RU2776846C2 - Bicyclic compounds as allosteric shp2 inhibitors - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention is aimed at SHP2 inhibitors and their use in the treatment of diseases. Pharmaceutical compositions containing these inhibitors are also disclosed.

EFFECT: obtaining compounds for the treatment of diseases.

72 cl, 1 tbl, 52 ex

Description

This application claims the benefit of U.S. Provisional Application No. 62/449,530, filed January 23, 2017, the contents of which are incorporated herein by reference in its entirety.

The field of technology to which the invention belongs

The present invention relates to SHP2 protein tyrosine phosphatase inhibitors useful in the treatment of diseases or disorders. In particular, the present invention relates to compounds and compositions that inhibit SHP2, to methods for the treatment of diseases associated with SHP2, and to methods for the synthesis of such compounds.

Background of the invention

SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the PTPNl1 gene that is involved in many cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction via the Ras-mitogen-activated protein kinase, JAK-STAT, or phosphoinositol-3-kinase-AKT signaling pathways.

SHP2 contains two N-terminal Src-type 2 homologous domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. Two SH2 domains control the intracellular localization and regulation of SHP2 functions. The molecule is in an inactive, self-inhibited conformation, stabilized by a system of bonds formed by the residues of both the N–SH2– and PTP domains. Stimulation with, for example, cytokines or growth factors opens the catalytic site, resulting in enzymatic activation of SHP2.

Mutations in the PTPNl1 gene, and consequently in SHP2, have been identified in several human diseases such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and rectum. Therefore, SHP2 is a very promising target for the development of new treatments for various diseases. The compounds of the present invention fulfill the need for small molecules that inhibit SHP2 activity.

Brief description of the invention

The present invention relates to compounds capable of inhibiting SHP2 activity. The present invention also provides a method for preparing the compounds disclosed herein, pharmaceutical preparations containing such compounds, and methods for using such compounds and compositions for the control of diseases or disorders associated with impaired SHP2 activity.

One aspect of the present invention relates to compounds of formula I,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S( O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ may be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Another aspect of the present invention relates to compounds of formula I,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ may be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Another aspect of the present invention relates to compounds of formula II,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S( O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C (O)OR ^b , -C ₃ -C ₈ cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ in each case is selected from the group consisting of -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle, C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , when wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more of

–C ₁ –C ₆ alkyl, –OH, –NH ₂ , –OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ may be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Another aspect of the present invention relates to compounds of formula III,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S( O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

X ¹ represents N or C;

X ² represents N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ may be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

One aspect of the present invention relates to compounds of formula IV,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that heteroaryl is not

or

;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, -OR ⁵ , halogen, -NO ₂ , -CN,

–NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ ,

–S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ or –CO ₂ R ⁵ , each alkyl, alkenyl , cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

–CHF ₂ or –CH ₂ F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C ₃ -C ₈ cycloalkyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more of

–OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ ,

–NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl is not attached through a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl, or -C ₁ -C ₆ alkyl, each alkyl or cycloalkyl being optionally substituted with one or more -NH ₂ , where 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3–8 membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R³ can be combined with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

One aspect of the present invention relates to compounds of formula IV, which are compounds of formula IV-Q,

,

,

and to their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl, provided that the heteroaryl is not

or

;

R ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN or

–NR ⁵ R ⁶ ;

Y ¹ is -S- or a direct link;

X ¹ represents N or C;

X ² is N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl or -NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ ;

Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

R ³ is combined with R ^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of –C ₁ –C ₆ alkyl, –OH, –NH ₂ ,

–(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Another aspect of the present invention relates to methods of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers).

Another aspect of the present invention relates to methods for inhibiting SHP2. The method comprises administering to a patient in need thereof an effective amount of one or more of the compounds disclosed herein (e.g., compounds of formula I', I, II, III, IV, or V and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof). ).

Another aspect of the present invention is directed to pharmaceutical compositions containing one or more of the compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further contain an excipient, diluent or surfactant. The pharmaceutical composition may be effective in treating a disease associated with SHP2 modulation in a subject in need thereof.

Another aspect of the present invention relates to methods of treating a disease associated with SHP2 modulation in a subject in need thereof, which comprises administering to the subject an effective amount of a pharmaceutical composition containing one or more of the compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers).

Another aspect of the present invention relates to methods for inhibiting SHP2, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition containing one or more compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers).

Another aspect of the present invention relates to one or more compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), for use in the treatment or prevention of a disease associated with SHP2 modulation. One aspect of the present invention relates to pharmaceutical compositions containing one or more of the compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), and a pharmaceutically acceptable carrier, for use in the treatment or prevention of a disease associated with SHP2 modulation.

Another aspect of the present invention relates to the use of one or more compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation. Another aspect of the present invention relates to the use of pharmaceutical compositions containing one or more of the compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

Another aspect of the present invention relates to one or more compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), for use as a medicinal product. Another aspect of the present invention relates to pharmaceutical compositions containing one or more of the compounds disclosed herein (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), for use as a drug. In some embodiments, the drug is used to treat or prevent a disease associated with SHP2 modulation.

The present invention also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2.

Detailed description of the invention

In a first aspect, compounds of formula I' are described,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, wherein B, X ¹ , X ² , R ² , R ³ , R ⁴ and Y ² are as described above.

In another aspect, compounds of formula I are described,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, wherein A, B, X ¹ , X ² , R ¹ , R ² , R ³ , Y ¹ , Y ² and n are as described above.

In another aspect, compounds of formula II are described,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, wherein A, B, X ¹ , X ² , R ¹ , R ² , R ³ , Y ² and n are as described above.

In another aspect, compounds of formula III are described,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, wherein A, B, X ¹ , X ² , R ¹ , R ² , R ³ , Y ² and n are as described above.

In a first aspect, compounds of formula IV are described,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, wherein B, X ¹ , X ² , R ² , R ³ , R ⁴ and Y ² are as described above.

Details of the present invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present invention, illustrative methods and materials are described below. Other features, objects and advantages of the present invention will become apparent from the description and from the claims. In the description and the appended claims, the singular forms also include the plural forms, unless the context clearly indicates otherwise. Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art to which the present invention belongs. All patents and publications mentioned in this specification are incorporated herein by reference in their entirety.

general information

The singular forms used in the present invention may refer to one or more (i.e., at least one) grammatical entities. For example, "element" can mean one element or more than one element.

The term "and/or" is used in the present invention to possibly mean either "and" or "or" unless otherwise indicated.

As used herein, the terms "optional" or "optional" may mean that the event or circumstance described below may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" can encompass both "aryl" and "substituted aryl" as defined herein. With respect to any group containing one or more substituents, one of ordinary skill in the art will appreciate that such groups are not intended to introduce any substitution or substitution schemes that are sterically impractical, impossible to synthesize, and/or unstable in terms of its nature.

The term "optionally substituted" is intended to mean that a given chemical moiety (eg, an alkyl group) may be (but need not be) linked to other substituents (eg, heteroatoms). For example, an alkyl group that is optionally substituted may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may contain substituents other than hydrogen. For example, at any point in the chain, it may be linked to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" may mean that the given chemical moiety may contain other functional groups, but does not necessarily contain any additional functional groups.

The term "aryl" can mean cyclic, aromatic hydrocarbon groups that contain from 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. If the group contains two aromatic rings (bicyclic, etc.), then the aromatic rings of the aryl group can be connected at one point (for example, biphenyl) or fused (for example, naphthyl). The aryl group may optionally be substituted with one or more substituents, eg 1-5 substituents, at any point of attachment. Illustrative substituents include, without limitation -H, -halogen, -O-C ₁ -C ₆ alkyl, -C ₁ -C ₆ alkyl, -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₆ alkynyl, -C ₂ -C ₆ alkenyl, −C ₂ –C ₆ alkynyl, −OH, −OP(O)(OH) ₂ , −OC(O)C ₁ –C ₆ alkyl, −C(O)C ₁ –C ₆ alkyl,

-OC(O)OC ₁ -C ₆ alkyl, -NH ₂ , -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ -C ₁ -C ₆ alkyl, -S(O)NHC ₁ -C ₆ alkyl and -S(O)N(C ₁ -C ₆ alkyl) ₂ . The substituents themselves may optionally be substituted.

Unless specifically defined otherwise, the term "heteroaryl" may mean a monovalent or multivalent monocyclic aromatic radical or a polycyclic aromatic radical with 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, S, P, and O, wherein the remaining atoms in the ring are C. Heteroaryl, as defined herein, may also mean a bicyclic heteroaromatic group, where the heteroatom is selected from N, S, P, and O. The term may also include multiple fused ring systems that contain at least one such aromatic ring, with multiple fused ring systems further described below. The term may also include multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings), where a heteroaryl group as defined above may be fused to one or more rings selected from heteroaryls (to form, for example, naphthyridinyl, such as 1,8-naphthyridinyl), heterocycles (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as formation, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (with the formation, for example, indazolyl) with the formation of a system of several fused rings. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements. It should be understood that the individual rings of the multiple fused ring system may be connected in any order relative to each other. It should also be understood that the point of attachment of the multi-fused ring system (as defined above for heteroaryl) may be at any position of the multi-fused ring system, including the heteroaryl, heterocycle, aryl or carbocycle portion of the multi-fused ring system, and at any suitable atom of the multi-fused ring system from several fused rings, including a carbon atom and a heteroatom (for example, nitrogen). The heteroaromatic radical may optionally be independently substituted with one or more substituents as described herein. Examples include, without limitation, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazolyl, benzimidazolyl, thieno[3, 2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyrazinyl, indazolyl, 1-methyl-1 H -indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl , thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1 ,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1 ,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, isoindolin-1-one, indolin-2-one, pyrrolo[ 2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[ 1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ ² -pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, benzo[ d ]isoxazolyl, benzo [ d ]oxazolyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, 2-methylbenzo[ d ]oxazolyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidyl, 2,3-dihydrobenzofuranyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3, 2-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, 1-methyl-1 H -benzo[ d ][1,2,3 ]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, quinoxalinyl, benzo[c][ 1,2,5]oxadiazolyl, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 3 ,4-dihydro-2 H -benzo[b][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2 ,1–b][ 1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, benzo[ d ][1,3]dioxolyl, pyrazolo[1,5- a ]pyridinyl and derivatives of any of the above compounds.

"Alkyl" may mean a straight or branched saturated hydrocarbon. C ₁ -C ₆ alkyl groups contain from 1 to 6 carbon atoms. Examples of the C ₁ -C ₆ alkyl group may include, without limitation, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, and neopentyl.

The term "alkenyl" may mean an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched, containing from about 2 to about 6 carbon atoms in the chain. Some alkenyl groups may contain from about 2 to about 4 carbon atoms in the chain. "Branched" may mean that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to the linear alkenyl chain. Illustrative alkenyl groups may include, without limitation, ethenyl, propenyl, n-butenyl, and isobutenyl. C ₂ -C ₆ alkenyl group is an alkenyl group containing 2 to 6 carbon atoms.

The term "alkynyl" may mean an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and which may be straight or branched, while containing from about 2 to about 6 carbon atoms in the chain. Some alkynyl groups may contain from about 2 to about 4 carbon atoms in the chain. "Branched" may mean that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to the linear alkynyl chain. Illustrative alkynyl groups may include, without limitation, ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. C ₂ -C ₆ alkynyl group is an alkynyl group containing 2 to 6 carbon atoms.

The term "cycloalkyl" can mean monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups may include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. C ₃ -C ₈ cycloalkyl is a cycloalkyl group containing 3 to 8 carbon atoms. The cycloalkyl group may be fused (eg decalin) or internally bridged (eg norbornane).

The term "cycloalkenyl" can mean monocyclic, non-aromatic, unsaturated carbon rings containing 4-18 carbon atoms. Examples of cycloalkenyl groups may include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. C ₄ -C ₈ cycloalkenyl is a cycloalkenyl group containing 4 to 8 carbon atoms.

In some embodiments, the terms "heterocyclyl" or "heterocycloalkyl" or "heterocycle" may mean monocyclic or polycyclic 3-24-membered rings containing carbon atoms and heteroatoms selected from oxygen, phosphorus, nitrogen and sulfur, and among carbon atoms or ring heteroatoms do not have common delocalized π-electrons (aromaticity). Heterocyclyl rings may include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide oxepinil, diazepinil, tropanil and homotropanil. The heterocyclyl or heterocycloalkyl ring may also be fused or internally bridged, for example, may be a bicyclic ring.

In some embodiments, "heterocyclyl" or "heterocycloalkyl" or "heterocycle" may be a saturated, partially saturated, or unsaturated mono- or bicyclic ring containing 3-24 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise indicated, may be bonded at a carbon or nitrogen atom, while the -CH ₂ - group may optionally be replaced by -C(O)-, or the sulfur atom in the ring may be optionally oxidized to form S –oxides. "Heterocyclyl" may be a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, which, unless otherwise indicated, may be linked at a carbon or nitrogen atom, wherein the -CH ₂ - group may optionally be replaced by -C(O)-, or the sulfur atom in the ring may be optionally oxidized to form S-oxide(s). Non-limiting examples and suitable meanings of the term "heterocyclyl" may include thiazolidinyl, pyrrolidinyl, pyrrolidin-2-one, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2 -oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4 -thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl , homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl, indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl and 1-isoquinolonyl.

As used herein, the term "halogen" or "halide" may mean a fluoro-, chloro-, bromo-, or iodo-group.

The term "carbonyl" may mean a functional group containing a carbon atom connected to an oxygen atom through a double bond. In this document, it may be abbreviated as "oxo", C(O) or C=O.

"Spirocycle" or "spirocyclic" can mean bicyclic ring systems based on carbon atoms, in which both rings are connected through one atom. The rings may be different in size and nature, or be identical in size and nature. Examples may include, without limitation, spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecan. One or both rings in a spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spirocycle may be replaced by a heteroatom (eg O, N, S or P). C ₅ -C ₁₂ spirocycle is a spirocycle containing 5 to 12 carbon atoms. One or more carbon atoms may be replaced by a heteroatom.

The term "spirocyclic heterocycle", "spiroheterocyclyl", or "spiroheterocycle" is intended to mean a spirocycle where at least one of the rings is a heterocycle (eg, at least one of the rings is furanyl, morpholinyl, or piperadinyl). The spirocyclic heterocycle may contain from 5 to 12 atoms, at least one of which is a heteroatom selected from N, O, S and P.

The present invention also includes pharmaceutical compositions containing an effective amount of one or more compounds of the present invention and a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier, diluent, or excipient" may include, without limitation, any adjuvant, carrier, adjuvant, glidant, sweetener, diluent, preservative, colorant/colorant, flavor enhancer, a surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier approved by the United States Food and Drug Administration as acceptable for human or pet consumption .

The present invention may include pharmaceutically acceptable salts of the compounds described herein. Illustrative "pharmaceutically acceptable salts" may include, for example, water-soluble and water-insoluble salts such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate , bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavularate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride , hydroxynaphthoate, iodide, setionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucat, napsilate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, 1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, c uramate, tannate, tartrate, theoclate, tosylate, triethiodide and valerate.

The term "pharmaceutically acceptable salt" also includes both acid addition salts and base addition salts. The term "pharmaceutically acceptable acid addition salt" may mean those salts that retain the biological efficacy and free base properties that are not biologically or otherwise undesirable and that can be formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid , ethanesulfonic acid, 2-hydroxyethanesulfonic acid slots, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid , oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p- toluenesulfonic acid, trifluoroacetic acid, undecylenic acid slots, etc.

The term "pharmaceutically acceptable base addition salt" may mean those salts that retain the biological efficacy and free acid properties that are not biologically or otherwise undesirable. Such salts can be obtained by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases may include, without limitation, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. For example, inorganic salts may include, but are not limited to, ammonium, sodium , potassium, calcium and magnesium. Salts derived from organic bases may include, without limitation, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dinol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N -ethylpiperidine, polyamine resins, etc.

The term "tautomers" can mean a range of compounds that have the same number and type of atoms, but differ in their ability to form bonds and are in equilibrium with each other. "Tautomer" is a single representative of this series of compounds. Typically, a single tautomer is depicted, but a given single structure may be understood to represent all possible tautomers that may exist. Examples include keto-enol tautomerism. Where a ketone is depicted, both the enol and ketone forms may be understood to be part of the present invention.

For example, the compounds of the present invention may be in tautomeric form. In some embodiments of Formula I, II, III, or IV, R ² may be -OH and the tautomers of the compounds may be in equilibrium:

.

.

The present invention may include prodrugs of the compounds described herein. As used herein, the term "prodrug" may mean a compound that is amenable to in vivo conversion via metabolic pathways (eg, hydrolysis) to a compound of the present invention. In addition, as used herein, the term "prodrug" can be a drug that is inactive in the body, but can generally be converted to the active compound in the body, either during or after absorption from the gastrointestinal tract. The conversion of a prodrug to an active compound in the body can be accomplished chemically or biologically (ie, using an enzyme).

The present invention may include solvates of the compounds described in this document. The term "solvate" may mean a complex of various stoichiometric composition, which is formed by a dissolved component and a solvent. For the purposes of the present invention, such solvents cannot interfere with the manifestation of the biological activity of the dissolved component. Examples of suitable solvents may include, without limitation, water, MeOH, EtOH and AcOH. Solvates where the solvent molecule is water are generally referred to as hydrates. Hydrates may include compositions containing stoichiometric amounts of water, as well as compositions containing varying amounts of water.

The present invention may include isomers of the compounds described herein. The term "isomer" can mean compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may relate to the structure (geometric isomers) or the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of the present invention may contain one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures, and as single enantiomers or diastereomers.

The present invention may include stereoisomers of the compounds described herein. The term "stereoisomers" can mean a series of compounds that have the same number and type of atoms and have the same ability to form bonds between these atoms, but differ in three-dimensional structure. The term "stereoisomer" can mean any representative of this series of compounds. For example, a stereoisomer may be an enantiomer or a diastereomer.

In addition, the present invention may cover all geometric and positional isomers. For example, if a compound of the present invention includes a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are within the scope of the present invention. If the compound contains a double bond, the substituent may be in the E- or Z-configuration. If the compound contains a disubstituted cycloalkyl, then the cycloalkyl substituent may be in the cis- or trans-configuration.

The term "enantiomers" can mean a pair of stereoisomers that are non-superimposable mirror images of each other. The term "enantiomer" may mean a single representative of a given pair of stereoisomers. The term "racemic" may mean a 1:1 mixture of a pair of enantiomers. The present invention may include the enantiomers of the compounds described herein. Each compound disclosed herein includes all enantiomers that correspond to the general structure of the compound. The compounds may be present in racemic or enantiomerically pure form, or in any other form relevant to stereochemistry. In some embodiments, the compounds may be the ( S ) enantiomer. In other embodiments, the compounds may be the ( R ) enantiomer. In some other embodiments, the compounds may be (+)- or (-)-enantiomers.

In some embodiments, the implementation of the compounds and compositions of the present invention can be enriched to obtain predominantly one enantiomer of the compounds described in this document. An enantiomerically enriched mixture may contain, for example, at least 60 mol. percent of one enantiomer or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or even 100 mol. percent. In some embodiments, a compound described herein enriched in one enantiomer may be substantially free of the other enantiomer, where "substantially free" may mean that the substance in question is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% compared to the amount of the other enantiomer, for example, in the composition or in the mixture of compounds. For example, if a composition or mixture of compounds contains 98 grams of the first enantiomer and 2 grams of the second enantiomer, we can say that it contains 98 mol. percent of the first enantiomer and only 2 mol. percent of the second enantiomer.

The term "diastereomers" may refer to a number of stereoisomers that cannot be superimposed by rotation around single bonds. For example, compounds with double bonds in the cis- and trans-positions, compounds with endo- and exo-substitution in bicyclic ring systems, and compounds containing several stereogenic centers with different relative configurations can be considered diastereomers. The term "diastereomer" may mean any representative of this series of compounds. In some of the examples presented, a single diastereomer or a mixture of diastereomers can be prepared by the synthetic method. The present invention may include diastereomers of the compounds described herein.

In some embodiments, the implementation of the compounds and compositions of the present invention can be enriched to obtain predominantly one diastereomer of the compounds disclosed in this document. Diastereomerically enriched mixture may contain, for example, at least 60 mol. percent of one diastereomer or more preferably at least 75, 99, 95, 96, 97, 98, 99 or even 100 mol. percent.

The compounds described herein further include all pharmaceutically acceptable isotopically labeled compounds. An "isotopically labeled" or "radioactively labeled" compound may be a compound where one or more atoms are replaced or replaced by an atom with an atomic mass or mass number different from that normally found in nature (i.e., . which are found in nature). For example, in some embodiments, in the compounds described herein, the hydrogen atoms are replaced or replaced by one or more deuterium or tritium atoms. Certain isotopically labeled compounds of the present invention, such as those in which a radioactive isotope has been introduced, may be useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³ H, and carbon 14, i.e., ¹⁴ C, may be particularly suitable for this purpose due to their ease of introduction and the availability of means of detection. Substitution with heavier isotopes such as deuterium, i.e. ² H, may provide some therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage required, and therefore may be preferred in some circumstances. . Suitable isotopes that can be incorporated into the compounds described herein include, without limitation, ² H (also referred to as D, i.e. deuterium), ³ H (also referred to as T, i.e. tritium), ¹¹ C, ¹³ C , ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. Substitution with positron active isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N may be useful in positron emission tomography (PET) studies.

The term "effective amount" when used with respect to a compound may be an amount effective to treat or prevent a disease in a subject as described herein.

As used in the present invention, the term "carrier" may encompass carriers, excipients and diluents and may mean a material, composition or carrier medium such as a liquid or solid excipient, diluent, adjuvant, solvent or encapsulation material involved in the transfer or transporting a pharmaceutical agent from one organ or body part to another organ or body part of the subject.

The term "treatment" in relation to a subject may mean the normalization of at least one symptom of a disorder present in the subject. "Treatment" may include elimination, normalization, or at least partial amelioration of the disorder.

The term "prevent" or "warning" in relation to a subject may mean preventing the subject from being affected by a disease or disorder. Prevention may include prophylactic treatment. For example, prevention may include administering to a subject one or more of the compounds disclosed herein before the subject is affected by the disease, wherein the administration will prevent the subject from being affected by the disease.

The term "disorder" is used in the present invention and can be used interchangeably with the terms "disease", "condition", or "illness", unless otherwise indicated.

As used herein, the term "administer", "administer" or "administration" refers to either direct administration to a subject of one or more compounds of the present invention, or a pharmaceutically acceptable salt of one or more compounds of the present invention, or a composition containing one or more compounds of the present invention, or to the administration to the subject of a prodrug that is a derivative or analogue of one or more compounds of the present invention, or pharmaceutically acceptable salts of one or more compounds of the present invention, or compositions, which can result in the formation of an equivalent amount of the active compound in the subject's body .

A "patient" or "subject" may be a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate such as a monkey, chimpanzee, baboon, or rhesus.

Compounds of the present invention

The compounds of the present invention include compounds of formula I', I, II, III, IV or V and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers of any of the above compounds.

In one or more embodiments of compounds of formula I, the compound is represented by formula I-A,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

A is aryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ can be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In one or more embodiments of compounds of formula I, the compound is represented by formula I-B,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

A is heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S( O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl or heteroaryl is not attached through a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl, or -C ₁ -C ₆ alkyl, each alkyl or cycloalkyl being optionally substituted with one or more -NH ₂ , where 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3–8 membered cycloalkyl;

R^b independently in each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ can be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-A,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-A, the compound is represented by formula II-A1,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic or polycyclic heterocycle or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -OH or -NH ₂ .

In one or more embodiments of compounds of formula II-A, the compound is represented by formula II-A2,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-A, the compound is represented by formula II-A3,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-B,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B1,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

C, together with the carbon atom to which it is attached, forms a 3-12-membered monocyclic or polycyclic heterocycle or a 5-12-membered spiroheterocycle, while the heterocycle or spiroheterocycle is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -OH or -NH ₂ .

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B2,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B3,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B4,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B5,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II-B, the compound is represented by formula II-B6,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-C,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

C forms a 3-12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiro heterocycle is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, or -NH ₂ .

In one or more embodiments of compounds of formula II-C, the compound is represented by formula II-C1,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-D,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

C forms a 3-12-membered monocyclic or polycyclic heterocycle, wherein the heterocycle or spiro heterocycle is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, or -NH ₂ .

In one or more embodiments of compounds of formula II-D, the compound is represented by formula II-D1,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-E,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-F,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula II, the compound is represented by formula II-G,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where R ² is aryl or heteroaryl.

In one or more embodiments of compounds of formula III, the compound is represented by formula III-A,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula III-A, the compound is represented by formula III-A1,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic or polycyclic heterocycle or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -OH or -NH ₂ .

In one or more embodiments of compounds of formula III-A, the compound is represented by formula III-A2,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In one or more embodiments of compounds of formula III-A, the compound is represented by formula III-A3,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers.

In some embodiments, the compounds of the present invention are compounds of formula IV,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that heteroaryl is not

or

;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, -OR ⁵ , halogen, -NO ₂ , -CN,

–NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ ,

–S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ or –CO ₂ R ⁵ , each alkyl, alkenyl , cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C ₃ -C ₈ cycloalkyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more of

–OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ ,

–NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl is not attached through a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; wherein the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R³ can be combined with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In one or more embodiments of Formula IV, ^R4 is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы IV Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы I Y¹ представляет собой прямую связь.In one or more embodiments of formula IV, R ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of Formula IV, Y ¹ is -S-. In one or more embodiments of Formula IY ¹ is a direct bond.

In one or more embodiments of compounds of formula IV, Y ² is -(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula IV, Y ² is -NR ^a -.

In one or more embodiments of Formula IV, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula IV, A is phenyl. In one or more embodiments of Formula IV, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV, A is pyridinyl. In one or more embodiments of Formula IV, A is indazolyl. In one or more embodiments of formula IV, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, R ¹ is independently at each occurrence —H, —OR ⁵ , halogen, —C ₁ —C ₆ alkyl, —CN, or —NR ⁵ R ⁶ . In one or more embodiments of formula IV, R ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of formula IV, R ¹ is independently at each occurrence —H or —OR ⁵ . In one or more embodiments of formula IV, R ¹ is independently at each occurrence —H or halogen. In one or more embodiments of formula IV, R ¹ is independently at each occurrence —H or

–NR ⁵ R ⁶ . In one or more embodiments of Formula IV, R ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, R ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, R ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, R ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV, R ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, R ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of Formula IV, R ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV R² represents -H. In one or more embodiments of formula IV R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of formula IV R² is -OH. In one or more embodiments of formula IV R² represents -NR⁵R⁶. In one or more embodiments of formula IV R² represents –NH₂.

In one or more embodiments of Formula IV, R ^a is -H.

In one or more embodiments of Formula IV, R ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of formula IV, R ³ is an optionally substituted 3-12-membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV, R ³ is an optionally substituted 3-12-membered monocyclic heterocycle. In one or more embodiments of Formula IV, R ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV, R ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, R ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12– a membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, R ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12-membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1. In one or more embodiments of formula IV, R ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or several of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle which is optionally substituted with one or several of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV, R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV, X ¹ is N and X ² is N. In one or more embodiments of Formula IV, X ¹ is C and X ² is CH. In one or more embodiments of Formula IV, X ¹ is C and X ² is N. In one or more embodiments of Formula IV, X ¹ is N and X ² is CH.

