invention further relates to a compound of formula (X) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N

[0320] The present invention further relates to a compound of formula (X) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N

[0321] The present invention further relates to a compound of formula (X) wherein n is 1

[0322] The present invention further relates to a compound of formula (X) wherein R 1 and R 2 are each H

[0323] The present invention further relates to a compound of formula (X) wherein each R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo It also relates to compounds.

[0324] The present invention further relates to compounds of formula (X) wherein each R 10 is H.

[0325] The present invention further relates to compounds of formula (X) wherein Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 is as defined above.

[0326] The present invention further relates to compounds of formula (X) wherein Y 2 is O.

[0327] The present invention further relates to compounds of formula (X) wherein p is 1.

[0328] The present invention further relates to compounds of formula (X) wherein R 5 is H or (C1-C 10 ) alkyl.

[0329] The present invention further relates to compounds of formula (X) wherein R 5 is H.

[0330] The present invention further relates to compounds of formula (X) wherein R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R -(C6-C 14 ) aryl, R 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine; wherein each R 14 is independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1-4 groups selected from (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, also relates to a compound according to formula (X).

[0331] The present invention further provides that n is 1; p is 1; R 1 and R 2 are each H; R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) al koxy and halo; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1-C 10 ) alkyl; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14-(C1 to C 10 ) selected from the group consisting of alkylamines; wherein R 14 is, independently of one another, H, (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl, (C6 to C 14 ) aryl, (C2 to C9) he teroaryl, (C1 to C 10 ) alkylamine, (C1 to C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1 to C 10 ) alkyl, (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, (C3 to C 10 ) cycloalkyl or (C2 to C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from (C1 to C 10 ) alkyl, (C3 to C 10 ) cycloalkyl, (C2 to C9) heterocycloalkyl , (C6 to C 14 ) aryl, (C2 to C9) heteroaryl, HO-, halo or H2N-, also relates to a compound according to formula (X).

[0332] The present invention further relates to a compound according to formula (X) wherein R 5 is H and Y 2 is O.

[0333] The present invention further relates to formula (XI) [wherein, n is 1, 2 or 3; p is 0, 1 or 2; R and R 1 and R 2 are, independently of one another, H, (C1 to C 10 ) alkyl, (C1 to C 10is selected from alkylamine, (C1-C 10 ) alkoxy- or NH2; T 1 is CR 10 ; T 2 is CR 10 ; T 3 is CR 10 ; Y 1 and Y 2 are each independently selected from O, S, NR 18 or CR 18 R 19 ; Z 1 are each independently selected from H, halo or (C1-C 10 ) alkyl; R 5 is selected from the group consisting of H, (C1-C 10 ) alkyl, HO-, halo and H2N- ; R 6 is selected from H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) hetero cycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C 10 ) alkyl-C( O)O-, COOH-(C1-C 10 ) alkyl-, COOH-(C3-C 10 ) cycloalkyl-, (C1-C 10 ) alkoxy-, R 14 -(C1-C 10 ) alkyl-, R 14 -(C3-C 10 ) cycloalkyl, R 14 -(C2-C9) heterocycloalkyl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl, R 14 -(C2-C 10)Alkylnyl, R 14 -(C1-C 10 )Alkylamine, R 14 -((C1-C 10 )Alkyl)2amine, and R 14 -C(O)-selected from the group consisting of; wherein R 14 is, each independently, H, (C1-C 10 )Alkyl, (C3-C 10 )Cycloalkyl, (C2-C9)Heterocycloalkyl, (C6-C 14 )Aryl, (C2-C9)He teroaryl, (C1-C 10 )Alkylamine, (C1-C 10 )Alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-selected from the group consisting of; wherein each (C1-C 10 )Alkyl, (C6-C 14 )Aryl, (C2-C9)Heteroaryl, (C3-C 10 )Cycloalkyl or (C2-C9)Heterocycloalkyl is (C1-C 10 )Alkyl, (C3-C 10 )Cycloalkyl, (C2-C9)Heterocycloalkyl , (C6-C 14 )Aryl, (C2-C9)Heteroaryl, (C1-C 10 )Alkylamine, ((C1-C 10 )Alkyl)2amine, (C1-C3)Alkynylamine, (C1-C 10 ) Alkyl-C(O)O-, COOH-(C1-C 10 )Alkyl, COOH-(C3-C 10 )Cycloalkyl, (C1-C 10 )Alkoxy-, (C1-C 10 )Alkoxy-(C1-C 10 )Alkyl-, (C3-C 10 )Cycloalkyl-O-, (C2-C9)Heterocycloalkyl yl-O-, (C6-C14 ) Aryl - O -, (C2 - C9) heteroaryl - O -, HO - and is optionally further substituted by 1 to 4 groups selected from halo or H2N - [wherein]] also relates to compounds of

[0334] The present invention further relates to compounds of formula (XI) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; and X

[0335] The present invention further relates to compounds of formula (XI) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; and X

[0336] The present invention further relates to compounds of formula (XI) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; and X

[0337] The present invention further relates to compounds of formula (XI) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; and X

[0338] The present invention further relates to compounds of formula (XI) wherein X 2 is CR 7 ; X3 is CR 7 ; X 4 is CR 7 ; X 5 is N, and also relates to the compound according to formula (XI).

[0339] The present invention further relates to a compound according to formula (XI) wherein X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 ; and also relates to the compound according to formula (XI).

[0340] The present invention further relates to a compound according to formula (XI) wherein X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 ; and also relates to the compound according to formula (XI).

[0341] The present invention further relates to a compound according to formula (XI) wherein X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is N, and also relates to the compound according to formula (XI).

[0342] The present invention further relates to a compound according to formula (XI) wherein X 2 is N; X 3 is N; X 4 is CR 7 ; X 5 is N ; and also relates to the compound according to formula (XI).

[0343] The present invention further relates to a compound according to formula (XI) wherein X 2 is N; X 3 is CR 7 ; X 4 is N; X 5 is N ; and also relates to the compound according to formula (XI).

[0344] The present invention further relates to a compound according to formula (XI) wherein X 2 is CR 7 ; X 3 is N; X 4 is N; X 5 is CR 7 ; and X

[0345] The present invention further relates to a compound according to formula (XI) wherein X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is N; and X

[0346] The present invention further relates to a compound according to formula (XI) wherein X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is N; and X

[0347] The present invention further relates to a compound according to formula (XI) wherein n is 1

[0348] The present invention further relates to a compound according to formula (XI) wherein R 1 and R 2 are each H

[0349] The present invention further relates to a compound according to formula (XI) wherein each R 10 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy and halo ; and X

[0350] The present invention further relates to a compound according to formula (XI) wherein each R 10 is H

[0351] The present invention further relates to a compound according to formula (XI) wherein Y 1 is O; and Y 2 is O, S, NR 18 or CR 18 R 19 and the present invention further relates to a compound according to formula (XI) wherein Y

[0352] is O 2 and the present invention further relates to a compound according to formula (XI) wherein p is 1

[0353] and the present invention further relates to a compound according to formula (XI) wherein R

[0354] is H or (C1-C 5 )alkyl 10 and the present invention further relates to a compound according to formula (XI) wherein R

[0355] is H 5 and the present invention further relates to a compound according to formula (XI) wherein R

[0356] is selected from the group consisting of H, (C1-C 6 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heteroaryl, R 10 -(C6-C )aryl, R 14 -(C2-C9) 14 )heteroaryl and R 14 -(C1-C )alkylamine; 14 wherein each R 10 is independently selected from the group consisting of H, (C1-C )alkyl, (C3-C 14 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 10 )aryl, (C2-C9)he 10 )heteroaryl, (C1-C 14 )alkylamine, (C1-C )alkylamine, (C1-C 10 )alkylamine, (C1-C 10) selected from the group consisting of alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo or H2N-, also relates to a compound according to formula (XI).

[0357] The present invention further provides that n is 1; p is 1; R 1 and R 2 are each H; R 10 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alk oxy and halo; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1-C 10 ) alkyl; R 6 is H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heteroaryl, R 14 -(C6-C 14 ) aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 ) alkylamine; wherein R 14is, independently of each other, H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, and F2HC-; wherein each (C1-C 10 )alkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C3-C 10 )cycloalkyl or (C2-C9)heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, HO-, halo or H2N-, also relates to a compound according to formula (XI).

[0358] The present invention further relates to a compound according to formula (XI) wherein R 5 is H and Y 2 is O.

[0359] The present invention further relates to a compound of formula (XII) [wherein, n is 1, 2 or 3; p is 0, 1 or 2; R and R 1 and R 2 are each independently selected from H, (C1-C 10 )alkyl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy- or NH2-; T 1is CR 10 ; T 2 is CR 10 ; T 3 is CR 10 ; Y 1 and Y 2 are each independently selected from O, S, NR 18 or CR 18 R 19 ; Z 1 are each independently selected from H, halo or (C1 - C 10 )alkyl; R 5 is selected from the group consisting of H, (C1 - C 10 )alkyl, HO-, halo and H2N- ; R 6 is H, (C1 - C 10 )alkyl, (C3 - C 10 )cycloalkyl, (C2 - C9)hetero cycloalkyl, (C6 - C 14 )aryl, (C2 - C9)heteroaryl, (C1 - C 10 )alkylamine, ((C1 - C 10 )alkyl)2amine, (C1 - C 10 )alkyl - C( O)O-, COOH-(C1 - C 10 )alkyl-, COOH-(C3 - C 10 )cycloalkyl-, (C1 - C 10 )alkoxy-, R 14 -(C1 - C 10 )alkyl-, R 14 -(C3 - C 10 )cycloalkyl, R 14 -(C2 - C9)heterocycloalkyl, R 14 -(C6 - C 14 )a ryl, R 14 -(C2 - C9)heteroaryl, R 14 -(C2 - C 10 )alkylnyl, R 14 -(C1 - C 10 )alkylamine, R14 -((C1 to C 10 )alkyl)2amine, R 14 -C (O)-selected from the group consisting of; wherein R 14 is, independently of each other, H, (C1 to C 10 )alkyl, (C3 to C 10 )cycloalkyl, (C2 to C9)heterocycloalkyl, (C6 to C 14 )aryl, (C2 to C9)he teroaryl, (C1 to C 10 )alkylamine, (C1 to C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, F2HC-selected from the group consisting of; wherein each (C1 to C 10 )alkyl, (C6 to C 14 )aryl, (C2 to C9)heteroaryl, (C3 to C 10 )cycloalkyl or (C2 to C9)heterocycloalkyl is ( C1 to C 10 )alkyl, (C3 to C 10 )cycloalkyl, (C2 to C9)heterocycloalkyl, (C6 to C 14 )aryl, (C2 to C9)heteroaryl, (C1 to C 10 )alkylamine, ((C1 to C 10 )alkyl)2amine, (C1 to C3)alkynylamine, (C1 to C 10 )alkyl-C(O)O-, COOH-(C1 to C 10 )alkyl, COOH-(C3 to C 10 )cycloalkyl, (C1 to C 10 )alkoxy-, (C1 to C 10 )alkoxy-(C1 to C 10 )alkyl-, (C3 to C 10 )cycloalkyl-O-, (C2 to C9)heterocycloalkyl-O-, (C6 to C 14 )aryl-O-, (C2 to C9)heteroaryl-O-, HO- , optionally further substituted by 1 to 4 groups selected from halo, H2N- also relates to compounds of

[0360] The present invention further relates to X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 also relates to compounds of formula (XII).

[0361] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 also relates to compounds of formula (XII).

[0362] The present invention further relates to X 2 is CR 7 ; X 3 is N; X 4 is CR 7 ; X 5 is CR 7 also relates to compounds of formula (XII).

[0363] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is N; X 5 is CR 7 also relates to compounds of formula (XII).

[0364] The present invention further relates to X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR​7 and; X 5 is also relates to the compound according to formula (XII), wherein X is N.

[0365] The present invention further relates to the compound according to formula (XII), wherein X is N; X 2 is N; X 3 is N; X 4 is CR 7 and; X 5 is CR 7 also relates to the compound according to formula (XII).

[0366] The present invention further relates to the compound according to formula (XII), wherein X is N; X 2 is N; X 3 is CR 7 and; X 4 is N; X 5 is CR 7 also relates to the compound according to formula (XII).

[0367] The present invention further relates to the compound according to formula (XII), wherein X is N; X 2 is N; X 3 is CR 7 and; X 4 is CR 7 and; X 5 is N, also relates to the compound according to formula (XII).

[0368] The present invention further relates to the compound according to formula (XII), wherein X is N; X 2 is N; X 3 is N; X 4 is CR 7 and; X 5 is N also relates to the compound according to formula (XII).

[0369] The present invention further relates to the compound according to formula (XII), wherein X is N; X 2 is N; X 3 is CR 7 and; X 4 is N; X 5 is N also relates to the compound according to formula (XII).

[0370] The present invention further relates to the compound according to formula (XII), wherein X is CR 2 is CR7 and X 3 is N; X 4 is N; X 5 is CR 7 The present invention also relates to a compound according to formula (XII).

[0371] The present invention further relates to X 2 is CR 7 and X 3 is N; X 4 is CR 7 and X 5 is N. The present invention also relates to a compound according to formula (XII).

[0372] The present invention further relates to X 2 is CR 7 and X 3 is CR 7 and X 4 is N; X 5 is N. The present invention also relates to a compound according to formula (XII).

[0373] The present invention further relates to a compound according to formula (XII) wherein n is 1.

[0374] The present invention further relates to R 1 and R 2 each being H. The present invention also relates to a compound according to formula (XII).

[0375] The present invention further relates to each R 10 being H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy or halo, and being selected from the group consisting of these. The present invention also relates to a compound according to formula (XII).

[0376] The present invention further relates to each R 10 being H. The present invention also relates to a compound according to formula (XII).

[0377] The present invention further relates to Y 1 being O; Y 2 ​is O, S, NR 18 or CR 18 R 19 and relates also to the compounds according to formula (XII).

[0378] The present invention further relates to compounds according to formula (XII) wherein Y 2 is O.

[0379] The present invention further relates to compounds according to formula (XII) wherein p is 1.

[0380] The present invention further relates to compounds according to formula (XII) wherein R 5 is H or (C1-C 10 )alkyl.

[0381] The present invention further relates to compounds according to formula (XII) wherein R 5 is H.

[0382] The present invention further relates to compounds according to formula (XII) wherein R 6 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl , (C2-C9)heteroaryl, R 14 -(C6-C 14 )aryl, R 14 -(C2-C9) heteroaryl and R 14 -(C1-C 10 )alkylamine; wherein R 14 is each independently selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)he teroaryl, (C1-C 10 )alkylamine, (C1-C 10 )alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, F2HC-; wherein each (C1-C10 ) Alkyl, (C6 - C 14 ) Aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) Cycloalkyl or (C2 - C9) heterocycloalkyl is optionally further substituted by 1 - 4 groups selected from ( C1 - C 10 ) Alkyl, (C3 - C 10 ) Cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) Aryl, (C2 - C9) heteroaryl, HO -, halo, H2N - and also relates to a compound according to formula (XII).

[0383] The present invention further provides that n is 1; p is 1; R 1 and R 2 are each H; R 10 is H, (C1 - C 10 ) Alkyl, (C3 - C 10 ) Cycloalkyl, (C1 - C 10 ) Al Oxy and halo and is selected from the group consisting of; Y 1 is O; Y 2 is O, S, NR 18 or CR 18 R 19 ; R 5 is H or (C1 - C 10 ) Alkyl; R 6 is H, (C1 - C 10 ) Alkyl, (C3 - C 10 ) Cycloalkyl, (C2 - C9) heteroaryl, R 14 -(C6 - C 14 ) Aryl, R 14 -(C2 - C9) heteroarylR 14 -(C1 - C 10 ) Alkylamine and is selected from the group consisting of; wherein R 14 are each independently H, (C1 - C 10 ) Alkyl, (C3 - C 10 ) Cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C14 ) aryl, (C2-C9) he teroaryl, (C1-C 10 ) alkylamine, (C1-C 10 ) alkoxy-, HO-, F2HC-O-, F3C-C(O)-, F3C-, F2HC- selected from the group consisting of; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from ( C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, HO-, halo, H2N-, and also relates to a compound according to formula (XII).

[0384] The present invention further relates to a compound according to formula (XII) wherein R 5 is H and Y 2 is O.

[0385] The present invention further relates to the following: 3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine, (S)-4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine, 6-methoxy-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-6-Methoxy-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (R)-6-Methoxy-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-((8-Methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-((1-methylazetidin-3-yl)oxy)-3H-imidazo[4,5-b]pyridine, 6-(Difluoromethyl)-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-6-(Difluoromethyl)-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (R)-6-(Difluoromethyl)-3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-((8-Methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-(((2R,3S)-8-Methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-(((2S,3R)-8-Methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-(((2S,3S)-8-Methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-(((2R,3R)-8-Methoxy-2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-((2-(6-(1,1-Difluoroethyl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (R)-3-((2-(6-(1,1-Difluoroethyl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-3-((2-(6-(1,1-Difluoroethyl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-((8-Methoxy-2-(6-(trifluoromethyl)pyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-3-((8-Methoxy-2-(6-(trifluoromethyl)pyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (R)-3-((8-Methoxy-2-(6-(trifluoromethyl)pyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, Azetidin-1-yl(3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanone, (S)-Azetidin-1-yl (3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanone, (S)-Azetidin-1-yl (3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanone, 3-((2-(6-Cyclopropylpyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-3-((2-(6-Cyclopropylpyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (R)-3-((2-(6-Cyclopropylpyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, 3-((8-Fluoro-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(2-methyl-1H-imidazol-1-yl)-3H-imidazo[4,5-b]pyridine, 3-((8-Methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(3-methoxyazetidin -1-yl)-3H-imidazo[4,5-b]pyridine 4-(3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine (R)-4-(3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine (R)-3-((8-Methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-((1-methylazetidin-3-yl)oxy)-3H-imidazo[4,5-b]pyridine (S)-3-((8-Methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-((1-methylazetidin-3-yl)oxy)-3H-imidazo[4,5-b]pyridine (R)-Azetidin-1-yl(3-((8-methoxy-2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methanone 3-((2-(6-(2-Fluoropropan-2-yl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, (S)-3-((2-(6-(2-Fluoropropan-2-yl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine, and (R)-3-((2-(6-(2-Fluoropropan-2-yl)pyridin-3-yl)-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine also relates to a compound according to formula (I) or formula (II) selected from:

[0386] The present invention further relates to formula (XIII): [wherein, [wherein, V 101 is C, N, O or S, r is 0, 1, 2, 3, 4 or 5; wherein when V 101 is C, r is 0, 1, 2, 3, 4 or 5, wherein when V 101 is N, r is 1 and R 102 is absent; wherein when V 101 is O, r is 1 and R 101 and R 102 are absent; wherein when V 101 is S, r is 1 and R 101 and 102 are absent; s is 1, 2, 3 or 4;

[0387] X 101 、X 102 、X 103 、X 104 and X 105 are each independently selected from N, NR 107 or CR 107 and each R is independently H, (C1-C 107 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 10 )aryl, (C2-C9)hetero aryl, (C2-C 14 )alkylnyl, (C1-C )alkylamine, ((C1-C 10 )alkyl)2amine, (C2-C 10 )alkynylamine, C(O)-, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl-, COOH-(C3-C 10 )cycloalkyl-, (C1-C 10 )alkoxy-, R 10 )cycloalkyl-, (C1-C 10 )alkoxy-, R 108-(C1~C 10 )alkyl-, R 108 -(C3~C 10 )cycloalkyl, R 108 -(C2~C9)heterocycloalkyl, R 108 -(C6~C 14 )aryl, R 108 -(C2~C9)heteroaryl, R 108 -(C2~C 10 )alkynyl, R 108 -(C1~C 10 )alkylamine, R 108 -((C1~C 10 )alkyl)2amine, R 108 -(C2~C 10 )alkynylamine, R 108 -C(O)-, R 108 -(C1~C 10 )alkyl-C(O)O-, R 108 -(C1~C 10 )alkoxy-, (C3~C 10 ) cycloalkyl-O-, (C2~C9)heterocycloalkyl-O-, (C6~C 14 )ari -yl-O-, (C2~C9)heteroaryl-O-, R 108 -(C3~C 10 )cycloalkyl-O-, R 108 -(C2~C9)heterocycloalkyl-O-, R 108 -(C6~C 14 )ari -yl-O-, R 108 -(C2~C9)heteroaryl-O-, HO-, halo, cyano, H2N-, (CH3)HN-, (CH3)2N-, R 108 R 109 N-, R 108 R 109 N(O)C-, R 108 (R 109 C(O))N-, R 108 R 109 NC(O)O-, R 108 C(O)-, R 108 R 109 NC(O)R 108 N-, (C1~C10 ) Alkyl-OC(O)R 108 N-, (C3-C 10 ) Cycloalkyl-OC(O)R 108 N-, (C2-C9) Heterocycloalkyl-OC(O)R 108 N-, (C6-C 14 ) Aryl-OC(O)R 108 N-, (C2-C9) Heteroaryl-OC(O)R 108 N-, F3C-, F2HC-, CH3F2C-, FH2C-, CH3FHC- , (CH3)2FC-; NC-, (C1-C 10 ) Alkyl(O)P-, (C1-C 10 ) Alkyl-S-, (C1-C 10 ) Alkyl-S-(C1-C 10 ) Alkyl-, (C3-C 10 ) Cycl oalkyl-S-, (C6-C 14 ) Aryl-S-, (C2-C9) Heteroalkyl-S- , (C2-C9) Heterocycloalkyl-S-, (C2-C9) Heteroaryl-S-, (C1-C 10 ) Alkyl-S(O)-, (C3-C 10 ) Cycloalkyl-S(O)-, (C6- C 14 ) Aryl-S(O)-, (C2-C9) Heterocycloalkyl-S(O)-, (C2 ~C9) Heteroaryl-S(O)-, (C3-C 10 ) Alkyl-S(O)2-, (C3-C 10 ) Cycloalkyl-S(O)2-, (C6-C 14 ) Aryl-S(O)2-, (C2-C9 ) Heterocycloalkyl-S(O)2-, (C2-C9) Heteroaryl-S(O)2-, R 108 R 109 NS(O)2-, (C1-C 10 ) Alkyl-S(O)2R 108 N-, (C3-C 10 ) Cycloalkyl-S(O)2R 108 N-, (C6-C 14)Aryl-S(O)2R 108 N-、 (C2-C9)heterocycloalkyl-SO2R 108 N-、and (C2-C9) heteroaryl-S(O)2R 108 selected from the group consisting of N-; wherein R 108 and R 109 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, ( C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) ari -yl-O-, (C2-C9) heteroaryl-O-, HO-, halo, (CH3)2N-, and H2N-; or R 108 and R 109 together form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; wherein each (C1-C 10 ) alkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C3-C 10 ) cycloalkyl or (C2-C9) heterocycloalkyl is ( C1-C 10 ) alkyl, (C3-C10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- , halo, or H2N-, and is optionally further substituted by 1 to 4 groups selected therefrom ;