In one or more embodiments of formula IV, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of Formula IV, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV, B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of formula IV, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula IV, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of formula IV, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV, B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of formula IV, B is substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of formula IV, B is substituted with one or more oxo. In one or more embodiments of Formula IV, B is substituted with one or more -C_one-C₆alkyls. In one or more embodiments of Formula IV, B is substituted with one or more -OH. In one or more embodiments of Formula IV, B is substituted with one or more –NH₂. In one or more embodiments of Formula IV, B is substituted with one or more -CF₃. In one or more embodiments of Formula IV, B is substituted with one or more -CHF₂. In one or more embodiments of Formula IV, B is substituted with one or more -CH₂F. In one or more embodiments of Formula IV, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

a) R ⁴ is H;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой –S–;a) R ⁴ is

, A is monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is -S-;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 3-12 membered monocyclic heterocycle, the heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH,

–NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the points of attachment, is a monocyclic 5-12-membered heterocycle, with the heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is C and X ² is N;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments, the Formula IV compounds of the present invention and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers are characterized by one, two, or three or more of the following:

, A представляет собой моноциклический или полициклический арил или пиридинил, и Y¹ представляет собой прямую связь;a) R ⁴ is

, A is a monocyclic or polycyclic aryl or pyridinyl, and Y ¹ is a direct bond;

b) X ¹ is N and X ² is CH;

c) B, including the atoms at the attachment points, is a monocyclic 5 to 12 membered heteroaryl, with the heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

d) R ² is -H, -C ₁ -C ₆ alkyl or -NH ₂ ;

e) Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

f) R ³ is combined with R ^a to form a 5- to 12-membered spiro-heterocycle, the spiro-heterocycle being optionally substituted with one or more of -C ₁ -C ₆ alkyl,

-OH, -NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments of formula IV, the compound is represented by formula IV-A,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X ^B1 represents N, NR ⁹ , CR ⁹ , S or O; X ^B2 is N, NR ⁹ , CR ⁹ , S or O; and X ^B3 is N, NR ⁹ , CR ⁹ , S or O, where R ⁹ is independently at each occurrence -H, -C ₁ -C ₆ alkyl,

-OH, -NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B1, X^B2 and X^B3 does not represent CR⁹, or provided that if each of X^B1, X^B2 and X^B3 is a CR⁹, then X^one must be N.

In some embodiments of Formula IV-AX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B1 is CR ⁹ . In some embodiments of formula IV-AX ^B1 is S. In some embodiments of formula IV-AX ^B1 is O. In some embodiments of formula IV-AX ^B2 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B2 is CR ⁹ . In some embodiments of formula IV-AX ^B2 is S. In some embodiments of formula IV-AX ^B2 is O. In some embodiments of formula IV-AX ^B3 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B3 is CR ⁹ . In some embodiments of Formula IV-AX, ^B3 is S. In some embodiments of Formula IV-AX, ^B3 is O.

In some embodiments of Formula IV-AX, ^B1 is N, NR ⁹ , or CR ⁹ ; X ^B2 is N, NR ⁹ or CR ⁹ ; and X ^B3 is N, NR ⁹ or CR ⁹ . In some embodiments of Formula IV-AX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B1 is CR ⁹ . In some embodiments of Formula IV-AX, ^B2 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B2 is CR ⁹ . In some embodiments of Formula IV-AX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-AX, ^B3 is CR ⁹ .

In some embodiments of Formula IV-AR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV-AR ⁹ is H.

, где

является одинарной связью или двойной связью для удовлетворения требованиям правил валентности, представляет собой

,

,

,

,

,

,

,

,

,

,

,

или

.In some embodiments of Formula IV-A

, where

is a single bond or a double bond to meet the requirements of the valency rules, is

,

,

,

,

,

,

,

,

,

,

,

or

.

In one or more embodiments of formula IV-AR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы IV–A Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы IV–A Y¹ представляет собой прямую связь.In one or more embodiments of formula IV-AR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of Formula IV-AY ¹ is -S-. In one or more embodiments of Formula IV-AY ¹ is a direct bond.

In one or more embodiments of compounds of formula IV-AY ² is

-(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula IV-AY ² is -NR ^a -.

In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-A, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-A, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-A, A is phenyl. In one or more embodiments of Formula IV-A, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-A, A is pyridinyl. In one or more embodiments of Formula IV-A, A is indazolyl. In one or more embodiments of Formula IV-A, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-A, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-A, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, AR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of formula IV-AR ¹ independently at each occurrence is -H or halogen. In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, AR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV - AR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV-AR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, AR ⁵ and R ⁶ are each independently -H. In one or more embodiments of Formula IV-AR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of Formula IV-A R² represents -H. In one or more embodiments of Formula IV-A R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of Formula IV-A R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, AR ² is -OH. In one or more embodiments of Formula IV, AR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, AR ² is -NH ₂ .

In one or more embodiments of Formula IV-AR, ^a is -H.

In one or more embodiments of formula IV-AR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of formula IV-AR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-AR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-AR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV - AR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, AR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-A, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, AR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-A, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV - AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-AR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle that is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-AX ¹ is N and X ² is N. In one or more embodiments of Formula IV-AX ¹ is C and X ² is CH. In one or more embodiments of formula IV-AX ¹ is C and X ² is N. In one or more embodiments of formula IV-AX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-B,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, while R⁹ independently in each case represents –H, –C_one-C₆alkyl, –OH, –NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B4, X^B5, X^B6 and X^B7 does not represent CR⁹, or provided that if each of X^B4, X^B5, X^B6 and X^B7is a CR⁹, then X^one should be N.

In some embodiments of Formula IV-BX, ^B4 is N. In some embodiments of Formula IV-BX, ^B4 is CR ⁹ . In some embodiments of Formula IV-BX, ^B5 is N. In some embodiments of Formula IV-BX, ^B5 is CR ⁹ . In some embodiments of Formula IV-BX, ^B6 is N. In some embodiments of Formula IV-BX, ^B6 is CR ⁹ . In some embodiments of Formula IV-BX, ^B7 is N. In some embodiments of Formula IV-BX, ^B7 is CR ⁹ . In some embodiments of Formula IV-BX ^B4 is N, X ^B5 is CR ⁹ , X ^B6 is N, and X ^B7 is CR ⁹ . In some such embodiments, R ⁹ is independently at each occurrence -H.

In some embodiments of Formula IV - BR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV - BR ⁹ is H.

In one or more embodiments of formula IV, BR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы IV–B Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы IV–B Y¹ представляет собой прямую связь.In one or more embodiments of formula IV-BR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of Formula IV-BY ¹ is -S-. In one or more embodiments of Formula IV-BY ¹ is a direct link.

In one or more embodiments of the compounds of formula IV-BY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of the compounds of formula IV-BY ² is -NR ^a -.

In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-B, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-B, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-B, A is phenyl. In one or more embodiments of Formula IV-B, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-B, A is pyridinyl. In one or more embodiments of Formula IV-B, A is indazolyl. In one or more embodiments of formula IV-B A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-B, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-B, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, BR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, BR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, BR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV, BR ¹ is independently at each occurrence —H or halogen. In one or more embodiments of formula IV, BR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, BR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, BR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, BR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of formula IV, BR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV, BR ⁵ and R ⁶ are independently at each occurrence —H or —C ₁ —C ₆ alkyl. In one or more embodiments of Formula IV, BR ⁵ and R ⁶ are each independently -H. In one or more embodiments of Formula IV, BR ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-B R² represents -H. In one or more embodiments of Formula IV-B R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-B R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, BR ² is -OH. In one or more embodiments of formula IV, BR ² is -NR ⁵ R ⁶ . In one or more embodiments of formula IV, BR ² is -NH ₂ .

In one or more embodiments of Formula IV-BR, ^a is -H.

In one or more embodiments of Formula IV, BR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula IV-BR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-BR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-BR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV—BR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, BR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-B, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—BR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, BR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-B, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV—BR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -BR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-BR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV - BR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -BR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-BR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-BX ¹ is N and X ² is N. In one or more embodiments of Formula IV-BX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-BX ¹ is C and X ² is N. In one or more embodiments of Formula IV-BX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-C,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers.

In one or more embodiments of formula IV, CR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы IV–C Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы IV–C Y¹ представляет собой прямую связь.In one or more embodiments of Formula IV, CR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of Formula IV, CY ¹ is -S-. In one or more embodiments of Formula IV, CY ¹ is a direct link.

In one or more embodiments of Formula IV-C A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-C A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of formula IV-C A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-C A is phenyl. In one or more embodiments of Formula IV-C A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-C, A is pyridinyl. In one or more embodiments of Formula IV-C, A is indazolyl. In one or more embodiments of Formula IV-C A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-C, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-C, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, CR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, CR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of formula IV, CR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of formula IV, CR ¹ is independently at each occurrence —H or halogen. In one or more embodiments of Formula IV, CR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, CR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, CR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of formula IV, CR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, CR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV, CR ⁵ and R ⁶ are independently at each occurrence —H or —C ₁ —C ₆ alkyl. In one or more embodiments of Formula IV, CR ⁵ and R ⁶ are each independently -H. In one or more embodiments of Formula IV, CR ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-C R² represents -H. In one or more embodiments of Formula IV-C R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-C R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, CR ² is -OH. In one or more embodiments of Formula IV, CR ² is -NR ⁵ R ⁶ . In one or more embodiments of formula IV, CR ² is -NH ₂ .

In one or more embodiments of Formula IV—CR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, CR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-C R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, CR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-C R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV—CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV, CR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-CX ¹ is N and X ² is N. In one or more embodiments of Formula IV-CX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-CX ¹ is C and X ² is N. In one or more embodiments of Formula IV-CX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-C B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-C B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-C B, including atoms at the attachment points, is an optionally substituted monocyclic 7-12 membered heterocycle.

In one or more embodiments of formula IV-C B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-C, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-C B, including atoms at the attachment points, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-C, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-C B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-C B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-C, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-C, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of Formula IV, CB is substituted by one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-C, B is substituted with one or more oxo. In one or more embodiments of Formula IV–C, B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of Formula IV-C, B is substituted with one or more -OH. In one or more embodiments of Formula IV-C, B is substituted with one or more -NH₂. In one or more embodiments of formula IV-C B is substituted with one or more -CF₃. In one or more embodiments of Formula IV-C, B is substituted with one or more -CHF₂. In one or more embodiments of Formula IV-C, B is substituted with one or more -CH₂F. In one or more embodiments of Formula IV-C, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-D,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic heterocycle, a 3-12-membered polycyclic heterocycle, or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted with one or more of -C ₁ - C ₆ alkyl, –OH, –NH ₂ , oxo, heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In some embodiments of Formula IV-D, ring C is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , -OH, -(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH, –CF ₃ ,

–CHF ₂ or –CH ₂ F. In some such embodiments, n is 1. In some embodiments of Formulas IV–D, ring C is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –(CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1.

In some embodiments of formulas IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered monocyclic heterocycle. In some embodiments of formulas IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered polycyclic heterocycle. In some embodiments of formula IV-D, together with the nitrogen atom to which it is attached, is an optionally substituted 5-12-membered spiro heterocycle.

. В некоторых вариантах осуществления формулы IV–D кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

. В некоторых вариантах осуществления формулы IV–D кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

.In some embodiments of formulas IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-D, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

.

In one or more embodiments of Formula IV-DR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы IV–D Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы IV–D Y¹ представляет собой прямую связь.In one or more embodiments of Formula IV-DR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of Formula IV, DY ¹ is -S-. In one or more embodiments of formula IV-DY ¹ is a direct bond.

In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-D, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-D, A is phenyl. In one or more embodiments of Formula IV-D, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-D, A is pyridinyl. In one or more embodiments of Formula IV-D, A is indazolyl. In one or more embodiments of Formula IV-D, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-D, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-D, n is independently at each occurrence 1 or 2.

In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula IV-DR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV-DR ¹ , independently at each occurrence, is -H or halogen. In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, DR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV-DR ¹ , independently at each occurrence, is -H, -CN, or halogen.

In one or more embodiments of formula IV-DR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of formulas IV-DR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of Formula IV-DR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-D R² represents -H. In one or more embodiments of Formula IV-D R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-D R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, DR ² is -OH. In one or more embodiments of Formula IV, DR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, DR ² is -NH ₂ .

In one or more embodiments of Formula IV-DX ¹ is N and X ² is N. In one or more embodiments of Formula IV-DX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-DX ¹ is C and X ² is N. In one or more embodiments of Formula IV-DX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-D B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-D B, including atoms at the attachment points, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-D B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-D B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-D, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula IV-D, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-D, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-D B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of Formula IV-D, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-D, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-D, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of the formula

IV–DB is substituted by one or more of –C ₁ –C ₆ alkyl, –OH, –NH ₂ , oxo, –(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-D, B is substituted with one or more oxo. In one or more embodiments of Formula IV–D, B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of Formula IV-D, B is substituted with one or more -OH. In one or more embodiments of Formula IV–D, B is substituted with one or more –NH₂. In one or more embodiments of Formula IV-D, B is substituted with one or more -CF₃. In one or more embodiments of Formula IV-D, B is substituted with one or more -CHF₂. In one or more embodiments of Formula IV-D, B is substituted with one or more -CH₂F. In one or more embodiments of Formula IV-D, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-E,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X ^B1 represents N, NR ⁹ , CR ⁹ , S or O; X ^B2 is N, NR ⁹ , CR ⁹ , S or O; and X ^B3 is N, NR ⁹ , CR ⁹ , S or O, where R ⁹ is independently at each occurrence -H, -C ₁ -C ₆ alkyl,

-OH, -NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B1, X^B2 and X^B3 does not represent CR⁹, or provided that if each of X^B1, X^B2 and X^B3 is a CR⁹, then X^one must be N.

In some embodiments of Formula IV-EX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B1 is CR ⁹ . In some embodiments of Formula IV-EX, ^B1 is S. In some embodiments of Formula IV-EX, ^B1 is O. In some embodiments of Formula IV-EX, ^B2 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B2 is CR ⁹ . In some embodiments of Formula IV-EX, ^B2 is S. In some embodiments of Formula IV-EX, ^B2 is O. In some embodiments of Formula IV-EX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B3 is CR ⁹ . In some embodiments of Formula IV-EX, ^B3 is S. In some embodiments of Formula IV-EX, ^B3 is O.

In some embodiments of Formula IV-EX, ^B1 is N, NR ⁹ , or CR ⁹ ; X ^B2 is N, NR ⁹ or CR ⁹ ; and X ^B3 is N, NR ⁹ or CR ⁹ . In some embodiments of Formula IV-EX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B1 is CR ⁹ . In some embodiments of Formula IV-EX, ^B2 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B2 is CR ⁹ . In some embodiments of Formula IV-EX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-EX, ^B3 is CR ⁹ .

In some embodiments of Formula IV-ER ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV-ER ⁹ is H.

, где

является одинарной связью или двойной связью для удовлетворения требованиям правил валентности, представляет собой

,

,

,

,

,

,

,

,

,

,

,

или

.In some embodiments of Formula IV-E

, where

is a single bond or a double bond to meet the requirements of the valency rules, is

,

,

,

,

,

,

,

,

,

,

,

or

.

In one or more embodiments of compounds of formula IV—EY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula IV-EY ² is -NR ^a -.

In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-E, A is monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-E, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-E, A is phenyl. In one or more embodiments of Formula IV-E, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-E, A is pyridinyl. In one or more embodiments of Formula IV-E, A is indazolyl. In one or more embodiments of Formula IV-E, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-E, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-E, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, ER ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, ER ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, ER ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV, ER ¹ is independently at each occurrence —H or halogen. In one or more embodiments of formula IV, ER ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, ER ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, ER ¹ is independently at each occurrence -H, halogen, or -NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of formula IV, ER ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, ER ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV - ER ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, ER ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formula IV-ER ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-E R² represents -H. In one or more embodiments of Formula IV-E R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-E R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, ER ² is -OH. In one or more embodiments of Formula IV, ER ² is -NR ⁵ R ⁶ . In one or more embodiments of formula IV, ER ² is -NH ₂ .

In one or more embodiments of Formula IV-ER, ^a is -H.

In one or more embodiments of Formula IV, ER ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of formula IV-ER ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-ER ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-ER ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV-ER ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, ER ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-E, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV–ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, – NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, ER ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-E, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -ER ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-ER, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-EX ¹ is N and X ² is N. In one or more embodiments of Formula IV-EX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-EX ¹ is C and X ² is N. In one or more embodiments of Formula IV-EX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-F,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, while R⁹ independently in each case represents –H, –C_one-C₆alkyl, –OH, –NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B4, X^B5, X^B6 and X^B7 does not represent CR⁹, or provided that if each of X^B4, X^B5, X^B6 and X^B7is a CR⁹, then X^one should be N.

In some embodiments of formula IV-FX ^B4 is N. In some embodiments of formula IV-FX ^B4 is CR ⁹ . In some embodiments of Formula IV-FX ^B5 is N. In some embodiments of Formula IV-FX ^B5 is CR ⁹ . In some embodiments of formula IV-FX ^B6 is N. In some embodiments of formula IV-FX ^B6 is CR ⁹ . In some embodiments of formula IV-FX ^B7 is N. In some embodiments of formula IV-FX ^B7 is CR ⁹ . In some embodiments of Formula IV-FX, ^B4 is N, X ^B5 is CR ⁹ , X ^B6 is N, and X ^B7 is CR ⁹ . In some such embodiments, R ⁹ is independently at each occurrence -H.

In some embodiments of Formula IV-FR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV-FR ⁹ is H.

In one or more embodiments of compounds of formula IV-FY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of the compounds of formula IV-FY ² is -NR ^a -.

In one or more embodiments of Formula IV-F A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-F A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-F A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-F A is phenyl. In one or more embodiments of Formula IV-F A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-F, A is pyridinyl. In one or more embodiments of Formula IV-F, A is indazolyl. In one or more embodiments of formula IV-F A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-F, n is independently each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-F, n is independently each occurrence 1 or 2.

In one or more embodiments of formula IV, FR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, FR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, FR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV - FR ¹ is independently at each occurrence -H or halogen. In one or more embodiments of formula IV, FR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, FR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, FR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of formula IV, FR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, FR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV-FR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, FR ⁵ and R ⁶ are each independently -H. In one or more embodiments of formula IV-FR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of Formula IV-F R² represents -H. In one or more embodiments of formula IV-F R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of Formula IV-F R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of Formula IV-F R² is -OH. In one or more embodiments of Formula IV-F R² represents -NR⁵R⁶. In one or more embodiments of Formula IV-F R² represents –NH₂.

In one or more embodiments of Formula IV-FR, ^a is -H.

In one or more embodiments of Formula IV - FR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of formula IV-FR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-FR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-FR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV-FR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, FR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formula IV-F R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, FR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-FR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle that is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV - FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—FR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-FX ¹ is N and X ² is N. In one or more embodiments of Formula IV-FX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-FX ¹ is C and X ² is N. In one or more embodiments of Formula IV-FX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-G,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers.

In one or more embodiments of Formula IV-G, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-G, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-G, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-G, A is phenyl. In one or more embodiments of Formula IV-G, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-G, A is pyridinyl. In one or more embodiments of Formula IV-G, A is indazolyl. In one or more embodiments of Formula IV-G, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-G, n is independently each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-G, n is independently each occurrence 1 or 2.

In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence —H, —OR ⁵ , halogen, —C ₁ —C ₆ alkyl, —CN, or —NR ⁵ R ⁶ . In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of formula IV, GR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence —H or halogen. In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, GR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, GR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, GR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV, GR ⁵ and R ⁶ are independently at each occurrence —H or —C ₁ —C ₆ alkyl. In one or more embodiments of Formula IV, GR ⁵ and R ⁶ are each independently -H. In one or more embodiments of Formula IV, GR ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-G R² represents -H. In one or more embodiments of Formula IV-G R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-G R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, GR ² is -OH. In one or more embodiments of Formula IV, GR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, GR ² is -NH ₂ .

In one or more embodiments of Formula IV—GR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, GR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-G, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, GR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-G, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV—GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle which is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—GR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of − C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-GX ¹ is N and X ² is N. In one or more embodiments of Formula IV-GX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-GX ¹ is C and X ² is N. In one or more embodiments of Formula IV-GX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-G, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-G, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-GB, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-G, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of formula IV-GB, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of the formula

IV–GB is substituted by one or more of –C ₁ –C ₆ alkyl, –OH, –NH ₂ , oxo, –(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-G, B is substituted with one or more oxo. In one or more embodiments of Formula IV–G, B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of formula IV-GB, B is substituted with one or more -OH. In one or more embodiments of Formula IV–G, B is substituted with one or more –NH₂. In one or more embodiments of Formula IV–G, B is substituted with one or more –CF₃. In one or more embodiments of Formula IV–G, B is substituted with one or more –CHF₂. In one or more embodiments of Formula IV–G, B is substituted with one or more –CH₂F. In one or more embodiments of Formula IV-G, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-H,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic heterocycle, a 3-12-membered polycyclic heterocycle, or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted with one or more of -C ₁ - C ₆ alkyl, –OH, –NH ₂ , oxo, heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In some embodiments of Formula IV–H, ring C is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH, –CF ₃ ,

–CHF ₂ or –CH ₂ F. In some such embodiments, n is 1. In some embodiments of Formula IV–H, ring C is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –(CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1.

In some embodiments of formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered monocyclic heterocycle. In some embodiments of formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered polycyclic heterocycle. In some embodiments of formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5-12-membered spiro heterocycle.

. В некоторых вариантах осуществления формулы IV–H кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

. В некоторых вариантах осуществления формулы IV–H кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

.In some embodiments of Formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of Formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of Formula IV-H, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

.

In one or more embodiments of Formula IV-H A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-H A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-H A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-H A is phenyl. In one or more embodiments of Formula IV-H A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-H A is pyridinyl. In one or more embodiments of Formula IV-H A is indazolyl. In one or more embodiments of formula IV-HA, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-H, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-H, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, HR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, HR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, HR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV, HR ¹ is independently at each occurrence —H or halogen. In one or more embodiments of Formula IV, HR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, HR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, HR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of formula IV, HR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, HR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV—HR ⁵ and R ⁶ are independently at each occurrence —H or —C ₁ —C ₆ alkyl. In one or more embodiments of Formula IV, HR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of Formula IV, HR ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-H R² represents -H. In one or more embodiments of Formula IV-H R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-H R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, HR ² is -OH. In one or more embodiments of formula IV, HR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, HR ² is -NH ₂ .

In one or more embodiments of Formula IV—HX ¹ is N and X ² is N. In one or more embodiments of Formula IV—HX ¹ is C and X ² is CH. In one or more embodiments of Formula IV—HX ¹ is C and X ² is N. In one or more embodiments of Formula IV—HX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-H B, including atoms at the attachment points, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-H, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-H B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-H B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-H, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV—H B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of formula IV, HB is substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-H, B is substituted with one or more oxo. In one or more embodiments of Formula IV—H B is substituted with one or more -C_one-C₆alkyls. In one or more embodiments of Formula IV—H B is substituted with one or more -OH. In one or more embodiments of Formula IV—H B is substituted with one or more -NH₂. In one or more embodiments of Formula IV, H B is substituted with one or more -CF₃. In one or more embodiments of Formula IV—H B is substituted with one or more -CHF₂. In one or more embodiments of Formula IV—H B is substituted with one or more -CH₂F. In one or more embodiments of Formula IV—H, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-I,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X ^B1 represents N, NR ⁹ , CR ⁹ , S or O; X ^B2 is N, NR ⁹ , CR ⁹ , S or O; and X ^B3 is N, NR ⁹ , CR ⁹ , S or O, where R ⁹ is independently at each occurrence -H, -C ₁ -C ₆ alkyl,

-OH, -NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B1, X^B2 and X^B3 does not represent CR⁹, or provided that if each of X^B1, X^B2 and X^B3 is a CR⁹, then X^one must be N.

In some embodiments of Formula IV-IX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B1 is CR ⁹ . In some embodiments of Formula IV-IX, ^B1 is S. In some embodiments of Formula IV-IX, ^B1 is O. In some embodiments of Formula IV-IX, ^B2 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B2 is CR ⁹ . In some embodiments of Formula IV-IX, ^B2 is S. In some embodiments of Formula IV-IX, ^B2 is O. In some embodiments of Formula IV-IX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B3 is CR ⁹ . In some embodiments of Formula IV-IX, ^B3 is S. In some embodiments of Formula IV-IX, ^B3 is O.

In some embodiments of Formula IV-IX, ^B1 is N, NR ⁹ , or CR ⁹ ; X ^B2 is N, NR ⁹ or CR ⁹ ; and X ^B3 is N, NR ⁹ or CR ⁹ . In some embodiments of Formula IV-IX, ^B1 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B1 is CR ⁹ . In some embodiments of Formula IV-IX, ^B2 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B2 is CR ⁹ . In some embodiments of Formula IV-IX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-IX, ^B3 is CR ⁹ .

In some embodiments of Formula IV-IR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV-IR ⁹ is H.

, где

является одинарной связью или двойной связью для удовлетворения требованиям правил валентности, представляет собой

,

,

,

,

,

,

,

,

,

,

,

или

.In some embodiments of Formula IV-I

, where

is a single bond or a double bond to meet the requirements of the valency rules, is

,

,

,

,

,

,

,

,

,

,

,

or

.

In one or more embodiments of compounds of formula IV-IY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of the compounds of formula IV-IY ² is -NR ^a -.

In one or more embodiments of Formula IV-I, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-I, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-I, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-I, A is phenyl. In one or more embodiments of Formula IV-I, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-I, A is pyridinyl. In one or more embodiments of Formula IV-I, A is indazolyl. In one or more embodiments of Formula IV-I, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-I, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-I, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV-IR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, IR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, IR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of formula IV-IR ¹ independently at each occurrence is -H or halogen. In one or more embodiments of Formula IV, IR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, IR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV-IR ¹ is independently at each occurrence -H, halogen, or -NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV—IR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV - IR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV-IR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of formulas IV-IR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formulas IV-IR ⁵ and R ⁶ independently at each occurrence are -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-I R² represents -H. In one or more embodiments of Formula IV-I R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-I R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of formula IV-I R² is -OH. In one or more embodiments of formula IV-I R² represents -NR⁵R⁶. In one or more embodiments of formula IV-I R² represents –NH₂.

In one or more embodiments of Formula IV-IR, ^a is -H.

In one or more embodiments of Formula IV - IR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula IV-IR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-IR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-IR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV-IR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, IR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-I, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, IR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-IR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formula IV-IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formula IV-IR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle which is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-IX ¹ is N and X ² is N. In one or more embodiments of Formula IV-IX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-IX ¹ is C and X ² is N. In one or more embodiments of Formula IV-IX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-J,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, while R⁹ independently in each case represents –H, –C_one-C₆alkyl, –OH, –NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B4, X^B5, X^B6 and X^B7 does not represent CR⁹, or provided that if each of X^B4, X^B5, X^B6 and X^B7is a CR⁹, then X^one must be N.

In some embodiments of Formula IV-JX ^B4 is N. In some embodiments of Formula IV-JX ^B4 is CR ⁹ . In some embodiments of Formula IV-JX ^B5 is N. In some embodiments of Formula IV-JX ^B5 is CR ⁹ . In some embodiments of Formula IV-JX ^B6 is N. In some embodiments of Formula IV-JX ^B6 is CR ⁹ . In some embodiments of Formula IV-JX, ^B7 is N. In some embodiments of Formula IV-JX, ^B7 is CR ⁹ . In some embodiments of Formula IV-JX ^B4 is N, X ^B5 is CR ⁹ , X ^B6 is N, and X ^B7 is CR ⁹ . In some such embodiments, R ⁹ is independently at each occurrence -H.

In some embodiments of Formula IV-JR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV-JR ⁹ is H.

In one or more embodiments of the compounds of formula IV-JY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of the compounds of formula IV-JY ² is -NR ^a -.

In one or more embodiments of Formula IV-J A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-J A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-J A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-J A is phenyl. In one or more embodiments of Formula IV-J A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-J, A is pyridinyl. In one or more embodiments of Formula IV-J, A is indazolyl. In one or more embodiments of Formula IV-J A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-J, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-J, n is independently at each occurrence 1 or 2.

In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV-JR ¹ , independently at each occurrence, is -H or halogen. In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, JR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV-JR ¹ , independently at each occurrence, is -H, -CN, or halogen.

In one or more embodiments of formulas IV-JR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of formulas IV-JR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formulas IV-JR ⁵ and R ⁶ independently at each occurrence are -C ₁ -C ₆ alkyl.

In one or more embodiments of Formula IV-J R² represents -H. In one or more embodiments of Formula IV-J R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of Formula IV-J R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of Formula IV-J R² is -OH. In one or more embodiments of Formula IV-J R² represents -NR⁵R⁶. In one or more embodiments of Formula IV-J R² represents –NH₂.

In one or more embodiments of Formula IV-JR, ^a is -H.

In one or more embodiments of Formula IV–JR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula IV-JR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-JR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-JR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV-JR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, JR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-J R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV-JR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, JR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formulas IV-JR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV–JR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5–12 membered spiro heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, JR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formulas IV-JR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV–JR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, JR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formulas IV-JR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-JX ¹ is N and X ² is N. In one or more embodiments of Formula IV-JX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-JX ¹ is C and X ² is N. In one or more embodiments of Formula IV-JX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-K,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers.

In one or more embodiments of Formula IV-K, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-K, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-K, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-K, A is phenyl. In one or more embodiments of Formula IV-K, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-K, A is pyridinyl. In one or more embodiments of Formula IV-K, A is indazolyl. In one or more embodiments of formula IV-K A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-K, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-K, n is independently at each occurrence 1 or 2.

In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, KR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV-KR ¹ , independently at each occurrence, is -H or halogen. In one or more embodiments of formula IV, KR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of Formula IV, KR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV-KR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, KR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formulas IV-KR ⁵ and R ⁶ independently at each occurrence are -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-K R² represents -H. In one or more embodiments of Formula IV-K R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-K R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, KR ² is -OH. In one or more embodiments of Formula IV, KR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, KR ² is -NH ₂ .

In one or more embodiments of Formula IV—KR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, KR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-K, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, KR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-K, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV - KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV - KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV-KR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10- to 12-membered spiro heterocycle that is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-KX ¹ is N and X ² is N. In one or more embodiments of Formula IV-KX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-KX ¹ is C and X ² is N. In one or more embodiments of Formula IV-KX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-K B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of Formula IV-K, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-K B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-K B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-K, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-K B, including atoms at the attachment points, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of formula IV-K, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-K B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-K B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-K, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-K, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of formula IV, KB is substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-K, B is substituted with one or more oxo. In one or more embodiments of Formula IV–K, B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of Formula IV-K, B is substituted with one or more -OH. In one or more embodiments of Formula IV–K, B is substituted with one or more –NH₂. In one or more embodiments of formula IV-K B is substituted with one or more -CF₃. In one or more embodiments of Formula IV–K, B is substituted with one or more –CHF₂. In one or more embodiments of Formula IV–K, B is substituted with one or more –CH₂F. In one or more embodiments of Formula IV-K, B is substituted with one or more -(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-L,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic heterocycle, a 3-12-membered polycyclic heterocycle, or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted with one or more of -C ₁ - C ₆ alkyl, –OH, –NH ₂ , oxo, heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In some embodiments of Formula IV-L, ring C is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , -OH, -(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH, –CF ₃ ,

–CHF ₂ or –CH ₂ F. In some such embodiments, n is 1. In some embodiments of formulas IV-L, ring C is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –(CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1.

In some embodiments of formula IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered monocyclic heterocycle. In some embodiments of formula IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered polycyclic heterocycle. In some embodiments of formula IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5-12-membered spiro heterocycle.

. В некоторых вариантах осуществления формулы IV–L кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

. В некоторых вариантах осуществления формулы IV–L кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

.In some embodiments of formulas IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-L, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

.

In one or more embodiments of Formula IV-LA, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula IV-LA, A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula IV-LA, A is a monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-LA, A is phenyl. In one or more embodiments of Formula IV-LA, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-LA, A is pyridinyl. In one or more embodiments of Formula IV-LA, A is indazolyl. In one or more embodiments of Formula IV-LA, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula IV-L, n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-L, n is independently at each occurrence 1 or 2.

In one or more embodiments of formula IV, LR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, LR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, LR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of formula IV-LR ¹ is independently at each occurrence -H or halogen. In one or more embodiments of Formula IV, LR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, LR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of formula IV, LR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV, LR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of formula IV-LR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of Formula IV-LR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of formulas IV-LR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formula IV-LR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-L R² represents -H. In one or more embodiments of formula IV-L R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-K R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, LR ² is -OH. In one or more embodiments of Formula IV, LR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, LR ² is -NH ₂ .

In one or more embodiments of Formula IV-LX ¹ is N and X ² is N. In one or more embodiments of Formula IV-LX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-LX ¹ is C and X ² is N. In one or more embodiments of Formula IV-LX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-L, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-L, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is a monocyclic 7-12 membered heteroaryl.

In one or more embodiments of Formula IV-L, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-L, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-L, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of Formula IV, LB is substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-L, B is substituted with one or more oxo. In one or more embodiments of Formula IV–L, B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of Formula IV-L, B is substituted with one or more -OH. In one or more embodiments of Formula IV–L, B is substituted with one or more –NH₂. In one or more embodiments of Formula IV–L, B is substituted with one or more –CF₃. In one or more embodiments of Formula IV–L, B is substituted with one or more –CHF₂. In one or more embodiments of Formula IV–L, B is substituted with one or more –CH₂F. In one or more embodiments of Formula IV-L, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-M,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X ^B1 represents N, NR ⁹ , CR ⁹ , S or O; X ^B2 is N, NR ⁹ , CR ⁹ , S or O; and X ^B3 is N, NR ⁹ , CR ⁹ , S or O, where R ⁹ is independently at each occurrence -H, -C ₁ -C ₆ alkyl,

-OH, -NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B1, X^B2 and X^B3 does not represent CR⁹, or provided that if each of X^B1, X^B2 and X^B3 is a CR⁹, then X^one must be N.

In some embodiments of Formula IV-MX ^B1 is N or NR ⁹ . In some embodiments of Formula IV-MX ^B1 is CR ⁹ . In some embodiments of Formula IV-MX ^B1 is S. In some embodiments of Formula IV-MX ^B1 is O. In some embodiments of Formula IV-MX ^B2 is N or NR ⁹ . In some embodiments of Formula IV-MX, ^B2 is CR ⁹ . In some embodiments of Formula IV-MX ^B2 is S. In some embodiments of Formula IV-MX ^B2 is O. In some embodiments of Formula IV-MX ^B3 is N or NR ⁹ . In some embodiments of Formula IV-MX, ^B3 is CR ⁹ . In some embodiments of Formula IV-MX ^B3 is S. In some embodiments of Formula IV-MX ^B3 is O.

In some embodiments of formula IV-MX ^B1 is N, NR ⁹ or CR ⁹ ; X ^B2 is N, NR ⁹ or CR ⁹ ; and X ^B3 is N, NR ⁹ or CR ⁹ . In some embodiments of Formula IV-MX ^B1 is N or NR ⁹ . In some embodiments of Formula IV-MX ^B1 is CR ⁹ . In some embodiments of formula IV-MX ^B2 is N or NR ⁹ . In some embodiments of Formula IV-MX, ^B2 is CR ⁹ . In some embodiments of Formula IV-MX, ^B3 is N or NR ⁹ . In some embodiments of Formula IV-MX, ^B3 is CR ⁹ .

In some embodiments of Formula IV, MR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV, MR ⁹ is H.

, где

является одинарной связью или двойной связью для удовлетворения требованиям правил валентности, представляет собой

,

,

,

,

,

,

,

,

,

,

,

или

.In some embodiments of Formula IV-M

, where

is a single bond or a double bond to meet the requirements of the valency rules, is

,

,

,

,

,

,

,

,

,

,

,

or

.

In one or more embodiments of compounds of formula IV - MY ² is

-(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula IV, MY ² is -NR ^a -.

In one or more embodiments of formula IV-M R² represents -H. In one or more embodiments of Formula IV-M R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-M R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, MR ² is -OH. In one or more embodiments of Formula IV, MR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, MR ² is -NH ₂ .

In one or more embodiments of formula IV-MR ^a is -H.

In one or more embodiments of Formula IV, MR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of formula IV-MR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of formula IV-MR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of formula IV-MR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV-MR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, MR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formulas IV-M, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, MR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formulas IV-M, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV—MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle that is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—MR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-MX ¹ is N and X ² is N. In one or more embodiments of Formula IV-MX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-MX ¹ is C and X ² is N. In one or more embodiments of Formula IV-MX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-N,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, while R⁹ independently in each case represents –H, –C_one-C₆alkyl, –OH, –NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that if X^one is C, then at least one of X^B4, X^B5, X^B6 and X^B7 does not represent CR⁹, or provided that if each of X^B4, X^B5, X^B6 and X^B7is a CR⁹, then X^one should be N.

In some embodiments of formula IV-NX ^B4 is N. In some embodiments of formula IV-NX ^B4 is CR ⁹ . In some embodiments of Formula IV-NX ^B5 is N. In some embodiments of Formula IV-NX ^B5 is CR ⁹ . In some embodiments of formula IV-NX ^B6 is N. In some embodiments of formula IV-NX ^B6 is CR ⁹ . In some embodiments of Formula IV-NX ^B7 is N. In some embodiments of Formula IV-NX ^B7 is CR ⁹ . In some embodiments of Formula IV-NX ^B4 is N, X ^B5 is CR ⁹ , X ^B6 is N, and X ^B7 is CR ⁹ . In some such embodiments, R ⁹ is independently at each occurrence -H.

In some embodiments of Formula IV - NR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula IV - NR ⁹ is H.

In one or more embodiments of compounds of formula IV-NY ² is

-(CR ^a ₂ ) _m -. In one or more embodiments of the compounds of formula IV-NY ² is -NR ^a -.

In one or more embodiments of formula IV-N R² represents -H. In one or more embodiments of formula IV-N R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-N R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, NR ² is -OH. In one or more embodiments of Formula IV, NR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, NR ² is -NH ₂ .

In one or more embodiments of formula IV-NR ^a is -H.

In one or more embodiments of Formula IV, NR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula IV-NR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula IV-NR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of Formula IV-NR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, NR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-N, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, NR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of formulas IV-N, R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle that is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV—NR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10- to 12-membered spiro heterocycle that is optionally substituted by one or more of − C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-NX ¹ is N and X ² is N. In one or more embodiments of Formula IV-NX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-NX ¹ is C and X ² is N. In one or more embodiments of Formula IV-NX ¹ is N and X ² is CH.

In some embodiments of formula IV, the compound is represented by formula IV-O,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers.

In one or more embodiments of formula IV-O R² represents -H. In one or more embodiments of formula IV-O R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-O R² represents –H, –OH, –NR⁵R⁶,

–C ₁ –C ₆ alkyl or –NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, OR ² is -OH. In one or more embodiments of Formula IV, OR ² is -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, OR ² is -NH ₂ .

In one or more embodiments of Formula IV-OR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, OR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-O R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV–OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, – NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, OR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula IV-O R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered polycyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of Formula IV–OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5–12 membered spiro heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of Formula IV, -OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV–OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5–12 membered spiro heterocycle which is optionally substituted with one or more of − C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV–OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of –C ₁ –C ₆ alkyl, –NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula IV, -OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle, which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of Formula IV–OR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of − C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of Formula IV-OX ¹ is N and X ² is N. In one or more embodiments of Formula IV-OX ¹ is C and X ² is CH. In one or more embodiments of Formula IV - OX ¹ is C and X ² is N. In one or more embodiments of Formula IV - OX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-O, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-O B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-O, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-O, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of formula IV-OB is substituted by one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-O, B is substituted with one or more oxo. In one or more embodiments of Formula IV–O B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of Formula IV-O, B is substituted with one or more -OH. In one or more embodiments of formula IV–O B is substituted with one or more –NH₂. In one or more embodiments of formula IV-O B is substituted with one or more -CF₃. In one or more embodiments of formula IV-O B is substituted with one or more -CHF₂. In one or more embodiments of Formula IV–O B is substituted with one or more –CH₂F. In one or more embodiments of Formula IV-O, B is substituted with one or more -(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-P,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where:

C, together with the nitrogen atom to which it is attached, forms a 3-12-membered monocyclic heterocycle, a 3-12-membered polycyclic heterocycle, or a 5-12-membered spiro-heterocycle, while the heterocycle or spiro-heterocycle is optionally substituted with one or more of -C ₁ - C ₆ alkyl, –OH, –NH ₂ , oxo, heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In some embodiments of Formula IV-P, ring C is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , -OH, -(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH, –CF ₃ ,

-CHF ₂ or -CH ₂ F. In some such embodiments, n is 1. In some embodiments of Formula IV-P, ring C is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1.

In some embodiments of formula IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered monocyclic heterocycle. In some embodiments of formula IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 3-12-membered polycyclic heterocycle. In some embodiments of Formula IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted 5- to 12-membered spiro heterocycle.

. В некоторых вариантах осуществления формулы IV–P кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

. В некоторых вариантах осуществления формулы IV–P кольцо C, вместе с атомом азота, к которому оно присоединено, представляет собой необязательно замещенный

.In some embodiments of formulas IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

. In some embodiments of formulas IV-P, ring C, together with the nitrogen atom to which it is attached, is an optionally substituted

.

In one or more embodiments of formula IV-P R² represents -H. In one or more embodiments of Formula IV-P R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-P R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of formula IV-P R² is -OH. In one or more embodiments of formula IV-P R² represents -NR⁵R⁶. In one or more embodiments of formula IV-P R² represents –NH₂.

In one or more embodiments of Formula IV-PX ¹ is N and X ² is N. In one or more embodiments of Formula IV-PX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-PX ¹ is C and X ² is N. In one or more embodiments of Formula IV-PX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-P B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula IV-P B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula IV-P B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula IV-P B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-P, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of formula IV-P B, including atoms at the attachment points, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of formula IV-P B, including atoms at the attachment points, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula IV-P B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula IV-P B, including atoms at the attachment points, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-P, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-P B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of Formula IV, PB is substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , oxo, -(CH ₂ ) _n NH ₂ ,

–(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula IV-P, B is substituted with one or more oxo. In one or more embodiments of Formula IV–P B is substituted with one or more –C_one-C₆alkyls. In one or more embodiments of formula IV-P B is substituted with one or more -OH. In one or more embodiments of Formula IV–P B is substituted with one or more –NH₂. In one or more embodiments of formula IV - P B is substituted with one or more -CF₃. In one or more embodiments of Formula IV–P B is substituted with one or more –CHF₂. In one or more embodiments of Formula IV–P B is substituted with one or more –CH₂F. In one or more embodiments of Formula IV-P, B is substituted with one or more –(CH₂)_nNH₂. In some such embodiments, n is 1.

In some embodiments of formula IV, the compound is represented by formula IV-Q,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl, provided that the heteroaryl is not

or

;

R ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN or

–NR ⁵ R ⁶ ;

Y ¹ is -S- or a direct link;

X ¹ represents N or C;

X ² represents N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl or -NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ ;

Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

R ³ is combined with R ^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of –C ₁ –C ₆ alkyl, –OH, –NH ₂ ,

–(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In one or more embodiments of Formula IV–QY ¹ is –S–. In one or more embodiments of Formula IV-QY ¹ is a direct bond.

In one or more embodiments of Formula IV-Q, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula IV-Q, A is phenyl. In one or more embodiments of Formula IV-Q, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula IV-Q, A is pyridinyl. In one or more embodiments of Formula IV-Q, A is indazolyl.

In one or more embodiments of Formula IV-Q, n is independently each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula IV-Q, n is independently each occurrence 1 or 2.

In one or more embodiments of Formula IV, QR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of Formula IV, QR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of Formula IV-QR ¹ , independently at each occurrence, is -H or halogen. In one or more embodiments of Formula IV, QR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of Formula IV, QR ¹ is independently at each occurrence -H, -OR ⁵ or

–NR ⁵ R ⁶ . In one or more embodiments of Formula IV—QR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula IV—QR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of formula IV—QR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula IV-QR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of formulas IV-QR ⁵ and R ⁶ independently at each occurrence are -C ₁ -C ₆ alkyl.

In one or more embodiments of formula IV-Q R² represents -H. In one or more embodiments of formula IV-Q R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of -OH, halo, -OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula IV-Q R² is -OH. In one or more embodiments of formula IV-Q R² represents -NR⁵R⁶. In one or more embodiments of formula IV-Q R² represents –NH₂.

In one or more embodiments of Formula IV—QR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, QR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1.

In one or more embodiments of Formula IV—QR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of Formula IV, QR ³ and R ^a , together with the atom to which they are attached, are combined to form 3-12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1.

In one or more embodiments of Formula IV—QR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, QR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1.

In one or more embodiments of Formula IV—QR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of formula IV, QR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1.

In one or more embodiments of Formula IV-QX ¹ is N and X ² is N. In one or more embodiments of Formula IV-QX ¹ is C and X ² is CH. In one or more embodiments of Formula IV-QX ¹ is C and X ² is N. In one or more embodiments of Formula IV-QX ¹ is N and X ² is CH.

In one or more embodiments of formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12 membered heterocycle.

In one or more embodiments of formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula IV-Q, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is a monocyclic 7-12 membered heteroaryl.

In one or more embodiments of Formula IV-Q, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula IV-Q, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula IV-Q, B is substituted with one or more

–(CH ₂ ) _n OH. In some such embodiments, n is 1. In one or more embodiments of Formula IV-QB is substituted with one or more oxos. In one or more embodiments of formula IV-QB is substituted with one or more -C ₁ -C ₆ alkyl. In one or more embodiments of Formula IV, QB is substituted with one or more -OH. In one or more embodiments of formula IV, QB is substituted with one or more -NH ₂ . In one or more embodiments of Formula IV, QB is substituted with one or more -CF ₃ . In one or more embodiments of Formula IV, QB is substituted with one or more -CHF ₂ . In one or more embodiments of formula IV-QB is substituted with one or more -CH ₂ F. In one or more embodiments of formula IV-QB is substituted with one or more -(CH ₂ ) _n NH ₂ . In some such embodiments, n is 1.

In one or more embodiments, a compound of the present invention (eg, a compound of formula I', I, II, III, or IV) may be selected from:

one

,

, 2

, 3

, four

, 5

, 6

, 7

, eight

, 9

, ten

, eleven

, 12

, 13

, fourteen

, fifteen

, 16

, 17

, eighteen

, 19

, twenty

, 21

, 22

, 23

, 24

, 25

, 26

, 27

, 28

, 29

, thirty

, 31

, 32

, 33

, 34

, 35

, 36

, 37

, 38

, 39

, 40

, 41

, 42

, 43

, 44

, 45

, 46

, 47

, 48

, 49

, fifty

, 51

and 52

,

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers of any of the above compounds.

In some embodiments, the compounds of the present invention are compounds of formula V,

,

,

and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers, where:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that heteroaryl is not

or

;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, -OR ⁵ , halogen, -NO ₂ , -CN,

–NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ ,

–S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ or –CO ₂ R ⁵ , each alkyl, alkenyl , cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C ₃ -C ₈ cycloalkyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more of

–OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ ,

–NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl is not attached through a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; wherein the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R³ can be combined with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

R ¹⁰ is -H or -C ₁ -C ₆ alkyl;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

In one or more embodiments of the formula, VR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы V Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы V Y¹ представляет собой прямую связь.In one or more embodiments of the formula, VR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of the formula, VY ¹ is -S-. In one or more embodiments of the formula, VY ¹ is a direct bond.

In one or more embodiments of compounds of formula VY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula VY ² is -NR ^a -.

In one or more embodiments of compounds of formula VR ¹⁰ is -H. In one or more embodiments of compounds of formula VR ¹⁰ is -C ₁ -C ₆ alkyl.

In one or more embodiments of formula V A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of formula V A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of formula V A is a monocyclic or polycyclic aryl. In one or more embodiments of formula V A is phenyl. In one or more embodiments of formula V A is monocyclic or polycyclic heteroaryl. In one or more embodiments of formula V A is pyridinyl. In one or more embodiments of formula V A is indazolyl. In one or more embodiments of formula V A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of the formula, V n is independently at each occurrence 0, 1, 2, or 3. In one or more embodiments of the formula, V n is independently at each occurrence 1 or 2.

In one or more embodiments of the formula, VR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of the formula, VR ¹ is independently at each occurrence —OR ⁵ or halogen. In one or more embodiments of the formula, VR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of the formula, VR ¹ is independently at each occurrence -H or halogen. In one or more embodiments of the formula, VR ¹ is independently at each occurrence –H or

–NR ⁵ R ⁶ . In one or more embodiments of the formula, VR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of the formula, VR ¹ is independently at each occurrence —H, halogen, or —NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of the formula, VR ¹ is independently at each occurrence —H, methyl, fluorine, chlorine, or —NH ₂ . In one or more embodiments of the formula, VR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of the formulas, VR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments, formulas VR ⁵ and R ⁶ are each independently -H. In one or more embodiments of formula VR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of formula V R² represents -H. In one or more embodiments of formula V R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of formula V R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of formula V R² is -OH. In one or more embodiments of formula V R² represents -NR⁵R⁶. In one or more embodiments of formula V R² represents –NH₂.

In one or more embodiments of Formula VR, ^a is –H.

In one or more embodiments of Formula VR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula VR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula VR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of Formula VR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of formula VR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

-(CH ₂ ) _n OH, -CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12-membered a monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle that is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of formula VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of formula VR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12-membered polycyclic heterocycle which is optionally substituted with one or several of -C ₁ -C ₆ alkyl, - (CH ₂ ) _n NH ₂ or

-NH2 _. In some such embodiments, n is 1. In one or more embodiments of formula VR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle that is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of the formula, VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12-membered spiro heterocycle that is optionally substituted with one or more from –C ₁ –C ₆ alkyl, –(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle that is optionally substituted with one or more of -C ₁ –C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of formula VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

-CF ₃ , -CHF ₂ , or -CH ₂ F. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more from –C ₁ –C ₆ alkyl, –(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of the formulas, VR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle that is optionally substituted with one or more of -C ₁ –C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of formula V, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of Formula V, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heterocycle. In one or more embodiments of formula V, B, including atoms at the points of attachment, is an optionally substituted monocyclic 7-12-membered heterocycle.

In one or more embodiments of Formula V, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of formula V, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula V, B, including atoms at the points of attachment, is an optionally substituted monocyclic or polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula V, B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In one or more embodiments of Formula V, B, including atoms at the points of attachment, is a monocyclic 7-12 membered heteroaryl.

In one or more embodiments of Formula V, B, including atoms at the points of attachment, is an optionally substituted polycyclic 5-12 membered heteroaryl. In one or more embodiments of Formula V, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

In one or more embodiments of Formula V, B is substituted with one or more

–(CH₂)_nOh. In some such embodiments, n is 1. In one or more embodiments of Formula V, B is replaced by one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. In one or more embodiments of Formula V, B is substituted with one or more oxo. In one or more embodiments of Formula V, B is substituted with one or more

–C ₁ –C ₆ alkyls. In one or more embodiments of the formula, VB is substituted with one or more

-OH. In one or more embodiments of the formula, VB is substituted with one or more –NH ₂ . In one or more embodiments of the formula, VB is substituted with one or more -CF ₃ . In one or more embodiments of the formula, VB is substituted with one or more -CHF ₂ . In one or more embodiments of the formula, VB is substituted with one or more -CH ₂ F. In one or more embodiments of the formula, VB is substituted with one or more -(CH ₂ ) _n NH ₂ . In some such embodiments, n is 1.

In some embodiments of formula V, the compound is represented by formula V-A,

,

,

and its corresponding pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers and isomers, where X^B4 is N or CR⁹; X^B5 is N or CR⁹; X^B6 is N or CR⁹; and X^B7 is N or CR⁹, while R⁹ independently in each case represents –H, –C_one-C₆alkyl, –OH, –NH₂, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In some embodiments of formula V-AX ^B4 is N. In some embodiments of formula V-AX ^B4 is CR ⁹ . In some embodiments of formula V-AX ^B5 is N. In some embodiments of formula V-AX ^B5 is CR ⁹ . In some embodiments of formula V-AX ^B6 is N. In some embodiments of formula V-AX ^B6 is CR ⁹ . In some embodiments of formula V-AX ^B7 is N. In some embodiments of formula V-AX ^B7 is CR ⁹ .

In some embodiments of Formula V-AR ⁹ is -(CH ₂ ) _n OH and n is 1. In some embodiments of Formula V-AR ⁹ is H.

In one or more embodiments of compounds of formula V-AR ¹⁰ is -H. In one or more embodiments of compounds of formula V-AR ¹⁰ is -C ₁ -C ₆ alkyl.

In one or more embodiments of Formula V-AR ⁴ is H.

. В некоторых таких вариантах осуществления Y¹ представляет собой –S– или прямую связь. В одном или нескольких вариантах осуществления формулы V–A Y¹ представляет собой –S–. В одном или нескольких вариантах осуществления формулы V–A Y¹ представляет собой прямую связь.In one or more embodiments of formula V-AR ⁴ is

. In some such embodiments, Y ¹ is -S- or a direct bond. In one or more embodiments of the formula, V-AY ¹ is -S-. In one or more embodiments of the formula V-AY ¹ is a direct link.

In one or more embodiments of compounds of formula V-AY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of compounds of formula V-AY ² is -NR ^a -.

In one or more embodiments of Formula V-A, A is a monocyclic or polycyclic cycloalkyl. In one or more embodiments of Formula V-A, A is monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of Formula V-A, A is monocyclic or polycyclic aryl. In one or more embodiments of Formula V-A, A is phenyl. In one or more embodiments of Formula V-A, A is monocyclic or polycyclic heteroaryl. In one or more embodiments of Formula V-A, A is pyridinyl. In one or more embodiments of Formula V-A, A is indazolyl. In one or more embodiments of Formula V-A, A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl.

In one or more embodiments of Formula V-A, n is independently each occurrence 0, 1, 2, or 3. In one or more embodiments of Formula V-A, n is independently each occurrence 1 or 2.

In one or more embodiments of the formula, V-AR ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN, or -NR ⁵ R ⁶ . In one or more embodiments of formula V-AR ¹ is independently at each occurrence -H, -OR ⁵ or halogen. In one or more embodiments of the formula, V-AR ¹ is independently at each occurrence -H or -OR ⁵ . In one or more embodiments of formula V-AR ¹ is independently at each occurrence -H or halogen. In one or more embodiments of the formula, V-AR ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . In one or more embodiments of the formula, V-AR ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . In one or more embodiments of the formula, V-AR ¹ is independently at each occurrence -H, halogen, or -NR ⁵ R ⁶ . In some such embodiments, both R ⁵ and R ⁶ are –H. In one or more embodiments of Formula V-AR ¹ , independently at each occurrence, is -H, methyl, fluorine, chlorine, or -NH ₂ . In one or more embodiments of formula V-AR ¹ is independently at each occurrence -H, -CN, or halogen.

In one or more embodiments of formula V-AR ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl. In one or more embodiments of the formulas, V-AR ⁵ and R ⁶ are independently at each occurrence -H. In one or more embodiments of the formulas V-AR ⁵ and R ⁶ are independently at each occurrence -C ₁ -C ₆ alkyl.

In one or more embodiments of Formula V-A R² represents -H. In one or more embodiments of Formula V-A R² represents -C_one-C₆alkyl, with each alkyl optionally substituted with one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In some such embodiments, R² is methyl. In one or more embodiments of Formula V-A R² represents –H, –OH, –NR⁵R⁶, –C_one-C₆alkyl or –NH₂; wherein each alkyl is optionally substituted by one or more of –OH, halo, –OR⁵ or -NR⁵R⁶. In one or more embodiments of Formula V-A R² is -OH. In one or more embodiments of Formula V-A R² represents -NR⁵R⁶. In one or more embodiments of Formula V-A R² represents –NH₂.

In one or more embodiments of Formula V-AR, ^a is -H.

In one or more embodiments of Formula V-AR ³ is an optionally substituted

–C ₁ –C ₆ alkyl. In one or more embodiments of Formula V-AR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula V-AR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of Formula V-AR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of formula V-AR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of the formula, V–AR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered monocyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH₂)_nNH₂ or -NH₂. In some such embodiments, n is 1. In one or more embodiments of Formula V-A R³ and R^a together with the atom to which they are attached are combined to form a 3–12 membered monocyclic heterocycle which is optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of formula V-AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, - NH ₂ , –OH, –(CH ₂ ) _n NH ₂ ,

–(CH ₂ ) _n OH, –CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of the formula, V–AR ³ and R ^a , together with the atom to which they are attached, are combined to form 3–12 -membered polycyclic heterocycle which is optionally substituted by one or more of -C ₁ -C ₆ alkyl,

–(CH ₂ ) _n NH ₂ or –NH ₂ . In some such embodiments, n is 1. In one or more embodiments of formula V-AR ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle that is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

-CHF ₂ or -CH ₂ F.