[0388] T 101 、T 102 and T 103 are each independently selected from N or CR 110 ; provided that each R is independently H, (C1-C 110 ) alkyl, (C3-C 10 ) cyclo 10 alkyl, (C2-C9) heterocycloalkyl, (C6-C ) aryl, (C2-C9) he 14 ) heteroaryl, (C2-C ) alkylnyl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C2-C C 10 ) alkynylamine, C(O)-, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10) Alkyl-, COOH-(C3~C 10 ) Cycloalkyl-, (C1~C 10 ) Alkoxy-, R 110A -(C1~C 10 ) Alkyl-, R 110A -(C3~C 10 ) Cycloalkyl, R 110A -(C2~C9) Heterocycloalkyl 、R 110A -(C6~C 14 ) Aryl, R 110A -(C2~C9) Heteroaryl, R 110A -( C2~C 10 ) Alkylnyl, R 110A -(C1~C 10 ) Alkylamine, R 110A -((C1~ C 10 ) Alkyl)2amine, R 110A -(C2~C 10 ) Alkynylamine, R 110A -C(O)-, R 110A -(C1~C 10 ) Alkyl-C(O)O-, R 110A -(C1~C 10 ) Alkoxy-, (C3~C 10 ) Cycloalkyl-O-, (C2~C9) Heterocycloalkyl-O-, (C6~C 14 ) Aryl-O-, (C2~C9) Heteroaryl-O-, R 110A -(C3~C 10 ) Cycloalkyl-O-, R 110A -(C2~C9) Heterocycloalkyl-O-, R 110A -(C6~C 14 ) Aryl-O-, R 110A -(C2~C9) Heteroaryl-O-, HO- 、 Halo, Cyano, H2N-, (CH3)HN-, (CH3)2N-, R 110A R 111 N-, R 110A R 111 N(O)C-, R 110A (R 111 C(O))N-, R 110A R111 NC(O)O−, R 110A C(O)−, R 110A R 111 NC(O)R 110A N−, (C1 - C 10 ) alkyl - OC(O)R 110A N−, (C3 - C 10 ) cycloalkyl - OC(O)R 110A N−, (C2 - C9) hetero cycloalkyl - OC(O)R 110A N−, (C6 - C 14 ) aryl - OC(O)R 110A N−, (C2 - C9) heteroaryl - OC(O)R 110A N−, F3C−, F2HC−, CH3F2C−, FH2C−, CH3FHC−, (CH3)2FC−; NC−, (C1 - C 10 ) al kyl(O)P−, (C1 - C 10 ) alkyl - S−, (C1 - C 10 ) alkyl - S - (C1 - C 10 ) alkyl−, (C3 - C 10 ) cycloalkyl - S−, (C6 - C 14 ) aryl - S−, (C2 - C9) heteroalkyl - S−, (C2 - C9) heterocycloalkyl - S−, (C2 - C9) heteroaryl - S−, (C1 - C 10 ) alkyl - S(O)−, (C3 - C 10 ) cycloalkyl - S(O)−, (C6 - C 14 ) aryl - S(O)−, (C2 - C9) hetero cycloalkyl - S(O)−, (C2 - C9) heteroaryl - S(O)−, (C3 - C 10 ) alkyl - S(O)2−, (C3 - C 10 ) cycloalkyl - S(O)2−, (C6 - C 14 ) aryl - S(O)2−, (C2 - C9) heterocycloalkyl - S(O)2−, (C2 - C9) heteroaryl - S(O)2−, R 110A R 111 NS(O)2−, (C1 - C 10 ) alkyl - S(O)2R110A N-, (C3 - C 10 ) cycloalkyl - S(O)2R 110A N-, (C6 - C 14 ) aryl - S(O)2R 110A N-, (C2 - C9) heterocycloalkyl - SO2R 110A N-, or (C2 - C9) heteroaryl - S(O)2R 110A selected from the group consisting of N - ; wherein R 110A and R 111 are each independently H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2amine, (C1 - C3) alkynylamine, (C1 - C 10 ) alkyl - C(O)O -, COOH - (C1 - C 10 ) alkyl, COOH - (C3 - C 10 ) cycloalkyl, (C1 - C 10 ) alkoxy -, (C1 - C 10 ) alkoxy - (C1 - C 10 ) alkyl -, (C3 - C 10 ) cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O -, (C6 - C 14 ) ari - yl - O -, (C2 - C9) heteroaryl - O -, HO -, halo, (CH3)2N -, H2 N - selected from the group consisting of; or R 110A and R 111 together form a 3 - to 10 - membered cycloalkyl, heterocyclic alkyl, aryl or heteroaryl ring; wherein each (C1 - C 10 ) alkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C3 - C10 ) A cycloalkyl or (C2-C9) heterocycloalkyl is optionally further substituted by 1 to 4 groups selected from C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 ) alkyl, COOH-(C3-C 10 ) cycloalkyl, (C1-C 10 ) alkoxy-, (C1-C 10 ) alkoxy-(C1-C 10 ) alkyl-, (C3-C 10 ) cycloalkyl-O-, (C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, HO- , halo, H2N- and is optionally further substituted by

[0389] Y 101 is O, S, NR 112 or CR 112 R 113 and where R 112 is absent or R 112 and R 113 are each independently H, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl , (C6-C 14 ) aryl, (C2-C9) heteroaryl, (C1-C 10 ) alkylamine, ((C1-C 10 ) alkyl)2amine, (C1-C3) alkynylamine, (C1-C 10 ) alkyl-C(O)O-, COOH-(C1-C 10 )alkyl, COOH-(C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl -O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO- , halo, and H2N-; R 101 forms a carbonyl together with the carbon to which it is attached, and R 102 is absent, or R 101 and R 102 are each independently H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2 -C9)heterocycloalkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO-, halo, and H2N-, or R 101 and R 102 form a 3- to 10-membered ring together with the carbon to which they are attached; R 104 is H, (C1-C 10 )alkyl, (C3-C 10)Cycloalkyl, (C2-C9)he terocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl- , (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-,( C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO-, halo, and H2N- selected from the group consisting of, or R 104 and R 105 are, together with the carbon to which they are attached form a 3- to 10-membered ring; R 105 is absent, or H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl l, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)hetero aryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alkynylamine, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocyclo alkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO-, halo, and H2N- selected from the group consisting of;

[0390] R 106is H, (C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) hetero cycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C2 - C 10 ) alkylnyl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2amine , (C2 - C 10 ) alkynylamine, C(O)-, (C1 - C 10 ) alkyl - C(O)O-, COOH - (C1 - C 10 ) alkyl -, COOH - (C3 - C 10 ) cycloalkyl -, (C1 - C 10 ) alkoxy -, R 114 -(C1 - C 10 ) alkyl -, R 114 -(C3 - C 10 ) cy cloalkyl, R 114 -(C2 - C9) heterocycloalkyl, R 114 -(C6 - C 14 ) ari -yl, R 114 -(C2 - C9) heteroaryl, R 114 -(C2 - C 10 ) alkylnyl, R 114 -(C1 - C 10 ) alkylamine, R 114 -((C1 - C 10 ) alkyl)2amine, R 114 - (C2 - C 10 ) alkynylamine, R 114 -C(O)-, R 114 -(C1 - C 10 ) alkyl - C(O)O-, R 114 -(C1 - C 10 ) alkoxy -, (C3 - C 10 ) cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O-, (C6 - C 14 ) aryl - O-, (C2 - C9) heteroaryl - O-, R 114-(C3 to C 10 ) cycloalkyl - O -, R 114 -(C2 to C9) heterocycloalkyl - O -, R 114 -(C6 to C 14 ) aryl - O -, R 114 - (C2 to C9) heteroaryl - O -, HO -, halo, cyano, H2N -, (CH3)HN -, (CH3)2N -, R 114 R 115 N -, R 114 R 115 N(O)C -, R 114 (R 115 C(O))N -, R 114 R 115 NC(O)O -, R 114 C(O) -, R 114 R 115 NC(O)R 114 N -, (C1 to C 10 ) alkyl - OC(O)R 114 N -, (C3 to C 10 ) cycloalkyl - OC( O)R 114 N -, (C2 to C9) heterocycloalkyl - OC(O)R 114 N -, (C6 to C 14 ) aryl - OC(O)R 114 N -, (C2 to C9) heteroaryl - OC(O)R 114 N -,, F3C -, F2HC -, CH3F2C -, FH2C -, CH3FHC -, (CH3)2FC -; NC -, (C1 to C 10 ) alkyl(O)P -, (C1 to C 10 ) alkyl - S -, (C1 to C 10 ) alkyl - S - (C1 to C 10 ) alkyl -,, (C3 to C 10 ) cycloalkyl - S -,, (C6 to C 14 ) aryl - S -,, (C2 to C9) heteroalkyl - S -,, (C2 to C9) hete rocycloalkyl - S -,, (C2 to C9) heteroaryl - S -,, (C1 to C 10 ) alkyl -S(O) -,, (C3 to C 10)Cycloalkyl-S(O)-, (C6-C 14 )Aryl-S(O)-, (C2-C9) Heterocycloalkyl-S(O)-, (C2-C9) Heteroaryl-S(O)-, (C3-C 10 )Alkyl-S(O)2-, (C3-C 10 )Cycloalkyl -S(O)2-, (C6-C 14 )Aryl-S(O)2-, (C2-C9) Heterocycloalkyl -S(O)2-, (C2-C9) Heteroaryl-S(O)2-, R 114 R 115 NS(O)2-, (C1-C 10 )Alkyl-S(O)2R 114 N-, (C3-C 10 )Cycloalkyl-S (O)2R 114 N-, (C6-C 14 )Aryl-S(O)2R 114 N-, (C2-C9) Hetero Cycloalkyl-SO2R 114 N-, and (C2-C9) Heteroaryl-S(O)2R 114 N- selected from the group consisting of; wherein, R 114 and R 115 are each independently, H, (C1-C 10 )Alkyl, (C3-C 10 )Cycloalkyl, (C2-C9) Heterocycloalkyl, (C6-C 14 )Aryl, ( C2-C9) Heteroaryl, (C1-C 10 )Alkylamine, ((C1-C 10 )Alkyl)2amine, (C1-C3) Alkynylamine, (C1-C 10 )Alkyl-C(O)O-, COOH-(C1-C 10 )Alkyl, COOH-(C3-C 10 )Cycloalkyl, (C1-C 10 )Alkoxy-, (C1-C 10 )Alkoxy-(C1-C 10 )Alkyl-, (C3-C 10) Cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O -, (C6 - C 14 ) aryl - O -, (C2 - C9) heteroaryl - O -, HO -, F2HC - O -, halo, (C H3)2N -, H2N -, F3C - C(O) -, F3C -, and F2HC - are selected from the group consisting of; or R 114 and R 115 together form a 3 - to 10 - membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring; wherein each (C1 - C 10 ) alkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C3 - C 10 ) cycloalkyl or (C2 - C9) heterocycloalkyl is ( C1 - C 10 ) alkyl, (C3 - C 10 ) cycloalkyl, (C2 - C9) heterocycloalkyl, (C6 - C 14 ) aryl, (C2 - C9) heteroaryl, (C1 - C 10 ) alkylamine, ((C1 - C 10 ) alkyl)2amine, (C1 - C3) alkynylamine, (C1 - C 10 ) alkyl - C(O)O -, COOH - (C1 - C 10 ) alkyl, COOH - (C3 - C 10 ) cycloalkyl, (C1 - C 10 ) alkoxy -, (C1 - C 10 ) alkoxy - (C1 - C 10 ) alkyl -, (C3 - C 10 ) cycloalkyl - O -, (C2 - C9) heterocycloalkyl - O -, (C6 - C 14 ) aryl - O -, (C2 - C9) heteroaryl - O -, HO - , halo, or H2N - and is optionally further substituted by 1 to 4 groups selected from; ;

[0391] R103 is N or CR 116 and where R 116 is selected from the group consisting of H, (C1-C 10 )alkyl, (C3-C 10 )cycloalkyl, (C2-C9)heterocycloalkyl, (C6-C 14 )aryl, (C2-C9)heteroaryl, (C1-C 10 )alkylamine, ((C1-C 10 )alkyl)2amine, (C1-C3)alk ynylamine, (C1-C 10 )alkyl-C(O)O-, COOH-(C1-C 10 )alkyl, COOH-(C3-C 10 )cycloalkyl, (C1-C 10 )alkoxy-, (C1-C 10 )alkoxy-(C1-C 10 )alkyl-, (C3-C 10 )cycloalkyl-O-, (C2-C9)heterocycloalkyl-O-, (C6-C 14 )aryl-O-, (C2-C9)heteroaryl-O-, HO-, halo, and H2N-, or when s is 1, R 116 and R 104 together with the carbon to which they are attached form formula (XIV):

Chemical formula

[0392] The present invention further provides that X 1 is N; X 2 is N; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C and / or X 3 is CH; X 4 is CR 7 ; X 5 is CH; X 7 also relates to a compound according to formula (XIII) or formula (XIV) wherein is CH.

[0393] The present invention further relates to X 1 is N; X 2 is CR 7 ; X 3 is CR 7 ; X 4 is CR 7 ; X 5 is CR 7 ; X 6 is N; X 7 is CR 7 ; X 8 is C; X 9 is C; and / or X 2 is CH; X 3 is CH; X 4 is CR 7 ; X 5 is CH; X 7 also relates to a compound according to formula (XIII) or formula (XIV) wherein is CH.

[0394] A method of treating a disease or disorder mediated by colony stimulating factor-1 receptor (CSF-1R), or a disease or disorder in which CSF-1R is involved in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to formula (I) or formula (II).

[0395] A method for treating a disease or disorder, comprising administering to a subject an effective amount of a compound according to formula (I) or formula (II), wherein the disease or disorder is a neurological disease and an immune-mediated disease including multiple sclerosis, ALS, Huntington's disease, lupus, lupus nephritis and rheumatoid arthritis in a subject in need of such treatment.

[0396] A pharmaceutical composition comprising a compound of formula (I) or formula (II).

Mode for Carrying Out the Invention

[0397] The present invention relates to a colony stimulating factor-1 receptor inhibitor (“CSF-1R inhibitor”). The CSF-1R inhibitor of the present invention is a small molecule capable of passing through the blood-brain barrier and reaching the central nervous system (CNS). The present invention also relates to a pharmaceutical preparation comprising a CSF-1R inhibitor, and to the use of a CSF-1R inhibitor and a pharmaceutical composition comprising a CSF-1R inhibitor for treating a disease. The present invention further relates to the use of a CSF-1R inhibitor and a pharmaceutical composition comprising a CSF-1R inhibitor for treating immune-mediated diseases (including but not limited to multiple sclerosis, lupus nephritis, rheumatoid arthritis), and for treating neurological diseases (including but not limited to amyotrophic lateral sclerosis (ALS) and Huntington's disease). The CSF-1R inhibitor of the present invention can be used to inhibit c-FMS, the cellular receptor for colony stimulating factor-1 (CSF-1).

[0398] Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the CNS that causes intermittent relapses and progressive neurological deterioration. Activated microglial cells and macrophages contribute to CNS damage and play an important role in disease progression and neurodegeneration in multiple sclerosis. These activated innate immune cells are involved in antigen presentation and can generate inflammatory and neurotoxic mediators that are harmful to neurons and oligodendrocytes. CSF-1R is a receptor tyrosine kinase expressed in macrophages, monocytes and microglial cells and is one of the promising targets for the therapeutic modulation of effector functions.

[0399] The CSF-1R inhibitor of the present invention is particularly useful for the treatment of multiple sclerosis, and in in vitro and in vivo preclinical medical research, it has shown a reduction in the production of inflammatory cytokines / chemokines and nitric oxide, inhibition of the proliferation and activation of macrophages / microglial cells, preservation of the phagocytic activity of macrophages and microglial cells, inhibition of CNS infiltration in multiple in vivo disease models, protection from demyelination in rat brain slice cultures, and therapeutic benefit in mouse disease models. What these data suggest is that inhibiting CNS macrophage / microglial effector functions through CSF-1R antagonism results in neuroprotection in multiple sclerosis by reducing inflammation, demyelination, and axonal loss.

[0400] In one embodiment, the present invention relates to a pharmaceutical composition comprising a CSF-1R inhibitor according to formula (I) and formula (II). In another embodiment of the present invention, the pharmaceutical composition comprising a CSF-1R inhibitor according to formula (I) and formula (II) is administered in an effective amount to achieve the desired therapeutic effect. A person skilled in the art can determine the effective amount of the pharmaceutical composition comprising a CSF-1R inhibitor according to formula (I) and formula (II) according to the individual and symptoms to be treated.

[0401] In one embodiment of the present invention, the CSF-1R inhibitor and the pharmaceutical composition comprising the CSF-1R inhibitor can be used for the treatment of immune-mediated diseases. In another embodiment of the present invention, the CSF-1R inhibitor and the pharmaceutical composition comprising the CSF-1R inhibitor can be used for the treatment of multiple sclerosis. In yet another embodiment of the present invention, the CSF-1R inhibitor and the pharmaceutical composition comprising the CSF-1R inhibitor can be used for the treatment of lupus nephritis.

[0402] In one embodiment of the present invention, a CSF-1R inhibitor and a pharmaceutical composition containing the CSF-1R inhibitor can be used for the treatment of neurological diseases. In another embodiment of the present invention, a CSF-1R inhibitor and a pharmaceutical composition containing the CSF-1R inhibitor can be used for the treatment of ALS.

[0403] In one embodiment of the present invention, a CSF-1R inhibitor and a pharmaceutical composition containing the CSF-1R inhibitor can be used for the inhibition of c-FMS, a cell receptor for colony-stimulating factor-1 (CSF-1).

[0404] The CSF-1R inhibitor of the present invention is administered alone or in a pharmaceutical composition containing one or more CSF-1R inhibitors. Suitable pharmaceutical compositions can contain a CSF-1R inhibitor and one or more pharmaceutically acceptable excipients. The form in which the CSF-1R inhibitor is administered, such as a powder, tablet, capsule, solution, suspension or emulsion, depends to some extent on the route by which it is administered. The CSF-1R inhibitor is administered, for example, orally or by injection. Suitable excipients include, but are not limited to, inorganic or organic materials such as gelatin, albumin, lactose, starch, stabilizers, solubilizers, emulsifiers, salts and buffers. Pharmaceutically acceptable excipients suitable for intra-articular formulations such as solutions or suspensions include, but are not limited to, commercially available inert gels or liquids.

[0405] The CSF-1R inhibitor and the pharmaceutical composition containing the CSF-1R inhibitor can be administered alone or in combination with one or more additional drugs. The additional drugs administered in combination with the CSF-1R inhibitor and the pharmaceutical composition containing the CSF-1R inhibitor of the present invention include therapies for the treatment of immune-mediated diseases and neurological diseases including multiple sclerosis, lupus nephritis and ALS. The additional drugs can be administered simultaneously with the CSF-1R inhibitor and the pharmaceutical composition containing the CSF-1R inhibitor. The additional drugs can also be administered in a series with the CSF-1R inhibitor and the pharmaceutical composition containing the CSF-1R inhibitor.

[0406] The in vitro and in vivo effects of the CSF-1R inhibitor and the preparation method of the preferred CSF-1R inhibitor of the present invention are described in the examples.

[0407] Specific embodiments of the present disclosure are described herein with reference to preparation methods and schemes, but such embodiments are merely illustrative and it should be understood that they merely exemplify a minority of the many possible specific embodiments that can represent the application of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art who benefit from the present disclosure, and are considered to be included within the spirit and scope of the present disclosure further defined within the scope of the appended claims and are considered to be included within the spirit and scope of the present disclosure.