In one or more embodiments of formula V-AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of the formula V–AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5–12 membered spiro heterocycle that is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of the formulas V-AR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle that is optionally substituted by one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

In one or more embodiments of formula V-AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12 membered spiro heterocycle which is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -NH ₂ , –OH, –(CH ₂ ) _n NH ₂ , –(CH ₂ ) _n OH,

–CF ₃ , –CHF ₂ , or –CH ₂ F. In one or more embodiments of the formula V–AR ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10–12 membered spiro heterocycle that is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -(CH ₂ ) _n NH ₂ or -NH ₂ . In some such embodiments, n is 1. In one or more embodiments of the formulas V-AR, ³ and R ^a , together with the atoms to which they are attached, are combined to form a 10-12-membered spiro heterocycle that is optionally substituted with one or more of - C ₁ -C ₆ alkyl,

-OH, -NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

.In one or more embodiments of formula I', IV or VR ⁴ is H. In one or more embodiments of formula I', I, IV or VR ⁴ is

.

In one or more embodiments of formula I', I, II, III, IV, or V A is a 5-12 membered monocyclic or polycyclic cycloalkyl. In one or more embodiments of formula I', I, II, III, IV, or V A is a monocyclic or polycyclic heterocycloalkyl. In one or more embodiments of formula I', I, II, III, IV or V A is a monocyclic or polycyclic aryl. In one or more embodiments of formula I', I, II, III, IV or V A is a monocyclic or polycyclic heteroaryl.

In one or more embodiments of Formula I', I, IV, or VY ¹ is -S-. In one or more embodiments of Formula I', I, IV, or VY ¹ is a direct bond.

In one or more embodiments of Formula I', I, II, III, IV, or VY ² is -NR ^a -. In one or more embodiments of formula I', I, II, III, IV, or VY ² is -(CR ^a ₂ ) _m -. In one or more embodiments of Formula I', I, II, III, IV, or Y ² is -C(O)-. In one or more embodiments of Formula I', I, II, III, IV or VY ² is -C(R ^a ) ₂ NH- or -(CR ^a ₂ ) _m O-. In one or more embodiments of formula I', I, II, III, IV, or VY ² is -C(O)N(R ^a )-, -N(R ^a )C(O)-,

–S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(S)– or –C(S)N(R ^a )–. In one or more embodiments of Formula I', I, II, III, IV, or VY ² is -N(R ^a )C(O)N(R ^a )-, -N(R ^a )C(S)N (R ^a )–,

–OC(O)N(R ^a )–, –N(R ^a )C(O)O– or –C(O)N(R ^a )O–. In one or more embodiments of Formula I', I, II, III, IV or VY ² is -C(O)O-, -OC(O)- or -OC(O)O-.

In one or more embodiments of Formula I', I, II, III, IV, or VR ² is -OH. In one or more embodiments of formula I', I, II, III, IV, or VR ² is -C ₁ -C ₆ alkyl, with each alkyl optionally substituted with one or more of -OH, halogen, -OR ⁵ or - NR ⁵ R ⁶ . In one or more embodiments of formula I', I, II, III, IV, or VR ² is an optionally substituted -C ₂ -C ₆ alkenyl. In one or more embodiments of Formula I', I, II, III, IV, or VR ² is an optionally substituted

–C ₄ –C ₈ cycloalkenyl. In one or more embodiments of Formula I', I, II, III, IV or VR ² is an optionally substituted -C ₂ -C ₆ alkynyl. In one or more embodiments of Formula I', I, II, III, IV, or VR ² is an optionally substituted -C ₃ -C ₈ cycloalkyl. In one or more embodiments of formula I', I, II, III, IV or VR ² is an optionally substituted monocyclic or polycyclic heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O.

In one or more embodiments of Formula I', I, II, III, IV, or VR, ^a is -H. In one or more embodiments of Formula I', I, II, III, IV, or VR, ^a is -OH. In one or more embodiments of formula I', I, II, III, IV, or VR ^a is an optionally substituted -C ₃ -C ₈ cycloalkyl. In one or more embodiments of Formula I', I, II, III, IV, or VR, ^a is an optionally substituted

–C ₁ –C ₆ alkyl.

In one or more embodiments of formula I', I, II, III, IV, or V R^b is H. In one or more embodiments of formula I', I, II, III, IV, or V R^b is an optionally substituted

-C_one-C₆alkyl. In one or more embodiments of formula I', I, II, III, IV, or V R^b is an optionally substituted –C₃-C_eightcycloalkyl. In one or more embodiments of formula I', I, II, III, IV, or V R^b is an optionally substituted –C₂-C₆alkenyl. In one or more embodiments of formula I', I, II, III, IV, or V R^b is an optionally substituted monocyclic or polycyclic heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O.

In one or more embodiments of formula I', I, II, III, IV or VR ³ is an optionally substituted -C ₁ -C ₆ alkyl. In one or more embodiments of Formula I', I, II, III, IV or VR ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle. In one or more embodiments of Formula I', I, II, III, IV or VR ³ is an optionally substituted 3-12 membered monocyclic heterocycle. In one or more embodiments of Formula I', I, II, III, IV, or VR ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

In one or more embodiments of formula I', I, II, III, IV, or VR ³ and R ^a , together with the atom to which they are attached, are combined to form an optionally substituted 3-12-membered monocyclic heterocycle. In one or more embodiments of formula I', I, II, III, IV, or VR ³ and R ^a , together with the atoms to which they are attached, are combined to form an optionally substituted 3-12-membered polycyclic heterocycle. In one or more embodiments of formula I', I, II, III, IV, or VR ³ and R ^a , together with the atoms to which they are attached, are combined to form an optionally substituted 5-12-membered spiro-heterocycle.

In one or more embodiments of formula I', I, II, III, or IV, X ¹ is N. In one or more embodiments of formula I', I, II, III, or IV, X ¹ is C.

In one or more embodiments of Formula I', I, II, III, or IV, X ² is N. In one or more embodiments of Formula I', I, II, III, or IV, X ² is CH.

In one or more embodiments of Formula I', I, II, III, or IV, X ¹ is N and X ² is N. In one or more embodiments of Formula I', I, II, III, or IV, X ¹ is is N, and X ² is CH. In one or more embodiments of formula I', I, II, III, or IV, X ¹ is C and X ² is N. In one or more embodiments of formula I', I, II, III, or IV, X ¹ is is C, and X ² is CH.

In one or more embodiments of formula I', I, II, III, IV, or V, B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle. In one or more embodiments of formula I', I, II, III, IV or V B, including atoms at the attachment points, is a monocyclic 5-6 membered heterocycle. In one or more embodiments of formula I', I, II, III, IV or V B, including atoms at the points of attachment, is a monocyclic 7-12-membered heterocycle.

In one or more embodiments of formula I', I, II, III, IV or V B, including atoms at the points of attachment, is a polycyclic 5-12-membered heterocyclyl. In some embodiments, the heterocyclyl ring is fused. In one or more embodiments of Formula I', I, II, III, IV, or V, the heterocyclyl ring contains an internal bridge.

In one or more embodiments of Formula I', I, II, III, IV, or V, B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heteroaryl. In one or more embodiments of Formula I', I, II, III, IV, or V, B, including atoms at the points of attachment, is a monocyclic 5-6 membered heteroaryl. In one or more embodiments of formula I', I, II, III, IV, or V, B, including atoms at the points of attachment, is a monocyclic 7-12-membered heteroaryl.

In one or more embodiments of formula I', I, II, III, IV, or V, B, including atoms at the points of attachment, is a polycyclic 5-12-membered heteroaryl. In one or more embodiments of Formula I', I, II, III, IV, or V, the polycyclic heteroaryl is a plurality of fused rings as described above. The rings of a system of multiple fused rings may be connected to each other by fused, spiro and bridge bonds if permitted by valency requirements.

, и X¹ представляет собой N, с образованием таким образом

.In one or more embodiments of formula I', I, II, III, or IV, B, including atoms at attachment points, is

, and X ¹ is N, thus forming

.

, и X¹ представляет собой C, с образованием таким образом

.In one or more embodiments of formula I', I, II, III, or IV, B, including atoms at attachment points, is

, and X ¹ is C, thus forming

.

, и X¹ представляет собой C, с образованием таким образом

.In one or more embodiments of formula I', I, II, III, or IV, B, including atoms at attachment points, is

, and X ¹ is C, thus forming

.

In one embodiment of formula I, II, III, IV, or VR ² is an optionally substituted

-C ₁ -C ₆ alkyl, and B, including atoms at the attachment points, is an optionally substituted monocyclic 5-6 membered heteroaryl. In some instances of formula I, II, III, IV, or VR ² is an optionally substituted -C ₁ -C ₆ alkyl, and B, including atoms at the attachment points, is an optionally substituted monocyclic 5-membered heteroaryl. In some cases of formula I, II, III, IV or VR ² is an optionally substituted -C ₁ -C ₆ alkyl, and B, including atoms at the points of attachment, is an optionally substituted monocyclic 6-membered heteroaryl.

In one embodiment of formula I, II, III, IV, or VR ² is -OH and B, including atoms at the points of attachment, is an optionally substituted monocyclic 5-6 membered heteroaryl. In some instances of Formula I, II, III, IV, or VR ² is —OH, and B, including the atoms at the attachment points, is an optionally substituted monocyclic 5-membered heteroaryl. In some instances of formula I, II, III, IV, or VR ² is -OH, and B, including the atoms at the points of attachment, is an optionally substituted monocyclic 6-membered heteroaryl.

In one embodiment of formula I, II, III, IV or VY ¹ is -S- and A is an optionally substituted 5-12 membered monocyclic or polycyclic cycloalkyl. In some instances of formula I, II, III, IV or VY ¹ is -S- and A is an optionally substituted monocyclic or polycyclic heterocycloalkyl. In some instances of formula I, II, III, IV or VY ¹ is -S- and A is an optionally substituted monocyclic or polycyclic aryl. In some instances of formula I, II, III, IV or VY ¹ is S and A is an optionally substituted monocyclic or polycyclic heteroaryl.

In one embodiment of formula I, II, III, IV or VY ¹ is a direct bond and A is an optionally substituted 5-12 membered monocyclic or polycyclic cycloalkyl. In some instances of formula I, II, III, IV or VY ¹ is a direct bond and A is an optionally substituted monocyclic or polycyclic heterocycloalkyl. In some instances of formula I, II, III, IV or VY ¹ is a direct bond and A is an optionally substituted monocyclic or polycyclic aryl. In some instances of formula I, II, III, IV or VY ¹ is a direct bond and A is an optionally substituted monocyclic or polycyclic heteroaryl.

Methods for Synthesizing the Compounds of the Present Invention

Compounds of the present invention can be obtained in various ways, including methods conventional in chemistry. Suitable synthesis methods are illustrated in the following schemes.

Compounds of any of the formulas described herein can be prepared by methods known in the art of organic synthesis, which are represented in part by the following synthesis schemes and examples. From the schemes described below, it is quite clear that protective groups for sensitive or reactive groups are used, if necessary, in accordance with general principles or chemical practice. Operations on protecting groups are performed according to standard organic synthesis methods (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", third edition, Wiley, New York, 1999). Such groups are removed at an appropriate stage in the synthesis of the compound using methods that are obvious to those skilled in the art. The methods of selection, as well as the reaction conditions and the order of their implementation, must correspond to the preparation of the compounds of the present invention.

One of skill in the art will appreciate if a stereocenter is present in any of the compounds of the present invention. Accordingly, the present invention may include both possible stereoisomers (unless otherwise indicated in relation to synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. If a compound is to be obtained as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any suitable intermediate. Separation of the final product, intermediate or starting material can be carried out by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley–Interscience, 1994).

Getting connections

The compounds described herein can be obtained from commercially available starting materials or synthesized using known methods of organic, inorganic and/or enzymatic synthesis.

Compounds of the present invention can be obtained in various ways, well known to experts in the field of organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or variants thereof known to those skilled in the art. Such methods include, without limitation, the methods described below.

Scheme 1. Total synthesis of 1-(5-aryl (or heteroaryl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-4-amines.

The total synthesis of 1–(5–aryl (or heteroaryl)–6–methylimidazo[1,5–a]pyrazin–8–yl)–4–amines is shown in Scheme 1. 2–Chloro–3–cyano–5–methylpyrazine can be coupled with an appropriately substituted amine, brominated and then coupled with an appropriately substituted aryl- or heteroarylboronic acid in the presence of a palladium-based catalyst. Then the resulting biaryl compound can be subjected to formylation and cyclization reactions with the formation of an appropriately substituted imidazole-pyrazine. Additional deprotection and/or functionalization steps may be required to obtain the final compound.

Scheme 2. General synthesis of amino-imidazo[1,5-a]pyrazines (or an alternative bicyclic structure).

The overall synthesis of amino-imidazo[1,5-a]pyrazines (or an alternative bicyclic structure) is shown in Scheme 2. 5-Bromo-8-chloroimidazo[1,5-a]pyrazine (or an alternative bicyclic structure) can be reacted combinations with a substituted primary or secondary amine to give 5-bromo-imidazo[1,5-a]pyrazine-8-amine. The resulting intermediate can be coupled with a substituted aryl- or heteroarylthiol in the presence of a copper catalyst (eg CuI) or under SNAr conditions; alternatively, the resulting intermediate can be coupled with an appropriately substituted aryl- or heteroarylboronic acid in the presence of a Pd catalyst. Additional deprotection and/or functionalization steps may be required to obtain the final compound.

Methods of using the compounds and compositions of the present invention

Methods and uses of the present invention

Another aspect of the present invention relates to methods for treating a disease associated with SHP2 modulation in a subject in need thereof. The methods may include administering to a patient in need of treatment for diseases or disorders associated with SHP2 modulation, an effective amount of one or more compounds of the present invention (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers) or one or more pharmaceutical compositions of the present invention. In some embodiments, the disease may be, without limitation, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers. SHP2 is an important downstream signaling molecule to a variety of receptor tyrosine kinases, including platelet growth factor (PDGF-R), fibroblast growth factor (FGF-R), and epidermal growth factor (EGF-R) receptors. SHP2 is also an important downstream signaling molecule for activating the mitogen-activated protein kinase (MAP) pathway, which can lead to cell transformation, which is a prerequisite for cancer development. SHP2 knockdown significantly suppressed cell growth in lung cancer cell lines with SHP2 mutation or EML4/ALK translocations, as well as EGFR-amplifying breast cancers and esophageal cancers. SHP2 is also upregulated downstream of oncogenes in the signal transduction pathway in gastric carcinoma, anaplastic large cell lymphoma, and glioblastoma.

In addition, SHP2 plays a role in signaling by immune response checkpoint molecules, including, but not limited to, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In this context, modulation of SHP2 function can lead to immune activation, in particular to activation of anti-cancer immune responses.

Another aspect of the present invention is directed to a method for inhibiting SHP2. The method comprises administering to a patient in need thereof an effective amount of one or more compounds of the present invention (e.g., compounds of formula I', I, II, III, IV, or V and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof) or one or more pharmaceutical compositions of the present invention.

The present invention relates to compounds or compositions disclosed herein, which are capable of modulating the activity (eg, inhibition) of SHP2. The present invention also relates to the therapeutic use of such compounds and compositions.

One or more compounds or compositions of the present invention may be administered in effective amounts to treat or prevent a disorder and/or prevent its development in subjects. In some embodiments, SHP2 is inhibited after treatment with less than 1000 nM of a compound of the present invention. In some embodiments, SHP2 is inhibited after treatment with about 1 nM to about 10 nM of a compound of the present invention. In some embodiments, SHP2 is inhibited after treatment with less than about 1 nM of a compound of the present invention. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the present invention. In some embodiments, SHP2 is inhibited after treatment with about 100 nM to about 10 μM of a compound of the present invention.

Another aspect of the present invention relates to one or more compounds of the present invention (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers) or one or more compositions of the present invention for use in the treatment or prevention of a disease associated with SHP2 modulation. In some embodiments, the disease is Noonan's syndrome, Leopard's syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers. SHP2 is an important downstream signaling molecule to a variety of receptor tyrosine kinases, including platelet growth factor (PDGF-R), fibroblast growth factor (FGF-R), and epidermal growth factor (EGF-R) receptors. SHP2 is also an important downstream signaling molecule for activation of the mitogen-activated protein kinase (MAP) pathway, which can lead to cell transformation, which is a prerequisite for cancer development. SHP2 knockdown significantly suppressed cell growth in lung cancer cell lines with SHP2 mutation or EML4/ALK translocations, as well as EGFR-amplifying breast cancers and esophageal cancers. SHP2 is also upregulated downstream of oncogenes in the signal transduction pathway in gastric carcinoma, anaplastic large cell lymphoma, and glioblastoma.

In another aspect, the present invention relates to the use of one or more compounds of the present invention (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers) in the manufacture medicinal product for the treatment or prevention of a disease. In some embodiments, the implementation of the disease is associated with the modulation of SHP2.

In another aspect, the present invention relates to one or more compounds of the present invention (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers) for use in as a medicinal product. In some embodiments, the drug is used to treat or prevent a disease associated with SHP2 modulation.

In one aspect, the present invention relates to one or more compositions containing one or more compounds of the present invention (for example, compounds of formula I', I, II, III, IV or V and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers or isomers), for use as a drug. In some embodiments, the drug is used to treat or prevent a disease associated with SHP2 modulation.

Pharmaceutical compositions and routes of administration according to the present invention

Another aspect of the present invention relates to pharmaceutical compositions containing one or more compounds of the present invention and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an adjuvant, diluent or surfactant.

Compositions of the present invention may be prepared according to conventional blending, granulation, or coating processes, in that order, and pharmaceutical compositions of the present invention may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of one or more compounds of the present invention by weight or volume.

Administration of the compounds and compositions of the present invention may be by any route of administration of therapeutic agents. Such methods may include systemic or topical administration, for example, oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal, or topical routes of administration.

Depending on the intended route of administration, the compounds or pharmaceutical compositions of the present invention may be presented as solid, semi-solid or liquid dosage forms such as injectables, tablets, suppositories, pills, sustained release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions or the like, sometimes in unit doses and in accordance with normal pharmaceutical practice. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular forms, all forms being well known to those skilled in the pharmaceutical art.

Exemplary pharmaceutical compositions may include tablets and gelatin capsules containing one or more compounds of the present invention and a pharmaceutically acceptable carrier such as, but not limited to a) a diluent such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oil, or their mixtures, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as EPA or DHA or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose , mannitol, sorbitol, cellulose, sodium saccharin, glucose and/or glycine; b) a lubricant, eg silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if necessary; d) leavening agent, for example starches, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, color, flavor and sweetener; f) an emulsifier or dispersant such as Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucir, Vitamin E TGPS or other suitable emulsifier, and/or g) an absorption enhancing agent such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, in particular injectable, compositions can be obtained, for example, by dissolving, dispersing, etc. For example, one or more compounds of the present invention are dissolved in a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, glycerin, ethanol, etc., or mixed with it, thus forming an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles or serum proteins can be used to dissolve the compounds of the present invention.

One or more compounds or compositions of the present invention may also be formulated into a suppository which can be prepared from emulsions or suspensions of fatty acids using polyalkylene glycols such as propylene glycol as a carrier.

One or more compounds or compositions of the present invention may also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be obtained from a variety of phospholipids containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous drug solution to form a drug-encapsulating lipid layer as described, for example, in US Pat. No. 5,262,564, the contents of which are incorporated herein by reference.

One or more compounds or compositions of the present invention can also be delivered using monoclonal antibodies as separate carriers to which the compounds of the present invention are attached. The compounds of the present invention can also be attached to soluble polymers as carriers for targeted drug delivery. Such polymers may include polyvinylpyrrolidone, a pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl aspanamide phenol, or polyethylene oxide polylysine substituted with palmitic acid residues. In addition, one or more compounds of the present invention can be attached to polymers of the biodegradable class that are suitable for achieving controlled drug release, such as polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. In some embodiments, one or more compounds of the present invention are non-covalently bonded to a polymer, such as a polycarboxylic acid polymer, or a polyacrylate.

One or more compounds or compositions of the present invention can be delivered by parenteral administration. Parenteral administration of an injectable preparation is usually used for subcutaneous, intramuscular or intravenous injections and infusions. Injectable preparations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for dissolution in a liquid prior to injection.

Dosing regimens in accordance with the present invention

Dosing regimen using one or more compounds or compositions of the present invention can be selected taking into account many factors, including the type, species, age, weight, sex and health of the patient; the severity of the condition being treated; route of administration; the functioning of the kidneys or liver of the patient and the specific compound of the present invention used. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of drug needed to prevent, counteract, or halt the progression of the condition.

Effective dosage amounts of the compounds of the present invention, if used to produce the indicated effects, may range from about 0.5 mg to about 5000 mg of the compounds of the present invention as needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the compounds of the present invention, or their the amount can range from one value to another value in the list of doses. In some embodiments, the compositions are in the form of a tablet that can be divided along a break line.

If desired, an effective daily dose of one or more compounds or compositions of the present invention may be administered as one, two, three, four, five, six, or more portions of doses administered separately at appropriate intervals throughout the day, optionally as single doses. dosage forms. In some embodiments of the present invention, one or more compounds or compositions of the present invention, or mixtures thereof, can be administered two or three times a day. In some embodiments, one or more compounds or compositions of the present invention will be administered once a day.

In some embodiments, one or more of the compounds or compositions described herein may be used alone, or administered together, or concurrently, or used in combination with another type of therapeutic agent. "Co-administration" or "used in combination" can mean any form of administration of two or more different therapeutic compounds or compositions in which the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective in the body. For example, different therapeutic compounds or compositions can be administered either in the same formulation, or in a separate formulation, or simultaneously, sequentially, or by separate dosing of the individual components of the treatment. In some embodiments, the implementation of different therapeutic compounds or compositions can be entered with an interval between them within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours or weeks. Thus, an individual who receives such treatment may benefit from the combined action of different therapeutic compounds or compositions.

Sets

In some embodiments, the present invention also provides a pharmaceutical package or kit containing one or more containers filled with at least one compound or composition of the present invention. Optionally, such container(s) may be accompanied by an information sheet in the form prescribed by a government agency that regulates the manufacture, use, or sale of pharmaceuticals or biological products, such information sheet reflecting (a) the approval of that authority for the manufacture, use or sale for human administration, (b) instructions for use, or both. In some embodiments, the kit contains at least two containers, at least one of which contains at least one compound or composition of the present invention. In some embodiments, the kit contains at least two containers, and each of the at least two containers contains at least one compound or composition of the present invention.

In some embodiments, the kit includes additional materials to facilitate delivery of the claimed compounds and compositions. For example, the kit may include one or more of a catheter, tubing, infusion bag, syringe, and the like. In some embodiments, the compounds and compositions may be packaged in lyophilized form and the kit includes at least two containers: a container containing the lyophilized compounds or compositions, and a container containing a suitable amount of water, buffer, or other liquid suitable for re-dissolving the lyophilized material.

The foregoing applies to any of the compounds, compositions, methods, and uses described herein. The present invention specifically contemplates any combination of the features of such compounds, compositions, methods, and uses (singly or in combination) with the features described for the various kits described in this section.

Illustrative Embodiments

Some embodiments of the present invention are Embodiment I below.

Embodiment I-1. Compound of formula I',

,

,

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein:

;R ⁴ is H or

;

A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ ,

–SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ , or –CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted one or more of –OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S( O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including atoms at the points of attachment, is a monocyclic or polycyclic 5-12-membered heterocycle or a monocyclic or polycyclic 5-12-membered heteroaryl;

R ² is -H, -OR ^b , -NR ⁵ R ⁶ , -CN, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C(O)OR ^b , -C ₃ -C ₈ cycloalkyl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , −SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S (O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ ,

–NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ ,

–CHF ₂ or –CH ₂ F;

R ³ in each case is selected from the group consisting of -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle, C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , when wherein each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more of

–C ₁ –C ₆ alkyl, –OH, –NH ₂ , –OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R ³ may be combined with R ^a to form a 3-12 membered monocyclic or polycyclic heterocycle or a 5-12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, –NH ₂ , heteroaryl, heterocyclyl, –(CH ₂ ) _n NH ₂ , –COOR ^b , –CONHR ^b , –CONH(CH ₂ ) _n COOR ^b ,

–NHCOOR ^b , –CF ₃ , –CHF ₂ or –CH ₂ F;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Embodiment I-2. A compound according to embodiment I-1 wherein R ⁴ is -H.

.Embodiment I-3. A compound according to embodiment I-1, wherein R ⁴ is

.

Embodiment I-4. A compound according to embodiment I-1 or I-3, wherein A is a 5-12 membered monocyclic or polycyclic cycloalkyl.

Embodiment I-5. A compound according to embodiment I-1 or I-3, wherein A is a monocyclic or polycyclic heterocycloalkyl.

Embodiment I-6. A compound according to embodiment I-1 or I-3, wherein A is a monocyclic or polycyclic aryl.

Embodiment I-7. A compound according to embodiment I-1 or I-3, wherein A is a monocyclic or polycyclic heteroaryl.

Embodiment I-8. A compound according to any one of embodiments I-1 or I-3 to I-7, where Y ¹ is -S-.

Embodiment I-9. A compound according to any one of embodiments I-1 or I-3 through I-7, where Y ¹ is a direct bond.

Embodiment I-10. A compound according to any one of embodiments I-1-I-9, wherein Y ² is -NR ^a -.

Embodiment I-11. A compound according to any one of embodiments I-1 - I-9, wherein Y ² is -(CR ^a ₂ ) _m -.

Embodiment I-12. A compound according to any one of embodiments I-1-I-9, wherein Y ² is -C(O)-.

Embodiment I-13. A compound according to any one of embodiments I-1 to I-9, wherein Y ² is -C(R ^a ) ₂ NH- or -(CR ^a ₂ ) _m O-.

Embodiment I-14. A compound according to any one of Embodiments I-1-I-9 wherein Y ² is -C(O)N(R ^a )-, -N(R ^a )C(O)-, -S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(S)– or

–C(S)N(R ^a )–.

Embodiment I-15. A compound according to any one of Embodiments I-1-I-9, wherein Y ² is -N(R ^a )C(O)N(R ^a )-, -N(R ^a )C(S)N( R ^a )–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O– or

–C(O)N(R ^a )O–.

Embodiment I-16. A compound according to any one of Embodiments I-1-I-9, wherein Y ² is -C(O)O-, -OC(O)- or -OC(O)O-.

Embodiment I-17. A compound according to any one of embodiments I-1 - I-16, wherein R ² is -OR ^b .

Embodiment I-18. A compound according to any one of embodiments I-1-I-16 wherein R ² is an optionally substituted -C ₁ -C ₆ alkyl.

Embodiment I-19. A compound according to any one of embodiments I-1 - I-16, wherein R ² is -CN.

Embodiment I-20. A compound according to any one of embodiments I-1-I-16 wherein R ² is an optionally substituted -C ₂ -C ₆ alkenyl.

Embodiment I-21. A compound according to any one of embodiments I-1-I-16 wherein R ² is an optionally substituted -C ₄ -C ₈ cycloalkenyl.

Embodiment I-22. A compound according to any one of embodiments I-1-I-16 wherein R ² is an optionally substituted -C ₂ -C ₆ alkynyl.

Embodiment I-23. A compound according to any one of embodiments I-1-I-16 wherein R ² is an optionally substituted -C ₃ -C ₈ cycloalkyl.

Embodiment I-24. A compound according to any one of Embodiments I- ¹ -I-16 wherein R2 is an optionally substituted heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.

Embodiment I-25. A compound according to any one of Embodiments I- ¹ -I-16 wherein R2 is an optionally substituted heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O.

Embodiment I-26. A compound according to any one of embodiments I-1 - I-25, where R ^a is -H.

Embodiment I-27. A compound according to any one of embodiments I-1 - I-25, where R ^a is -OH.

Embodiment I-28. A compound according to any one of embodiments I-1-I-25, wherein R ^a is an optionally substituted -C ₃ -C ₈ cycloalkyl.

Embodiment I-29. A compound according to any one of embodiments I-1-I-25, wherein R ^a is optionally substituted -C ₁ -C ₆ alkyl.