[0408] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. Specific preferred methods are described herein in connection with the following preparation methods and schemes, but other compounds or methods can also be used in practice or testing.

[0409] Scheme 1: Preparation method A

Chemical formula

[0410] In reaction 1 of preparation method A, T 1 、T2 and T 3 is as defined above; G 1 is -CN, -CO2Me, -CONH2 or -CH2NHBOC, G 2 is -F, -I or -OBn; or G 1 is Br, B 2 is -Br or -OPMB Compound A-1 is converted to the corresponding compound A-2, which is done by reacting A-1 with an alpha-haloketone such as bromoketone R 6 (CO)CH(Br)(Z 1 ) etc. in the presence of a base such as cesium carbonate in a polar aprotic solvent such as acetonitrile at room temperature for 1 to 24 hours.

[0411] In reaction 2 of Preparation Method A, G 1 is -CN or -CONH2, G 2 is -F or -I; or G 1 is -Br, G 2 Compound A-2 where G is -Br or -OPMB is converted to compound A-3, which is done by reducing the ketone of A-2 with a reducing agent such as sodium borohydride in a suitable solvent or solvent mixture such as methanol or methanol / tetrahydrofuran at 0 °C for 1 hour.

[0412] In reaction 3 of Preparation Method A, G 1 is -CN, G 2 is -F, compound A-3 is converted to compound A-5, which is done by cyclizing A-3 in a polar aprotic solvent such as dimethylformamide in the presence of a base such as potassium carbonate at 80 °C for 24 hours. Alternatively, in reaction 3 of Preparation Method A, G 1 is -Br, G 2Compound A-3, where X is -Br, is converted to compound A-5 by refluxing A-3 in a polar aprotic solvent such as dimethylformamide for 48 hours in the presence of a catalyst such as copper(I) iodide, a base such as cesium carbonate, and a diamine ligand such as N,N-dimethylethylenediamine. Alternatively, in reaction 3 of Preparation Method A, when G 1 is -CONH2 and G 2 is -I Compound A-3 is converted to compound A-5 by cyclizing A-3 in a polar aprotic solvent such as dimethylformamide at 80 °C for 2 hours in the presence of a catalyst such as copper(I) iodide and a base such as sodium hydride.

[0413] In reaction 4 of Preparation Method A, when G 1 Compound A-5, where X is -CN or -CONH2, is converted to compound A-6 by reducing A-4 in an ethereal solvent such as tetrahydrofuran by refluxing for 1 to 16 hours in the presence of a reducing agent such as borane-tetrahydrofuran complex, or by starting at 0 °C in an ethereal solvent such as tetrahydrofuran in the presence of a reducing agent such as lithium aluminum hydride and warming to room temperature over 1 to 5 hours for reduction. Alternatively, in reaction 4 of Preparation Method A, when G 1 Compound A-5, where X is -CH2NHBOC, is converted to compound A-6 by deprotecting A-5 in a halogenated solvent such as dichloromethane at room temperature for 1 hour in the presence of an acid such as trifluoroacetic acid. Alternatively, in reaction 4 of Preparation Method A, when G 1Compound A-5, where [G] is -CO2Me, is converted to compound A-6. This is achieved by, first, reducing A-4 with a reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at 0 °C for 1 hour, starting from 0 °C. Second, converting it to an azide by reacting with a phosphoryl azide such as diphenylphosphoryl azide and a base such as 1,8-diazabicycloundec-7-ene in an ethereal solvent such as tetrahydrofuran, reacting at room temperature to reflux for 1 to 16 hours. Third, reducing it with a phosphine such as resin-bound triphenylphosphine in an aqueous solvent mixture such as a tetrahydrofuran / water mixture at reflux for 1 to 3 hours.

[0414] In reaction 5 of Preparation Method A, G 1 is -CO2Me or -CH2NHBOC, and compound A-2, where G 2 is -OBn, is converted to compound A-4. This is done by, first, deprotecting with a solid-supported catalyst such as palladium on carbon in the presence of hydrogen under hydrogenation conditions in an ethereal solvent such as tetrahydrofuran at room temperature for 1 to 5 hours. Second, reducing with a reducing agent such as sodium borohydride in a solvent mixture such as a tetrahydrofuran / methanol mixture at 0 °C for 30 minutes. Alternatively, in reaction 5 of Preparation Method A, G 1 is -Br, and compound A-2, where G 2 is -OPMB, is converted to compound A-4. This is achieved by, first, deprotecting with an acid such as trifluoroacetic acid in a halogenated solvent such as dichloromethane at room temperature for 1 to 5 hours. Second, reducing with a reducing agent such as sodium borohydride in a solvent mixture such as a tetrahydrofuran / methanol mixture at 0 °C for 30 minutes.

[0415] In Reaction 6 of Preparation Method A, compound A-4 is converted to compound A-5, which is achieved by reacting with a phosphine such as triphenylphosphine bonded to a resin, a carbon tetrahalide such as carbon tetrachloride, and a base such as triethylamine in a polar aprotic solvent such as acetonitrile under reflux for 1 to 15 hours. Alternatively, in Reaction 6 of Preparation Method A, compound A-4 is converted to compound A-5, which is achieved by reacting with a phosphine such as triphenylphosphine and an azodicarboxylate such as bis(2-methoxyethyl) azodicarboxylate in an ether solvent such as tetrahydrofuran over a period of 3 to 20 hours from room temperature to reflux.

[0416] In Reaction 7 of Preparation Method A, T 1 、T 2 and T 3 are as defined above, G 1 is -CO2Me, and compound A-1 where G 2 is -OBn is converted to compound A-7, which is achieved by reacting A-1 with an alkylating reagent such as p-methoxy-benzyl chloride in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile under reflux for 20 hours.

[0417] In Reaction 8 of Preparation Method A, compound A-7 is converted to compound A-8, which is achieved by first reacting A-7 with a base such as lithium hydroxide in an aqueous solvent mixture such as a tetrahydrofuran / water mixture at room temperature for 45 minutes, second reacting with an amine or amine salt, such as ammonium chloride, an amide coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, and a base such as triethylamine in a polar aprotic solvent such as dimethylformamide at 50 °C for 20 hours, and third reducing in the presence of a reducing agent such as lithium aluminum hydride in an ether solvent such as tetrahydrofuran starting from 0 °C to reflux over 20 hours.

[0418] In Reaction 9 of Preparation Method A, G 1Convert compound A-5, where G is -Br, to compound A-9 , which is achieved by reacting A-5 with an organoboron compound such as 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) in an ethereal solvent such as 1,4-dioxane under reflux for 2 hours in the presence of a catalyst such as (1,1’-bis(diphenylphosphino)ferrocene)palladium(II) chloride and a base such as potassium acetate.

[0419] In reaction 10 of Preparation Method A, convert compound A-9 to compound A-10, which is achieved by reacting A-9 with an oxidizing agent such as sodium periodate in an acidic aqueous solvent mixture such as a tetrahydrofuran / water / hydrochloric acid mixture at room temperature for 16 hours.

[0420] In reaction 11 of Preparation Method A, convert compound A-5, where G is an ester, for example -CO2Me, to compound A-11, which is achieved by hydrolyzing A-5 with a base such as lithium hydroxide in an aqueous alcohol mixture such as a methanol / water mixture at room temperature for 16 hours. 1

[0421] In reaction 12 of Preparation Method A, convert compound A-11 to compound A-12, which is achieved by first reacting A-11 with a chlorinating reagent such as oxalyl chloride in the presence of a catalyst such as dimethylformamide in a halogenated solvent such as dichloromethane at room temperature for 1.5 hours, second reacting with a diazoalkane such as (trimethylsilyl)diazomethane in an aprotic solvent or solvent mixture such as a tetrahydrofuran / acetonitrile mixture from 0 °C to room temperature over 19 hours, and third reacting with an acid such as 48% aqueous hydrobromic acid in an aprotic solvent or solvent mixture such as a tetrahydrofuran / acetonitrile mixture at 0 °C for 10 minutes.

[0422] In reaction 13 of Preparation Method A, convert compound A-1, where G 1 is Br and G 2 is NH2, to compound A-13, which is achieved by reacting A-1 with R 1 where G is Br and G 2 is NH2, convert compound A-1 to compound A-13, which is achieved by reacting A-1 with R compound A-13, which is achieved by reacting A-1 with R6 CO2H(R 6 is as defined above ), etc. of carboxylic acid, an amide coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, and a base such as triethylamine are reacted at room temperature for 3 hours in a polar aprotic solvent such as dimethylformamide.

[0423] In Reaction 14 of Preparation Method A, Compound A-13 is converted to Compound A-14, which is achieved by reacting A-13 with a dicarboxylate such as diethyl azodicarboxylate and a phosphine such as triphenylphosphine in an aprotic solvent such as tetrahydrofuran at room temperature for 16 hours.

[0424] In Reaction 15 of Preparation Method A, Compound A-14 is converted to Compound A-15, which is achieved by reacting A-14 with a cyanide salt such as zinc(II) cyanide, a catalyst such as tris(dibenzylideneacetone)dipalladium, and a ligand such as 1,1'-bis(diphenylphosphino)ferrocene in a polar aprotic solvent such as dimethyl sulfoxide at 100 °C for 3 hours.

[0425] In Reaction 16 of Preparation Method A, Compound A-15 is converted to Compound A-16, which is achieved by reacting A-15 with a reducing agent such as Raney nickel in an alcohol such as methanol in the presence of ammonia and hydrogen at room temperature for 2 hours.

[0426] Scheme 2: Preparation Method B

Chemical Structure

[0427] In Reaction 1 of Preparation Method B, T 1 , T 2 and T 3 are as defined above, and G 3Compound B-1, which is -CH3, is converted to the corresponding compound B-2, which is done by reacting B-1 with a carbonyl compound such as aldehyde R 6 (CHO)(R 6 (as defined above) etc. in an aqueous alcohol mixture such as an ethanol / water mixture in the presence of a base such as potassium hydride at room temperature for 16 hours.

[0428] In reaction 2 of Preparation Method B, compound B-2 is converted to compound B-3, which is done by cyclizing compound B-2 in an aqueous alcohol mixture such as an ethanol / water mixture in the presence of a base such as sodium acetate under reflux for 17 hours.

[0429] In reaction 3 of Preparation Method B, compound B-3 is converted to compound B-4, which is done by reacting the ketone of compound B-3 with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at 65 °C for 20 hours.

[0430] In Reaction 4 of Preparation Method B, compound B-4 is converted to compound B-7, which is first reacted under reflux in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture with an organoborane such as potassium vinyltrifluoroborate, a catalyst such as palladium(II) chloride, a phosphine such as triphenylphosphine, and a base such as cesium carbonate. Second, it is reacted at room temperature for 1 hour in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture with an oxidation reagent system such as osmium tetroxide and sodium periodate. Third, it is reacted under reflux for 2 hours in an alcohol solvent such as methanol with an amine or amine salt, for example hydroxylamine hydrochloride, and a base such as sodium acetate. Fourth, it is reacted with a reducing agent such as zinc powder in an acid such as acetic acid at 40 °C for 2 hours. Alternatively, in Reaction 4 of Preparation Method B, compound B-4 is converted to compound B-7, which is first reacted with a cyanation reagent such as potassium hexacyanoferulate(II) trihydrate, a catalyst such as palladium(II) acetate, a base such as cesium carbonate, and a polar solvent or solvent mixture, for example an N-methyl-2-pyrrolidone / isopropanol mixture, from room temperature to 140 °C over 16 hours. Second, it is reduced at room temperature for 20 hours in an acidic aqueous alcohol mixture such as methanol and concentrated HCl in the presence of hydrogen using a solid supported catalyst such as palladium on carbon (10%).

[0431] In Reaction 5 of Preparation Method B, T 1 , T 2 and T 3 and Z 1 are as defined above, and compound B-1 in which G 3 is -H is converted to the corresponding compound B-5, which involves reacting B-1 with a carbonyl compound such as ketone R 6 (CO)CH3 (where R 6 is as described above) in an alcohol such as ethanol under reflux for 3 hours in the presence of a base such as 10 N sodium hydroxide.

[0432] ​In Reaction 6 of Preparation Method B, compound B-5 is converted to compound B-6, which is achieved by reacting B-5 first with a reducing reagent system such as zinc chloride and ammonium chloride at room temperature for 10 minutes in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture, and then reducing the carbonyl moiety with a reducing agent such as sodium borohydride in an alcohol such as methanol at 0 °C for 15 minutes. Alternatively, in Reaction 6 of Preparation Method B, compound B-5 is converted to compound B-6, which is achieved by reacting B-5 with a reducing reagent system such as cobalt(II) chloride and sodium borohydride in an ethereal solvent such as tetrahydrofuran at a temperature ranging from 0 °C to room temperature over 2 hours.

[0433] In Reaction 7 of Preparation Method B, compound B-6 is converted to compound B-7, which is achieved by cyclizing B-6 with an acid such as glacial acetic acid at 110 °C for 45 minutes. Alternatively, in Reaction 7 of Preparation Method B, compound B-6 is converted to compound B-7, which is achieved by cyclizing B-6 with a phosphine such as triphenylphosphine and an azodicarboxylate such as bis(2-methoxyethyl) azodicarboxylate in an ethereal solvent such as tetrahydrofuran over a period of 3 to 20 hours from room temperature to reflux.

[0434] In Reaction 8 of Preparation Method B, compound B-4 is converted to compound B-8, which is achieved by reacting B-4 with an organoborane compound such as (CH2CH)BF3K in the presence of a catalyst such as palladium(II) chloride, a phosphine such as triphenylphosphine, and a base such as cesium carbonate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture under reflux for 16 hours.

[0435] In Reaction 9 of Preparation Method B, compound B-8 is converted to compound B-9, which is achieved by oxidizing B-8 with an oxidizing reagent system such as osmium tetroxide and sodium periodate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at room temperature for 1 hour. by this.

[0436] In Reaction 10 of Preparation Method B, Compound B-9 is converted to Compound B-10, which is achieved by reacting B-9 with a reducing agent such as sodium borohydride in an alcohol such as methanol at 0 °C for 1 hour.

[0437] In Reaction 11 of Preparation Method B, Compound B-10 is converted to Compound B-11, which is achieved by reacting B-10 with a carbon tetrahalide such as carbon tetrabromide in an ethereal solvent such as tetrahydrofuran under reflux for 2 hours in the presence of a phosphine such as resin-bound triphenylphosphine.

[0438] In Reaction 12 of Preparation Method B, Compound B-4 is converted to Compound B-12, which is achieved by reacting B-4 with an organolithium reagent such as n-butyllithium and an organoborate such as tri-isopropoxyborane in an ethereal solvent such as tetrahydrofuran at a temperature ranging from -78 °C to room temperature over 30 minutes.

[0439] In Reaction 13 of Preparation Method B, Compound B-4 is converted to Compound B-13, which is achieved by reacting B-4 with an organoborane compound such as 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-oxaborolane) in an ethereal solvent such as 1,4-dioxane under reflux for 2 hours in the presence of a catalyst such as (1,1’-bis(diphenylphosphino)ferrocene)palladium(II) chloride and a base such as potassium acetate.

[0440] In Reaction 14 of Preparation Method B, Compound B-13 is converted to Compound B-12, which is achieved by reacting B-13 with an oxidizing reagent such as sodium periodate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at room temperature for 16 hours.

[0441] Scheme 3: Preparation Method C

Chemical Structure

[0442] In Reaction 1 of Preparation Method C, T1 , T 2 and T 3 are the compound C as defined above -1 is converted to the corresponding compound C-2, which is obtained by reacting C-1 with an alpha-haloester such as bromoester CH3O(C O)CH(Br)(R 6 )(R 6 is as defined above) etc. in an aprotic solvent such as acetone in the presence of a base such as potassium carbonate by refluxing for 16 hours.

[0443] In reaction 2 of Preparation Method C, compound C-2 is converted to compound C-3 (R 17 is as defined above ), which is obtained by reacting C-2 with an alkylating agent such as methyl iodide (for example, R 17 is methyl) etc. in an aprotic solvent such as acetone in the presence of a base such as potassium hydroxide by refluxing for 45 minutes.

[0444] In reaction 3 of Preparation Method C, compound C-3 is converted to compound C-4, which is obtained by reacting C-3 with a reducing agent such as borane-methyl sulfide complex in an ethereal solvent such as tetrahydrofuran at 50 °C for 16 hours.

[0445] In reaction 4 of Preparation Method C, compound C-4 is converted to compound C-5, which is obtained by reacting C-4 with a cyanide salt such as zinc(II) cyanide and tetrakis(triphenylphosphine)palladium(0) in a polar aprotic solvent such as diphenylformamide at 80 °C for 16 hours.

[0446] In reaction 5 of Preparation Method C, compound C-5 is converted to compound C-6, which is obtained by reacting C-5 with a reducing agent system such as nickel(II) chloride hexahydrate, sodium borohydride, and di-t-butyl dicarboxylate in an alcohol such as methanol at 0 °C to room temperature for 4 hours.

[0447] In Reaction 6 of Preparation Method C, compound C-6 is converted to compound C-7, which is achieved by reacting C-6 with an acid such as 4N hydrogen chloride in 1,4-dioxane at room temperature for 1 hour in a halogenated solvent such as dichloromethane.

[0448] Scheme 4: Preparation Method D

Chemical Structure

[0449] In Reaction 1 of Preparation Method C, T 1 , T 3 , R 3 and -R 10 are as defined above , for example, -R 10 is a compound that is -H, halo, cyano or (C1~C 10 ) alkoxy-. Compound D-1 is converted to compound D-2, which is achieved by reacting D-1 with an alkyl chloride (R )(R 4 )(R 5 )(R 6 )CCl(R 4 , R 5 and R 6 are as defined above) in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile at reflux for 23 hours.

[0450] In Reaction 2 of Preparation Method C, compound D-2 is converted to compound D-3, which is achieved by deprotecting D-2 with an acid such as trifluoroacetic acid in a halogenated solvent such as dichloromethane at room temperature for 30 minutes.

[0451] Scheme 5: Preparation Method E

Chemical Structure

[0452] In Reaction 1 of Preparation Method E, T 1 and T 2Compound E-1, as defined above, is converted to R 10 Compound E, which is as defined above and is, for example, (C1-C 10 ) alkoxy-, is converted to E-2 by reacting E-1 with an alkyl iodide (C1-C ) in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile under reflux for 16 hours. 10 This is achieved by reacting E-1 with an alkyl iodide (C1-C ) in the presence of a base such as potassium carbonate in a polar aprotic solvent such as acetonitrile under reflux for 16 hours.

[0453] In Reaction 2 of Preparation Method E, Compound E-2, where R 10 is as defined above, for example -H, halo, cyano or (C1-C 10 ) alkoxy-, is converted to Compound E-3 by reacting E-2 with an alcohol (R )(R 4 )(R 5 )(R 6 )COH (where R 4 , R 5 and R 6 are as defined above) in the presence of a base such as sodium hydride in a polar aprotic solvent such as dimethyl sulfoxide at room temperature for 2 hours.

[0454] In Reaction 3 of Preparation Method E, Compound E-3 is converted to Compound E-4 by first reacting E-3 with an organoboron compound such as potassium trifluoroborate (N-Boc-aminoethyl), a catalyst such as 2nd Gen XPhos precatalyst, a base such as cesium carbonate in a biphasic solvent system such as a toluene / water mixture under reflux for 20 hours, and then deprotecting with an acid such as trifluoroacetic acid in a halogenated solvent such as dichloromethane at room temperature for 30 minutes.

[0455] In Reaction 4 of Preparation Method E, Compound E-3 is converted to Compound E-5 by reacting E-3 with an organoboron compound such as potassium vinyltrifluoroborate in the presence of a catalyst such as palladium(II) chloride, a phosphine such as triphenylphosphine, and a base such as cesium carbonate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture under reflux for 16 hours.

[0456] In Reaction 5 of Preparation Method E, Compound E-5 is converted to Compound E-6, which is achieved by reacting E-5 with an oxidizing agent system such as osmium tetroxide and sodium periodate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at room temperature for 1 hour.

[0457] In Reaction 6 of Preparation Method E, Compound E-6 is converted to Compound E-7, which is achieved by reacting E-6 with a reducing agent such as sodium borohydride in an alcohol such as methanol at 0 °C for 1 hour.

[0458] In Reaction 7 of Preparation Method E, Compound E-7 is converted to Compound E-8, which is achieved by reacting E-7 with a carbon tetrahalide such as carbon tetrabromide in the presence of a phosphine such as resin-bound triphenylphosphine in an ethereal solvent such as tetrahydrofuran under reflux for 2 hours.

[0459] In Reaction 8 of Preparation Method E, Compound E-3 is converted to Compound E-9, which is achieved by reacting E-3 with an organolithium reagent such as n-butyllithium and an organoborate such as tri-isopropoxyborate in an ethereal solvent such as tetrahydrofuran from -78 °C to room temperature over 30 minutes.

[0460] In Reaction 9 of Preparation Method E, Compound E-3 is converted to Compound E-10, which is achieved by reacting E-3 with an organoboron compound such as 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) in the presence of a catalyst such as (1,1’-bis(diphenylphosphino)ferrocene)palladium(II) chloride and a base such as potassium acetate in an ethereal solvent such as 1,4-dioxane under reflux for 2 hours.

[0461] In Reaction 10 of Preparation Method E, Compound E-10 is converted to Compound E-9, which is achieved by reacting E-10 with an oxidizing agent such as sodium periodate in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at room temperature for 16 hours.