Embodiment I-30. A compound according to any one of embodiments I-1 through I-29, where R^b represents -H.

Embodiment I-31. A compound according to any one of embodiments I-1 through I-29, where R^b is an optionally substituted –C_one-C₆alkyl.

Embodiment I-32. A compound according to any one of embodiments I-1 through I-29, where R^b is an optionally substituted –C₃-C_eightcycloalkyl.

Embodiment I-33. A compound according to any one of embodiments I-1 through I-29, where R^b is an optionally substituted –C₂-C₆alkenyl.

Embodiment I-34. A compound according to any one of embodiments I-1 through I-29, where R^b is an optionally substituted heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O.

Embodiment I-35. A compound according to any one of embodiments I-1-I-34, wherein R ³ is an optionally substituted -C ₁ -C ₆ alkyl.

Embodiment I-36. A compound according to any one of embodiments I-1-I-34 wherein R ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle.

Embodiment I-37. A compound according to any one of embodiments I-1-I-34, wherein R ³ is an optionally substituted 3-12 membered monocyclic heterocycle.

Embodiment I-38. A compound according to any one of embodiments I-1-I-34, wherein R ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

Embodiment I-39. A compound according to any one of embodiments I-1-I-25 or I-30-I-34, wherein R ³ and R ^a , together with the atom to which they are attached, are combined to form an optionally substituted 3-12-membered monocyclic heterocycle.

Embodiment I-40. A compound according to any one of embodiments I-1-I-25 or I-30-I-34, wherein R ³ and R ^a , together with the atoms to which they are attached, are combined to form an optionally substituted 3-12-membered polycyclic heterocycle.

Embodiment I-41. A compound according to any one of embodiments I-1-I-25 or I-30-I-34, wherein R ³ and R ^a , together with the atoms to which they are attached, are combined to form an optionally substituted 5-12-membered spiro heterocycle .

Embodiment I-42. A compound according to any one of Embodiments I-1 through I-41, wherein X ¹ is N and X ² is N.

Embodiment I-43. A compound according to any one of embodiments I-1-I-41 wherein X ¹ is N and X ² is CH.

Embodiment I-44. A compound according to any one of Embodiments I-1-I-41 wherein X ¹ is C and X ² is N.

Embodiment I-45. A compound according to any one of embodiments I-1-I-41 wherein X ¹ is C and X ² is CH.

Embodiment I-46. A compound according to any of the previous embodiments wherein B, including the atoms at the points of attachment, is a monocyclic 3-12 membered heteroaryl.

, и X¹ представляет собой N, с образованием таким образом

.Embodiment I-47. A compound according to any one of Embodiments I-1 through I-41, where B, including the atoms at the points of attachment, is

, and X ¹ is N, thus forming

.

, и X¹ представляет собой C, с образованием таким образом

.Embodiment I-48. A compound according to any one of Embodiments I-1 through I-41, where B, including the atoms at the points of attachment, is

, and X ¹ is C, thus forming

.

, и X¹ представляет собой C, с образованием таким образом

.Embodiment I-49. A compound according to any one of Embodiments I-1 through I-41, where B, including the atoms at the points of attachment, is

, and X ¹ is C, thus forming

.

Embodiment I-50. The connection, which is

.

.

Embodiment I-51. The connection, which is

.

.

Embodiment I-52. A pharmaceutical composition containing a compound according to any one of embodiments I-1 to I-51 and a pharmaceutically acceptable carrier.

Embodiment I-53. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments I-1 through I-51.

Embodiment I-54. The method according to embodiment I-53, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers.

Embodiment I-55. A compound according to any one of embodiments I-1 through I-51 for use in the treatment or prevention of a disease associated with SHP2 modulation.

Embodiment I-56. The use of a compound according to any one of embodiments I-1 to I-51 in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

Some embodiments of the present invention are Embodiment II below.

Embodiment II-1. Compound of formula IV,

,

,

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that heteroaryl is not

or

;

R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -OH, -OR ⁵ , halogen, -NO ₂ , -CN,

–NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ ,

–S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , –C(O)R ⁵ or –CO ₂ R ⁵ , each alkyl, alkenyl , cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more of –OH, halogen,

–NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ ,

–NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl;

Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–;

X ¹ represents N or C;

X ² is N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃,

–CHF ₂ or –CH ₂ F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl,

-C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C ₃ -C ₈ cycloalkyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more of

–OH, halogen, –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ ,

–NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl is not attached through a nitrogen atom;

Y ² is –NR ^a –, –(CR ^a ₂ ) _m –, –C(O)–, –C(R ^a ) ₂ NH–, –(CR ^a ₂ ) _m O–, –C(O) N(R ^a )–,

–N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(O)N( R ^a )–, –N(R ^a )C(S)N(R ^a )–,

–C(O)O–, –OC(O)–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O–, –C(O)N(R ^a ) O–, –N(R ^a )C(S)–,

–C(S)N(R ^a )– or –OC(O)O–; wherein the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ;

R ^a is independently at each occurrence -H, -D, -OH, -C ₃ -C ₈ cycloalkyl or

-C ₁ -C ₆ alkyl, with each alkyl or cycloalkyl optionally substituted with one or more

–NH ₂ , and 2 R ^a together with the carbon atom to which they are both attached can be combined to form a 3-8-membered cycloalkyl;

R^b independently at each occurrence is –H, –D, –C_one-C₆alkyl, -C₃-C_eightcycloalkyl,

-C ₂ -C ₆ alkenyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, cycloalkyl, alkenyl or heterocycle is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ ,

–S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ ,

–NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl, heteroaryl, –(CH ₂ ) _n OH, –C ₁ –C ₆ alkyl, –CF ₃ , –CHF ₂ or -CH ₂ F;

R ³ is -H, -C ₁ -C ₆ alkyl, 3-12-membered monocyclic or polycyclic heterocycle,

-C ₃ -C ₈ cycloalkyl or -(CH ₂ ) _n -R ^b , where each alkyl, heterocycle or cycloalkyl is optionally substituted with one or more of -C ₁ -C ₆ alkyl, -OH, -NH ₂ , -OR ^b , –NHR ^b , –(CH ₂ ) _n OH, heterocyclyl or spiroheterocyclyl; or

R³ can be combined with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , –NO ₂ or –CN;

R ⁷ and R ⁸ are independently at each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl,

-C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Embodiment II-2. A compound according to embodiment II-1 wherein Y ² is -NR ^a -.

Embodiment II-3. A compound according to embodiment II-1 wherein Y ² is -(CR ^a ₂ ) _m -.

Embodiment II-4. A compound according to embodiment II-1 wherein Y ² is -C(O)-.

Embodiment II-5. A compound according to embodiment II-1 wherein Y ² is -C(R ^a ) ₂ NH- or -(CR ^a ₂ ) _m O-.

Embodiment II-6. The compound according to embodiment II-1, wherein Y ² is

–C(O)N(R ^a )–, –N(R ^a )C(O)–, –S(O) ₂ N(R ^a )–, –N(R ^a )S(O) ₂ –, –N(R ^a )C(S)– or –C(S)N(R ^a )–.

Embodiment II-7. The compound according to embodiment II-1, wherein Y ² is

–N(R ^a )C(O)N(R ^a )–, –N(R ^a )C(S)N(R ^a )–, –OC(O)N(R ^a )–, –N(R ^a )C(O)O– or –C(O)N(R ^a )O–.

Embodiment II-8. A compound according to embodiment II-1 wherein Y ² is -C(O)O-,

–OC(O)– or –OC(O)O–.

Embodiment II-9. A compound according to any one of embodiments II-1 - II-8, wherein R ^a is -H.

Embodiment II-10. A compound according to any one of embodiments II-1 to II-8 wherein R ^a is -OH.

Embodiment II-11. A compound according to any one of embodiments II-1 to II-8 wherein R ^a is an optionally substituted -C ₃ -C ₈ cycloalkyl.

Embodiment II-12. A compound according to any one of embodiments II-1 to II-8 wherein R ^a is optionally substituted -C ₁ -C ₆ alkyl.

Embodiment II-13. A compound according to any of embodiments II-1 to II-12, where R^b represents -H.

Embodiment II-14. A compound according to any of embodiments II-1 to II-12, where R^b is an optionally substituted –C_one-C₆alkyl.

Embodiment II-15. A compound according to any of embodiments II-1 to II-12, where R^b is an optionally substituted –C₃-C_eightcycloalkyl.

Embodiment II-16. A compound according to any of embodiments II-1 to II-12, where R^b is an optionally substituted –C₂-C₆alkenyl.

Embodiment II-17. A compound according to any of embodiments II-1 to II-12, where R^b is an optionally substituted heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O.

Embodiment II-18. A compound according to any one of embodiments II-1 to II-17 wherein R ³ is an optionally substituted -C ₁ -C ₆ alkyl.

Embodiment II-19. A compound according to any one of embodiments II-1 to II-17 wherein R ³ is an optionally substituted 3-12 membered monocyclic or polycyclic heterocycle.

Embodiment II-20. A compound according to any one of embodiments II-1 to II-17 wherein R ³ is an optionally substituted 3-12 membered monocyclic heterocycle.

Embodiment II-21. A compound according to any one of embodiments II-1 to II-17 wherein R ³ is an optionally substituted 5-12 membered polycyclic heterocycle.

Embodiment II-22. A compound according to any one of embodiments II-1 to II-8, where R³ and R^a together with the atom to which they are attached are combined to form a 3–12-membered monocyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂.

Embodiment II-23. A compound according to any one of embodiments II-1 to II-8, where R³ and R^a together with the atoms to which they are attached are combined to form a 3–12-membered polycyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-24. A compound according to any one of embodiments II-1 to II-8, where R³ and R^a together with the atoms to which they are attached are combined to form a 5–12-membered spiro heterocycle, with the spiro heterocycle optionally substituted by one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-25. A compound according to embodiment II-22 or II-23 wherein the heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyl.

Embodiment II-26. A compound according to any of embodiments II-22, II-23, or II-25, wherein the heterocycle is optionally substituted with one or more -(CH ₂ ) _n NH ₂ , where n is 1.

Embodiment II-27. A compound according to any one of embodiments II-22, II-23, II-25, or II-26, wherein the heterocycle is optionally substituted with one or more -NH ₂ .

Embodiment II-28. A compound according to embodiment II-24 wherein the spiro heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyls.

Embodiment II-29. A compound according to embodiment II-24 or II-28 wherein the spiro heterocycle is optionally substituted with one or more –(CH ₂ ) _n NH ₂ where n is 1.

Embodiment II-30. A compound according to any one of embodiments II-24, II-28 or II-29 wherein the spiro heterocycle is optionally substituted with one or more -NH ₂ .

Embodiment II-31. A compound according to embodiment II-1, wherein the compound of formula IV is a compound of formula IV-Q,

,

,

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, wherein:

;R ⁴ is H or

;

или

;A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl, provided that the heteroaryl is not

or

;

R ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN or

–NR ⁵ R ⁶ ;

Y ¹ is -S- or a direct link;

X ¹ represents N or C;

X ² is N or CH;

B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F;

R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl or -NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ ;

Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ;

R ³ is combined with R ^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiro heterocycle, with each heterocycle or spiro heterocycle optionally substituted with one or more of –C ₁ –C ₆ alkyl, –OH, –NH ₂ ,

–(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl;

R ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl;

m is independently at each occurrence 1, 2, 3, 4, 5, or 6; and

n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

Embodiment II-32. A compound according to embodiment II-31 wherein R ³ and R ^a , together with the atom to which they are attached, are combined to form a 3-12 membered monocyclic heterocycle, wherein the heterocycle is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂.

Embodiment II-33. A compound according to embodiment II-31 wherein R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 3-12 membered polycyclic heterocycle, wherein the heterocycle is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-34. A compound according to embodiment II-31 wherein R ³ and R ^a , together with the atoms to which they are attached, are combined to form a 5- to 12-membered spiro heterocycle, wherein the spiro heterocycle is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-35. A compound according to embodiment II-32 or II-33 wherein the heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyl.

Embodiment II-36. A compound according to any one of embodiments II-32, II-33 or II-35 wherein the heterocycle is optionally substituted with one or more -(CH ₂ ) _n NH ₂ where n is 1.

Embodiment II-37. A compound according to any one of embodiments II-32, II-33, II-35, or II-36, wherein the heterocycle is optionally substituted with one or more -NH ₂ .

Embodiment II-38. A compound according to embodiment II-34 wherein the spiro heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyls.

Embodiment II-39. A compound according to embodiment II-34 or II-38 wherein the spiro heterocycle is optionally substituted with one or more –(CH ₂ ) _n NH ₂ where n is 1.

Embodiment II-40. A compound according to any one of embodiments II-34, II-38 or II-39 wherein the spiro heterocycle is optionally substituted with one or more -NH ₂ .

.Embodiment II-41. A compound according to any of embodiments II-1 - II-40, wherein R ⁴ is

.

Embodiment II-42. A compound according to any one of embodiments II-1 to II-41 wherein A is a monocyclic or polycyclic aryl.

Embodiment II-43. A compound according to embodiment II-42 wherein A is phenyl.

Embodiment II-44. A compound according to any one of embodiments II-1 to II-41 wherein A is a monocyclic or polycyclic heteroaryl.

Embodiment II-45. A compound according to embodiment II-44 wherein A is pyridinyl.

Embodiment II-46. A compound according to any one of embodiments II-1 - II-45, wherein Y ¹ is -S-.

Embodiment II-47. A compound according to any one of embodiments II-1 through II-45, wherein Y ¹ is a direct bond.

Embodiment II-48. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H, -OR ⁵ or halogen.

Embodiment II-49. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ .

Embodiment II-50. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H, halogen, or -NR ⁵ R ⁶ .

Embodiment II-51. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H or -OR ⁵ .

Embodiment II-52. A compound according to embodiment II-48-I-51 wherein R ⁵ is -H or -C ₁ -C ₆ alkyl.

Embodiment II-53. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H or halogen.

Embodiment II-54. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ .

Embodiment II-55. A compound according to any one of embodiments II-1 to II-47 wherein R ¹ is independently at each occurrence -H, methyl, fluorine, chlorine, or -NH ₂ .

Embodiment II-56. A compound according to any one of embodiments II-49, II-50, or II-54, wherein R ⁵ and R ⁶ are each independently -H or -C ₁ -C ₆ alkyl.

Embodiment II-57. A compound according to embodiment II-56 wherein R ⁵ and R ⁶ are each independently -H.

Embodiment II-58. A compound according to embodiment II-56 wherein R ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

Embodiment II-59. A compound according to any one of embodiments II-1-II-40 wherein R ⁴ is -H.

Embodiment II-60. A compound according to any one of embodiments II-1 - II-59, wherein R ² is -OH.

Embodiment II-61. A compound according to any one of embodiments II-1-II-59 wherein R ² is -C ₁ -C ₆ alkyl, wherein the alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ^{5 R6} .

Embodiment II-62. A compound according to any one of embodiments II-1 to II-59 wherein R ² is methyl.

Embodiment II-63. A compound according to any one of embodiments II-1 - II-59, wherein R ² is -NR ⁵ R ⁶ .

Embodiment II-64. A compound according to Embodiment II-63 wherein R ⁵ and R ⁶ are each independently -H.

Embodiment II-65. A compound according to embodiment II-63 wherein R ⁵ and R ⁶ are each independently -C ₁ -C ₆ alkyl.

Embodiment II-66. A compound according to any one of embodiments II-1 - II-59, wherein R ² is -H.

Embodiment II-67. A compound according to any one of embodiments II-1 - II-59, wherein R ² is -NH ₂ .

Embodiment II-68. A compound according to any one of embodiments II-1 to II-67 wherein X ¹ is N and X ² is N.

Embodiment II-69. A compound according to any one of embodiments II-1 to II-67 wherein X ¹ is N and X ² is CH.

Embodiment II-70. A compound according to any one of embodiments II-1 to II-67 wherein X ¹ is C and X ² is N.

Embodiment II-71. A compound according to any one of embodiments II-1 to II-67 wherein X ¹ is C and X ² is CH.

Embodiment II-72. A compound according to any one of embodiments II-1 to II-71 wherein B, including the atoms at the points of attachment, is a monocyclic 5-12 membered heterocycle, where each heterocycle is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-73. A compound according to any one of embodiments II-1 through II-71 wherein B, including the atoms at the points of attachment, is a polycyclic 5-12 membered heterocycle, where each heterocycle is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-74. A compound according to embodiment II-72 to II-73 wherein heterocycle B is substituted with one or more oxo.

Embodiment II-75. A compound according to any one of embodiments II-1-II-71 wherein B, including the atoms at the points of attachment, is a monocyclic 5-12 membered heteroaryl, where each heteroaryl is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-76. A compound according to any one of embodiments II-1-II-71 wherein B, including the atoms at the attachment points, is a polycyclic 5-12 membered heteroaryl, where each heteroaryl is optionally substituted with one or more of

-C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F.

Embodiment II-77. A compound according to embodiment II-75-II-76 wherein the heteroaryl B is substituted with one or more -C ₁ -C ₆ alkyl.

Embodiment II-78. A compound according to any one of embodiments II-75 to II-77 wherein the heteroaryl B is substituted with one or more -OH.

Embodiment II-79. A compound according to any one of embodiments II-75 to II-78 wherein the heteroaryl B is substituted with one or more -NH ₂ .

Embodiment II-80. A compound according to any one of embodiments II-75 to II-79 wherein the heteroaryl B is substituted with one or more -(CH ₂ ) _n NH ₂ .

Embodiment II-81. A compound according to any one of embodiments II-75-II-80 wherein the heteroaryl B is substituted with one or more -(CH ₂ ) _n OH.

Embodiment II-82. A compound according to embodiment II-80 or II-81, where n is 1.

Embodiment II-83. A compound according to any one of embodiments II-75-II-82 wherein the heteroaryl B is substituted with one or more -CF ₃ .

Embodiment II-84. A compound according to any one of embodiments II-75-II-83 wherein the heteroaryl B is substituted with one or more -CHF ₂ .

Embodiment II-85. A compound according to any of embodiments II-75-II-84 wherein the heteroaryl B is substituted with one or more -CH ₂ F.

Embodiment II-86. A compound selected from the group consisting of:

one

,

, 2

, 3

, four

, 5

, 6

, 7

, eight

, 9

, ten

, eleven

, 12

, 13

, fourteen

, fifteen

, 16

, 17

, eighteen

, 19

, twenty

, 21

, 22

, 23

, 24

, 25

, 26

, 27

, 28

, 29

, thirty

, 31

, 32

, 33

, 34

, 35

, 36

, 37

, 38

, 39

, 40

, 41

, 42

, 43

, 44

, 45

, 46

, 47

, 48

, 49

, fifty

, 51

and 52

,

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer of any of the above compounds.

Embodiment II-87. A pharmaceutical composition containing a compound according to any of embodiments II-1 to II-86, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, and a pharmaceutically acceptable carrier.

Embodiment II-88. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any of embodiments II-1 to II-86, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof .

Embodiment II-89. The method according to embodiment II-88, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers.

Embodiment II-90. A compound according to any of embodiments II-1 to II-86, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, for use as a drug.

Embodiment II-91. A compound according to any of embodiments II-1 to II-86, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer, or isomer thereof, for use in the treatment or prevention of a disease associated with SHP2 modulation.

Embodiment II-92. The use of a compound according to any of embodiments II-1 to II-86 or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

Embodiment II-93. A method for treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition according to embodiment II-87.

Embodiment II-94. The method according to embodiment II-93, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers.

Embodiment II-95. Pharmaceutical composition according to embodiment II-87 for use as a drug.

Embodiment II-96. A pharmaceutical composition according to embodiment II-87 for use in the treatment or prevention of a disease associated with SHP2 modulation.

Embodiment II-97. The use of a pharmaceutical composition according to embodiment II-87 in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

Examples

The present invention is further illustrated by the following Examples and Synthesis Examples, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples are provided to illustrate certain embodiments and are not intended to limit the scope of the present invention. Additionally, it should be understood that various other embodiments, modifications, and their equivalents may be applied, as may be apparent to those skilled in the art, without departing from the spirit of the present invention and/or the scope of the appended claims.

The definitions used in the following examples and other parts of this document are:

CH ₂ Cl ₂ , DCM methylene chloride, dichloromethane CH ₃ CN, MeCN acetonitrile CuI copper(I) iodide DIPEA diisopropylethylamine DMF N,N-dimethylformamide EtOAc ethyl acetate hour or hour hour _H2O water HCl hydrochloric acid _{K3PO4 _} potassium phosphate (tribasic) MeOH methanol min. minute _{Na2SO4 _} sodium sulfate NBS N-bromosuccinimide NMP N-methylpyrrolidone Pd(dppf)Cl ₂ [1,1′–bis(diphenylphosphino)ferrocene]dichloropalladium(II) POCl ₃ Phosphorus oxychloride

Example 1

Synthesis of 4-methyl-1-(6-methylimidazo[1,5-a]pyrazin-8-yl)piperidine-4-amine.

Stage 1

To a solution of diethylaminomalonate hydrochloride (25 g, 0.12 mol) in water (20 ml) was added solid sodium hydrogen carbonate until pH > 7 was reached. After extraction with ethyl acetate, the organic phase was separated and evaporated under reduced pressure. The residue was taken up in a methanolic ammonia solution (6 M, 300 ml) and the reaction mixture was heated in a high pressure reactor at 80° C. overnight. The resulting mixture was concentrated under reduced pressure, the residue was washed successively with methanol and diethyl ether to obtain aminomalonamide (10 g, 73%). ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.41 (s, 3H), 7.25 (s, 3H), 3.76 (s, 1H).

Stage 2

Sodium bisulfite (24 g, 0.23 mol) was added to 25 ml of 40% methylglyoxal solution, followed by gradual addition of 86 ml of water containing sodium hydroxide (0.86 g, 0.021 mol). The solution was heated to 80° C. for 1 hour, aminomalonamide (18 g, 0.15 mol) was added and the temperature of the solution was maintained at 80° C. for another 2 hours with stirring. Sodium acetate (32.78 g, 0.4 mol) was added, the solution was cooled to 20°C, and 25 ml of 30% hydrogen peroxide was gradually added with stirring at 60–65°C. After cooling to room temperature, the product was removed, washed with cold water to give 5-methyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (8.5 g, 36%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO– d6 ) δ 13.21 (s, 1H), 8.75 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H), 2, 37(s, 3H).

Stage 3

5-Methyl-3-oxo-3,4-dihydropyrazine-2-carboxamide (2.0 g, 0.013 mol) was suspended in Et ₃ N (3.63 ml, 0.026 mol), cooled to 0°C and reacted with 36.5 ml of POCl ₃ . The mixture was heated to reflux temperature for 2 hours and concentrated under reduced pressure. The resulting black oil was extracted with ether (5×50 ml) and the combined extracts were treated with 10% Na ₂ CO ₃ (150 ml). The organic layers were separated, washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give 3-chloro-5-methylpyrazine-2-carbonitrile (1.5 g, 75%) as a fluffy solid. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.77 (s, 1H), 2.63 (s, 3H).

Stage 4

3-Chloro-5-methylpyrazine-2-carbonitrile (1.1 g, 0.007 mol) was dissolved in anhydrous DMF (11 ml) and DIPEA (3.74 ml, 0.021 mol) was added. After stirring for 30 min. at room temperature was added in one portiontert-butyl-(4-methylpiperidin-4-yl)carbamate (1.84 g, 0.008 mol). The reaction mixture was stirred overnight at room temperature, then diluted with EtOAc and extracted with 2% NaCl (aq.). The organic layer was dried over Na₂SO_four and concentrated under reduced pressure. The desired product was purified by column chromatography (DCM/acetone 97:3) to givetert-butyl-N-[1-(3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate as a pale yellow solid (2.14 g, 90%).^oneH NMR (400 MHz, DMSO–d6) δ 7.97 (s, 1H), 6.67 (bs, 1H), 3.96 (dt, J=13.7, 4.3 Hz, 2H), 3.39 (dd, J=13, 4, 10.3 Hz, 2H), 2.42 (s, 3H), 2.15 (d, J=13.4 Hz, 2H), 1.51 (ddd, J=14.1, 10.6 , 3.9 Hz, 2H), 1.40 (s, 9H), 1.27 (s, 3H).

Stage 5

tert -Butyl- N- [1-(3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (1 g, 0.003 mol) was dissolved in anhydrous DCM (20 ml) and cooled to –78°C and 1 M DIBAL–H in hexanes (9 mL, 0.009 mol) was added in small portions. After 1 h, the reaction mixture was heated to room temperature, and a saturated solution of NH ₄ Cl (4 ml) and a saturated solution of sodium–potassium tartrate (30 ml) were added. This solution was stirred until the separation of the organic and aqueous layers. The aqueous layer was removed and the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude tert -butyl-N-{1-[3-(aminomethyl)-6-methylpyrazin-2-yl]-4-methylpiperidin- 4-yl}carbamate (1 g, 100%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO– d6 ) δ 8.01 (s, 1H), 6.53 (s, 2H), 3.72 (s, 2H), 3.19–3.08 (m, 3H ), 3.04–2.95 (m, 2H), 2.35 (s, 3H), 2.18–2.10 (m, 2H), 1.60–1.50 (m, 2H), 1.39(s, 9H), 1.27(s, 3H).

Stage 6

tert-Butyl-N-{1-[3-(aminomethyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (0.88 g, 0.002 mol) was dissolved in formic acid (17.6 ml) and stirred at 105°C for 2 hours. Formic acid was removed under reduced pressure. and the resulting red oil was partitioned between water and DCM. The organic layer was removed and the aqueous phase was made basic with NaHCO₃ (aq.) to pH 11, then extracted with a mixture of isopropyl alcohol and chloroform 1:3 (4×50 ml). The organic layers were combined, dried over MgSO_four and concentrated under reduced pressure. The desired product was purified by column chromatography (MeOH with NH₃ 3 M/DCM 0:100 to 3:97) to give 4-methyl-1-{6-methylimidazo[1,5-a]pyrazin-8-yl}piperidine-4-amine as a yellow oil (0.224 g , 25%).^oneH NMR (400 MHz, DMSO–d6) δ 8.38 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 4.37 (d, J=5.5 Hz, 2H), 3.19 (ddd , J=12.7, 9.0, 3.5 Hz, 2H), 3.13–3.04 (m, 3H), 2.36 (s, 3H), 1.57 (ddd, J=12 .9, 9.1, 3.8 Hz, 2H), 1.52–1.42 (m, 2H), 1.24 (s, 1H), 1.10 (s, 3H).

Stage 7

4-Methyl-1-{6-methylimidazo[1,5-a]pyrazin-8-yl}piperidine-4-amine (0.2 g, 0.55 mmol) suspended in POCl₃ (10 ml) and stirred at 90°C for 2 h. POCl₃ was removed under reduced pressure and the resulting solid was partitioned between water and DCM. The layers were separated, the aqueous layer was washed with NaHCO₃ (aq.) and was extracted with a mixture of isopropyl alcohol and chloroform 1:3. The organic layers were combined, dried over Na₂SO_fourand concentrated under reduced pressure. Purification by preparative TLC chromatography (1000 microns) (MeOH with NH₃ 3M/DCM 8:92; carried out ×2) provided 4-methyl-1-(6-methylimidazo[1,5-a]pyrazin-8-yl)piperidine-4-amine as a yellow oil (16.6 mg, 9%).^oneH NMR (400 MHz, DMSO–d6) δ 8.26 (s, 1H), 7.70 (s, 1H), 7.50 (t, J=1.1 Hz, 1H), 3.98–3.87 (m, 2H), 3 .75–3.63 (m, 2H), 2.12 (d, J=1.1 Hz, 3H), 1.54–1.41 (m, 4H), 1.09 (s, 3H); LC-MS (ESI) mass/charge: [M+H] calc. for C₁₃H_twentyN₅: 246.2; the found value is 246.3.

Example 2 Synthesis of 1-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-4-methylpiperidin-4-amine.

Stage 1

tert -Butyl- N- [1-(3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (1 g, 0.003 mol) was dissolved in anhydrous DMF (15 ml) and the reaction flask protected from light with aluminum foil. The reaction mixture was cooled to 0° C. and NBS (0.8 g, 0.004 mol) was added. The reaction mixture was stirred at room temperature for 72 hours and then washed with water and EtOAc. The organic phase was extracted with 10% NaCl (aq.) (3×100 ml). The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure to give tert -butyl- N- [1-(5-bromo-3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate as a pale yellow solid (1 g, 81%). ¹ H NMR (400 MHz, DMSO– d6 ) δ 6.69 (s, 1H), 4.00 (dt, J=14.1, 4.2 Hz, 2H), 3.46–3.35 (m , 2H), 2.15 (d, J=13.5 Hz, 2H), 1.50 (ddd, J=14.0, 10.7, 3.9 Hz, 2H), 1.40 (s, 9H), 1.26(s, 3H). UPLC[M+1] = 409.9.

Stage 2

tert-Butyl-N-[1-(5-bromo-3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate (0.2 g, 49 mmol) was suspended in EtOH (6.6 ml) and toluene (5 ml) and the resulting solution was degassed with argon for 15 min. Then added K₂CO₃ (0.34 g, 0.002 mol) followed by the addition of 2,3-dichlorophenylboronic acid (0.1 g, 53 mmol). The reaction mixture was degassed for an additional 15 minutes. and tetrakis(triphenylphosphine)palladium(0) (0.03 g, 2 mmol) was added. The reaction mixture was stirred at 80°C overnight. The solvent was concentrated under reduced pressure and the resulting solid was partitioned between water and DCM. The aqueous layer was extracted with DCM (2×100 ml). Purification by column chromatography (hexane/ethyl acetate 4:1) providedtert-butyl-N-{1-[3-cyano-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate as a pale yellow solid (0.35 g, ten%).^oneH NMR (400 MHz, DMSO–d6) δ 7.78 (dd, J=7.9, 1.8 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.46 (dd, J=7.6, 1.8 Hz, 1H), 6.71 (s, 1H), 4.14–4.05 (m, 2H), 3.48 (t, J=11.9 Hz, 2H), 2.24 ( s, 3H), 2.20 (d, J=14.0 Hz, 2H), 1.61–1.50 (m, 2H), 1.41 (s, 3H), 1.29 (s, 3H ); UPLC[M+1] = 475.55.

Stage 3

tert -Butyl- N- {1-[3-cyano-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (0.04 g, 8, 4 mmol) was dissolved in anhydrous DCM (2 mL) under Ar atmosphere, cooled to –78°C, and 1 M DIBAL–H in hexanes (0.3 mL, 25.1 mmol) was added in small portions. After 1 h, the reaction mixture was heated to room temperature, and a saturated solution _of NH4Cl (1 ml) and a saturated solution of sodium–potassium tartrate (7 ml) were added. The resulting solution was stirred until the separation of the organic and aqueous layers. The layers were separated and the organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude tert -butyl- N- {1-[3-(aminomethyl)-5-(2,3-dichlorophenyl)-6-methylpyrazine-2 -yl]-4-methylpiperidin-4-yl}carbamate (0.03 g, 75%), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.73 (dd, J=7.9, 1.7 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7, 43 (dd, J=7.7, 1.8 Hz, 1H), 6.57 (s, 1H), 3.77 (s, 2H), 3.27 (m, 3H), 3.19–3 .05 (m, 2H), 2.19 (d, J=1.9 Hz, 2H), 2.17–2.12 (m, 2H), 1.65–1.53 (m, 3H), 1.40 (s, 9H), 1.29 (d, J=3.9 Hz, 3H); UPLC[M+1] = 480.15.

Stage 4

tert-Butyl-N-{1-[3-(aminomethyl)-5-(2,3-dichlorophenyl)-6-methylpyrazin-2-yl]-4-methylpiperidin-4-yl}carbamate (0.08 g, 16.6 mmol) dissolved in formic acid (1.6 ml) and stirred at 105° C. for 2 hours. The formic acid was removed under reduced pressure and the resulting red oil was partitioned between water and DCM. Increased the basicity of the aqueous phase with NaHCO₃ (aq.) to pH 11, then extracted with a mixture of isopropyl alcohol and chloroform 1:3 (4×50 ml). The organic layers were combined, dried over MgSO_four and concentrated under reduced pressure. Purification by preparative TLC (MeOH with NH₃ 3 M/DCM 4:96) providedN-{[3-(4-amino-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methyl}formamide (0.017 g, 25%) as a yellow oil.^oneH NMR (400 MHz, DMSO–d6) δ 8.07 (d, J=1.6Hz, 1H), 7.74 (dd, J=7.9, 1.7Hz, 1H), 7.48 (t, J=7.8Hz , 1H), 7.43 (dd, J=7.7, 1.7 Hz, 1H), 4.42 (d, J=5.6 Hz, 2H), 3.31–3.14 (m, 3H), 2.20 (s, 3H), 1.66–1.47 (m, 4H), 1.13 (s, 3H). UPLC[M+1] = 409.5.

Stage 5

N-{[3-(4-amino-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methyl}formamide (0.017 g, 4.2 mmol) suspended in POCl₃ (1 ml) and stirred at 90°C for 2 hours, then at room temperature overnight. POCl₃ removed under reduced pressure. Purification by preparative HPLC provided 3.4 mg (21%) -amine.^oneH NMR (400 MHz, DMSO–d6) δ 8.28 (s, 1H), 7.93–7.83 (m, 2H), 7.64–7.50 (m, 3H), 4.07–3.97 (m, 2H), 3.82-3.72 (m, 2H), 1.95 (s, 3H), 1.76-1.61 (m, 4H), 1.34-1.19 (m, 3H); LC-MS (ESI) mass/charge: [M+H] calc. for C₁₉H₂₂Cl₂N₅: 390.1; the found value is 390.3.

Example 3. Synthesis of (1 R )-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine .

(1 R )-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine was synthesized by the method similar to the method in example 2, except that tert -butyl- N- [1-(3-cyano-6-methylpyrazin-2-yl)-4-methylpiperidin-4-yl]carbamate was replaced with tert -butyl- ( R )–(8–azaspiro[4.5]decan–1–yl)carbamate. 1H NMR 1H NMR (400 MHz, DMSO– d6 ) δ ^7.89–7.80 (m, 2H), 7.61–7.52 (m, 3H), 4.48–4.33 (m, 2H), 2.73 (t, J=7.4 Hz, 1H), 1.94 (s, 3H), 1.92–1.79 (m, 2H), 1.78–1.16 (m , 8H). LC-MS (ESI) mass/charge: [M+H] calc. for C ₂₂ H ₂₆ Cl ₂ N ₅ : 431.3; found value 431.5

Example 4. Synthesis of (1 R )–8–[6–amino–5–(2,3–dichlorophenyl)imidazo[1,5–a]pyrazin–8–yl]–8–azaspiro[4.5]decan–1– amine.

Stage 1

3-Bromo-6-chloropyrazine-2-amine (5.00 g, 24.0 mmol) and Na ₂ CO ₃ 10H ₂ O (20.6 g, 72.0 mmol) were suspended in dioxane:water 4: one. The solvent was degassed by bubbling argon through it and Pd(dppf)Cl ₂ (0.88 g, 1.20 mmol) was added. The reaction was carried out for 6 hours at 110°C. The reaction mixture was filtered through a Celite pad (AcOEt). The residue was purified by column chromatography (hexane:AcOEt, 9:1 -> 4:1) to give 4.63 g (70%) of 6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine. ¹ H NMR (400 MHz, DMSO– d6 ) δ 7.85 (s, 1H), 7.74 (dd, J=8.0, 1.6 Hz, 1H), 7.47 (t, J=7 .8 Hz, 1H), 7.39 (dd, J=7.6, 1.6 Hz, 1H), 6.70 (s, 2H). LC-MS (ESI) mass/charge: [M+H] found value 275.7.

Stage 2

6-Chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine (1.8 g, 6.56 mmol) was dissolved in DMF, then cooled to 0°C. At this temperature, NBS (1.75 g, 9.83 mmol) was added in one portion. The reaction was carried out at room temperature overnight. The reaction mixture was partitioned between DCM and water and the organic phase was washed with water and brine. The combined aqueous phases were then extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 2.14 g (92%) of 5-bromo-6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine. ¹ H NMR (400 MHz, DMSO– d6 ) δ 7.76 (dd, J=7.8, 1.8 Hz, 1H), 7.52–7.43 (m, 2H), 6.92 (s , 2H).

Stage 3

5-Bromo-6-chloro-3-(2,3-dichlorophenyl)pyrazine-2-amine (2.14 g, 6.05 mmol) was dissolved in anhydrous DMF, then CuCN (1.09 g, 12.1 mmol). The reaction was carried out overnight at 100°C. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude product (3.2 g, 176%) was used in the next step without purification. ¹ H NMR (300 MHz, DMSO- d6 ) δ 7.97 (s, 2H), 7.78 (d, J=7.6 Hz, 1H), 7.56-7.39 (m, 2H). LC-MS (ESI) mass/charge: [M - H] found value 498.6 (negative ionization).

Stage 4

5-Amino-3-chloro-6-(2,3-dichlorophenyl)pyrazine-2-carbonitrile (1.81 g, 6.04 mmol) was suspended in ACN, then Boc was added₂O (4.62 g, 21.2 mmol) followed by DMAP (0.04 g, 0.30 mmol). The reaction was carried out at room temperature overnight, then the next portion of DMAP (0.22 g, 1.81 mmol) was added. The reaction was continued at room temperature for 4 hours. The solvent was removed under reduced pressure, and the residue was adsorbed onto silica gel for purification. The crude product was purified by column chromatography to give 1.09 g (45%)tert-butyl-N-[6-chloro-5-cyano-3-(2,3-dichlorophenyl)pyrazin-2-yl]carbamate. ^oneH NMR (300 MHz, DMSO–d6) δ 10.65 (s, 1H), 7.76 (dd, J=7.6, 2.0 Hz, 1H), 7.54–7.42 (m, 2H), 1.30 (s, 9H). LC-MS (ESI) mass/charge: [M – H] found value 398.5 (negative ionization).

Stage 5

tert-Butyl-N-[6-chloro-5-cyano-3-(2,3-dichlorophenyl)pyrazin-2-yl]carbamate (1.09 g, 2.73 mmol) and DIPEA (1.43 ml, 8 .18 mmol) was dissolved in anhydrous DMF. After 15 minutes, N-{8-azaspiro[4.5]decan-1-yl}-2-methylpropan-2-sulfinamide (0.78 g, 3.00 mmol) was added and the reaction was carried out at room temperature overnight. The reaction mixture was partitioned between AcOEt and water. The separated aqueous layer was extracted with AcOEt. The combined organic phases were dried over MgSO_four, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to givetert-butyl-N-[5-cyano-3-(2,3-dichlorophenyl)-6-[(1R)-1-[(2-methylpropan-2-sulfinyl)amino]-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]carbamate (1.18 g, 70%).^oneH NMR (400 MHz, DMSO–d6) δ 9.80 (s, 1H), 7.66 (dd, J=6.9, 2.7 Hz, 1H), 7.46–7.39 (m, 2H), 5.05 (d, J=8.1 Hz, 1H), 4.55–4.40 (m, 2H), 3.28–3.12 (m, 3H), 2.01–1.82 (m, 4H), 1 .76–1.61 (m, 3H), 1.53–1.45 (m, 1H), 1.42–1.32 (m, 2H), 1.28 (s, 9H), 1.12 (s, 9H). LC-MS (ESI) mass/charge: [M+H] found value 622.9.

Stage 6

tert -Butyl-N-[5-cyano-3-(2,3-dichlorophenyl)-6-[(1 R )-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[4.5] decan-8-yl]pyrazin-2-yl]carbamate (0.50 g, 0.80 mmol) was dissolved in anhydrous DCM and cooled to -78°C. A 1 M solution of DIBAL-H in hexane (2.41 ml, 2.41 mmol) was added dropwise and the reaction was carried out at -78°C for 2 hours, and the mixture was allowed to warm to 0°C. The reaction was then quenched by adding sat. aq. NaHCO ₃ followed by the addition of sat. aq. Rochelle salt. This resulting mixture was stirred until separation of the organic and aqueous layers occurred. The aqueous layer was extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude tert -butyl-N-[5-(aminomethyl)-3-(2,3-dichlorophenyl)-6-[(1 R )-1- [(2-methylpropan-2-sulfinyl)amino]-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]carbamate (0.48 g, 95% yield), which was used in the next step without additional cleaning. ¹ H NMR (400 MHz, DMSO– d6 ) δ 9.27 (s, 1H), 7.65–7.57 (m, 1H), 7.46–7.34 (m, 2H), 5.06 –4.88 (m, 1H), 3.95–3.83 (m, 1H), 3.80 (s, 2H), 3.62–3.51 (m, 1H), 3.20 (q , J=7.7 Hz, 1H), 3.08–3.00 (m, 1H), 2.91 (q, J=12.7 Hz, 2H), 2.14–1.98 (m, 1H), 1.97–1.88 (m, 1H), 1.87–1.72 (m, 2H), 1.69–1.50 (m, 4H), 1.48–1.41 ( m, 1H), 1.40–1.30 (m, 2H), 1.21 (s, 9H), 1.14 (s, 9H). LC-MS (ESI) mass/charge: [M+H] found value 626.6.

Stage 7

tert -Butyl-N-[5-(aminomethyl)-3-(2,3-dichlorophenyl)-6-[(1 R )-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[ 4.5]Decan-8-yl]pyrazin-2-yl]carbamate (0.48 g, 0.77 mmol) was dissolved in anhydrous DCM and cooled to 0°C. Acetic and formic anhydride (0.39 ml, 5.37 mmol) was added dropwise and the reaction mixture was allowed to stir overnight at 4°C. Water (5 ml) was added, the layers were separated and the aqueous phase was extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure . The residue was purified by column chromatography to give 0.27 g (54%) tert -butyl-N-[3-(2,3-dichlorophenyl)-5-(formamidomethyl)-6-[(1 R )-1-[ (2-methylpropan-2-sulfinyl)amino]-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]carbamate as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.33 (s, 1H), 8.38-8.28 (m, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.64-7.59 (m, 1H), 7.43-7.38 (m, 2H), 4.98 (d, J=7.8 Hz, 1H), 4.43 (d, J= 5.6 Hz, 2H), 3.51 (s, 2H), 3.20 (q, J=7.8 Hz, 1H), 2.94 (q, J=12.1 Hz, 2H), 2 .04–1.90 (m, 2H), 1.83–1.73 (m, 2H), 1.68–1.61 (m, 2H), 1.58–1.52 (m, 1H) , 1.49–1.42 (m, 1H), 1.40–1.34 (m, 1H), 1.35–1.27 (m, 2H), 1.21 (s, 9H), 1 .14 (s, 9H). LC-MS (ESI) mass/charge: [M+H] found value 654.8.

Stage 8

tert -Butyl-N-[3-(2,3-dichlorophenyl)-5-(formamidomethyl)-6-[(1 R )-1-[(2-methylpropane-2-sulfinyl)amino]-8-azaspiro[ 4.5]decan-8-yl]pyrazin-2-yl]carbamate (0.10 g, 0.15 mmol) was mixed with polyphosphoric acid (1.00 g, 10.2 mmol). The reaction mixture was heated to 100° C. and the reaction was carried out at this temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. Purification by preparative HPLC provided ( 1R )-8-[6-amino-5-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan -1-amine in the form of a formate salt. ¹ H NMR (300 MHz, Methanol –d4 ) δ 8.49 (s, 3H), 7.81–7.67 (m, 2H), 7.55–7.46 (m, 2H), 7.41 (s, 1H), 4.45–4.25 (m, 2H), 3.66–3.54 (m, 2H), 2.35 (t, J=7.4 Hz, 2H), 2, 14-1.96 (m, 5H), 1.89-1.78 (m, 2H), 1.65-1.55 (m, 2H), 1.39-1.27 (m, 2H). LC-MS (ESI) mass/charge: [M+1] ⁺ calc. for C ₂₁ H ₂₅ N ₆ Cl ₂ : 431.1; the found value is 431.2.

Example 5 Synthesis of 1-[6-amino-5-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methylpiperidin-4-amine.

Stage 1

tert -Butyl- N- [6-chloro-5-cyano-3-(2,3-dichlorophenyl)pyrazin-2-yl]carbamate (0.7 g, 1.75 mmol) and DIPEA (0.92 ml, 5.25 mmol) was dissolved in anhydrous DMF. After 15 minutes, tert -butyl-(4-methylpiperidin-4-yl)carbamate (0.45 g, 0.21 mmol) was added and the reaction mixture was allowed to stir at room temperature for 72 h. The reaction mixture was diluted with EtOAc and washed with 5% NaCl solution. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert -butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-5-cyano-3-(2,3 -dichlorophenyl)pyrazin-2-yl]carbamate (0.99 g, 99%). ¹ H NMR (300 MHz, DMSO– d6 ) δ 7.66 (dd, J=7.4, 2.2 Hz, 1H), 7.47–7.36 (m, 2H), 6.70 (s , 1H), 4.13 (d, J=13.8 Hz, 2H), 3.45 (t, J=11.9 Hz, 2H), 2.18 (d, J=13.6 Hz, 2H ), 1.63–1.47 (m, 2H), 1.41 (s, 9H), 1.28 (s, 12H).

Stage 2

tert -Butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-5-cyano-3-(2,3-dichlorophenyl)pyrazin-2-yl]carbamate (0.83 g, 1 .44 mmol) was dried overnight with a vacuum pump and dissolved in anhydrous DCM. The solution was cooled to –60°C and 1 M DIBAL–H in hexane (10 mL, 10.1 mmol) was added dropwise. The reaction was carried out at –30°C for 4 h. After this time, the reaction mixture was heated to 0°C. The reaction was then quenched by adding sat. aq. NH ₄ Cl followed by sat. aq. sodium-potassium tartrate. This resulting mixture was stirred until the separation of the organic and aqueous layers. The aqueous layer was extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give crude tert -butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-5-(aminomethyl)-3-(2 ,3-Dichlorophenyl)pyrazin-2-yl]carbamate (0.6 g, 71% yield), which was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO– d6 ) δ 7.68–7.55 (m, 1H), 7.46–7.35 (m, 2H), 6.56 (s, 1H), 3.77 (s, 2H), 3.62–3.47 (m, 2H), 3.09 (m, 2H), 2.16 (m, 2H), 1.58 (m, 2H), 1.39 ( s, 9H), 1.28 (s, 3H). LC-MS (ESI) mass/charge: [M+H] found value 582.4.

Stage 3

tert -Butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-5-(aminomethyl)-3-(2,3-dichlorophenyl)pyrazin-2-yl]carbamate (0.6 g , 1.38 mmol) was dissolved in anhydrous DCM and cooled to 0°C in an ice bath. Acetic and formic anhydride (0.70 ml, 9.63 mmol) was added dropwise and the reaction continued overnight at 4°C. The reaction was quenched by adding water. The layers were separated and the next aqueous phase was extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure . The residue was purified by column chromatography to give 0.30 g (36%) tert -butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-5 -(formamidomethyl)pyrazin-2-yl]carbamate as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d6 ) δ 9.35 (s, 1H), 8.34 (d, J=6.1 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.62 (dt, J=7.6, 3.7 Hz, 1H), 7.47–7.34 (m, 2H), 6.59 (s, 1H), 4.43 (d , J=5.6 Hz, 2H), 3.30–3.21 (m, 3H), 3.10 (t, J=11.7 Hz, 2H), 2.17 (d, J=13, 2 Hz, 2H), 1.70–1.54 (m, 3H), 1.41 (s, 9H), 1.30 (s, 3H). LC-MS (ESI) mass/charge: [M+H] found value 610.2.

Stage 4

tert -Butyl- N- [6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)-5-(formamidomethyl)pyrazin-2-yl]carbamate (0.15 g , 0.25 mmol) was mixed with POCl ₃ (1.5 ml, 16.1 mmol). The reaction mixture was heated to 90° C. and stirred for 3 hours. POCl ₃ was removed under reduced pressure. Purification by preparative HPLC provided 4.5 mg of 1-[6-amino-5-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazin-8-yl]-4-methylpiperidin-4-amine. ¹ H NMR (400 MHz, DMSO- d6 ) δ 8.36 (s, 1H), 7.82-7.72 (m, 2H), 7.56-7.46 (m, 2H), 7.36 (s, 1H), 4.64 (s, 2H), 4.06 (s, 2H), 3.71 (s, 2H), 1.72 (s, 4H), 1.32 (s, 3H) . LC-MS (ESI) mass/charge: [M+1] ⁺ calc. for C ₁₈ H ₂₁ N ₆ Cl ₂ : 391.1; the found value is 391.2.

Example 6 Synthesis of ( 3S , 4S )-8-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-methylimidazo[1,2-a]pyrazin-8-yl} -3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a solution of propane-1,2-diamine (46.28 g, 624.34 mmol, 53.32 ml) in EtOH (2000 ml) was added diethyl propanedioate (100 g, 624.34 mmol, 94.34 ml) at 0° C. The mixture was stirred at 25° C. for 1.5 hours, then heated to 120° C. and stirred for 20 hours under O ₂ atmosphere. The resulting mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to give ethyl 3-hydroxy-5-methyl-pyrazine-2-carboxylate (24 g, 658.70 mmol, 21.10% yield) as a white solid substances. LCMS (ESI): mass/charge: [M +H] calc. for C ₈ H ₁₁ N ₂ O ₃ : 183.07; the found value is 183.1.

Stage 2

To a solution of ethyl 3-hydroxy-5-methylpyrazine-2-carboxylate (166 g, 911.21 mmol) in DCM (1500 ml) was added NBS (178.40 g, 1.00 mol) in one portion at 0°C in N ₂ atmosphere. The mixture was stirred at 25°C for 10 min. The resulting mixture was diluted with saturated aq. Na ₂ SO ₃ (1000 ml) and the aqueous phase was extracted with DCM. The combined organic phase was washed with brine (50 ml), dried with anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (230 g, crude) in as a dark brown solid. ¹ H NMR (400 MHz, CDCl3-d) δ ppm 4.54 (q, J = 7.13 Hz, 2 H) 2.77 (s, 1 H) 2.68 (s, 3 H) 1.46 (t, J =7.09Hz, 3H)

Stage 3

To a solution of ethyl 6-bromo-3-hydroxy-5-methylpyrazine-2-carboxylate (115 g, 440.49 mmol) and K ₂ CO ₃ (182.64 g, 1.32 mol) in DMF (2.1 k) PMB-Cl (103.48 g, 660.74 mmol, 89.98 ml) was added in one portion at 20°C under N ₂ atmosphere. The mixture was stirred at 50° C. for 2 hours. The resulting mixture was diluted with water and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine (200 ml), dried with anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by column chromatography to give ethyl 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-carboxylate (60 g, 35.73% yield) as a white solid. LCMS (ESI): mass/charge [M +Na] calc. for C ₁₆ H ₁₇ BrN ₂ O ₄ Na: 403.04; the found value is 403.1.

Stage 4

To a solution of ethyl 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-carboxylate (150 g, 393.47 mmol) in MeOH (1300 ml) was added a solution of LiOH (47.12 g, 1.97 mol) in H ₂ O (400 ml) at 25°C. The mixture was stirred at 25° C. for 15 hours. Aqueous HCl (1 M) was added dropwise to the resulting mixture until the reaction mixture reached pH=6. The resulting mixture was diluted with H ₂ O (2000 ml) and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine (100 ml), dried with anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-carboxylic acid ( 138 g, crude) as a light yellow solid. LCMS (ESI): mass/charge [M +Na] calc. for C ₁₄ H ₁₃ BrN ₂ O ₄ Na: 375.01; the found value is 375.1.

Stage 5

To a solution of 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-carboxylic acid (100 g, 283.15 mmol) and DPPA (116.89 g, 424.73 mmol, 92.04 ml) in toluene (1800 ml) were added in one portion TEA (57.30 g, 566.30 mmol, 78.82 ml) and t -BuOH (209.87 g, 2.83 mol, 270.80 ml) in an atmosphere N2 _. The resulting mixture was stirred at 110°C for 1 h, the Mixture was diluted with H ₂ O (1000 ml) and the aqueous phase was extracted with EtOAc. The combined organic fractions were washed with brine (10 ml), dried with anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10:1 to 0:1) to give 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-amine ( 5 g, 15.42 mmol, 5.45% yield) and tert -butyl-N-[6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazin-2-yl]carbamate (90 g, 212.12 mmol, 74.91% yield as white solids. LCMS (ESI): mass/charge [M +H] calc. for C ₁₈ H ₂₃ BrN ₃ O ₄ : 424.08; the found value is 424.2.

Stage 6

To a solution of K ₂ CO ₃ (87.95 g, 636.36 mmol) in MeOH (1000 ml) was added tert -butyl-N-[6-bromo-3-[(4-methoxyphenyl)methoxy]-5- methylpyrazin-2-yl]carbamate (90 g, 212.12 mmol) at 70°C. The reaction mixture was stirred at 70°C for 15 h. The resulting reaction mixture was filtered and concentrated under reduced pressure to give 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-amine (90 g, crude ) as a white solid. ¹ H NMR (400 MHz, CDCl3-d) δ ppm 7.38 (d, J =8.68 Hz, 2 H) 6.99-6.86 (m, 2 H) 5.30 (s, 2 H ) 4.87 (br s, 2 H) 3.87–3.77 (m, 3 H) 2.49–2.38 (m, 3 H).

Stage 7

To a 40% solution of 2-chloroacetaldehyde (272.42 g, 1.39 mol, 223.29 ml) in H ₂ O was added 6-bromo-3-[(4-methoxyphenyl)methoxy]-5-methylpyrazine-2-amine (50 g, 154.24 mmol) at 25°C. The reaction mixture was stirred at 120°C for 1 h. The resulting precipitate was purified by reverse phase column chromatography to give 5-bromo-6-methyl-imidazo[1,2-a]pyrazin-8-ol (7 g, 30 .70 mmol, 19.90% yield as a white solid. LCMS (ESI): mass/charge [M +H] calc. for C ₇ H ₇ BrN ₃ O: 227.97; the found value is 228.1.

Stage 8

A solution of 5-bromo-6-methyl-imidazo[1,2-a]pyrazin-8-ol (5 g, 21.93 mmol) and TEA (2.22 g, 21.93 mmol, 3.05 ml) in POCl₃ (100.86 g, 657.76 mmol, 61.12 ml) heated to 120°C for 0.5 h. The resulting reaction mixture was concentrated under reduced pressure. The resulting precipitate was diluted with ethyl acetate (200 ml) and sat. aq. NaHCO₃ (400 ml). The organic layer was removed, washed with water, dried over Na₂SO_four and concentrated under reduced pressure. The remaining residue was purified by column chromatography (SiO₂, petroleum ether/ethyl acetate=15:1) to give 5-bromo-8-chloro-6-methyl-imidazo[1,2-a]pyrazine (3.83 g, 10.78 mmol, 49.19% yield, purity 69.41%) as a white solid.^oneH NMR (400 MHz, CDCl3–d) δ ppm 7.93 (d,J=0.88 Hz, 1 H) 7.87 (d,J=1.10 Hz, 1 H) 2.66 (s, 3 H) LCMS: mass/charge: [M + H] calc. for C₇H₅BrClN₃: 245.94; the found value is 245.9.

Stage 9

To a solution of 5-bromo-8-chloro-6-methylimidazo[1,2-a]pyrazine (135 mg, 547 µmol) in DMA ( 5.46 ml) -2-oxa-8-azaspiro[4.5]decane-8-dichloride (159 mg, 656 µmol) and DIPEA (474 µl, 2.73 mmol). The reaction mixture was stirred at 100°C for 1 h. The resulting reaction mixture was concentrated under reduced pressure and the remaining residue was purified using column chromatography (0–10% MeOH/CH ₂ Cl ₂ ) to give (3 S ,4 S )–8 -(5-bromo-6-methylimidazo[1,2-a]pyrazin-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. LCMS (ESI): mass/charge: [Μ+H] calc. for C ₁₆ H ₂₃ BrN ₅ O: 380.1; the found value is 380.4.