[0462] Scheme 6: Preparation Method F

Chemical Structure

[0463] In Reaction 1 of Preparation Method F, T 1 , T 2 and T 3 are as defined above. Compound F -1 is converted to Compound F-2, which is achieved by reacting F-1 with an alpha-haloketone such as bromoketone R 6 (CO)CH2Br (R 6 is as defined above) and a base such as potassium carbonate in a polar aprotic solvent such as dimethylformamide at a temperature ranging from 0 °C to room temperature over 1.5 hours.

[0464] In Reaction 2 of Preparation Method F, Compound F-2 is converted to Compound F-3, which is achieved by reacting F-2 with a reducing agent such as sodium borohydride in an alcohol such as methanol at 0 °C for 1 hour.

[0465] In Reaction 3 of Preparation Method F, Compound F-3 is converted to Compound F-4, which is achieved by reacting F-3 with a cyanide salt such as zinc(II) cyanide and a catalyst such as tetrakis(triphenylphosphine)palladium(0) in a polar aprotic solvent such as dimethylformamide at 90 °C for 4 hours.

[0466] In Reaction 4 of Preparation Method F, Compound F-4 is converted to Compound F-5, which is achieved by cyclizing F-4 in a polar aprotic solvent such as dimethylformamide in the presence of a base such as potassium carbonate at 80 °C for 24 hours.

[0467] In Reaction 5 of Preparation Method F, compound F-5 is converted to compound F-6, which is achieved by reacting F-5 with a reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at 0 °C for 1 hour.

[0468] In Reaction 6 of Preparation Method F, compound F-6 is converted to compound F-7, which is achieved by reacting F-6 with a reducing agent such as sodium borohydride in an alcohol such as methanol at 0 °C for 1 hour.

[0469] In Reaction 7 of Preparation Method F, compound F-7 is converted to compound F-8, which is achieved by reacting F-7 with a carbon tetrahalide such as carbon tetrabromide in the presence of a phosphine such as resin-bound triphenylphosphine in an ethereal solvent such as tetrahydrofuran under reflux for 2 hours.

[0470] Scheme 7: Preparation Method G [Chemical Formula]

[0471] In Reaction 1 of Preparation Method G, compound A-5, where T 1 , T 2 , T 3 , R 6 and Z 1 are as defined above, and compound A-5 where G is -CO2Me is converted to compound G-1, which is achieved by reacting A-5 with a reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at 0 °C for 1 hour. 1 In Reaction 2 of Preparation Method G, compound G-1 is converted to G-2, which is achieved by reacting G-1 with a carbon tetrahalide such as carbon tetrabromide in the presence of a phosphine such as resin-bound triphenylphosphine in an ethereal solvent such as tetrahydrofuran under reflux for 2 hours.

[0472]

[0473] ​In reaction 3 of Preparation Method G, T 1 , T 2 , T 3 , R 6 and Z 1 are as defined above , and G 1 converts compound A-5, which is Br, to G-3, which involves reacting A-5 with an organolithium reagent such as n- butyllithium, followed by dimethylformamide, in an ethereal solvent such as tetrahydrofuran at -78 °C to room temperature for 1 hour.

[0474] In reaction 4 of Preparation Method G, compound G-1 is converted to compound G-3, which is achieved by reacting G-1 with an oxidizing reagent such as Dess-Martin periodinane in a halogenated solvent such as dichloromethane at room temperature for 30 minutes, or by reacting G-1 with an oxidizing reagent such as manganese(IV) oxide in a halogenated solvent such as dichloromethane at room temperature for 22 hours.

[0475] Scheme 8: Preparation Method H

Chemical Structure

[0476] In reaction 1 of Preparation Method H, X 2 , X 3 , X 4 and X 5 are as defined above; LG represents a leaving group such as -F or -Cl, and compound H-1 is converted to compound H-2, which involves reacting H-1 with an amine R *1 NH2 (R *1 NH2 represents, for example, compound A-6, A-8, B-7, C-7, D-3 or E-4 as defined above) in acetonitrile at reflux for 2 - 16 hours in the presence of a base such as diisopropylethylamine.

[0477] In reaction 2 of Preparation Method H, compound H-2 is converted to compound H-3, which is achieved by reacting H-2 with a reducing agent system such as zinc chloride and ammonium chloride, in an aqueous ether / alcohol mixture such as a tetrahydrofuran / methanol / water mixture at room temperature for 1 hour, or by reacting H-2 with a reducing agent such as iron in an acid such as acetic acid at 100 °C for 30 minutes.

[0478] In reaction 3 of Preparation Method H, compound H-3 is converted to compound H-4, which is achieved by reacting H-3 with an orthoester (EtO)3CR 7 (R 7 is as defined above ), in the presence of an acid such as p-toluenesulfonic acid, in an alcohol such as ethanol, under reflux for 1 to 4 hours.

[0479] In reaction 4 of Preparation Method H, compound H-3 is converted to compound H-5, which is achieved by reacting H-3 with sodium nitrate, in the presence of an acid such as acetic acid, at room temperature for 2 hours.

[0480] Scheme 9: Preparation Method I

Chemical Structure

[0481] In reaction 1 of Preparation Method I, X 3 , X 4 and X 5 are as defined above, and compound I -1 is converted to compound I-2, where X 3 , X 4 , X 5 , T 1 , T 2 and T 3 are as defined above. This is achieved by reacting I-1 with amine compound A-8 (as defined above, where R 1 and R 2 each independently represent H, and G 2 is -OBn), and diisopropylethylamine, etc. It is carried out by refluxing for 2 to 16 hours in a polar aprotic solvent such as acetonitrile in the presence of a base.

[0482] In Reaction 2 of Preparation Method I, Compound I-2 is converted to Compound I-3, which is achieved by reacting I-2 with a reducing agent system such as zinc chloride and ammonium chloride, and in an aqueous ether / alcohol mixture such as a tetrahydrofuran / methanol / water mixture at room temperature for 1 hour.

[0483] In Reaction 3 of Preparation Method I, Compound I-3 is converted to Compound I-4, which is achieved by reacting I-3 with an orthoester (EtO)3CR such as triethyl orthoformate 7 (R 7 is as defined above ), and in the presence of an acid such as p-toluenesulfonic acid, refluxing in an alcohol such as ethanol for 1 to 4 hours.

[0484] In Reaction 4 of Preparation Method I, Compound I-4 is converted to Compound I-5, which is achieved by reacting I-4 with an acid such as glacial acetic acid at 110 °C for 20 hours.

[0485] In Reaction 5 of Preparation Method I, Compound I-5 is converted to Compound I-6, which is achieved by reacting I-5 with an alpha-haloketone such as bromoketone R 6 (CO)CH(Br)(Z 1 ), and in the presence of a base such as cesium carbonate, reacting in a polar aprotic solvent such as acetonitrile at room temperature for 1 to 24 hours.

[0486] In reaction 6 of Preparation Method I, compound I-6 is converted to compound I-7, which is first deprotected under hydrogenation conditions at room temperature for 1 to 5 hours in an ethereal solvent such as tetrahydrofuran in the presence of a solid-supported catalyst such as carbon-supported palladium, second reduced with a reducing agent such as sodium borohydride at 0 °C for 30 minutes in a solvent mixture such as a tetrahydrofuran / methanol mixture, and third reacted with a phosphine such as resin-bound triphenylphosphine, a carbon tetrahalide such as carbon tetrachloride, a base such as triethylamine, in acetonitrile under reflux for 1 to 15 hours.

[0487] Scheme 10: Preparation Method J

Chemical formula

[0488] In reaction 1 of Preparation Method J, X 3 , X 4 , X 5 , X 7 and X 8 are as defined above, for example X is, for example X 2 and X 8 are independently C or N, and compound J-1 where X 9 is C is converted to compound J-2, which is achieved by reacting J-1 with a formylating reagent such as phosphorus oxychloride in dimethylformamide from 0 °C to room temperature over 16 hours.

[0489] In reaction 2 of Preparation Method J, compound J-2 is converted to compound J-3, which is achieved by reacting J-2 with a sulfonylhydrazide such as p-toluenesulfonylhydrazide in an ethereal solvent such as 1,4-dioxane at 100 °C for 2 hours.

[0490] In reaction 3 of Preparation Method J, compound J-3 is converted to compound J-4, which is achieved by reacting J-3 with a boronic acid compound R *2 B(OH)2 (R *2B(OH)2 (which represents, for example, compound A-10, B-12 or E-9 defined above) is reacted at 100 °C for 16 hours in an ethereal solvent such as 1,4-dioxane in the presence of a base such as potassium carbonate.

[0491] Scheme 11: Preparation Method K

Chemical formula

[0492] In reaction 1 of preparation method K, X 2 , X 3 , X 4 , X 5 , X 7 and X 8 are as defined above. For example, X 2 and X 8 are independently C or N, and compound K 9 where X -1 is converted to compound K-2, which is achieved by reacting K-1 with a bromide compound R *3 Br [where R *3 Br represents, for example, compound A-5 (where G 1 is Br), B-4, C-4, E-2 or E-3 as defined above] in the presence of a base such as n-butyllithium in tetrahydrofuran at -78 °C for 30 minutes.

[0493] In reaction 2 of preparation method K, compound K-2 is converted to compound K-3, which is achieved by reacting K-2 with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at room temperature for 30 minutes.

[0494] Scheme 12: Preparation Method L

Chemical formula

[0495] In reaction 1 of preparation method L, X 2 , X 3 , X 4 , X5 and X 7 is as defined above For example, X 2 and X 8 are, independently, C, and X 9 is C or N, or For example, X 2 and X 8 are, independently, C or N, X 9 Convert the compound L-1 where X is C to the compound L-2, which is achieved by reacting L-1 with a brominating reagent such as N-bromosuccinimide in a polar aprotic solvent such as dimethylformamide at 0 °C for 1.5 hours. Convert the compound L-2 to the compound L-3 in Reaction 2 of Preparation Method L, which is achieved by, firstly, reacting L-2 with an organometallic reagent such as ethylmagnesium bromide in an ethereal solvent such as tetrahydrofuran at room temperature for 30 minutes, and secondly, reacting with the aldehyde compound R

[0496] *4 CHO (R *4 CHO represents, for example, the compound B-9, E-6, F-6 or G-3 defined above) at room temperature for 0.5 - 3 hours.

[0497] Convert the compound L-3 to the compound L-4 in Reaction 3 of Preparation Method L, which is achieved by reacting L-3 with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at room temperature for 30 minutes.

[0498] Scheme 13: Preparation Method M

Chemical formula

[0499] In Reaction 1 of Preparation Method M, convert the amine compound R *1 NH2 (R *1 NH2 represents, for example, the compound A-6, A-8, B-7, C-7, D-3 or E-4 defined above) to the compound M-1, which is achieved by, firstly, R *1NH2 is 1,1-bis(methylthio)-2-nitro ethylene is reacted with it in reflux in an alcohol such as ethanol for 19 hours, and second, hydrazine such as hydrazine hydrate is reacted with it in reflux in an alcohol such as ethanol for 2.5 hours.

[0500] In Reaction 2 of Preparation Method M, compound M-1 is converted to compound M-2 where each R 10 is independently as defined above, which is by reacting M-1 with a 1,2-dicarbonyl compound such as dihydroxal in an aqueous ether-alcohol mixture such as a tetrahydrofuran / ethanol / water mixture at room temperature for 19 hours in the presence of a base such as sodium carbonate.

[0501] In Reaction 3 of Preparation Method M, compound M-2 is converted to compound M-3, which is first by reacting M-1 with a reducing agent such as iron in an acid such as glacial acetic acid at 125 °C for 10 minutes, and second, an orthoester (EtO)3CR such as triethyl orthoformate 7 (R 7 is as defined above is reacted in reflux in an alcohol such as ethanol for 1 hour in the presence of an acid such as p-toluenesulfonic acid.

[0502] Scheme 14: Preparation Method N

Chemical Structure

[0503] In Reaction 1 of Preparation Method N, X 2 , X 3 and X 5 are as defined above for compound N -1 is converted to compound N-2, which is by reacting N-1 with an alpha-bromoketone compound BrCH2(CO)R *5 (BrCH2(CO)R *5 represents, for example, compound A-12 as defined above) in reflux in a polar aprotic solvent such as acetonitrile for 48 hours.

[0504] In the reaction 2 of Preparation Method N, compound N-2 is converted to compound N-3, which is achieved by, first, reacting N-2 with a reducing agent such as sodium borohydride in an alcohol such as methanol at room temperature for 30 minutes, and second, reacting with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at room temperature for 2 hours.

[0505] Scheme 15: Preparation Method O

Chemical Structure

[0506] In the reaction 1 of Preparation Method O, X 2 , X 3 , X 4 , X 5 and X 7 are as defined above. Compound O-1 is converted to compound O-2, which is achieved by reacting O-1 with an azodicarboxylate such as bis(2-methoxyethyl) azodicarboxylate, a phosphine such as triphenylphosphine, and an alcohol compound HOCH2R (HOCH2R *6 (HOCH2R *6 represents, for example, compound B-10, E-7, F-7 or G-1 as defined above) in an ethereal solvent such as tetrahydrofuran at room temperature for 3 hours, or by reacting O-1 with (tributylphosphoranylidene)acetonitrile and an alcohol compound HOCH2R *6 (HOCH2R *6 represents, for example, compound B-10, E-7, F-7 or G-1 as defined above) in an aromatic solvent such as toluene at 100 °C for 1 hour.

[0507] Scheme 16: Preparation Method P

Chemical Structure

[0508] In the reaction 1 of Preparation Method P, compound P-1 (wherein X 101 , X102 , X 103 , X 104 and X 105 are as defined above. For example, in the formula, X 102 , X 103 or X 104 is independently N; where Hal represents halogen) is converted to P-2 or P-3, which involves reacting P-1 with a catalyst such as a precatalyst of 2nd Gen XPhos palladium, a base such as potassium phosphate, and (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R *7 [where (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R *7 represents, for example, the compounds A-9, B-13 or E-10 defined above] and an organoborate compound such as (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at 80 °C for 15 hours to convert to P-2, or reacting P-1 with a catalyst such as a precatalyst of 2nd Gen XPhos palladium, a base such as potassium phosphate, and a boronic acid compound (HO)2BR *8 [where (HO)2BR *8 represents, for example, the compounds A-10, B-12 or E-9 defined above respectively] in an aqueous ethereal solvent mixture such as a tetrahydrofuran / water mixture at 80 °C for 15 hours to convert to P-3, either of which is the case.

[0509] Scheme 17: Preparation method Q

Chemical formula

[0510] In reaction 1 of preparation method Q, X 2 , X 3 , X 4 and X 7 are as defined above to convert compound Q-1 to compound Q-2, which involves reacting Q-1 with a catalyst such as palladium(II) acetate, a phosphine such as tricyclohexylphosphine, a base such as potassium phosphate, and a bromine compound BrCH2R *9 (BrCH2R *9(which represents, for example, compound B-11, E-8, F-8 or G-2 defined above) is obtained by reacting it under reflux for 18 hours in a two-phase solvent mixture such as a toluene / water mixture.

[0511] In reaction 2 of Preparation Method Q, compound Q-2 is converted to compound Q-3, which is achieved by reacting Q-2 with an acid such as trifluoroacetic acid in a halogenated solvent such as dichloromethane at room temperature for 30 minutes.

[0512] Scheme 18: Preparation Method R

Chemical Structure

[0513] In reaction 1 of Preparation Method R, X 3 , X 4 and X 7 are as defined above, and compound R -1 is converted to compound R-2, which is achieved by first reacting R-1 with an organometallic reagent such as ethylmagnesium bromide in an ethereal solvent such as tetrahydrofuran at room temperature for 30 minutes, and second, reacting it with an aldehyde compound R *4 CHO (R *4 CHO represents, for example, compound B-9, E-6, F-6 or G-3 defined above) at room temperature for 0.5 to 3 hours.

[0514] In reaction 2 of Preparation Method R, compound R-2 is converted to compound R-3, which is achieved by reacting R-2 with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at room temperature for 30 minutes.

[0515] Scheme 19: Preparation Method S

Chemical Structure

[0516] In reaction 1 of Preparation Method S, X 103 , X 104 , X 105 , X 106, X 107 and X 108 are as defined above. For example, X 103 is N, and X 108 is NR 117 and, for example, R 117 is H. Compound S-1 is converted to compound S-2, which involves, first, reacting S-1 with a first molar equivalent of an organometallic reagent such as n-butyllithium in an ethereal solvent such as tetrahydrofuran at -78 °C for 30 minutes, second, reacting with a second molar equivalent of an organometallic reagent such as t-butyllithium in an ethereal solvent such as tetrahydrofuran at -78 °C for 15 minutes, and third, reacting with an aldehyde compound R *4 CHO (where R *4 CHO represents, for example, compound B-9, E-6, F-6 or G-3 as defined above) at -78 °C to room temperature over 40 minutes.

[0517] In reaction 2 of preparation method S, compound S-2 is converted to compound S-3, which involves reacting S-2 with an organosilane such as triethylsilane in an acid such as trifluoroacetic acid at room temperature for 30 minutes.

[0518] Scheme 20: Preparation method T [Chemical formula]

[0519] In reaction 1 of preparation method T, an aldehyde compound R *4 CHO (where R *4 CHO represents, for example, compound B-9, E-6, F-6 or G-3 as defined above) is converted to compound T-1, which involves reacting R *4 CHO with 3-(phenylamino)propanenitrile in the presence of a base such as sodium methoxide in a polar aprotic solvent such as dimethyl sulfoxide at 95 °C for 1 hour.

[0520] In reaction 2 of Preparation Method T, compound T-1 is converted to compound T-2, which is achieved by reacting T-2 with guanidine hydrochloride in alcohol such as ethanol at 70 °C for 48 hours in the presence of a base such as potassium t-butoxide.

[0521] Scheme 21: Preparation Method U

Chemical formula

[0522] In reaction 1 of Preparation Method U, an organoborate compound, for example, (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R *7 [wherein, (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R *7 represents, for example, compound A-9, B-13 or E-10 defined above] is converted to an alcohol compound U-1 (R *7 -OH), which is achieved by reacting (4,4,5,5-tetramethyl-1,3,2-dioxaborolyl)-R *7 with sodium borate hydrate in a tetrahydrofuran / water mixture at room temperature for 16 hours.

[0523] In reaction 2 of Preparation Method U, the alcohol compound U-1 (R *7 -OH) is converted to X 101 , X 104 and X 105 which are compounds U-2 as defined above, which is achieved by reacting U-1 (R *7 - OH) with methyl 4-chloropicolinate in dimethyl sulfoxide from room temperature to 100 °C for 5 hours in the presence of sodium hydride.

[0524] In reaction 3 of Preparation Method U, compound U-2 is converted to compound U-3, which is achieved by reacting U-2 with an amine such as methylamine in ethanol at 125 °C for 30 minutes in the presence of sodium cyanide.

[0525] Scheme 22: Preparation Method V

Chem.

[0526] Sonogashira coupling: In reaction 1 of Preparation Method V, X 1 、X 2 、X 3 、X 5 、X 6 、X 7 、X 8 、X 9 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、T 1 、T 2 、T 3 、Y 1 、n and m are as defined above and Hal is I, Br or Cl, compound V-1 is converted to compound V-2 where R 7 is as defined above (C2-C 10 ) alkynyl, (C2-C 10 ) alkynylamine, R 8 -(C2-C 10 ) alkynyl or R 8 -(C2-C 10 ) alkynylamine, by reacting V-1 with an alkyne, a catalyst system such as copper(I) iodide and bis(triphenylphosphine)palladium(II) chloride, and an amine such as piperidine in a microwave reactor at 100 °C for 30 minutes.

[0527] Suzuki coupling: In reaction 2 of Preparation Method V, X 1 、X 2 、X 3 、X 5 、X 6 、X 7 、X 8 、X 9 、R 1 、R 2 、R3 , R 4 , R 5 , R 6 , T 1 , T 2 , T 3 , Y 1 , n and m are as defined above , Hal is a compound V-1 of I, Br or Cl, R 7 is as defined above , (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl, (C2-C9) heterocycloalkyl, (C6-C 14 ) aryl, (C2-C9) heteroaryl, R 8 -(C1-C 10 ) alkyl-, R 8 -(C3-C 10 ) cycloalkyl, R 8 -(C2-C9) heterocycloalkyl, R 8 -(C6-C 14 ) aryl or R 8 -(C2-C9) heteroaryl is converted to compound V-3, which is obtained by reacting V-1 with an organoboron compound, a catalyst such as palladium(II) acetate, a ligand such as tricyclohexylphosphine, and a base such as tribasic potassium phosphate in a biphasic solvent mixture such as a toluene / water mixture under reflux for 1-18 hours. , base in a biphasic solvent mixture such as a toluene / water mixture under reflux for 1-18 hours.