Stage 10

The vessel was loaded with ( 3S , 4S )–8–(5–bromo–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan -4-amine (162 mg, 425 µmol), 2-amino-3-chloropyridine-4-potassium thiolate (126 mg, 637 µmol), Pd ₂ (dba) ₃ (23.2 mg, 25.4 µmol), Xantphos (24.5 mg, 42.5 µmol). The reaction vessel was evacuated and purged with N ₂ three times. Dioxane and DIPEA (221 μl, 1.27 mmol) were added and the reaction mixture was stirred at 140° C. for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The remaining residue was purified by preparative phase HPLC to give ( 3S , 4S )-8-(5-((2-amino-3-chloropyridin-4-yl)thio)-6-methylimidazo[1,2-a] pyrazin-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (60.0 mg, 130 µmol, 30.7%) as formic acid salt. ¹ H NMR (500 MHz, Methanol -d4 ) δ 8.53 (s, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.55 (d, J=5.5 Hz, 1H), 7.51 (d, J=1.2 Hz, 1H), 5.74 (d, J=5.6 Hz, 1H), 5.23 (dd, J=31.5, 13.9 Hz, 3H), 4.38–4.24 (m, 1H), 4.02 (d, J=9.0 Hz, 1H), 3.90 (d, J=9.1 Hz, 1H), 3.69-3.51 (m, 2H), 2.50 (s, 3H), 1.97-1.86 (m, 3H), 1.75 (d, J=13.3 Hz, 1H) , 1.31 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge: [Μ+H] calc. for C ₂₁ H ₂₇ ClN ₇ OS: 460.2; the found value is 460.5.

Example 7 Synthesis of ( 3S,4S )–8–(5–(3–chlorophenyl)–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[ 4.5]decane-4-amine.

( 3S,4S )–8–(5–bromo–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4 –amine (125 mg, 328 µmol), (3-chlorophenyl)boronic acid (61.4 mg, 393 µmol), Pd(dppf)Cl ₂ DCM (53.5 mg, 65.6 µmol) and K ₂ CO ₃ (181 mg, 1.31 mmol). The vessel was then evacuated and purged with N ₂ three times. Degassed ACN (3.28 ml) was added and the reaction mixture was stirred at 105° C. for 2 hours. The resulting reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to give ( 3S , 4S )-8-(5-(3-chlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl)-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-amine (48.0 mg, 116 µmol, 35.5%) as formic acid salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.53 (s, 1H), 7.61–7.53 (m, 2H), 7.48 (dd, J=4.8, 1.6 Hz , 2H), 7.39 (dt, J=7.0, 1.8 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 5.06–4.89 (m, 3H), 4.31 (qd, J=6.6, 4.4 Hz, 1H), 4.00 (d, J=9.0 Hz, 1H), 3.89 (d, J=9.0 Hz, 1H), 3.45 (dddd, J=35.4, 13.9, 10.8, 3.1 Hz, 2H), 2.17 (s, 3H), 2.00–1.81 ( m, 3H), 1.77–1.69 (m, 1H), 1.31 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge: [Μ+H] calc. for C ₂₂ H ₂₇ ClN ₅ O: 412.2; the found value is 412.4.

Example 8 Synthesis of ( 3S,4S )–8–(5–(1H–indazol–6–yl)–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa– 8-azaspiro[4.5]decan-4-amine.

( 3S,4S )–8–(5–(2,3–dichlorophenyl)–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5] decan-4-amine was synthesized by a method similar to the method in example 7, except that (3-chlorophenyl)boronic acid was replaced by (1H-indazol-6-yl)boronic acid. The product was isolated as the formic acid salt. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.54 (s, 1H), 8.19 (d, J=1.0 Hz, 1H), 8.01 (dd, J=8.3, 0 .9 Hz, 1H), 7.64 (q, J=1.1 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.23–7.13 (m, 2H ), 4.37–4.26 (m, 1H), 4.00 (d, J=8.9 Hz, 1H), 3.89 (d, J=8.9 Hz, 1H), 3.58 –3.39 (m, 3H), 2.67 (s, 2H), 2.21 (s, 3H), 2.02–1.82 (m, 3H), 1.75 (d, J=13 .2 Hz, 1H), 1.31 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₃ H ₂₈ N ₇ O: 418.2; the found value is 418.5.

Example 9. Synthesis of (3 S ,4 S )-8-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl)-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine.

( 3S,4S )–8–(5–bromo–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4 -amine (100 mg, 262 µmol), (2,3-dichlorophenyl)boronic acid (59.9 mg, 314 µmol), Antphos (19.4 mg, 52.4 µmol), Pd (OAc) ₂ (5, 88 mg, 26.2 µmol) and K ₃ (PO) ₄ (166 mg, 786 µmol). The mixture was evacuated under reduced pressure for 10 minutes. before adding to degassed dioxane (2.61 ml). The resulting mixture was degassed and allowed to stir at 125° C. overnight in a closed vessel. The resulting reaction mixture was filtered through a Celite pad, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC to give ( 3S , 4S )-8-(5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (17.0 mg, 38.0 µmol, 14.6%) as formic acid salt. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.56 (s, 1H), 7.78 (dd, J=8.1, 1.6 Hz, 1H), 7.60–7.51 (m , 1H), 7.51–7.39 (m, 2H), 7.01 (d, J=1.2 Hz, 1H), 4.91 (d, J=2.1 Hz, 1H), 4 .84–4.79 (m, 1H), 4.35–4.24 (m, 1H), 3.96 (d, J=8.8 Hz, 1H), 3.83 (d, J=8 .7 Hz, 1H), 3.73–3.51 (m, 2H), 3.17 (d, J=4.7 Hz, 1H), 2.10 (s, 3H), 2.04–1 .85 (m, 3H), 1.77 (dd, J=33.3, 13.4 Hz, 1H), 1.27 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₂ H ₂₆ Cl ₂ N ₅ O: 446.1; the found value is 446.3.

Example 10. Synthesis of (3 S ,4 S )–8–(5–(3–chloro–2–fluorophenyl)–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2– oxa-8-azaspiro[4.5]decan-4-amine.

(3 S ,4 S )–8–(5–(3–chloro–2–fluorophenyl)–6–methylimidazo[1,2–a]pyrazin–8–yl)–3–methyl–2–oxa–8– azaspiro[4.5]decan-4-amine was synthesized by a method similar to the method in example 9, except that (2,3-dichlorophenyl)boronic acid was replaced by (3-chloro-2-fluorophenyl)boronic acid. ¹ H NMR (500 MHz, methanol- d6 ) δ 7.72 (ddd, J=7.8, 7.1, 1.9 Hz, 1H), 7.53-7.35 (m, 3H), 7 .17 (q, J=1.5 Hz, 1H), 4.99–4.88 (m, 2H), 4.37–4.23 (m, 1H), 3.97 (d, J=8 .8 Hz, 1H), 3.84 (d, J=8.7 Hz, 1H), 3.73–3.44 (m, 2H), 3.18 (d, J=5.0 Hz, 1H ), 2.16 (d, J=1.6 Hz, 3H), 2.00–1.85 (m, 3H), 1.84–1.69 (m, 1H), 1.28 (dd, J=6.5, 1.6 Hz, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₂ H ₂₆ ClFN ₅ O: 430.2; the found value is 430.4.

Example 11 Synthesis of (3S,4S) -8-[5-(3-chlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[ 4.5]decane-4-amine.

Stage 1

K ₂ CO ₃ (210.41 g, 1.52 mol) at 75°C. The mixture was stirred at 75° C. for 1 hour. After completion, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The remaining residue was triturated with EtOAc (500 ml) and filtered. The resulting filtrate was concentrated under reduced pressure to give methyl 3-acetonylimidazole-4-carboxylate (144 g, 41.54% yield) as a yellow solid. LCMS: mass/charge [M+H] calc. for C ₈ H ₁₁ N ₂ O ₃ : 183.07; the found value is 183.3.

Stage 2

To a solution of methyl 3-acetonylimidazole-4-carboxylate (130 g, 713.59 mmol) in CH ₃ COOH (700 ml) CH ₃ COONH ₄ (275.03 g, 3.57 mol) was added in one portion at 130°C . The reaction mixture was stirred at 130°C for 48 h. After completion, the mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography to give 6-methylimidazo[1,5-a]pyrazin-8-ol (40 g , 230.64 mmol, 32.32% yield as a yellow solid. LCMS: mass/charge [M+H] calc. for C ₈ H ₁₁ N ₂ O ₃ : 150.06; the found value is 150.02.

Stage 3

To a solution of 6-methylimidazo[1,5-a]pyrazin-8-ol (10 g, 67.05 mmol) in DMF (300 ml) was added NBS (12.17 g, 68.39 mmol) in one portion at 0° C. The mixture was stirred at 0°C for 5 min. Upon completion, the reaction mixture was quenched by adding aq. Na ₂ SO ₃ (60 ml) which gave the product as a white solid. The solid was filtered and the filter cake was dried under reduced pressure to give 5-bromo-6-methyl-imidazo[1,5-a]pyrazin-8-ol (11.1 g, 72.6% yield) as a white solid substances. ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 11.13 (br s, 1 H) 8.28 (s, 1 H) 7.88 (s, 1 H) 2.18 (s, 3 H) .

Stage 4

POCl ₃ (146.85 g, 957.73 mmol, 89 ml) at 25°C under positive nitrogen pressure. The mixture was heated to 120°C and stirred for 45 minutes at 120°C. After completion, excess POCl ₃ was removed under reduced pressure. The mixture was then quenched with sat. aq. NaHCO ₃ (100 ml) with the removal of all remaining POCl ₃ . The resulting mixture was poured into water (300 ml) and stirred for 2 minutes. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-8-chloro-6-methyl-imidazo[1,5-a]pyrazine (7.8 g, 78.24% yield) as a yellow solid. ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.63 (s, 1 H) 7.97 (s, 1 H) 2.53 (s, 3 H) LCMS: mass/charge: [M+H ] calc. for C ₇ H ₆ BrClN ₃ : 245.94; the found value is 245.90.

Stage 5

5-Bromo-8-chloro-6-methylimidazo[1,5-a]pyrazine (450 mg, 1.82 mmol) was added to the flask containing 2-methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propan-2-sulfinamide (842 mg, 2.18 mmol) and DMA (9.09 ml), followed by the addition of DIEA (1.58 ml, 9.10 mmol). The mixture was stirred at 130°C for 20 minutes, after which LCMS indicated almost complete conversion to the product. The solvent was removed under reduced pressure and the residue was partitioned between water/NH_fourOH and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over MgSO_four and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography to give N–[(3S,4S)–8–{5–bromo–6–methylimidazo[1,5–a]pyrazin–8–yl}–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–yl]–2–methylpropan–2 -sulfinamide (364 mg, 41.3%) as a yellow oil. LC-MS (ESI): mass/charge: [M+H] calc. for C₁₆H₂₂BrN₅O: 380.1; the found value is 380.1.

Stage 6

N–[(3 S ,4 S )–8–{5–bromo–6–methylimidazo[1,5–a]pyrazin–8–yl}–3–methyl–2–oxa–8–azaspiro[4.5]decane -4-yl]-2-methylpropan-2-sulfinamide (90 mg, 185 µmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with DCM (30.2 mg, 37.0 µmol ), K ₂ CO ₃ (102 mg, 740 µmol) and (3-chlorophenyl)boronic acid (37 mg, 240 µmol) were weighed into a 2-dram vessel equipped with a screw cap with a membrane and a magnetic stirrer. The reaction vessel was purged 3 times with N ₂ . ACN (1.84 ml, degassed by purging with N ₂ for 1 hour) was added to counterbalance N ₂ and the headspace of the reaction vessel was purged 3 times with N ₂ . The mixture was placed in a heating block preheated to 105° C. and stirred vigorously for 1.5 hours. The mixture was filtered through celite, evaporated to dryness and redissolved in MeOH (4 ml). HCl (4N in dioxane, 2 ml) was added and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC to give (3S,4S) -8-[5-(3-chlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (22.1 mg, 53.6 µmol, 29%) as a white solid. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.56 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.65–7.56 (m, 2H ), 7.52 (td , J= 1.7, 0.6 Hz, 1H), 7.42 (dt, J=7.0, 1.7 Hz, 1H), 4.45–4.35 ( m, 2H), 4.35–4.30 (m, 1H), 4.00 (d, J=9.0 Hz, 1H), 3.89 (d, J=9.0 Hz, 1H), 3.48 (ddd, J=13.8, 10.4, 3.5 Hz, 1H), 3.40 (ddd, J=13.8, 10.9, 2.9 Hz, 1H), 3, 35–3.33 (m, 1H), 2.12 (s, 3H), 2.00–1.86 (m, 3H), 1.77 (d, J=13.2 Hz, 1H), 1 .32 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₂ H ₂₆ ClN ₅ O: 412.2; the found value is 412.3.

Example 12 Synthesis of ( 3S,4S )–8–(5–(3–chloro–2–fluorophenyl)–6–methylimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa– 8-azaspiro[4.5]decan-4-amine.

Stage 1

5-Bromo-8-chloro-6-methylimidazo[1,5-a]pyrazine (850 mg, 3.44 mmol) and N-[(3S,4S)-8-chloro-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]chloranamine (903 mg, 3.78 mmol) was suspended in ACN (17.2 ml) and DIPEA (2.97 ml, 17.2 mmol) was added. The mixture was heated to 100° C. in a sealed 40 ml vial. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give ( 3S,4S )-8-(5-bromo-6-methylimidazo[1,5-a]pyrazin-8-yl)-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-amine (1.20 g, 92.3%). LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₆ H ₂₂ BrN ₅ O: 380.1; the found value is 380.1.

Stage 2

( 3S,4S )–8–(5–bromo–6–methylimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–amine ( 465 mg, 1.21 mmol) was dissolved in DCM (3.10 ml) and Boc ₂ O (414 μl, 1.81 mmol) was added followed by TEA (250 μl, 1.81 mmol). The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The crude residue was purified by column chromatography to give 244 mg (42%) tert -butyl-(( 3S , 4S )-8-(5-bromo-6-methylimidazo[1,5-a]pyrazin-8-yl )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate. LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₁ H ₃₀ BrN ₅ O ₃ : 480.1; the found value is 480.2.

Stage 3

Added to the vesseltert–butyl–((3S,fourS)–8–(5–bromo–6–methylimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–yl) carbamate (60 mg , 124 µmol), (3-chloro-2-fluorophenyl)boronic acid (25.8 mg, 148 µmol), Antphos (9.18 mg, 24.8 µmol), Pd(OAc)₂ (2.78 mg, 12.4 µmol) and K₃(PO)_four (78.9 mg, 372 µmol). The mixture was evacuated in a centralized vacuum system for 10 min. before adding to degassed dioxane (1.24 ml). The resulting mixture was filled with N₂ and evacuated three times before stirring at 125°C overnight in a closed vessel. The resulting reaction mixture was filtered through a Celite pad with DCM and MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography using 10% MeOH/DCM to givetert–butyl–((3S,fourS)–8–(5–(3–chloro–2–fluorophenyl)–6–methylimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan– 4-yl) carbamate. LCMS (ESI): mass/charge [Μ+H] calc. for C₂₇H₃₄ClFN₅O₃: 530.2; the found value is 530.2.

Stage 4

To a solution of tert -butyl-((3S,4S)-8-(5-(3-chloro-2-fluorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl)-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-yl)carbamate (28 mg, 52.8 µmol) in MeOH (264 µl) was added 4 M HCl in dioxane (132 µl, 528 µmol). The reaction mixture was stirred at 40°C for 2 h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give ( 3S,4S )–8–(5–(3–chloro–2–fluorophenyl)–6 -methylimidazo[1,5-a]pyrazin-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (3.0 mg, 13.2%) as formic salt acids. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.56 (s, 3H), 7.83 (s, 1H), 7.76–7.66 (m, 2H), 7.50–7.38 (m, 2H), 4.91 (s, 1H), 4.83 (d, J=1.8 Hz, 1H), 4.44–4.24 (m, 1H), 3.96 (d, J=8.9 Hz, 1H), 3.82 (d, J=8.8 Hz, 1H), 3.63-3.43 (m, 2H), 3.17 (d, J=4.7 Hz, 1H), 2.10 (s, 3H), 2.01–1.87 (m, 1H), 1.79 (dd, J=36.5, 14.2 Hz, 3H), 1.28 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₂ H ₂₆ ClFN ₅ O: 430.2; the found value is 430.1.

Example 13 Synthesis of ( 3S,4S )-8-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-methylimidazo[1,5-a]pyrazin-8-yl}-3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

K ₂ CO ₃ (210.41 g, 1.52 mol) at 75°C. The mixture was stirred at 75° C. for 1 hour. After completion, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The remaining residue was triturated with EtOAc (500 ml) and filtered. The resulting filtrate was concentrated under reduced pressure to give methyl 3-acetonylimidazole-4-carboxylate (144 g, 41.54% yield) as a yellow solid. LCMS: mass/charge [M+H] calc. for C ₈ H ₁₁ N ₂ O ₃ : 183.07; the found value is 183.3.

Stage 2

To a solution of methyl 3-acetonylimidazole-4-carboxylate (130 g, 713.59 mmol) in CH ₃ COOH (700 ml) was added CH ₃ COOHNH ₃ (275.03 g, 3.57 mol) in one portion at 130°C . The reaction mixture was stirred at 130°C for 48 h. After completion, the mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase column chromatography to give 6-methylimidazo[1,5-a]pyrazin-8-ol (40 g , yield 32.3%) as a yellow solid. LCMS: mass/charge: [M+H] calc. for C ₈ H ₁₁ N ₂ O ₃ : 150.06; the found value is 150.02.

Stage 3

To a solution of 6-methylimidazo[1,5-a]pyrazin-8-ol (10 g, 67.05 mmol) in DMF (300 ml) was added NBS (12.17 g, 68.39 mmol) in one portion at 0° C. The mixture was stirred at 0°C for 5 min. Upon completion, the reaction mixture was quenched by adding aq. Na ₂ SO ₃ (60 ml) which gave the product as a white solid. The solid was filtered and the filter cake was dried under reduced pressure to give 5-bromo-6-methyl-imidazo[1,5-a]pyrazin-8-ol (11.1 g, 72.6% yield) as a white solid substances. ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 11.13 (br s, 1 H) 8.28 (s, 1 H) 7.88 (s, 1 H) 2.18 (s, 3 H) .

Stage 4

POCl ₃ (146.85 g, 957.73 mmol, 89 ml) at 25°C under positive nitrogen pressure. The mixture was heated to 120°C and stirred for 45 minutes at 120°C. After completion, excess POCl ₃ was removed under reduced pressure. The mixture was then quenched with sat. aq. NaHCO ₃ (100 ml) with the removal of all remaining POCl ₃ . The resulting mixture was poured into water (300 ml) and stirred for 2 minutes. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5-bromo-8-chloro-6-methyl-imidazo[1,5-a]pyrazine (7.8 g, 78.24% yield) as a yellow solid. ¹ H NMR (400 MHz, Methanol –d4 ) δ ppm 8.63 (s, 1 H) 7.97 (s, 1 H) 2.53 (s, 3 H) LCMS: mass/charge: [M+H ] calc. for C ₇ H ₆ BrClN ₃ : 245.94; the found value is 245.90.

Stage 5

To a solution of 5-bromo-8-chloro-6-methylimidazo[1,5-a]pyrazine (450 mg, 1.82 mmol) and 2-methyl-N-(( 3S,4S )-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-yl)propan-2-sulfinamide (842 mg, 2.18 mmol) in DMA (9.09 ml) was added DIEA (1.58 ml, 9.10 mmol). The resulting reaction mixture was stirred at 130°C for 20 min. The reaction mixture was concentrated under reduced pressure and the remaining residue was partitioned between water/NH ₄ OH and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over MgSO ₄ and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography to give N-[( 3S , 4S )-8-{5-bromo-6-methylimidazo[1,5-a]pyrazin-8-yl}-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropan-2-sulfinamide (364 mg, 41.3%) as a yellow oil. LC-MS (ESI): mass/charge: [M+H] calc. for C ₁₆ H ₂₂ BrN ₅ O: 380.1; the found value is 380.1.

Stage 6

N–((3S, 4S )–8–(5– bromimidazo [1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan– 4-yl)-2-methylpropan-2-sulfinamide (60 mg, 123 µmol), 2-amino-3-chloropyridin-4-potassium thiolate (36.5 mg, 184 µmol) Pd2(dba)3 (6.74 mg, 7.37 µmol), Xantphos (7.05 mg, 12.2 µmol) and DIPEA (64.1 µl, 369 µmol). The reaction vessel was evacuated and purged with N ₂ three times. Dioxane was added and the solution was stirred at 140° C. for 3 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (0–10% MeOH/DCM) to give N–(( 3S , 4S )–8–(5–((2–amino–3–chloropyridin–4–yl)thio) -6-methylimidazo[1,5-a]pyrazin-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide. LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₅ H ₃₅ ClN ₇ O ₂ S ₂ : 564.2; the found value is 564.5.

Stage 7

To a solution of N–((3 S ,4 S )–8–(5–((2–amino–3–chloropyridin–4–yl)thio)–6–methylimidazo[1,5–a]pyrazin–8–yl )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (100 mg, 177 µmol) in MeOH (1.76 ml) was added 4 M HCl ( 440 µl, 1.76 mmol) in dioxane. The reaction mixture was stirred at 35°C for 1 h. The resulting reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give ( 3S,4S )–8–{5–[(2–amino–3–chloropyridine– 4-yl)sulfanyl]-6-methylimidazo[1,5-a]pyrazin-8-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (20.0 mg, 24 .5%) in the form of a salt of formic acid. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.53 (s, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.57 (d, J=5.6 Hz, 1H), 5.82 (d, J=5.5 Hz, 1H), 4.61–4.44 (m, 3H), 4.36–4.25 (m, 1H), 3.99 (d, J=9.0 Hz, 1H), 3.87 (d, J=9.0 Hz, 1H), 3.55 (dddd, J=38.4, 13.8, 10.1, 3 .8 Hz, 2H), 2.44 (d, J=1.9 Hz, 3H), 2.01–1.84 (m, 3H), 1.77 (d, J=13.8 Hz, 1H ), 1.30 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge: [Μ+H] calc. for C ₂₁ H ₂₇ ClN ₇ OS: 460.2; the found value is 460.5.

Example 14 Synthesis of 1-[7-(2,3-dichlorophenyl)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl]-4-methylpiperidin-4-amine.

Stage 1

To a solution of 7-bromo-4-chloro-[ 1,2,5 ]thiadiazolo[3,4-c]pyridine (160 mg, 638 µmol) in DMA (3.18 ml) -4-yl)carbamate (409 mg, 1.91 mmol) and DIPEA (555 µl, 3.19 mmol). The reaction mixture was stirred in a closed vessel at 100° C. for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to remove as much DMA as possible. The residue was purified by column chromatography using 0-10% MeOH/DCM to give the desired product, which is tert -butyl-(1-(7-bromo-[1,2,5]thiadiazolo[3,4-c]pyridine -4-yl)-4-methylpiperidin-4-yl)carbamate. LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₆ H ₂₂ BrN ₅ O ₂ S: 427.07; the found value is 427.9.

Stage 2

Tert -butyl-(1-(7-bromo-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidin-4-yl)carbamate (60 mg, 140 µmol), (2,3-dichlorophenyl)boronic acid (40.0 mg, 210 µmol), Pd(dppf)Cl ₂ DCM (22.8 mg, 28.0 µmol) and K ₂ CO ₃ (77, 3 mg, 560 µmol). The contents of the vessel were evacuated in a centralized vacuum system for 15 min. before adding to degassed ACN (1.39 ml). The resulting mixture was filled with N ₂ and was evacuated three times before stirring at 100°C overnight in a closed vessel. The resulting reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography using 0-10% MeOH/DCM to give the desired product, which is tert -butyl-(1-(7-(2,3-dichlorophenyl)-[1,2 ,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidin-4-yl)carbamate. LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₂ H ₂₅ Cl ₂ N ₅ O ₂ S: 493.11; the found value is 493.9.

Stage 3

To a solution of tert -butyl-(1-(7-(2,3-dichlorophenyl)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidin-4-yl) carbamate (69 mg, 139 μmol) in methanol (1.38 ml) was added 4 M HCl in dioxane (347 μl, 1.39 mmol). The reaction mixture was stirred in a closed vessel at 35°C for 1 h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC using 5-35% ACN+0.1% formic acid/H ₂ O+0, 1% formic acid to obtain the desired product, which is 1-(7-(2,3-dichlorophenyl)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidine- 4-amine (30.0 mg, 54.7%), as a salt of formic acid. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.54 (s, 2H), 8.00 (s, 1H), 7.63 (dd, J=7.3, 2.2 Hz, 1H), 7.48-7.31 (m, 2H), 4.01-3.83 (m, 4H), 1.97 (t, J=4.9 Hz, 4H), 1.57 (s, 3H) . LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₇ H ₁₈ Cl ₂ N ₅ S: 394.1; the found value is 394.1.

Example 15 Synthesis of 4–((4–(4–amino–4–methylpiperidin–1–yl)–[1,2,5]thiadiazolo[3,4–c]pyridin–7–yl)thio)–3– chloropyridine-2-amine.

Stage 1

tert -Butyl-(1-(7-bromo-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidin-4-yl)carbamate ( 60 mg, 140 µmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (36.5 mg, 184 µmol), 2-amino-3-chloropyridine-4-potassium thiolate (41.7 mg, 210 µmol), Pd ₂ (dba) ₃ (12.8 mg, 14.0 µmol), Xantphos (16.2 mg, 28.0 µmol) and DIPEA (73.0 µl, 420 µmol). The mixture was degassed and degassed dioxane (1.39 ml) was added. The reaction vessel was evacuated and purged with N ₂ three times before stirring under microwave conditions at 140° C. for 3 hours. The mixture was filtered through a Celite pad, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography to give the desired product, which is t -butyl-(1-(7-((2-amino-3-chloropyridin-4-yl)thio)-[1,2 ,5]thiadiazolo[3,4-c]pyridin-4-yl)-4-methylpiperidin-4-yl)carbamate. LCMS (ESI): mass/charge: [Μ+H] calc. for C ₂₁ H ₂₆ ClN ₇ O ₂ S ₂ : 507.13; the found value is 508.1.

Stage 2

To a solution of tert -butyl-(1-(7-((2-amino-3-chloropyridin-4-yl)thio)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl) -4-methylpiperidin-4-yl)carbamate (61 mg, 120 μmol) in methanol (1.20 ml) was added 4 M HCl in dioxane (300 μl, 1.20 mmol). The reaction mixture was stirred in a closed vessel at 35°C for 1 h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give 4-((4-(4-amino-4-methylpiperidin-1-yl) -[1,2,5]thiadiazolo[3,4-c]pyridin-7-yl)thio)-3-chloropyridine-2-amine (40.0 mg, 98.0 μmol, 81.7%) as salts of formic acid. ¹ H NMR (500 MHz, methanol -d4 ) δ 8.50 (d, J=37.7 Hz, 1H), 8.28 (s, 1H), 7.45 (d, J=5.6 Hz, 1H), 5.80 (d, J=5.5 Hz, 1H), 4.03–3.90 (m, 4H), 2.07–1.87 (m, 4H), 1.57 (d , J=0.9 Hz, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₆ H ₁₉ ClN ₇ S ₂ : 408.1; the found value is 408.2.

Example 16 Synthesis of (3S,4S)– 8–{8–[(2–amino–3–chloropyridin–4–yl)sulfanyl]pyrido[4,3–d]pyrimidin–5–yl}–3–methyl– 2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

8-Bromo-5-chloropyrido[4,3-d]pyrimidine (179 mg, 732 µmol) and ( 3S,4S )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (175 mg, 732 µmol) was dissolved in DMA (3.66 ml) and DIPEA (1.27 ml, 7.32 mmol) was added at room temperature. The mixture was heated to 120°C for 3 h. The solvent was removed under reduced pressure and the crude residue was purified by silica gel chromatography to give (3S,4S) –8–{8–bromopyrido[4,3–d]pyrimidine–5– yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (182 mg, 65.9%) as a yellow solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₆ H ₂₀ BrN ₅ O: 379.3; the found value is 379.9.