[0528] Amination coupling reaction: In reaction 3 of Preparation Method V, X 1 , X 2 , X 3 , X 5 , X 6 , , X 7 , X 8 , X 9 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T 1 , T 2 , T 3 , Y1 , n and m are as defined above, and Hal is a compound V-1 which is I, Br or Cl, and R 7 is , H2N-, (CH3)HN- or (CH3)2N- or R as defined above 8 R 9 is converted to a compound V-4 which is R

[0529] N-, and this is done by reacting compound V-1 with a primary or secondary amine, a catalyst such as a 3rd generation BrettPhos precatalyst, a ligand such as RuPhos, a base such as sodium t-butoxide in an ethereal solvent such as 1,4-dioxane at 100 °C for 1 to 16 hours, or by reacting V-1 with a primary or secondary amine, a catalyst such as copper(I) iodide, a ligand such as L-proline, a base such as potassium carbonate in a polar aprotic solvent such as dimethyl sulfoxide at 150 °C for 1 to 6 hours to convert it to V-4, or by reacting V-1 with an aromatic heterocycle such as 1-H-imidazole, a catalyst such as copper(I) iodide, a diamine ligand such as N,N'-dimethyl-1,2-cyclohexanediamine, a base such as potassium carbonate in a polar aprotic solvent such as dimethylformamide at 135 °C for 3 to 16 hours to convert it to V-4. 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T 1 , T 2 , T 3 , Y 1 , n and m are , as defined above, and Hal is a compound V-1 which is I, Br or Cl, and R 7 is the (C1-C 10 ) alkoxy-, R 8 -(C1-C 10 ) alkoxy-, ( C2-C9) heterocycloalkyl-O-, (C6-C 14 ) aryl-O-, (C2-C9) heteroaryl-O-, R 8 -(C3-C 10 ) heterocycloalkyl-O-, R 8 -(C2-C9) heterocycloalkyl-O-, R 8 -(C6-C 14 ) aryl-O- or R 8 -(C2-C9) heteroaryl-O- as defined above, and compound V-5 is obtained by reacting V-1 with an alcohol, a catalyst such as copper(I) iodide, a ligand such as 1,10-phenanthroline, and a base such as cesium carbonate in a polar solvent such as an alcohol or dimethyl sulfoxide at 110 °C for 1 to 20 hours, or by reacting V-1 with an alcohol, a catalyst such as the third-generation RockPhos, and a base such as cesium carbonate in a nonpolar solvent such as toluene at 100 °C for 5 to 20 hours to convert it to V-5.

[0530] Cyanation reaction: In reaction 5 of Preparation method V, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T 1 , T 2 , T 3 , Y 1, n and m are as defined above, and Hal converts compound V-1, which is I, Br or Cl, to compound V-6, which is achieved by reacting V-1 with a cyanide salt such as zinc(II) cyanide and a catalyst such as tetrakis(triphenylphosphine)palladium(0) in a polar aprotic solvent such as dimethylformamide at 100 °C for 3 hours.

[0531] Scheme 23: Preparation method W

Chemical formula

[0532] In reaction 1 of preparation method W, X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , X 9 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T 1 , T 2 , T 3 , Y 1 , n and m are as defined above, and convert compound W-1 to compound W-2, which is achieved by reacting W-1 with a base such as lithium hydroxide monohydrate in an aqueous ethereal alcohol mixture such as a water / tetrahydrofuran / methanol mixture at room temperature for 1 hour.

[0533] In reaction 2 of preparation method W, compound W-2 is converted to compound W-3 where R 7 is the R 8 R 9 N(O)C - and this is achieved by reacting W-2 with an amine, O-(benzotriazole By reacting with an amide coupling reagent such as -1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and a base such as diisopropylethylamine in a halogenated solvent such as dichloromethane at room temperature for 30 minutes.

[0534] In Reaction 3 of Preparation Method W, compound W-1 is converted to compound W-4, which is achieved by reacting W-1 with a reducing agent such as lithium aluminum hydride in an ethereal solvent such as tetrahydrofuran at room temperature for 30 minutes.

[0535] In Reaction 4 of Preparation Method W, compound W-4 is converted to compound W-5, which is achieved by reacting W-4 with an oxidizing reagent such as manganese(IV) oxide in a halogenated solvent such as dichloromethane at room temperature for 22 hours.

[0536] In Reaction 5 of Preparation Method W, compound W-5 is converted to compound W-6, where R 7 is the (C2 - C9) hetero aryl or R 8 -(C2 - C9) heteroaryl as defined above, which is achieved by reacting W-5 with a 1,2-dicarbonyl compound such as glyoxal and an amine salt such as ammonium acetate in a polar aprotic solvent such as N-methyl-2-pyrrolidone at 120 °C for 16 hours.

[0537] As used herein, the term "amino" means a functional group having one nitrogen atom and one or two hydrogen atoms. Amino is generally used herein to refer to primary, secondary, or tertiary amines, and one of ordinary skill in the art can easily identify which type it is based on the context in which this term is used in the present disclosure. The terms "amine" or "amine group" or "ammonia group" are derived from ammonia (NH3). Means a functional group containing a nitrogen atom. The amine group is preferably a primary amine, which means that nitrogen is bonded to two hydrogen atoms and one substituent containing a substituted or unsubstituted alkyl group, aryl group, aliphatic group or aromatic group. The amine group may also be a secondary amine, which means that nitrogen is bonded to one hydrogen atom and two substituents containing a substituted or unsubstituted alkyl group, aryl group, aliphatic group or aromatic group, as defined below. The amine group may also be a tertiary amine, which means that nitrogen is bonded to three substituents containing a substituted or unsubstituted alkyl group, aryl group, aliphatic group or aromatic group. The amine group may also be a quaternary amine, which means that the specified amine group may be bonded to a fourth group, resulting in a positively charged ammonium group.

[0538] Any or all of the amines in the present invention may be in the free amine form (i.e., -NH2 for a primary amine), or a pharmaceutically acceptable Protonated form having an anion [i.e., -NH3 - Y - (Y - is a pharmaceutically acceptable anion)] and is understood to be.

[0539] As used herein, the term "amide group" means a functional group containing a carbonyl group linked to nitrogen. "Carbonyl group" means a functional group containing a carbon atom double-bonded to an oxygen atom, represented by (C=O).

[0540] The term "alkane" means a saturated hydrocarbon bonded by single bonds. The alkane can be linear or branched. "Cycloalkane" means a saturated hydrocarbon ring bonded by single bonds.

[0541] As used herein, the term "(C1-C 10) "Alkyl" means a saturated, straight-chain, branched-chain or cyclic hydrocarbon consisting essentially of 1 to 10 carbon atoms and the corresponding number of hydrogen atoms. Typically, a straight-chain or branched-chain group has 1 to 10 carbon atoms, or more typically, 1 to 5 carbon atoms. Exemplary (C1-C alkyl groups include methyl (represented by -CH3), ethyl (represented by -CH2-CH3) and n-propyl, isopropyl, n-butyl, isobutyl, etc. Other (C1- 10 ) alkyl groups will be readily apparent to those skilled in the art who will benefit from the present disclosure. When used herein, the term "(C2-C9) heteroalkyl" means a saturated, straight-chain, branched-chain or cyclic hydrocarbon consisting essentially of 2 to 10 atoms, where 2 to 9 of the atoms are carbon and the remaining atoms are selected from the group consisting of nitrogen, sulfur and oxygen. Exemplary (C2-C9) heteroalkyl groups will be readily apparent to those skilled in the art who will benefit from the present disclosure. C 10 )

[0542] When used herein, the term "(C3-C

[0543] ) cycloalkyl" means a non-aromatic, saturated hydrocarbon group forming at least one ring and consisting essentially of 3 to 10 carbon atoms and the corresponding number of hydrogen atoms. (C3-C 10 ) cycloalkyl can be monocyclic or polycyclic. The individual rings of a polycyclic cycloalkyl group can have different connectivities, for example, in addition to covalent substitution, fused bonds, bridging bonds, spiro bonds, etc. Exemplary (C3-C 10 ) cycloalkyl groups include cyclopropyl, cyclobutyl and the like. 10 ) cycloalkyl groups include cyclopropyl, cyclobutyl Cyclopropyl substituted with cyclohexyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo-octanyl, octahydro-pentalenyl, spiro-decanyl, cyclobutyl, cyclobutyl substituted with cyclopentyl, cyclohexyl substituted with cyclopropyl, and the like. Other (C3-C 10 ) cycloalkyl groups will be readily apparent to those skilled in the art who receive the benefits of this disclosure .

[0544] As used herein, the term “(C2-C9) heterocycloalkyl” means a non-aromatic group having 3 to 10 atoms that forms at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur, and oxygen. The (C2-C9) heterocycloalkyl group can be monocyclic or polycyclic. The individual rings of such polycyclic heterocycloalkyl groups can have different connectivities, for example, in addition to covalent substitution, fused bonds, bridging bonds, spiro bonds, etc. Exemplary (C2-C9) heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperidin-2-onyl, piperidin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl, 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl, octahydro-1H-indolyl, and the like. The (C2-C9) heterocycloalkyl group is typically attached to the main structure through a carbon atom or a nitrogen atom.Other (C2-C9) heterocycloalkyl groups will be readily apparent to those of ordinary skill in the art who benefit from the present disclosure.

[0545] The term "aliphatic group" or "aliphatic" means a non-aromatic group consisting of carbon and hydrogen, which may optionally contain one or more double bonds and / or triple bonds. In other words, an aliphatic group is any group consisting of carbon and hydrogen that does not contain aromatic functionality. Aliphatic groups may be linear, branched or cyclic and typically contain from about 1 to about 24 carbon atoms.

[0546] The term "aryl group" can be used interchangeably with "aryl", "aryl ring", "aromatic", "aromatic group" and "aromatic ring". Aryl groups include carbocyclic aromatic groups typically having 6 to 14 ring carbon atoms. Aryl groups also include heteroaryl groups typically having 5 to 14 ring carbon atoms and having one or more heteroatoms selected from nitrogen, oxygen and sulfur.

[0547] As used herein, the term "(C6-C 14 ) aryl" means an aromatic functional group having 6 to 14 carbon atoms that forms at least one ring .

[0548] As used herein, the term "(C2-C9) heteroaryl" means an aromatic functional group having 5 to 10 atoms forming at least one ring, wherein 2 to 9 of the ring atoms are carbon and the remaining ring atoms are selected from the group consisting of nitrogen, sulfur, and oxygen. The (C2-C9) heteroaryl group can be monocyclic or polycyclic. The individual rings of such polycyclic heteroaryl groups can have different connectivities, for example, in addition to covalent substitution, fused bonds, etc. Exemplary (C2-C9) heteroaryl groups include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-thiadinyl, 1,2,3-thiadinyl, 1,3,5-thiadinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, and benzoxazinyl, etc. The (C2-C9) heteroaryl is typically bonded to the main structure through a carbon atom, but one of ordinary skill in the art will recognize when a particular other atom, such as a heteroatom, can be bonded to the main structure. Other (C2-C9) heteroaryl groups will be readily apparent to those of ordinary skill in the art who benefit from this disclosure.

[0549] The term "alkynyl" means a functional group containing a triple-bonded carbon represented by (C2-C 10 ) alkynyl-.

[0550] As used herein, the term "alkylamine" refers to a (C1-C 10 ) alkylamine and ((C1-C ) alkyl)2amine, which contains a primary, secondary, or tertiary amine group in place of one hydrogen atom, and means a (C1-C 10 ) alkyl. 10

[0551] The term "alkynylamine" refers to a (C2-C 10 ) alkylamine, which contains a triple bond carbon and one amine group, and means a (C2-C ) group. 10

[0552] The term "alkoxy" refers to a (C1-C 10 ) alkyl bonded to oxygen, and is represented by (C1-C 10 ) alkyl-O- or (C1-C 10 ) alkoxy-. The term "alkoxy alkyl" refers to a (C1-C 10 ) alkyl bonded to another (C1-C 10 ) alkyl through oxygen, and is represented by (C1-C 10 ) alkyl-O-(C1-C 10 ) alkyl or (C1 -C 10 ) alkoxy-(C1-C 10 ) alkyl-.

[0553] The term "alkyl ester" refers to a (C1 -C 10 ) alkyl that contains an ester group in place of one hydrogen atom, and is represented by -O(O)C-(C1-C 10 ) alkyl.

[0554] The term "alkyl acid" refers to a (C1-C 10 ) alkyl that contains a carboxylic acid group in place of one hydrogen atom, and is represented by (C1-C 10 ) alkyl-COOH.

[0555] The term "aliphatic acid" means an acid of a non-aromatic hydrocarbon and is represented by (C1-C 10 )alkyl-CO OH and (C3-C 10 )cycloalkyl-COOH.

[0556] The term "dicarbonyl" refers to an organic molecule containing two or more adjacent carbonyl groups. The carbonyl group represented by C=O can be, for example, an aldehyde, a ketone, and other groups having an oxygen atom double-bonded to a carbon atom. Examples include, but are not limited to, glyoxal, methylglyoxal, dimethylglyoxal, and 3-deoxyglucosone.

[0557] The term "halo" or "Hal" means an ion of fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At).

[0558] The term "methoxy" means an alkyl (C1) containing oxygen in place of one hydrogen atom and is represented by -(O)CH3. and is represented by -(O)CH3.

[0559] The term "polyol" means an alcohol containing a plurality of hydroxyl (-OH) groups.

[0560] "Substituted" means substitution of one or more non-carbon substituents for carbon in an alkyl group, a heterocyclic group, or an aryl group. The non-carbon substituents are selected from nitrogen, oxygen, and sulfur.

[0561] "Unsubstituted" means that the group consists of only hydrogen and carbon.

[0562] A 3- to 10-membered ring means a closed ring; a 3- to 10-membered ring can be acyclic, aromatic, or heterocyclic.

[0563] The term "pharmaceutically acceptable anion" means an anion suitable for pharmaceutical use. Pharmaceutically acceptable anions include, but are not limited to, halide ions, carbonate ions, bicarbonate ions, sulfate ions, bisulfate ions, hydroxide ions, nitrate ions, persulfate ions, phosphate ions, sulfite ions, acetate ions, ascorbate ions, benzoate ions, citrate ions, dihydrogen citrate ions, hydrogen citrate ions, oxalate ions, succinate ions, tartrate ions, taurocholate ions, glycolate ions, and cholate ions.

[0564] All pharmaceutically acceptable salts, prodrugs, tautomers, hydrates, and solvates of the compounds disclosed in the present invention are also within the scope of this disclosure.

[0565] Compounds disclosed in the present invention that are basic in nature can generally form a wide variety of different salts with various inorganic acids and / or organic acids. Such salts are generally pharmaceutically acceptable for administration to animals and humans, but it is often desirable in practice to initially isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds can be readily prepared using conventional techniques, for example, by treating the basic compound with approximately an equivalent amount of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. The desired solid salt is obtained upon careful evaporation of the solvent.

[0566] Acids that can be used to prepare pharmaceutically acceptable acid addition salts of a basic compound are those that can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chlorides, bromides, iodides, nitric acid, sulfuric acid or bisulfuric acid, phosphoric acid or acid phosphates, acetic acid, lactic acid, citric acid or acid citrates, tartaric acid or bitartrates, succinic acid, maleic acid, fumaric acid, gluconates, saccharic acids, benzoic acid, methanesulfonic acid and salts of pamoic acid [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

[0567] For example, the compounds disclosed in the present invention that are acidic in nature and contain, for example, a COOH or tetrazole moiety can generally form a wide variety of different salts with various inorganic bases and / or organic bases. Such salts are generally pharmaceutically acceptable for administration to animals and humans, but it is often desirable in practice to initially isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an alkaline reagent, followed by conversion of the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, for example, by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then preferably evaporating the resulting solution to dryness under reduced pressure. Alternatively, they can also be prepared by mixing together a low alcoholic solution of the acidic compound with the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In either case, it is preferred that stoichiometric amounts of the reagents be used to ensure completion of the reaction and maximum product yield of the desired solid salt.

[0568] Bases that can be used to prepare pharmaceutically acceptable base addition salts of a basic compound are those that can form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts, such as N-methylglucamine-(meglumine), lower alkanolammonium, and other such bases of organic amines.

[0569] Isotopically labeled compounds are also within the scope of the present disclosure. As used herein, "isotopically labeled compound" refers to a compound of the invention, including its pharmaceutically acceptable salts and its prodrugs as described herein, wherein one or more atoms are replaced with an atom having an atomic weight or mass number different from the atomic weight or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed in the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, respectively, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.

[0570] Isotopically labeled compounds of the invention can be useful in tissue distribution assays of drugs and / or substrates. Tritiated ( 3 H) and carbon- 14( 14 C) labeled compounds are particularly preferred because of the ease of their preparation and detection. . Further, substitution with heavier isotopes such as deuterium ( 2 H) can provide certain therapeutic advantages. This can be achieved, which is brought about by greater metabolic stability, for example an increase in the in vivo half-life, or a reduction in the required dosage, and is thus preferred in some situations. The isotope-labeled compounds disclosed in the present invention can be prepared by any means known in the art, including their pharmaceutically acceptable salts and their prodrugs.

[0571] The stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed in the present invention, as well as racemic, diastereomeric, and other mixtures of such isomers, are within the scope of this disclosure.

[0572] The compounds, salts, prodrugs, hydrates, and solvates disclosed in the present invention can exist in several tautomeric forms, including enol and imine forms as well as keto and enamine forms, as well as geometric isomers, and mixtures thereof. Tautomers exist as mixtures of tautomeric sets in solution. In the solid form, usually one tautomer is dominant. Even if only one tautomer is described, all tautomers are within the scope of this disclosure.

[0573] Atropisomers are also within the scope of this disclosure. Atropisomers refer to compounds that can be separated into isomers with restricted rotation.

[0574] This disclosure also provides a pharmaceutical composition comprising at least one compound disclosed in the present invention and at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be any such carrier known in the art, including those described in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit., 1985). The pharmaceutical compositions of the compounds disclosed in the present invention can be prepared by conventional means known in the art, including, for example, mixing at least one compound disclosed in the present invention with a pharmaceutically acceptable carrier.

[0575] The pharmaceutical compositions disclosed in the present invention can be used in animals or humans. Therefore, the compounds disclosed in the present invention are formulated as pharmaceutical compositions in a form suitable for oral, buccal, parenteral (e.g., intravenous, intramuscular or subcutaneous), topical, rectal or intranasal administration, or for administration by inhalation or insufflation.

[0576] The compounds disclosed in the present invention are also formulated for sustained delivery by methods well known to those skilled in the art. Examples of such formulations are found in U.S. Pat. Nos. 3,119,742, 3,492,397, 3,538,214, 4,060,598 and 4,173,626.

[0577] For oral administration, the pharmaceutical composition can take the form of, for example, tablets or capsules, which are prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); diluents (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets are coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as dry products for dissolution in water or other suitable vehicle before use. Such liquid preparations are prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats ); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and / or preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate or sorbic acid).

[0578] For oral administration, the composition can be in the form of tablets or lozenges formulated by conventional methods.

[0579] The compounds disclosed in the present invention are formulated for parenteral administration by injection, including the use of conventional catheter insertion techniques or infusion. Injectable formulations are presented in unit dosage forms, for example, in ampoules or in multi-dose containers, together with added preservatives. The composition may take the form of, for example, a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending agents, stabilizers and / or dispersing agents recognized by those skilled in the art. Alternatively, the active ingredient may be in the form of a powder for reconstitution before use with a suitable vehicle, for example sterile pyrogen-free distilled water.

[0580] For topical administration, the compounds disclosed in the present invention are formulated as ointments or creams.

[0581] The compounds disclosed in the present invention are also formulated in rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0582] For nasal administration or administration by inhalation, the compounds disclosed in the present invention are conveniently delivered from a pump spray container in the form of a solution or suspension, squeezed out or pumped out by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer using a suitable high-pressure gas such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit is determined by the supply of a valve that delivers a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the compounds disclosed in the present invention. Capsules and cartridges (e.g., made of gelatin) for use in an inhaler or injector are formulated to contain a powder mix of the compounds disclosed in the present invention and a suitable powder base such as lactose or starch.

[0583] For the treatment or prevention of CSF-1R-related disease states, the proposed dosages of the compounds disclosed in the present invention for oral, parenteral or buccal administration to an average adult are from about 0.1 mg to about 2000 mg. In certain embodiments, the proposed dosage is from about 0.1 mg to about 200 mg of active ingredient per unit dosage. Irrespective of the proposed dosage, administration of the compound can be, for example, 1 to 4 times per day.

[0584] For the treatment or prevention of the symptoms listed above, aerosol formulations are preferably adjusted such that in an average adult, each metered dose or "puff" of the aerosol contains from about 20 mg to about 10,000 mg, preferably from about 20 mg to about 1000 mg, of the compound disclosed in the present invention. The total daily dose by aerosol is in the range of about 100 mg to about 100 mg. In certain embodiments, the total daily dose by aerosol is generally in the range of about 100 mg to about 10 mg. Administration may be several times a day, for example 2, 3, 4 or 8 times, and for example 1, 2 or 3 doses may be given each time.

[0585] For the treatment or prevention of the symptoms listed above, aerosol-formulated preparations are preferably adjusted such that in an average adult, each metered dose or "puff" of the aerosol contains a formulation comprising from about 0.01 mg to about 1000 mg of the compound disclosed in the present invention. In certain embodiments, each metered dose or "puff" of the aerosol contains a formulation comprising from about 0.01 mg to about 100 m g of the compound disclosed in the present invention. In certain embodiments, each metered dose or "puff" of the aerosol contains a formulation comprising from about 1 mg to about 10 mg of the compound disclosed in the present invention. Administration may be several times a day, for example 2, 3, 4 or 8 times, and for example 1, 2 or 3 doses may be given each time.

[0586] Also within the scope of the present disclosure are pharmaceutical compositions and methods of treatment or prevention comprising administering a prodrug of at least one compound disclosed in the present invention.

[0587] Non-limiting examples of suitable CSF-1R inhibitors according to formula (I) and formula (II) are presented in the following examples. It is understood that any or all of the amines of the structures presented in the inhibitors according to formula (I) and formula (II) presented in the following examples may be in the free amine form or in the protonated form having a pharmaceutically acceptable anion. Preferred pharmaceutically acceptable anions include, but are not limited to, halide ions, carbonate ions, bicarbonate ions, sulfate ions, bisulfate ions, hydroxide ions, nitrate ions, persulfate ions, phosphate ions, sulfite ions, acetate ions, ascorbate ions, benzoate ions, citrate ions, dihydrogen citrate ions, hydrogen citrate ions, oxalate ions, succinate ions, tartrate ions, taurocholate ions, glycolate ions and cholate ions. Most preferred pharmaceutically acceptable anions include chloride ions, carbonate ions and bicarbonate ions. It is understood that any or all of the CSF-1R inhibitors according to formula (I) and formula (II) may also be in the racemic form or in the enantiomeric form of the racemate.

Examples

[0588] Synthesis method Certain embodiments of the present disclosure are described with reference to the preparations and schemes shown below; it should be understood that such embodiments are merely examples and are merely illustrative except for a few of the many possible specific embodiments that can illustrate the use of the principles of the present disclosure. Various changes and modifications to the preparations, schemes and examples will be apparent to those skilled in the art who will benefit from the present disclosure.

[0589]

Chemical formula

[0590]

Chemical formula

[0591] The following examples show the compounds of formula (I) and formula (XIII) synthesized according to the above scheme.

[0592] Example 1-1: Synthesis of 4-(1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-2-methylbut-3-yn-2-amine Example 1-1-1: Preparation of 4-iodo-3-(2-(4-methoxyphenyl)-2-oxoethoxy)benzamide To a stirred solution of 3-hydroxy-4-iodobenzamide (1.90 g, 7.23 mmol) in N,N-dimethylformamide (20 mL) were added 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.80 g, 7.86 mmol) and potassium carbonate (2.00 g, 14.47 mmol). The mixture was stirred at room temperature. After 1 hour, the mixture was diluted with brine (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (silica gel, eluent 5% methanol in dichloromethane) to give 1.60 g (55%) of 4-iodo-3-(2-(4-methoxyphenyl)-2-oxoethoxy)benzamide as a yellow solid.

[0593] Example 1-1-2: Preparation of 3-(2-hydroxy-2-(4-methoxyphenyl)ethoxy)-4-iodobenzamide To a stirred solution of 4-iodo-3-(2-(4-methoxyphenyl)-2-oxoethoxy)benzamide (1.60 g, 3.89 mmol) in methanol (25 mL) was slowly added sodium borohydride (0.158 g, 4.18 mmol) at 0 °C. The resulting mixture was stirred at 0 °C. After 1 hour, the mixture was diluted with brine (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (silica gel, eluent 5% methanol in dichloromethane) to give 3-(2-hydroxy-2-(4-methoxyphenyl)ethoxy)-4-iodobenzamide 1.50 g (94%) as a yellow solid.

[0594] Example 1-1-3: Preparation of 2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide To a stirred solution of 3-(2-hydroxy-2-(4-methoxyphenyl)ethoxy)-4-iodobenzamide (0.78 g, 1.88 mmol) in N,N-dimethylformamide (15 mL) were added sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.75 mmol) and copper(I) iodide (0.36 g, 1.88 mmol). The resulting mixture was heated to 80 °C. After 2 hours, the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, eluent 1 - 2% methanol in dichloromethane) to give 2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide 0.41 g (76%) as a white solid.

[0595] Example 1-1-4: Preparation of (2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine To a stirred solution of 2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (0.43 g, 1.51 mmol) in tetrahydrofuran (10 mL) was added 1.0 M borane-tetrahydrofuran complex (30 mL, 30 mmol). The resulting mixture was heated to reflux. After 16 h, the mixture was cooled to room temperature and quenched by slowly adding methanol (20 mL). The mixture was stirred at room temperature. After 2 h, the mixture was concentrated. The crude product was purified by chromatography (silica gel, eluent 10% methanol in dichloromethane) to give 0.32 g (75%) of (2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine as a yellow solid.

[0596] Example 1-1-5: Preparation of 4-iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-nitroaniline To a stirred solution of (2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine (0.25 g, 0.92 mmol) in acetonitrile (25 mL) were added 2-fluoro-4-iodo-1-nitrobenzene (0.27 g, 1.01 mmol) and potassium carbonate (0.26 mg, 1.85 mmol). The resulting mixture was heated to reflux. After 1 h, the mixture was cooled to room temperature and filtered. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, eluent 10% methanol in dichloromethane) to give 0.24 g (50%) of 4-iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-nitroaniline as a yellow solid.

[0597] Example 1-1-6: 4-Iodo-N 1 -((2-(4-methoxyphenyl)-2,3-di hydrobenzo[b][1,4]dioxin-6-yl)methyl)benzene-1,2-diamine Preparation 4-Iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)methyl)-2-nitroaniline (0.26 g, 0.51 mmol) in ethanol (20 mL) and water (5 mL) was stirred and suspended, and iron powder (0.14 g, 2.52 mmol) and ammonium chloride (0.13 g, 2.52 mmol) were added. The resulting mixture was heated to reflux. After 1 hour, the mixture was cooled to room temperature and filtered. The filtrate was concentrated. The crude product was purified by chromatography (neutral alumina, eluent: 5% methanol in dichloromethane) to obtain 4-iodo-N 1 -((2-(4-methoxyphenyl) -2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)benzene-1,2-diamine 0.23 g (91%) as a yellow solid.

[0598] Example 1-1-7: Preparation of 5-iodo-1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazole 4-Iodo-N 1 -((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b [1,4]dioxin-6-yl)methyl)benzene-1,2-diamine (0.22 g, 0.42 mmol) in N,N-dimethylformamide (30 mL) was stirred, and triethyl orthoformate (0.46 g, 3.09 mmol) and p-toluenesulfonic acid monohydrate (0.038 g, 0.22 mmol) were added. The mixture was stirred at room temperature. After 1 hour, the mixture was diluted with water (150 mL), and the resulting precipitate was collected by filtration. The crude product was purified by chromatography (neutral alumina, eluent: 2% methanol in dichloromethane) to obtain 5-iodo-1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazole 0.20 g (93%) as a yellow solid.

[0599] Example 1-1-8: Preparation of 4-(1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-2-methylbut-3-yn-2-amine To a stirred solution of 5-iodo-1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazole (0.17 g, 0.34 mmol) in tetrahydrofuran (3 mL) were added 2-methylbut-3-yn-2-amine (0.057 g, 0.68 mmol), copper(I) iodide (0.026 g, 0.14 mmol), piperidine (0.15 g, 1.70 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.048 g, 0.068 mmol). The mixture was heated to 60 °C in a microwave reactor. After 30 minutes, the mixture was cooled to room temperature and filtered. The crude product was purified by chromatography (preparative HPLC) to give 0.029 g (19%) of 4-(1-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)-2-methylbut-3-yn-2-amine as a yellow solid: 1 H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.88 (s, 1H), 7.35 - 7.30 (m, 3H), 7.25 (d, J = 8.5 Hz, 1H), 6.97 - 6.93 (m, 3H), 6.77 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 8.5, 2.0 Hz, 1H), 5.26 (s, 2H), 5.07 - 5.05 (m, 1H), 4.32 - 4.30 (m, 1H), 4.03 - 3.99 (m, 1H), 3.84 (s, 3H), 1.54 (s, 6H) ppm; (M+1) = 454.

[0600] Example 1-2: Synthesis of 4-(3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Example 1-2-1: Preparation of 5-iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine (2-(4-Methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine (0.51 g, 1.87 mmol, Example 1-1-4) in acetonitrile (10 mL) was added to a stirred solution of 2-chloro-5-iodo-3-nitropyridine (0.64 g, 2.25 mmol) and diisopropylethylamine (0.60 g, 4.68 mmol). The resulting bright yellow mixture was heated to reflux. After 5 hours, the mixture was cooled to room temperature and diluted with water (40 mL). The mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, 0 - 33% ethyl acetate / hexane eluent) to give 0.81 g (84%) of 5-iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine as a yellow solid.

[0601] Example 1-2-2: 5-Iodo-N 2 -((2-(4-methoxyphenyl)-2,3-di hydrobenzo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine Preparation To a stirred solution of 5-iodo-N-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine (0.81 g, 1.57 mmol) in acetic acid (15 mL) was added iron powder (0.61 g, 10.96 mmol). The mixture was heated to 100 °C and as the mixture warmed, the initial bright yellow color gradually darkened to a grayish-brown. After 45 minutes, the grayish-brown suspension was cooled to room temperature and diluted with ethyl acetate (50 mL). The resulting suspension was further filtered through celite with the addition of more ethyl acetate (30 mL). The filtrate was washed with brine (1×25 mL) and 1N sodium hydroxide solution (3×25 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 5-iodo-N 2 -((2-(4-methoxyphenyl)-2,3-dihydroben zo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine 0.77 g (100%) as a brownish solid.

[0602] Example 1-2-3: Preparation of 6-iodo-3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine 5-iodo-N 2 -((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b A stirred suspension of 3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine (0.77 mg, 1.57 mmol) in ethanol (15 mL) was added with triethyl orthoformate (0.70 g, 4.70 mmol) and p-toluenesulfonic acid monohydrate (0.014 g, 0.078 mmol). The mixture was heated to reflux. After 30 minutes, the brownish solution was cooled to room temperature. The mixture was diluted with water (40 mL) and extracted with dichloromethane (2×30 mL). The combined organic phases were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, eluent 2M ammonia / methylene chloride in 1 - 5% methanol) to give 0.54 g (70%) of 6-iodo-3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine as a yellowish brown solid.

[0603] Example 1-2-4: Preparation of 4-(3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine To a stirred solution of 6-iodo-3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.10 g, 0.20 mmol) in piperidine (3.5 mL) was added 2-methylbut-3-yn-2-amine (0.021 g, 0.24 mmol), copper(I) iodide (0.008 g, 0.040 mmol) and bis(triphenylphosphine)palladium (II) Chloride (0.014 g, 0.020 mmol) was added. The mixture was heated to 100 °C in a microwave reactor. After 30 minutes, the reaction mixture was diluted with 5N ammonium hydroxide solution (30 mL) and extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, eluent 2M ammonia / methylene chloride in 1 - 5% methanol) to give 0.060 g (66%) of 4-(3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine as an off-white solid: 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.02 (s, 1H), 7.34 - 7.30 (m, 2H), 6.96 - 6.92 (m, 3H), 6.89 (d, J = 2.0 Hz, 1H), 6.83 (dd, J = 8.3, 2.1 Hz, 1H), 5.36 (s, 2H), 5.04 (dd, J = 8.9, 2.3 Hz, 1H), 4.29 (dd, J = 11.5, 2.4 Hz, 1H), 3.99 (dd, J = 11.5, 9.0 Hz, 1H), 3.82 (s, 3H), 1.77 (br s, 2H), 1.53 (s, 6H) ppm; (M+1) = 455.

[0604] Example 1-2-5: Chiral Separation of 4-(3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine The racemic 4-(3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine was subjected to SFC preparative purification (21.2×250 mm LUX-3 column, 50% methanol / 0.2% diethylamine modifier, flow rate 45 g / min, 100 bar pressure, sample concentration 20 mg / mL) to obtain the individual enantiomers (absolute configuration not specified).

[0605] Examples 1 - 3: Synthesis of 3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine To a stirred solution of 6-iodo-3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.19 g, 0.38 mmol, Example 1 - 2 - 3) in dimethyl sulfoxide (3.5 mL) were added 1-methylpiperazine (0.046 g, 0.46 mmol), L-proline (0.011 g, 0.091 mmol), potassium carbonate (0.18 g, 1.33 mmol), and copper(I) iodide (0.009 g, 0.047 mmol). The resulting pale yellow suspension was heated to 150 °C. After 16 hours, the mixture was cooled to room temperature and diluted with 3N ammonium hydroxide solution (15 mL). The mixture was extracted with dichloromethane (3×20 mL). The combined organic phases were washed with water (2×15 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 12 g, 1 - 10% methanol / dichloromethane eluent) to give 0.048 g (27%) of 3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine as an off-white solid: 11H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.5 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.33 - 7.29 (m, 2H), 6.79 - 7.00 (m, 5H), 5.33 (s, 2H), 5.03 (dd, J = 9.0, 2.4 Hz, 1H), 4.29 (dd, J = 11.5, 2.4 Hz, 1H), 3.99 (dd, J = 11.5, 9.0 Hz, 1H), 3.82 (s, 3H), 3.19 - 3.33 (m, 4H), 2.57 - 2.70 (m, 4H), 2.38 (s, 3H) ppm (M+1) = 472.

[0606] Examples 1-4: Synthesis of 3-((2-(4-Methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine To a stirred solution of 6-iodo-3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.15 g, 0.30 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.3 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.076 g, 0.36 mmol), cesium carbonate (0.30 g, 0.91 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.030 mmol). The resulting mixture was heated to 100 °C. After 7 hours, the mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was filtered through Celite and the filtrate was concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 90% ethyl acetate / heptane eluent) to give a beige oil which crystallized on standing. The beige solid was treated with acetonitrile and water and the resulting precipitate was collected by filtration to give 0.050 g (37%) of 3-((2-(4-methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 1.9 Hz, 1H), 8.56 (s, 1H), 8.29 - 8.19 (m, 2H), 7.97 (d, J = 0.9 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.02 - 6.93 (m, 3H), 6.90 (d, J = 1.2 Hz, 2H), 5.39 (s, 2H), 5.12 (dd, J = 8.5, 2.4 Hz, 1H), 4.33 (dd, J = 11.6, 2.5 Hz, 1H), 4.04 (dd, J = 11.6, 8.5 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H).

[0607] Example 1-5: Synthesis of 4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Example 1-5-1: Preparation of 4-iodo-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzamide To a stirred solution of 3-hydroxy-4-iodobenzamide (1.36 g, 5.16 mmol) in N,N-dimethylformamide (20 mL) were added potassium carbonate (1.95 g, 14.08 mmol) and 2-bromo-1-(6-methoxypyridin-3-yl)ethanone (1.08 g, 4.69 mmol). The resulting reaction mixture was heated to 80 °C. After 2 hours, the mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with dichloromethane (2 × 40 mL). The combined organic extracts were washed with water (40 mL) and brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 0 - 100% ethyl acetate / heptane eluent) to give 0.89 g (46%) of 4-iodo-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzamide as a yellowish-brown solid.

[0608] Example 1-5-2: Preparation of 3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)-4-iodobenzamide To a stirred solution of 4-iodo-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzamide (0.89 g, 2.15 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was added sodium borohydride (0.16 g, 4.30 mmol). The resulting mixture was stirred at room temperature. After 16 h, the mixture was quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to give 0.89 g (100%) of 3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)-4-iodobenzamide as an off-white solid.

[0609] Example 1-5-3: Preparation of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide To a stirred solution of 3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)-4-iodobenzamide (0.93 g, 2.24 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% dispersion in oil, 0.27 g, 6.71 mmol). The reaction was stirred at room temperature for 15 min, then copper(I) iodide (0.43 g, 2.24 mmol) was added. The mixture was heated to 80 °C. After 3 h, the mixture was cooled to room temperature and diluted with water (75 mL). The mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, 1 - 10% methanol / dichloromethane eluent) to give 0.40 g (63%) of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide as a yellowish-brown solid.

[0610] Example 1-5-4: Preparation of (2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine A stirred solution of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide (0.40 g, 1.40 mmol) in tetrahydrofuran (10 mL) was treated with 1.0 M borane-tetrahydrofuran complex (5.6 mL, 5.60 mmol). The mixture was heated to reflux. After 2 hours, the mixture was cooled to 0 °C. Methanol (5 mL) was slowly added to quench the reaction, and the resulting mixture was heated to reflux. After 1 hour, the mixture was cooled to room temperature and concentrated. The residue was dissolved in tetrahydrofuran (20 mL) and 1 N hydrochloric acid solution (10 mL). The resulting mixture was heated to reflux. After 2 hours, the mixture was cooled to room temperature and the pH of the mixture was adjusted to approximately 7 by addition of 1 N sodium hydroxide solution. The neutral mixture was extracted with dichloromethane (3 × 25 mL). The combined organic phases were washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated to give 0.38 g (100%) of (2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine as an oil.

[0611] Example 1-5-5: Preparation of 5-Iodo-N-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine (2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine (0.38 g, 1.40 mmol) in a stirred solution in acetonitrile (10 mL) was added 2-chloro-5-iodo-3-nitropyridine (0.48 g, 1.67 mmol) and diisopropylethylamine (0.54 g, 4.19 mmol). The resulting yellow mixture was heated to reflux. After 4 hours, the mixture was cooled to room temperature and diluted with water (40 mL). The mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, 0 - 33% ethyl acetate / hexane eluent) to give 0.35 g (48%) of 5-iodo-N-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine as a yellow solid.

[0612] Example 1-5-6: 5-Iodo-N 2 -((2-(6-Methoxypyridin-3-yl)- Preparation of 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine To a stirred suspension of 5-iodo-N-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3-nitropyridin-2-amine (0.35 g, 0.67 mmol) in acetic acid (8 mL) was added iron powder (0.26 g, 4.71 mmol). The mixture was heated to 100 °C and as the mixture warmed, the initial bright yellow gradually darkened to grayish brown. After 45 minutes, the grayish brown suspension was cooled to room temperature and diluted with ethyl acetate (50 mL). The resulting suspension was further filtered through Celite with the addition of ethyl acetate (25 mL). The filtrate was washed with brine (1 × 25 mL) and 1N sodium hydroxide solution (3 × 25 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to give 5-iodo-N 2 -((2-(6-Methoxypyridin-3-yl)-2, 3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine (0.30 g, 91%) was obtained as an orange solid.

[0613] Example 1-5-7: Preparation of 6-Iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine 5-Iodo-N 2 -((2-(6-methoxypyridin-3-yl)-2,3-dihydro benzo[b][1,4]dioxin-6-yl)methyl)pyridine-2,3-diamine (0.300 g, 0.61 mmol) in ethanol (10 mL) was stirred and suspended, and triethyl orthoformate (0.27 g, 1.84 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.031 mmol) were added. The resulting mixture was heated to reflux. After 30 minutes, the brownish solution was cooled to room temperature and diluted with water (40 mL). The mixture was extracted with dichloromethane (3 × 25 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, eluent 2M ammonia / methylene chloride in 1 - 5% methanol) to give 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine 0.30 g (98%) as a yellowish brown solid.

[0614] Example 1-5-8: Preparation of 4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine To a stirred solution of 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.22 g, 0.45 mmol) in piperidine (3.5 mL) were added 2-methylbut-3-yn-2-amine (0.047 g, 0.53 mmol), copper(I) iodide (0.017 mg, 0.089 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.031 mg, 0.044 mmol). The mixture was heated to 100 °C in a microwave reactor. After 30 minutes, the reaction mixture was diluted with 5N ammonium hydroxide solution (30 mL) and extracted with dichloromethane (3 × 25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 12 g, eluent 2M ammonia / methylene chloride in 1 - 5% methanol) to give 0.16 g (79%) of 4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine, also known as GENZ-882706 and RA03546849, as an off-white solid: 1 H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.03 (s, 1H), 7.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.87 - 6.96 (m, 2H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.36 (s, 2H), 5.07 (dd, J = 8.7, 2.3 Hz, 1H), 4.30 (dd, J = 11.6, 2.3 Hz, 1H), 4.02 (dd, J = 11.6, 8.7 Hz, 1H), 3.95 (s, 3H), 1.80 (br s, 2H), 1.53 (s, 6H) ppm; (M+1) = 456.

[0615] Example 1-5-9: 4-(3-((2-(6-Methoxypyridin-3-yl)-2,3- Dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Chiral Resolution The racemic 4-(3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine was subjected to SFC preparative purification (21.2×250 mm Chiralcel OJ column, 25% ethanol / 0.2% diethylamine modifier, flow rate 75 g / min) to obtain the individual enantiomers.

[0616] Example 1-6: Synthesis of 3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine As described in Example 1-3, the title compound was prepared from 3-((2-(6-Methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-b]pyridine (Example 1-5-7) and 1-methylpiperazine: 11H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.87 - 6.95 (m, 2H), 6.84 (dd, J = 8.3, 2.1 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.33 (s, 2H), 5.07 (dd, J = 8.8, 2.3 Hz, 1H), 4.29 (dd, J = 11.6, 2.3 Hz, 1H), 4.02 (dd, J = 11.6, 8.8 Hz, 1H), 3.95 (s, 3H), 3.14 - 3.30 (m, 4H), 2.60 - 2.70 (m, 4H), 2.38 (s, 3H) ppm; (M+1) = 473.

[0617] Examples 1 - 7: Synthesis of 3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile A solution of 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.10 g, 0.20 mmol, Example 1-5-7) in N,N-dimethylformamide (3 mL) was degassed using nitrogen. The mixture was treated with tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.019 mmol) and zinc cyanide (0.014 g, 0.12 mmol), and heated at 100 °C in a sealed vessel. After 3 hours, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and water, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 70% ethyl acetate / hexane eluent), and the isolated material was triturated with acetone / hexane to give 3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile 0.054 g (68%) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.76 (m, 2H), 8.71 (d, J = 1.8 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 8.6, 2.5 Hz, 1H), 7.00 (t, J = 1.2 Hz, 1H), 6.96 - 6.78 (m, 3H), 5.44 (s, 2H), 5.21 (dd, J = 8.4, 2.4 Hz, 1H), 4.37 (dd, J = 11.6, 2.5 Hz, 1H), 4.14 (dd, J = 11.6, 8.4 Hz, 1H), 3.84 (s, 3H).

[0618] Example 1-8: Synthesis of 6-(azetidin-1-yl)-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine 6-Iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.11 g, 0.22 mmol, Example 1-5-7) in a stirred solution of 1,2-dimethoxyethane (3 mL) was treated with palladium(II) acetate (0.003 mg, 0.013 mmol) and (R)-1-[(S P )-2-(dicyclohexylphosphino)ferro cenyl]ethyldicyclohexylphosphine (0.007 g, 0.012 mmol). The resulting yellow solution was treated with azetidine (0.025 g, 0.44 mmol) and solid sodium t-butoxide (0.042 g, 0.44 mmol). The mixture was heated to 100 °C in a sealed vessel. After 20 h, the mixture was cooled to room temperature and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 0-5% methanol / dichloromethane eluent) to give 6-(azetidin-1-yl)-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine 0.043 g (46%) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.24 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 8.6, 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 7.00 - 6.76 (m, 4H), 5.30 (s, 2H), 5.20 (dd, J = 8.4, 2.5 Hz, 1H), 4.36 (dd, J = 11.5, 2.5 Hz, 1H), 4.13 (dd, J = 11.5, 8.4 Hz, 1H), 3.92 - 3.74 (m, 4H), 3.32 (s, 3H), 2.37 - 2.27 (m, 2H) ppm; (M+1) = 430.

[0619] Example 1-9: Synthesis of 6-Cyclopropyl-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine To a mixture of 6-Iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.11 g, 0.21 mmol, Example 1-5-7), [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.016 g, 0.021 mmol), cesium carbonate (0.21 g, 0.66 mmol) and cyclopropylboronic acid (0.028 g, 0.33 mmol), 1,2-dimethoxyethane (3 mL) and water (0.3 mL) were added. The resulting mixture was heated to 100 °C in a sealed vessel. After 4 hours, additional amounts of catalyst and boronic acid were added and the mixture was stirred. After a total of 7 hours, the mixture was cooled to room temperature and diluted with ethyl acetate. The mixture was filtered through a short pad of silica gel and celite, and the residue was concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 0 - 5% methanol / dichloromethane eluent), followed by preparative HPLC (10 - 90% acetonitrile / water with 0.1% trifluoroacetic acid) to give 0.012 g (10%) of 6-Cyclopropyl-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (trifluoroacetate) as a white solid: 11H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 7.76 (dd, J = 8.5, 2.4 Hz, 2H), 7.00 - 6.98 (m, 1H), 6.92 - 6.90 (m, 2H), 6.86 (d, J = 8.5 Hz, 1H), 5.41 (s, 2H), 5.21 (dd, J = 8.3, 2.5 Hz, 1H), 4.37 (dd, J = 11.6, 2.5 Hz, 1H), 4.14 (dd, J = 11.6, 8.3 Hz, 1H), 3.85 (s, 3H), 2.16 - 2.06 (m, 1H), 1.05 - 0.96 (m, 2H), 0.83 - 0.75 (m, 2H) ppm; (M+1) = 415.

[0620] Examples 1 - 10: Synthesis of 4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine To a stirred solution of 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.23 g, 0.45 mmol, Example 1 - 5 - 7) in 1,4-dioxane (3 mL) were added morpholine (0.062 g, 0.70 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (0.012 g, 0.013 mmol), 2-di-cyclohex Xylphosphino-2’,6’-di-i-propoxy-1,1’-biphenyl (0.006 g, 0.013 mmol) and sodium t-butoxide (62.38 mg, 629.64 μmol) were added. The container was sealed and the contents were degassed under vacuum and refilled with nitrogen (3 times). The mixture was then heated to 110 °C. After 16 hours, the mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with brine (25 mL), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel gold column 24 g, 0 - 5% methanol / dichloromethane eluent) to give 0.066 g (32%) of 4-(3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)morpholine as a white solid: 1 H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 2.5 Hz, 1H), 8.21 - 8.17 (m, 1H), 7.96 (s, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.93 - 6.82 (m, 3H), 6.79 (d, J = 8.6 Hz, 1H), 5.34 (s, 2H), 5.07 (dd, J = 8.8, 2.5 Hz, 1H), 4.30 (dd, J = 11.6, 2.5 Hz, 1H), 4.02 (dd, J = 11.6, 8.8 Hz, 1H), 3.95 (s, 3H), 3.93 - 3.90 (m, 4H), 3.20 - 3.14 (m, 4H) ppm; (M+1) = 460.

[0621] Example 1 - 11: Synthesis of 6-methoxy-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine To a stirred solution of 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (0.26 g, 0.52 mmol, Example 1-5-7) in methanol (3.0 mL) were added copper(I) iodide (0.010 g, 0.052 mmol), 1,10-phenanthroline (0.019 g, 0.10 mmol) and cesium carbonate (0.34 g, 1.05 mmol). The mixture was heated at 110 °C in a sealed vessel. After 20 h, the mixture was cooled to room temperature and diluted with 5N ammonium hydroxide solution (50 mL) and dichloromethane (50 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel gold column 24 g, 0-5% methanol / dichloromethane eluent) to give 0.17 g of a white solid (containing 1,10-phenanthroline as an impurity). The material was dissolved in dichloromethane (30 mL) and washed with 1N hydrochloric acid solution (2×30 mL). The combined aqueous phases were made basic using 1N sodium hydroxide solution (ca. 60 mL) and the resulting milky white mixture was extracted with diethyl ether (3×15 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to give a colorless oil. The material was redissolved in diethyl ether (15 mL) and sonicated to give a precipitate. The solid was collected by filtration and dried to give 0.090 g (43%) of 6-methoxy-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine as a white solid: 11H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 2.6 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.97 (s, 1H), 7.61 - 7.58 (m, 2H), 6.93 - 6.88 (m, 2H), 6.84 (dd, J = 8.3, 2.2 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.35 (s, 2H), 5.07 (dd, J = 8.8, 2.5 Hz, 1H), 4.30 (dd, J = 11.6, 2.5 Hz, 1H), 4.02 (dd, J = 11.6, 8.8 Hz, 1H), 3.95 (s, 3H), 3.90 (s, 3H) ppm: (M+1) = 405.

[0622] Example 1-12: Synthesis of 4-(3-((2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Example 1-12-1: Preparation of tert-butyl (4-(benzyloxy)-3-hydroxybenzyl)carbamate A stirred solution of 3-hydroxy-4-benzyloxybenzaldehyde (4.05 g, 16.86 mmol) and t-butyl carbamate (3.02 g, 25.29 mmol) in acetonitrile (100 mL) was cooled to 0 °C while adding triethylsilane (5.94 g, 50.57 mmol) and trifluoroacetic acid (3.88 g, 33.71 mmol). The resulting yellow solution was stirred at 0 °C for 15 minutes and then the mixture was warmed to room temperature. After 3 hours, further amounts of t-butyl carbamate (1.00 g), triethylsilane (5.94 g) and trifluoroacetic acid (3.88 g) were added and the mixture was stirred at room temperature. After 20 hours, the mixture was concentrated and the residue was diluted with saturated sodium bicarbonate solution (150 mL). The mixture was extracted with diethyl ether (3 × 75 mL). The combined organic phases were washed with 1N sodium hydroxide solution (2 × 50 mL), 1N hydrochloric acid solution (2 × 50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel gold column 120 g, 0 - 10% ethyl acetate / dichloromethane eluent) to give a white solid. This material was triturated with heptane to give 2.25 g (41%) of t-butyl 4-(benzyloxy)-3-hydroxybenzylcarbamate as a white solid.

[0623] Example 1-12-2: Preparation of t-butyl (4-(benzyloxy)-3-((1-(4-methoxyphenyl)-1-oxopropan-2-yl)oxy)benzyl)carbamate To a stirred solution of t-butyl 4-(benzyloxy)-3-hydroxybenzylcarbamate (1.25 g, 3.79 mmol) in acetonitrile (40 mL) were added cesium carbonate (1.86 g, 5.69 mmol) and 2-bromo-1-(4-methoxyphenyl)propan-1-one (0.97 g, 3.79 mmol). After 2 hours, the mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column 40 g, 10 - 30% ethyl acetate / heptane eluent) to give 1.35 g (72%) of t-butyl 4-(benzyloxy)-3-((1-(4-methoxyphenyl)-1-oxopropan-2-yl)oxy)benzylcarbamate as a white solid.

[0624] Example 1 - 12 - 3: Preparation of t-butyl (4-hydroxy-3-((1-hydroxy-1-(4-methoxyphenyl)propan-2-yl)oxy)benzyl)carbamate A stirred solution of t-butyl 4-(benzyloxy)-3-((1-(4-methoxyphenyl)-1-oxopropan-2-yl)oxy)benzylcarbamate (1.35 g, 2.75 mmol) in tetrahydrofuran (30 mL) was treated with 10% palladium on carbon (hydrous) (0.89 g, 0.84 mmol). The mixture was degassed under vacuum and refilled with nitrogen (3 times). After the last evacuation, the atmosphere was replaced with hydrogen by balloon. The reaction mixture was stirred at room temperature. After 1 hour, the vessel was evacuated and the atmosphere was replaced with nitrogen. Tetrahydrofuran (50 mL) was added and the mixture was filtered through celite. The filtrate was diluted with methanol (10 mL) and the yellow solution was treated with sodium borohydride (0.13 g, 3.43 mmol) (gas evolution and mild exotherm were observed). After 90 minutes, the mixture was treated with water (2 mL) and concentrated. The residue was dissolved in ethyl acetate (75 mL) and washed with saturated sodium bicarbonate solution (75 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to give 1.18 g (>100%) of t-butyl 4-hydroxy-3-((1-hydroxy-1-(4-methoxyphenyl)propan-2-yl)oxy)benzylcarbamate as a colorless oil.

[0625] Example 1-12-4: Preparation of t-butyl ((2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)carbamate t-Butyl 4-hydroxy-3-((1-hydroxy-1-(4-methoxyphenyl) A solution of (1-methylethyl)oxy)benzylcarbamate (1.11 g, 2.75 mmol) and triphenylphosphine (0.98 g, 3.71 mmol) in tetrahydrofuran (30 mL) was stirred, and a solution of bis(2-methoxyethyl)azodicarboxylate (0.90 g, 3.71 mmol) in tetrahydrofuran (10 mL) was added thereto over 3 minutes. The resulting yellow solution was heated to reflux. After 3 hours, the mixture was cooled to room temperature and diluted with ethyl acetate (75 mL). The organic phase was washed with water (2×50 mL), 1N hydrochloric acid solution (50 mL), 1N sodium hydroxide solution (50 mL), and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel gold column 40 g, 10 - 25% ethyl acetate / heptane eluent) to obtain 0.50 g (47%) of t-butyl ((2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)carbamate as a white solid.

[0626] Example 1-12-5: Preparation of (2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine Trifluoroacetic acid (5.0 mL, 64.64 mmol) was added to a stirred solution of t-butyl ((2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)carbamate (0.50 g, 1.30 mmol) in dichloromethane (10 mL). After 30 minutes, the solution was concentrated, and the residue was dissolved in 5N ammonium hydroxide solution (20 mL). The basic mixture was extracted with dichloromethane (2×30 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to obtain 0.36 g (97%) of (2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine as a colorless oil.

[0627] Example 1-12-6: Preparation of 4-(3-((2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine As described in Examples 1-5-5 to 1-5-8, the title compound was prepared in 4 steps from (2-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine: 1 H NMR (400 MHz, chloroform-d) δ 8.46 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 1.9 Hz, 1H), 8.02 (s, 1H), 7.29 - 7.24 (m, 2H), 6.96 - 6.80 (m, 5H), 5.36 (s, 2H), 4.57 (d, J = 8.0 Hz, 1H), 4.08 (dq, J = 8.0, 6.4 Hz, 1H), 3.82 (s, 3H), 1.53 (s, 6H), 1.14 (d, J = 6.4 Hz, 3H) ppm: (M+1) = 469.

[0628] Example 1-13: Synthesis of 6-methoxy-3-((2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine Example 1-13-1: Preparation of (2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine As described in Examples 1-12-2 to 1-12-5, the title compound was prepared in 4 steps from 2-bromo-1-(6-methoxypyridin-3-yl)propan-1-one.

[0629] Example 1-13-2: Preparation of 6-Iodo-3-((2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine As described in Examples 1-5-5 to 1-5-7, in three steps from (2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine and 2-chloro-5-iodo-3-nitropyridine the title compound was prepared.

[0630] Example 1-13-3: Preparation of 6-Methoxy-3-((2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine As described in Example 1-11, the title compound was prepared from 6-iodo-3-((2-(6-methoxypyridin-3-yl)-3-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine and methanol: (about 55:45 trans / cis) 1 H NMR (400 MHz, chloroform-d) δ 8.23 - 8.20 (m, 1H), 8.16 - 8.12 (m, 1H), 8.00 - 7.96 (m, 1H), 7.60 - 7.57 (m, 1H), 7.57 - 7.53 (m, 1H), 6.93 - 6.72 (m, 4H), 5.35 (s, 2H), 5.12 (d, J = 2.6 Hz, 1H, cis isomer), 4.60 (d, J = 8.0 Hz, 1H, trans isomer), 4.51 - 4.43 (m, 1H, cis isomer), 4.13 - 4.04 (m, 1H, trans isomer), 3.99 - 3.88 (m, 9H), 1.17 (d, J = 6.3 Hz, 3H, trans isomer), 1.12 (d, J = 6.6 Hz, 3H, cis isomer) ppm; (M+1) = 419.

[0631] Example 1-14: Synthesis of 4-(3-((2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Example 1-14-1: Preparation of 3-(2-(2,4-dichlorophenyl)-2-oxoethoxy)-4-fluorobenzonitrile To a stirred and cooled (0 °C) suspension of 4-fluoro-3-hydroxybenzonitrile (5.00 g, 36.47 mmol) and potassium carbonate (10.08 g, 72.93 mmol) in N,N-dimethylformamide (80 mL) was added dropwise over 3 minutes a solution of 2-bromo-1-(2,4-dichlorophenyl)ethanone (9.77 g, 36.47 mmol) in N,N-dimethylformamide (10 mL). After 15 minutes, the cooling bath was removed and the mixture was warmed to room temperature. After 90 minutes, the mixture was recooled to 0 °C with the addition of water to afford a precipitate. The solid was collected by filtration, washed successively with water and then hexane, and dried to give 11.80 g (97%) of 3-(2-(2,4-dichlorophenyl)-2-oxoethoxy)-4-fluorobenzonitrile as an off-white solid.

[0632] Example 1-14-2: Preparation of 3-(2-(2,4-dichlorophenyl)-2-hydroxyethoxy)-4-fluorobenzonitrile Methanol (80 mL) was cooled to 0 °C while sodium borohydride (2.45 g, 64.76 mmol) was slowly added. After the addition was complete, the mixture was stirred at 0 °C for 15 minutes, and then 3-(2-(2,4-dichlorophenyl)-2-oxoethoxy)-4-fluorobenzonitrile (7.00 g, 21.60 mmol) was slowly added. A precipitate formed near the end of the addition, so an additional amount of methanol (70 mL) was added. The resulting suspension was warmed to room temperature. After 1 hour, the mixture was recooled to 0 °C, and then 0.1 N hydrochloric acid solution (20 mL) was added. The mixture was extracted with dichloromethane, and the combined organic phases were concentrated. The crude solid was triturated with dichloromethane, filtered, and then washed with hexane. The second trituration with dichloromethane / washing with hexane gave 5.90 g (84%) of 3-(2-(2,4-dichlorophenyl)-2-hydroxyethoxy)-4-fluorobenzonitrile as an off-white solid.

[0633] Example 1-14-3: Preparation of 2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile A stirred suspension of potassium carbonate (6.25 g, 45.22 mmol) and 3-(2-(2,4-dichlorophenyl)-2-hydroxyethoxy)-4-fluorobenzonitrile (5.90 g, 18.09 mmol) in N,N-dimethylformamide (60 mL) was heated to 80 °C. After 24 hours, the mixture was cooled to room temperature while adding water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude product was triturated with methanol, filtered to give 2.75 g of a white solid. The filtrate was concentrated, and the residue was purified (CombiFlash, silica gel column, 10 - 20% ethyl acetate / heptane eluent) to give an additional 0.73 g of a white solid. A total of 3.48 g (63%) of 2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile was obtained.

[0634] Example 1-14-4: Preparation of (2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine To a stirred and cooled (0 °C) solution of 2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile (3.48 g, 11.37 mmol) in tetrahydrofuran (60 mL) was added dropwise via syringe a 2.4 M solution of lithium aluminum hydride in ether (9.5 mL, 22.80 mmol). The mixture was stirred at 0 °C. After 30 minutes, the cooling bath was removed and the mixture was warmed to room temperature. After 4 hours, the mixture was recooled to 0 °C and diluted with Et2O. The mixture was quenched by slowly adding water (0.87 mL), 1 N sodium hydroxide solution ( 0.87 mL) and water (2.6 mL). The mixture was stirred at 0 °C for 1 hour. The resulting white suspension was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give 3.53 g (93%) of (2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine as a colorless oil which crystallized on standing.

[0635] Example 1-14-5: Preparation of 4-(3-((2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine The title compound was prepared in 4 steps from (2-(2,4-dichlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanamine, 2-chloro-5-iodo-3-nitropyridine and 2-methylbut-3-yn-2-amine as described in Examples 1-5-5 to 1-5-8: 11H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.58 (s, 2H), 8.48 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 2.0 Hz, 2H), 7.10 - 6.81 (m, 3H), 5.42 (q, J = 2.6 Hz, 3H), 4.44 (dd, J = 11.7, 2.4 Hz, 1H), 4.01 (dd, J = 11.7, 8.2 Hz, 1H), 3.61 - 3.31 (m, 1H), 1.65 (s, 4H) ppm; (M+1) = 493.

[0636] Example 1-15: Synthesis of 2,2,2-Trifluoro-N-((6-((6-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide Example 1-15-1: Preparation of 6-(Hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile The title compound was prepared from 6-formyl-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile as described in Example 1-14-2.

[0637] Example 1-15-2: Preparation of 6-((6-Bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile To a stirred solution of 6-(Hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile (1.16 g, 6.06 mmol) in toluene (17 mL) was added 2-(Tributylphosphoranylidene)acetonitrile (1.46 g, 6.06 mmol). The mixture was stirred at room temperature. After 10 minutes, 6-Bromo-3H-imidazo[4,5-b]pyridine (1.00 g, 5.05 mmol) was added to the mixture, and the resulting mixture It was heated to 90 °C. After 6 hours, the mixture was cooled to room temperature and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 80% ethyl acetate / hexane eluent) to give 0.82 g (44%) of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile as an off-white foam.

[0638] Example 1-15-3: Preparation of 6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile As described in Example 1-4, the title compound was prepared from 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

[0639] Example 1-15-4: (6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine As described in Example 1-14-4, the title compound was prepared from 6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carbonitrile.

[0640] Example 1-15-5: Preparation of 2,2,2-trifluoro-N-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide ((6 - ((6-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine (0.030 g, 0.079 mmol)) in dichloromethane (2 mL) was stirred and cooled (0 °C), and triethylamine (0.022 mL, 0.15 mmol) was added, followed by trifluoroacetic anhydride (0.007 mL, 0.079 mmol). The mixture was stirred at 0 °C. After 15 minutes, the cooling bath was removed and the mixture was warmed to room temperature. After 1 hour, the mixture was diluted with dichloromethane (10 mL) and saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 5% methanol / dichloromethane eluent) to give 2,2,2-trifluoro-N-((6-((6-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)acetamide 0.038 g (8%) as a white solid: 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.63 (d, J = 1.9 Hz, 1H), 8.53 (s, 1H), 8.30 - 8.17 (m, 2H), 7.96 (s, 1H), 7.00 - 6.77 (m, 3H), 5.36 (s, 2H), 4.38 - 4.20 (m, 2H), 3.94 (dd, J = 11.6, 6.6 Hz, 1H), 3.87 (s, 3H), 3.45 (d, J = 5.2 Hz, 2H) ppm; (M+1) = 473.

[0641] Example 1-16: Synthesis of 6-(3-Methoxyazetidin-1-yl)-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine As described in Examples 1-10, 6-iodo-3-((2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridine (Example 1-5-7) and 3-methoxy The title compound was prepared from zidovudine hydrochloride: 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 2.5 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.6, 2.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.95 - 6.76 (m, 4H), 5.31 (s, 2H), 5.07 (dd, J = 8.8, 2.5 Hz, 1H), 4.43 - 4.35 (m, 1H), 4.29 (dd, J = 11.6, 2.5 Hz, 1H), 4.22 - 4.15 (m, 2H), 4.02 (dd, J = 11.6, 8.8 Hz, 1H), 3.95 (s, 3H), 3.79 - 3.73 (m, 2H), 3.36 (s, 3H) ppm; (M+1) = 460.

[0642] Example 1-17: Synthesis of 2-methyl-4-(3-((2-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)but-3-yn-2-amine As described in Examples 1-5-1 to 1-5-8, the title compound was prepared in 8 steps from 3-hydroxy-4-iodobenzamide, 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one, 2-chloro-5-iodo-3-nitropyridine and 2-methylbut-3-yn-2-amine: 1 H NMR (400 MHz, chloroform-d) δ 8.45 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.01 (s, 1H), 7.52 (d, J = 0.8 Hz, 1H), 7.44 (s, 1H), 6.90 - 6.78 (m, 3H), 5.35 (s, 2H), 5.14 (dd, J = 7.9, 2.4 Hz, 1H), 4.32 (dd, J = 11.4, 2.5 Hz, 1H), 4.09 (dd, J = 11.4, 8.0 Hz, 1H), 3.90 (s, 3H), 1.53 (s, 6H); (M+H) = 429.

[0643] Example 1-18: Synthesis of 4-(3-(1-(2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-3H-imidazo[4,5-b]pyridin-6-yl)-2-methylbut-3-yn-2-amine Example 1-18-1: Preparation of methyl 4-(benzyloxy)-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzoate To a stirred solution of methyl 4-(benzyloxy)-3-hydroxybenzoate (3.37 g, 13.05 mmol) in N,N-dimethylformamide (20 mL) were added potassium carbonate (2.71 g, 19.57 mmol) and 2-bromo-1-(6-methoxypyridin-3-yl)ethanone (3.00 g, 13.05 mmol). The reaction was stirred at room temperature. After 16 h, the mixture was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by chromatography (CombiFlash, silica gel column, 0 - 50% ethyl acetate / heptane eluent) to give 3.81 g (72%) of methyl 4-(benzyloxy)-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzoate as a white solid.

[0644] Example 1-18-2: Preparation of methyl 4-(benzyloxy)-3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)benzoate As described in Example 1-14-2, the title compound was prepared from methyl 4-(benzyloxy)-3-(2-(6-methoxypyridin-3-yl)-2-oxoethoxy)benzoate.

[0645] Example 1-18-3: Preparation of methyl 4-hydroxy-3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)benzoate To a stirred solution of methyl 4-(benzyloxy)-3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)benzoate (3.53 g, 8.62 mmol) was added 10% palladium on carbon (0.92 g, 0.86 mmol). The mixture was degassed under vacuum and refilled with nitrogen (3 times). After the last evacuation, the atmosphere was replaced with hydrogen by balloon. The reaction mixture was heated to 65 °C. After 16 hours, the mixture was cooled to room temperature, the vessel was evacuated, and the atmosphere was replaced with nitrogen. The mixture was filtered through celite, and the filtrate was concentrated to give 2.39 g (87%) of methyl 4-hydroxy-3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)benzoate as a white solid.

[0646] Example 1-18-4: Preparation of methyl 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate As described in Example 1-12-4, the title compound was prepared from methyl 4-hydroxy-3-(2-hydroxy-2-(6-methoxypyridin-3-yl)ethoxy)benzoate.

[0647] Example 1-18-5: Preparation of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid ​To a stirred solution of methyl 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.69 g, 5.61 mmol) in 1:4 water / methanol (25 mL) was added lithium hydroxide (1.41 g, 56.10 mmol). The reaction was stirred at room temperature. After 16 h, the mixture was concentrated and the residue was dissolved in water. Adjusting the pH to about 5 with concentrated hydrochloric acid solution produced a precipitate. The mixture was filtered, the filter cake was washed with water and dried to give 1.56 g (97%) of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as a white solid.

[0648] Example 1-18-6: Preparation of N-methoxy-2-(6-methoxypyridin-3-yl)-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide To a stirred solution of 2-(6-methoxypyridin-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (1.56 g, 5.43 mmol) in N,N-dimethylformamide (15 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (4.26 g, 10.86 mmol), N,O-dimethylhydroxylamine hydrochloride (1.08 g, 10.86 mmol) and N,N-diisopropylethylamine (3.86 mL, 21.70 mmol). The mixture was stirred at room temperature. After 5 min, the mixture was diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water (3 × 40 mL) and brine, dried over magnesium sulfate, filtered and concentrated to give 1.51 g (84%) of the desired N-methoxy-2-(6-methoxypyridin-3-yl)-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamide as a colorless semi-solid.

[0649] Example 1-18-7: Preparation of 1-(2-(6-methoxypyridin-3-yl)-2,3-dihydroben...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, n is 0, 1, 2, 3, 4 or 5; m is 1, 2, 3 or 4; X １ is C, N or CR ７ and X ２ , X ３ , X ４ , X ５ , X ６ and X ７ are each independently N, NR ７ or CR ７ is selected from Here, each R ７ are independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ２ ~C １０ ) alkylnyl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C ２ ~C １０ ) alkynylamine, C(O)-, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl-, COOH-(C ３ ~C １０ ) cycloalkyl-, (C １ ~C １０ ) alkoxy-, R ８ - (C １ ~C １０ ) alkyl-, R ８ - (C ３ ~C １０ ) cycloalkyl, R ８ - (C ２ ~C ９ ) heterocycloalkyl, R ８ - (C ６ ~C １４ ) aryl, R ８ - (C ２ ~C ９ ) heteroaryl, R ８ - (C ２ ~C １０ ) alkylnyl, R ８ - (C １ ~C １０ ) alkylamine, R ８ -((C １ ~C １０ ) alkyl) ２ Amin, R. ８ - (C ２ ~C １０ ) alkynylamine, R ８ -C(O)-, R ８ - (C １ ~C １０ ) alkyl-C(O)O-, R ８ - (C １ ~C １０ ) alkoxy-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, R ８ - (C ３ ~C １０ ) Cycloalkyl-O-, R ８ - (C ２ ~C ９ ) Heterocycloalkyl-O-, R ８ - (C ６ ~C １４ ) Aryl-O-, R ８ - (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, cyano, H ２ N-, (CH ３ ) HN-, (CH ３ ) ２ N-, R ８ R ９ N-, R ８ R ９ N(O)C-, R ８ (R ９ C(O))N-,R ８ R ９ NC(O)O-,R ８ C(O)-, R ８ R ９ N.C.O.R. ８ N-, (C １ ~C １０ ) alkyl-OC(O)R ８ N-, (C ３ ~C １０ ) cycloalkyl-OC(O)R ８ N-, (C ２ ~C ９ ) Heterocycloalkyl-OC(O)R ８ N-, (C ６ ~C １４ ) Aryl-OC(O)R ８ N-, (C ２ ~C ９ ) Heteroaryl-OC(O)R ８ N-, F ３ C-, F ２ HC-, CH ３ F ２ C-, FH ２ C-, CH ３ FHC-, (CH ３ ) ２ FC-;NC-, (C １ ~C １０ ) alkyl(O)P-, (C １ ~C １０ ) alkyl-S-, (C １ ~C １０ ) alkyl-S-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-S-, (C ６ ~C １４ ) aryl-S-, (C ２ ~C ９ ) heteroalkyl-S-, (C ２ ~C ９ ) heterocycloalkyl-S-, (C ２ ~C ９ ) heteroaryl-S-, (C １ ~C １０ ) alkyl-S(O)-, (C ３ ~C １０ ) cycloalkyl-S(O)-, (C ６ ~C １４ ) aryl-S(O)-, (C ２ ~C ９ ) Heterocycloa Rukyru-S(O)-, (C ２ ~C ９ ) heteroaryl-S(O)-, (C ３ ~C １０ ) alkyl-S(O) ２ -, (C ３ ~C １０ ) cycloalkyl-S(O) ２ -, (C ６ ~C １４ ) aryl-S(O) ２ -, (C ２ ~C ９ ) Heterocycloalkyl-S(O) ２ -, (C ２ ~C ９ ) Heteroaryl-S(O) ２ -, R ８ R ９ N.S. (O) ２ -, (C １ ~C １０ ) alkyl-S(O) ２ R ８ N-, (C ３ ~C １０ ) cycloalkyl-S(O) ２ R ８ N-, (C ６ ~C １４ ) aryl-S(O) ２ R ８ N-, (C ２ ~C ９ ) Heterocycloalkyl-SO ２ R ８ N-, and (C ２ ~C ９ ) Heteroaryl-S(O) ２ R ８ N-; Here, R ８ and R ９ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, (CH ３ ) ２ N- and H ２ N-; Or R ８ and R ９ taken together form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Here, each (C １ ~C １０ ) alkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ３ ~C １０ ) cycloalkyl or (C ２ ~C ９ ) Heterocycloalkyl is (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, or H ２ N-; X ８ and X ９ are each independently selected from N or C; T １ , T ２ and T ３ are each independently N or CR １０ is selected from Here, each R １０ are independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ２ ~C １０ ) alkylnyl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C ２ ~C １０ ) alkynylamine, C(O)-, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl-, COOH-(C ３ ~C １０ ) cycloalkyl-, (C １ ~C １０ ) alkoxy-, R １０Ａ - (C １ ~C １０ ) alkyl-, R １０Ａ - (C ３ ~C １０ ) cycloalkyl, R １０Ａ - (C ２ ~C ９ ) heterocycloalkyl, R １０Ａ - (C ６ ~C １４ ) aryl, R １０Ａ - (C ２ ~C ９ ) heteroaryl, R １０Ａ - (C ２ ~C １０ ) alkylnyl, R １０Ａ - (C １ ~C １０ ) alkylamine, R １０Ａ -((C １ ~C １０ ) alkyl) ２ Amin, R. １０Ａ - (C ２ ~C １０ ) alkynylamine, R １０Ａ -C(O)-, R １０Ａ - (C １ ~C １０ ) alkyl-C(O)O-, R １０Ａ - (C １ ~C １０ ) alkoxy-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, R １０Ａ - (C ３ ~C １０ ) Cycloalkyl-O-, R １０Ａ - (C ２ ~C ９ ) Heterocycloalkyl-O-, R １０Ａ - (C ６ ~C １４ ) Aryl-O-, R １０Ａ - (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, cyano, H ２ N-, (CH ３ ) HN-, (CH ３ ) ２ N-, R １０Ａ R １１ N-, R １０Ａ R １１ N(O)C-, R １０Ａ (R １１ C(O))N-,R １０Ａ R １１ NC(O)O-,R １０Ａ C(O)-, R １０Ａ R １１ N.C.O.R. １０Ａ N-, (C １ ~C １０ ) alkyl-OC(O)R １０Ａ N-, (C ３ ~C １０ ) cycloalkyl-OC(O)R １０Ａ N-, (C ２ ~C ９ ) Heterocycloalkyl-OC(O)R １０Ａ N-, (C ６ ~C １４ ) Aryl-OC(O)R １０Ａ N-, (C ２ ~C ９ ) Heteroaryl-OC(O)R １０Ａ N-, F ３ C-, F ２ HC-, CH ３ F ２ C-, FH ２ C-, CH ３ FHC-, (CH ３ ) ２ FC-;NC-, (C １ ~C １０ ) alkyl(O)P-, (C １ ~C １０ ) alkyl-S-, (C １ ~C １０ ) alkyl-S-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-S-, (C ６ ~C １４ ) aryl-S-, (C ２ ~C ９ ) heteroalkyl-S-, (C ２ ~C ９ ) heterocycloalkyl-S-, (C ２ ~C ９ ) heteroaryl-S-, (C １ ~C １０ ) alkyl-S(O)-, (C ３ ~C １０ ) cycloalkyl-S(O)-, (C ６ ~C １４ ) aryl-S(O)-, (C ２ ~C ９ ) heterocycloalkyl-S(O)-, (C ２ ~C ９ ) heteroaryl-S(O)-, (C ３ ~C １０ ) alkyl-S(O) ２ -, (C ３ ~C １０ ) cycloalkyl-S(O) ２ -, (C ６ ~C １４ ) aryl-S(O) ２ -, (C ２ ~C ９ ) Heterocycloalkyl-S(O) ２ -, (C ２ ~C ９ ) Heteroaryl-S(O) ２ -, R １０Ａ R １１ N.S. (O) ２ -, (C １ ~C １０ ) alkyl-S(O) ２ R １０Ａ N-, (C ３ ~C １０ ) cycloalkyl-S(O) ２ R １０Ａ N-, (C ６ ~C １４ ) aryl-S(O) ２ R １０Ａ N-, (C ２ ~C ９ ) Heterocycloalkyl-SO ２ R １０Ａ N-, and (C ２ ~C ９ ) Heteroaryl-S(O) ２ R １０Ａ N-; Here, R １０Ａ and R １１ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, (CH ３ ) ２ N- and H ２ N-; Or R １０Ａ and R １１ taken together form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Here, each (C １ ~C １０ ) alkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ３ ~C １０ ) cycloalkyl or (C ２ ~C ９ ) Heterocycloalkyl is (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, or H ２ N-, Y １ , O, S, NR １２ Or CR １２ R １３ and Here, R １２ is absent, or R １２ and R １３ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, ( C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, and H ２ N-; R １ forms a carbonyl together with the carbon to which it is attached, R ２ is absent, or R １ and R ２ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, and H ２ N-, or R １ and R ２ together with the carbons to which they are attached form a 3- to 10-membered ring; R ４ is H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, and H ２ N-, or R ４ and R ５ together with the carbons to which they are attached form a 3- to 10-membered ring; R ５ is absent, or H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, and H ２ N-; R ６ is H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ２ ~C １０ ) alkylnyl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C ２ ~C １０ ) alkynylamine, C(O)-, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl-, COOH-(C ３ ~C １０ ) cycloalkyl-, (C １ ~C １０ ) alkoxy-, R １４ - (C １ ~C １０ ) alkyl-, R １４ - (C ３ ~C １０ ) cycloalkyl, R １４ - (C ２ ~C ９ ) heterocycloalkyl, R １４ - (C ６ ~C １４ ) aryl, R １４ - (C ２ ~C ９ ) heteroaryl, R １４ - (C ２ ~C １０ ) alkylnyl, R １４ - (C １ ~C １０ ) alkylamine, R １４ -((C １ ~C １０ ) alkyl) ２ Amin, R. １４ - (C ２ ~C １０ ) alkynylamine, R １４ -C(O)-, R １４ - (C １ ~C １０ ) alkyl-C(O)O-, R １４ - (C １ ~C １０ ) alkoxy-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, R １４ - (C ３ ~C １０ ) Cycloalkyl-O-, R １４ - (C ２ ~C ９ ) Heterocycloalkyl-O-, R １４ - (C ６ ~C １４ ) Aryl-O-, R １４ - (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, cyano, H ２ N-, (CH ３ ) HN-, (CH ３ ) ２ N-, R １４ R １５ N-, R １４ R １５ N(O)C-, R １４ (R １５ C(O))N-,R １４ R １５ NC(O)O-,R １４ C(O)-, R １４ R １５ N.C.O.R. １４ N-, (C １ ~C １０ ) alkyl-OC(O)R １４ N-, (C ３ ~C １０ ) cycloalkyl-OC(O)R １４ N-, (C ２ ~C ９ ) Heterogeneity Chloroalkyl-OC(O)R １４ N-, (C ６ ~C １４ ) Aryl-OC(O)R １４ N-, (C ２ ~C ９ ) Heteroaryl-OC(O)R １４ N-, F ３ C-, F ２ HC-, CH ３ F ２ C-, FH ２ C-, CH ３ FHC-, (CH ３ ) ２ FC-;NC-, (C １ ~C １０ ) alkyl(O)P-, (C １ ~C １０ ) alkyl-S-, (C １ ~C １０ ) alkyl-S-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-S-, (C ６ ~C １４ ) aryl-S-, (C ２ ~C ９ ) heteroalkyl-S-, (C ２ ~C ９ ) heterocycloalkyl-S-, (C ２ ~C ９ ) heteroaryl-S-, (C １ ~C １０ ) alkyl-S(O)-, (C ３ ~C １０ ) cycloalkyl-S(O)-, (C ６ ~C １４ ) aryl-S(O)-, (C ２ ~C ９ ) heterocycloalkyl-S(O)-, (C ２ ~C ９ ) heteroaryl-S(O)-, (C ３ ~C １０ ) alkyl-S(O) ２ -, (C ３ ~C １０ ) cycloalkyl-S(O) ２ -, (C ６ ~C １４ ) aryl-S(O) ２ -, (C ２ ~C ９ ) Heterocycloalkyl-S(O) ２ -, (C ２ ~C ９ ) Heteroaryl-S(O) ２ -, R １４ R １５ N.S. (O) ２ -, (C １ ~C １０ ) alkyl-S(O) ２ R １４ N-, (C ３ ~C １０ ) cycloalkyl-S(O) ２ R １４ N-, (C ６ ~C １４ ) aryl-S(O) ２ R １４ N-, (C ２ ~C ９ ) Heterocycloalkyl-SO ２ R １４ N-, and (C ２ ~C ９ ) Heteroaryl-S(O) ２ R １４ N-; Here, R １４ and R １５ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, F ２ HC-O-, halo, (CH ３ ) ２ N-, H ２ N-, F ３ C-C(O)-, F ３ C- and F ２ HC-; Or R １４ and R １５ taken together form a 3- to 10-membered cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; Here, each (C １ ~C １０ ) alkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C ３ ~C １０ ) cycloalkyl or (C ２ ~C ９ ) Heterocycloalkyl is (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, or H ２ N-; R ３ is N or CR １６ and Here, R １６ is H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, and H ２ N-, or When m is 1, R １６ and R ４ together with the carbons to which they are attached form the formula (II): 【Chemistry 2】 {During the ceremony, The dotted line represents an optional double bond, and p is 0, 1, 2, 3, 4 or 5; Z １ are each independently H, halo, (C １ ~C １０ ) alkyl, (C ２ ~C ９ ) heteroalkyl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C ２ ~C １０ ) alkynylamine, (C １ ~C １０ ) alkoxy or H ２ N-; Y ２ , O, S, NR １７ Or CR １７ R １８ and Here, R １７ is absent, or R １７ and R １８ are each independently H, (C １ ~C １０ ) alkyl, (C ３ ~C １０ ) cycloalkyl, (C ２ ~C ９ ) heterocycloalkyl, (C ６ ~C １４ ) aryl, (C ２ ~C ９ ) heteroaryl, (C １ ~C １０ ) alkylamines, ((C １ ~C １０ ) alkyl) ２ Amine, (C １ ~C ３ ) alkynylamine, (C １ ~C １０ ) alkyl-C(O)O-, COOH-(C １ ~C １０ ) alkyl, COOH-(C ３ ~C １０ ) cycloalkyl, (C １ ~C １０ ) alkoxy-, (C １ ~C １０ ) alkoxy-(C １ ~C １０ ) alkyl-, (C ３ ~C １０ ) cycloalkyl-O-, (C ２ ~C ９ ) heterocycloalkyl-O-, (C ６ ~C １４ ) aryl-O-, (C ２ ~C ９ ) Heteroaryl-O-, HO-, halo, or H ２ N- is selected from forming a compound according to or a pharma- ceutically acceptable salt thereof.

2. X １ is N; X ２ is N; X ３ is CR ７ and X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

3. X １ is N; X ２ is CR ７ and X ３ is CR ７ and X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

4. X １ is N; X ２ is CR ７ and X ３ is N; X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

5. X １ is N; X ２ is CR ７ and X ３ is CR ７ and X ４ is N; X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ is C The compound of claim 1 .

6. X １ is N; X ２ is CR ７ and X ３ is CR ７ and X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

7. X １ is N; X ２ is N; X ３ is N; X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

8. X １ is N; X ２ is N; X ３ is CR ７ and X ４ is N; X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

9. X １ is N; X ２ is N; X ３ is CR ７ and X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

10. X １ is N; X ２ is N; X ３ is N; X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

11. X １ is N; X ２ is N; X ３ is CR ７ and X ４ is N; X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

12. X １ is C; X ２ is N; X ３ is CR ７ and X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

13. X １ is C; X ２ is CR ７ and X ３ is CR ７ and X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

14. X １ is C; X ２ is CR ７ and X ３ is N; X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

15. X １ is C; X ２ is CR ７ and X ３ is CR ７ and X ４ is N; X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

16. X １ is C; X ２ is CR ７ and X ３ is CR ７ and X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

17. X １ is C; X ２ is N; X ３ is N; X ４ is CR ７ and X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

18. X １ is C; X ２ is N; X ３ is CR ７ and X ４ is N; X ５ is CR ７ and X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

19. X １ is C; X ２ is N; X ３ is CR ７ and X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

20. X １ is C; X ２ is N; X ３ is N; X ４ is CR ７ and X ５ is N; X ６ is N; X ７ is CR ７ and X ８ is C; X ９ The compound of claim 1 , wherein

Citation Information

Patent Citations

  • Benzimidazole derivative, production thereof, insecticide and acaricide comprising same as active ingredient

    JP1986151176A

  • Angiotensin II antagonists incorporating substituted 1,3-dibenzodioxoles or 1,3-benzodithiols

    JP1993239033A

  • Pyrrolopyrimidines as crf antagonists

    JP1995509726A

  • Imidazopyrimidines and imidazopyridines for treating neurological disorders

    JP2002507996A

  • Tyrosine kinase inhibitor

    JP2005530745A