Stage 2

3-Chloro-4-(potassiumsulfanyl)pyridine-2-amine (78.6 mg, 396 µmol), (3S,4S)-8-{8-bromopyrido[4,3-d]pyrimidin-5-yl}- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (100 mg, 264 µmol), Xantphos (30.5 mg, 52.8 µmol), Pd ₂ dba ₃ (24.1 mg, 26.4 µmol) and DIEA (91.7 µl, 528 µmol) were weighed into a microwave vessel equipped with a magnetic stirrer. The reaction vessel was purged with N ₂ and dioxane (2.63 ml) was added followed by the addition of DIEA (91.7 μl, 528 μmol). The headspace of the reaction vessel was refilled 3 times with N ₂ and the mixture was heated for 2 hours at 120° C. under microwave radiation. The resulting mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude residue was directly purified by preparative HPLC to give (3S,4S) -8-{8-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrido[4,3-d]pyrimidin-5-yl }-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (5.70 mg, 4.75%) as a yellow solid. ¹ H NMR (500 MHz, Methanol –d4 ) δ 9.57 (s, 1H), 9.25 (s, 1H), 8.65 (s, 1H), 8.42 (s, 1H), 7, 46 (d, J=5.6 Hz, 1H), 5.72 (d, J=5.6 Hz, 1H), 4.38–4.30 (m, 2H), 4.27 (d, J =13.7 Hz, 1H), 4.05 (d, J=9.1 Hz, 1H), 3.94 (d, J=9.1 Hz, 1H), 3.62 (ddd, J=14 .0, 11.1, 3.0 Hz, 1H), 3.52 (ddd, J=14.0, 11.3, 2.9 Hz, 1H), 3.49–3.47 (m, 1H ), 2.13–2.04 (m, 2H), 1.98 (d, J=13.4 Hz, 1H), 1.83 (d, J=13.3 Hz, 1H), 1.35 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge: [M+H] calc. for C ₂₁ H ₂₅ ClN ₇ OS: 458.1; the found value is 458.5.

Example 17 Synthesis of ( 1R )-8-[8-(2,3-dichlorophenyl)pyrido[4,3-d]pyrimidin-5-yl]-8-azaspiro[4.5]decan-1-amine.

Stage 1

To a solution of 8-bromo-5-chloropyrido[4,3-d]pyrimidine (25 mg, 102 µmol) in DMA (1 ml) was added 2-methyl-N-(( R )-8-azaspiro[4.5]decan- 1-yl)propan-2-sulfinamide (28.9 mg, 112 µmol) and DIPEA (88.8 µl, 510 µmol). The mixture was covered and stirred at 80° C. for 2 hours. According to LCMS, the reaction was complete. The resulting reaction mixture was diluted with EtOAc and H ₂ O. The organic layer was separated and then washed three more times with H ₂ O. The resulting organic layer was separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 0-100% EtOAc/heptane to give the desired product, which is N-(( R )-8-(8-bromopyrido[4,3-d]pyrimidin-5-yl)-8 -azaspiro[4.5]decan-1-yl)-2-methylpropan-2-sulfinamide (40.0 mg, 84.2%). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₀ H ₂₉ BrN ₅ OS: 466.12; the found value is 466.3.

Stage 2

N–(( R )–8–(8–bromopyrido[4,3–d]pyrimidin–5–yl)–8–azaspiro[4.5]decan–1–yl)–2–methylpropan–2– sulfinamide (20 mg, 42.8 µmol), (2,3-dichlorophenyl)boronic acid (12.2 mg, 64.1 µmol), potassium carbonate (17.6 mg, 128 µmol) and tetrakis (2.95 mg , 2.56 µmol). The contents of the vessel were evacuated under high vacuum for 10 minutes. before adding to degassed ethyl alcohol (548 µl). The resulting mixture was purged and evacuated with N ₂ three times and then stirred at 80° C. for 1 hour. The resulting reaction mixture was filtered through a Celite pad, rinsing with DCM and MeOH. The obtained filtrate was purified by column chromatography to give N–(( R )–8–(8–(2,3–dichlorophenyl)pyrido[4,3–d]pyrimidin–5–yl)–8–azaspiro[4.5]decane -1-yl)-2-methylpropan-2-sulfinamide (11 mg, 48.4%). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₇ H ₃₂ Cl ₂ N ₅ OS: 533.5; the found value is 533.3.

Stage 3

N–(( R )–8–(8–(2,3–dichlorophenyl)pyrido[4,3–d]pyrimidin–5–yl)–8–azaspiro[4.5]decan–1–yl)–2–methylpropan -2-sulfinamide (25 mg, 46.9 µmol) was dissolved in MeOH (2 ml) and then 4 M HCl in dioxane (1 ml, 4.00 mmol) was added. The mixture was stirred in a closed vessel for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give ( 1R )-8-[8-(2,3-dichlorophenyl)pyrido[4,3-d]pyrimidin-5-yl]-8-azaspiro[4.5]decan-1 -amine (8.79 mg, 43.9%) as a salt of formic acid. ¹ H NMR (500 MHz, methanol –d4 ) δ 9.59 (s, 1H), 9.19 (s, 1H), 8.57 (s, 1H), 8.34 (s, 1H), 7, 65 (dd, J=8.0, 1.6Hz, 1H), 7.42 (t, J=7.8Hz, 1H), 7.36 (dd, J=7.6, 1.6Hz , 1H), 4.17 (dd, J=25.8, 13.6 Hz, 3H), 3.51 (d, J=12.9 Hz, 2H), 3.19 (d, J=14, 3 Hz, 1H), 2.30–2.12 (m, 1H), 2.10–1.76 (m, 5H), 1.76–1.53 (m, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₂₂ H ₂₄ Cl ₂ N ₅ : 428.1; the found value is 428.4.

Example 18 Synthesis of (1R)-8-[8-(3-chlorophenyl)pyrido[4,3-d]pyrimidin-5-yl]-8-azaspiro[4.5]decan-1-amine.

(1 R )–8–[8–(3–chlorophenyl)pyrido[4,3–d]pyrimidin–5–yl]–8–azaspiro[4.5]decan–1–amine was synthesized by a method similar to the method in example 17 , except that (2,3-dichlorophenyl)boronic acid was replaced by (3-chlorophenyl)boronic acid. ¹ H NMR (500 MHz, methanol –d4 ) δ 9.58 (s, 1H), 9.29 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 7, 73 (t, J=1.9Hz, 1H), 7.59 (dt, J=7.6, 1.4Hz, 1H), 7.48 (t, J=7.8Hz, 1H), 7.43 (ddd, J=8.0, 2.1, 1.2 Hz, 1H), 4.18-4.01 (m, 3H), 3.52-3.41 (m, 2H), 3.23 (t, J=7.0 Hz, 1H), 2.29–2.17 (m, 1H), 2.07–1.78 (m, 5H), 1.78–1.53 ( m, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₂ H ₂₅ ClN ₅ : 394.2; the found value is 394.3.

Example 19 Synthesis of 4-(4-amino-4-methylpiperidin-1-yl)-7-(2,3-dichlorophenyl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one.

Stage 1

4-Chloro-1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 296 µmol) and tert -butyl-N-(4-methylpiperidin-4-yl)carbamate (317 mg , 1.48 mmol) was dissolved in DMA (1.47 ml) and DIPEA (514 μl, 2.96 mmol) was added. The mixture was heated to 110°C for 4 h, the solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography to give t -butyl-N-(4-methyl-1-{1-oxo-1H,2H, 3H-pyrrolo[3,4-c]pyridin-4-yl}piperidin-4-yl)carbamate (72.0 mg, 70.5%) as a brown solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₈ H ₂₆ N ₄ O ₃ : 347.2; the found value is 347.5.

Stage 2

tert -Butyl-N-(4-methyl-1-{1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}piperidin-4-yl)carbamate (100 mg, 288 µmol) was dissolved in MeCN (1.44 ml) and NBS (56.2 mg, 316 µmol) was added. After stirring for 30 min. at room temperature, the solvent was removed under reduced pressure, and the crude residue was purified by silica gel chromatography to give tert -butyl- N- (1-{7-bromo-1-oxo-1H,2H,3H-pyrrolo[3,4-c ]pyridin-4-yl}-4-methylpiperidin-4-yl)carbamate (98.0 mg, 80.3%) as a beige solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₈ H ₂₅ BrN ₄ O ₃ : 424.1; the found value is 423.7.

Stage 3

To a solution of tert -butyl- N- (1-{7-bromo-1-oxo-1H,2H,3H-pyrrolo[3,4-c]pyridin-4-yl}-4-methylpiperidin-4-yl)carbamate (80 mg, 0.19 mmol) in dioxane (3 ml) was added (2,3-dichlorophenyl)boronic acid (72 mg, 0.38 mmol) and PdCl ₂ (dppf) (15 mg, 0.019 mmol). Was added an aqueous solution of Cs ₂ CO ₃ (72 mg, 0.38 mmol) in 1 ml of water. The reaction mixture was covered and subjected to microwave radiation at 100°C for 2 hours Then it was cooled to room temperature, was extracted with EtOAc (3×15 ml). The combined organic layers were combined, washed with brine (5 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give the desired product as a white solid. The solid was taken up in dioxane (2 ml) and a solution of HCl in dioxane (1 M, 1 ml, excess) was added. The reaction mixture was stirred at room temperature for 2 h to give a yellow precipitate, which was filtered and air dried to give the HCl salt and 4-(4-amino-4-methylpiperidin-1-yl)-7-(2,3- dichlorophenyl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one (20 mg, 27%). ¹ H NMR (500 MHz, methanol –d4 ) δ 8.00 (s, 1H), 7.65 (t, J=6.3 Hz, 1H), 7.44–7.34 (m, 2H), 4.16 (s, 1H), 3.79 (s, 1H), 3.37 (s, 2H), 3.32 (s, 3H), 2.18 (s, 1H), 2.12 (d , J=13.2 Hz, 2H), 1.60 (s, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₁₉ H ₂₁ Cl ₂ N ₄ O: 391.1; the found value is 391.3.

Example 20 Synthesis of 7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-4-(4-amino-4-methylpiperidin-1-yl)-1H,2H,3H-pyrrolo[3,4 –c]pyridine–1–one.

3-Chloro-4-(potassiumsulfanyl)pyridine-2-amine (52.4 mg, 264 µmol), tert -butyl-N-(1-{7-bromo-1-oxo-1H,2H,3H-pyrrolo[ 3,4-c]pyridin-4-yl}-4-methylpiperidin-4-yl)carbamate (75 mg, 176 µmol), Xantphos (20.3 mg, 35.2 µmol) and Pd ₂ dba ₃ (16, 1 mg, 17.6 µmol) was added to the microwave vessel. The reaction vessel was purged with N ₂ and dioxane (1.75 ml) was added followed by DIEA (61.1 μl, 352 μmol). The headspace of the reaction vessel was refilled 3 times with N ₂ and the mixture was heated for 2 hours at 120° C. under microwave radiation. The crude mixture was cooled to room temperature and filtered through celite. The solvent was removed under reduced pressure and the residue was taken up in MeOH (1 ml). HCl in dioxane (4 M, 0.5 ml) was added and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the product was purified by preparative HPLC to give 4.6 mg (6%) 7–[( 2-amino-3-chloropyridin-4-yl)sulfanyl]-4-(4-amino-4-methylpiperidin-1-yl)-1H,2H,3H-pyrrolo[3,4-c]pyridin-1-one . ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.30 (d, J=0.7 Hz, 1H), 7.54 (d, J=6.4 Hz, 1H), 5.83 (d, J=5.6Hz, 1H), 4.64(s, 2H), 4.18(dt, J=14.2, 4.6Hz, 2H), 3.58-3.45(m, 2H ), 1.97–1.90 (m, 4H), 1.54 (s, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₁₈ H ₂₂ ClN ₆ OS: 405.1; the found value is 405.3.

Example 21 Synthesis of 1-{1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl]-4-methylpiperidin-4-yl}methanamine.

Stage 1

To a solution of 5-bromo-8-chloro-6-methylimidazo[1,2-a]pyrazine (500 mg, 2.02 mmol) in DMA (10.1 ml) was added tert -butyl-N-[(1-chloro -4-methylpiperidin-4-yl)methyl]carbamate (583 mg, 2.21 mmol) and DIPEA (1.75 ml, 10.1 mmol). The reaction mixture was stirred in a closed vessel at 100° C. for 1 hour. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give tert -butyl-N-[(1-{5-bromo-6-methylimidazo[1,2-a]pyrazin-8-yl}-4-methylpiperidin-4-yl)methyl] carbamate (580 mg, 65%) LCMS (ESI): mass/charge [M+H] calc. for C ₁₉ H ₂₉ BrN ₅ O ₂ : 438.1; the found value is 438.4.

Stage 2

(2,3-dichlorophenyl)boronic acid (121 mg, 638 µmol), (2,3-dichlorophenyl)boronic acid (121 mg, 638 µmol), AntPhos (34 mg, 91.2 µmol), K ₃ PO ₄ (288 mg, 1.36 mmol) and Pd(OAc) ₂ (10 mg, 45.6 µmol). The mixture was evacuated in a centralized vacuum system for 10 min. before adding to degassed dioxane (4.56 ml). The resulting mixture was filled with N ₂ and degassed three times before stirring at 110° C. for 2 hours. The resulting reaction mixture was filtered through a celite pad, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure and the residue was taken up in MeOH (2 ml). HCl (4 M in dioxane, 1 mL) was added and the mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to give 1–{1–[5–(2,3– dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl]-4-methylpiperidin-4-yl}methanamine (4.40 mg, 2.39%) as a colorless solid. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.57 (s, 1H), 7.79 (dd, J=8.1, 1.6 Hz, 1H), 7.58–7.52 (m , 1H), 7.49 (d , J= 1.3 Hz, 1H), 7.45 (dd, J=7.7, 1.6 Hz, 1H), 7.03 (d, J=1, 2 Hz, 1H), 4.85–4.76 (m, 2H), 3.80 (dtd, J=13.6, 10.3, 3.2 Hz, 2H), 2.92 (s, 2H ), 2.11 (s, 3H), 1.72 (ddt, J=13.4, 10.1, 3.7 Hz, 2H), 1.67–1.55 (m, 2H), 1, 24(s, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₀ H ₂₄ Cl ₂ N ₅ : 404.1; the found value is 404.1.

Example 22. Synthesis of (3 S ,4 S )-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-amine.

Stage 1

7-bromo-4-chloro-6-methylpyrazolo[1,5-a]pyrazine (300 mg, 1.21 mmol), N -[(3S,4S)-8-chloro-3- methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]chloranamine (352 mg, 1.45 mmol), DMA (6 ml) and N , N -diisopropylethylamine (1.05 ml, 6.04 mmol ). Then the flask was sealed and heated to 85°C. After stirring for 16 hours, the reaction mixture was cooled to room temperature and di- tert -butyl dicarbonate (1.05 g, 4.84 mmol) was added in one portion. After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate (30 ml) and water (10 ml) and the layers were separated. The organic solution was then washed successively with water (10 ml), half-saturated aqueous sodium chloride solution (10 ml) and saturated aqueous sodium chloride solution (10 ml). The organic solution was then dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to give an orange oil. This crude oil was purified by column chromatography to give tert -butyl- N -[( 3S,4S )-8-{7-bromo-6-methylpyrazolo[1,5-a]pyrazin-4-yl}-3-methyl -2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (475.7 mg, 82% yield) as a pale pink foam. LC-MS (ESI): mass/charge: [M+H] calc. for C ₂₁ H ₃₁ BrN ₅ O ₃ : 480.1; the found value is 480.0.

Stage 2

A 20 ml vessel was loaded with tert -butyl- N -[( 3S,4S )-8-{7-bromo-6-methylpyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate (200 mg, 0.4 mmol), (2,3-dichlorophenyl)boronic acid (95.3 mg, 0.5 mmol), tripotassium phosphate (263 mg, 1 .24 mmol), 4-(anthracen-9-yl)-3- tert -butyl-2,3-dihydro-1,3-benzoxaphosphol (30.8 mg, 0.08 mmol) and degassed dioxane (4 ml) . Then the resulting suspension was degassed for 10 min. before adding palladium(II) acetate (9.34 mg, 0.04 mmol) and the orange mixture was degassed for an additional 5 min. After this time, the vessel was sealed and heated to 105°C. After stirring for 2 hours, the reaction mixture was filtered through a small pad of celite, and then the filtrate was concentrated under reduced pressure. The resulting crude residue was purified by column chromatography to give tert -butyl- N -[( 3S,4S )-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazine-4- yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate as an orange oil with impurities. This oil was carried to the next stage without further processing. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₇ H ₃₄ Cl ₂ N ₅ O ₃ : 546.2; the found value is 546.1.

Stage 3

tert -butyl- N -[( 3S,4S )-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (227 mg, 0.4 mmol), DCM (2 ml) and TFA (0.5 ml) at room temperature. The resulting yellow solution was allowed to stir for 1 hour before concentrating the reaction mixture under reduced pressure to give an orange residue. This crude material was purified by preparative HPLC to give ( 3S,4S )-8-[7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-amine (6.9 mg, 3.7% yield) as fluffy white solid. ( 3S,4S )–8–[7–(2,3–dichlorophenyl)–6–methylpyrazolo[1,5–a]pyrazin–4–yl]–3–methyl–2–oxa–8–azaspiro[4.5] decan-4-amine in the form of formate salt. ¹ H NMR (500 MHz, methanol -d4 ) δ 8.53 (s, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.70 (dd, J=8.1, 1 .5 Hz, 1H), 7.46 (t, J=8.1, 7.6 Hz, 1H), 7.36 (dd, J=7.7, 1.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 4.41–4.26 (m, 3H), 3.99 (d, J=8.9 Hz, 1H), 3.87 (d, J= 9.0 Hz, 1H), 3.48-3.34 (m, 2H), 2.13 (s, 3H), 2.02-1.91 (m, 2H), 1.91-1.84 (m, 1H), 1.79–1.73 (m, 1H), 1.30 (d, J=6.5 Hz, 3H). LC-MS (ESI): mass/charge [M+H] calc. for C ₂₂ H ₂₆ Cl ₂ N ₅ O: 446.1; the found value is 446.4.

Example 23 Synthesis of ( 3S,4S )–8–[7–(2–chloro–3–methoxyphenyl)–6–methylpyrazolo[1,5–a]pyrazin–4–yl]–3–methyl–2–oxa– 8-azaspiro[4.5]decan-4-amine.

Stage 1

7-bromo-4-chloro-6-methylpyrazolo[1,5-a]pyrazine (300 mg, 1.2 mmol), N -[(3S,4S)-8-chloro-3- methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]chloranamine (352 mg, 1.5 mmol), DMA (6 ml) and N , N -diisopropylethylamine (1.05 ml, 6.04 mmol ). Then the flask was sealed and heated to 85°C. After stirring for 16 h, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was purified using column chromatography to obtain ( 3S,4S )-8-{8-bromo-7-methylimidazo[1,2-c ]pyrimidin-5-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (360 mg, 78%). LC-MS (ESI): mass/charge [M+H] calc. for C ₁₆ H ₂₃ BrN ₅ O: 380.1; the found value is 380.1.

Stage 2

To a solution of (3 S ,4 S )–8–{8–bromo–7–methylimidazo[1,2–c]pyrimidin–5–yl}–3–methyl–2–oxa–8–azaspiro[4.5]decan– 4-amine (75 mg, 0.2 mmol) and (2,3-dichlorophenyl)boronic acid (56 mg, 0.29 mmol) in DME (990 µl) and H ₂ O (197 µl) sodium carbonate (42 mg, 0.3944 mmol), then tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was added to the reaction mixture. The mixture was stirred at 100° C. for 1 hour. After cooling to room temperature, the mixture was filtered through a celite pad and the solvent was removed under reduced pressure. The crude residue was purified by preparative HPLC to give 10 mg (17%) of ( 3S,4S )-8-[7-(2-chloro-3-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyrazine-4- yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. ¹ H NMR (500 MHz, methanol –d4 ) δ 7.76 (d, J = 2.5 Hz, 1H), 7.43 (dd, J = 8.3, 7.6 Hz, 1H), 7, 23 (dd, J =8.4, 1.4Hz, 1H), 6.97 (dd, J =7.7, 1.4Hz, 1H), 6.90 (d, J =2.5Hz , 1H), 7.43 (dd, J = 8.7 Hz, 1H), 3.79 (d, J = 8.7 Hz, 1H), 3.79 (d, J = 13.8, 10, 3, 3.5 Hz, 1H), 3.46–3.37 (m, 1H), 3.11 (d, J = 4.9 Hz, 1H), 2.11 (s, 3H), 1, 94 (dddt, J =27.6, 14.1, 10.3, 3.9 Hz, 2H), 1.84-1.69 (m, 2H), 1.25 (d, J =6.5 Hz, 3H); LC-MS (ESI): mass/charge: [M+H] calc. for C ₂₃ H ₂₉ ClN ₅ O ₂ : 442.2; the found value is 442.4.

Example 24 Synthesis of 4-{[4-(4-amino-4-methylpiperidin-1-yl)pyrazolo[1,5-a]pyrazin-7-yl]sulfanyl}-3-chloropyridine-2-amine.

Stage 1

4-Chloropyrazolo[1,5-a]pyrazine (50 mg, 0.3 mmol), tert -butyl-N-(4-methylpiperidin-4-yl)carbamate (83 mg, 0.39 mmol), DMA (2 ml) and N , N -diisopropylethylamine (281 µl, 1.6 mmol). Then the flask was sealed and heated to 120°C. After 16 hours the reaction mixture was diluted with ethyl acetate (10 ml) and water (5 ml). The layers were separated and the organic phase was washed successively with water (5 ml) and saturated aqueous sodium chloride solution (5 ml). The washed organic solution was then dried over sodium sulfate. The dried solution was then filtered and the filtrate was concentrated to give an orange oil. The crude material was purified by column chromatography to give tert -butyl- N- (4-methyl-1-{pyrazolo[1,5-a]pyrazin-4-yl}piperidin-4-yl)carbamate (101 mg, 94% yield). .3%) as a pale yellow oil. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₇ H ₂₆ N ₅ O ₂ : 332.2; the found value is 332.0.

Stage 2

tert -Butyl- N- (4-methyl-1-{pyrazolo[1,5-a]pyrazin-4-yl}piperidin-4-yl)carbamate (101 mg, 0.3 mmol) was loaded into a 20 ml vessel and DMA (2.54 ml) before cooling to 0°C. After cooling, a solution of N -bromosuccinimide (57 mg, 0.3 mmol) in DMA (0.5 ml) was added dropwise to the mixture over 10 min. to obtain a burgundy solution. After 0.5 hours, the reaction mixture was diluted with water (5 ml) and ethyl acetate (10 ml). The biphasic mixture was separated and the organic solution was washed successively with water (5 ml) and saturated aqueous sodium chloride (5 ml). The combined aqueous washes were then extracted with ethyl acetate (10 ml) and the combined organic solutions were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to an orange oil, which was purified by column chromatography to give tert -butyl- N- (1-{7-bromopyrazolo[1,5-a]pyrazin-4-yl}-4-methylpiperidine- 4-yl)carbamate (37.3 mg, 30% yield) as a white solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₇ H ₂₅ BrN ₅ O ₂ : 410.1; the found value is 409.9.

Stage 3

tert -butyl- N- (1-{7-bromopyrazolo[1,5-a]pyrazin-4-yl}-4-methylpiperidin-4-yl)carbamate (37 mg, 0 .09 mmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (22 mg, 0.11 mmol), Xantphos (10 mg, 0.02 mmol), degassed dioxane (910 μl) and N,N -diisopropylethylamine (47.4 µl, 0.27 mmol). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes. and then tris(dibenzylideneacetone)dipalladium (8 mg, 0.01 mmol) was added to the vessel in one portion. The mixture was then degassed for an additional 5 minutes before being sealed. The mixture was then heated to 120° C. using microwave radiation and stirred for 1.5 h. After this time, the mixture was then filtered through a celite pad and concentrated to an orange oil. This oil was purified by column chromatography to give tert -butyl-(1-(7-((2-amino-3-chloropyridin-4-yl)thio)pyrazolo[1,5- a ]pyrazin-4-yl)- 4-methylpiperidin-4-yl)carbamate as an orange oil with impurities, which was then carried to the next stage without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₂ H ₂₉ ClN ₇ O ₂ S: 490.2; the found value is 490.5.

Stage 4

Tert -butyl- N- (1-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyrazin-4-yl}-4 -methylpiperidin-4-yl)carbamate (45 mg, 0.09 mmol), DCM (2 ml) and TFA (0.5 ml) to give a bright red-orange solution. This solution was stirred at 23°C for 1 h. After this time, the reaction mixture was concentrated to a red-orange oil, which was purified by preparative HPLC to give 4–{[4–(4–amino–4–methylpiperidine– 1-yl)pyrazolo[1,5-a]pyrazin-7-yl]sulfanyl}-3-chloropyridin-2-amine (17 mg, 0.04 mmol, 46%) as a white solid. 4–{[4–(4–Amino–4–methylpiperidin–1–yl)pyrazolo[1,5–a]pyrazin–7–yl]sulfanyl}–3–chloropyridine–2–amine as formate salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.13 (s, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.82 (s, 1H), 7.47 ( d, J=5.6 Hz, 1H), 7.14 (d, J=2.5 Hz, 1H), 5.67 (d, J=5.6 Hz, 1H), 4.43 (dt, J=13.9, 4.6Hz, 2H), 3.67 (dt, J=14.0, 6.9Hz, 2H), 1.96 (dd, J=6.8, 4.6Hz , 4H), 1.55 (s, 3H); LC-MS (ESI): mass/charge: [M+H] calc. for C ₁₇ H ₂₁ ClN ₇ S: 390.1; the found value is 390.4.

Example 25 Synthesis of ( 3S,4S )–8–{7–[(2–amino–3–chloropyridin–4–yl)sulfanyl]pyrazolo[1,5–a]pyrazin–4–yl}–3–methyl– 2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

4-chloropyrazolo[1,5-a]pyrazine (200 mg, 1.30 mmol), (3S,4S)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–amine (379 mg, 1.5 mmol), DMA (7 ml) andN,N-diisopropylethylamine (1 ml, 6.5 mmol). Then the flask was sealed and heated to 120°C. After stirring for 60 h, the reaction mixture was cooled to room temperature and di–tert-butyl dicarbonate (1.41 g, 6.5 mmol). After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate (20 ml) and water (5 ml) and the layers were separated. The organic solution was then washed successively with water (5 ml) and saturated aqueous sodium chloride (5 ml). The combined aqueous washes were then extracted with ethyl acetate (20 ml) and the combined organic solutions were dried over sodium sulfate. The dried solution was then filtered and the filtrate was concentrated to give an orange oil. This crude oil was purified by column chromatography to givetert-butyl-N–[(3S,4S)-3-methyl-8-{pyrazolo[1,5-a]pyrazin-4-yl}-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (503 mg, 100% yield) in green oil. LC-MS (ESI): mass/charge [M+H] calc. for C_twentyH_thirtyN₅O₃: 388.2; the found value is 388.1.

Stage 2

A 20 ml vessel was loaded with tert -butyl- N -[( 3S,4S )-3-methyl-8-{pyrazolo[1,5-a]pyrazin-4-yl}-2-oxa-8-azaspiro[4.5] decan-4-yl]carbamate (555 mg, 1.4 mmol) and DMA (11 ml). The resulting pale yellowish brown solution was then cooled to 0°C. After cooling, a solution of N -bromosuccinimide (227 mg, 1.28 mmol) in DMA (3 ml) was slowly added dropwise to the reaction mixture. The resulting solution was stirred for 1 hour at 0°C. After this time, the reaction mixture was diluted with water (15 ml) and ethyl acetate (15 ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml) and the combined organic solution was washed successively with water (2×10 ml) and saturated aqueous sodium chloride (10 ml). The washed organic solution was then dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to give an orange oil which was purified by column chromatography to give tert -butyl- N -[( 3S,4S )-8-{7-bromopyrazolo[1,5-a]pyrazin-4-yl }–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–yl]carbamate (92 mg, 14% yield) as a white foam. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₀ H ₂₉ BrN ₅ O ₃ : 466.1; the found value is 466.2.

Stage 3

Tert -butyl- N -[( 3S,4S )-8-{7-bromopyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate (53 mg, 0.1 mmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (27 mg, 0.1 mmol), Xantphos (13 .1 mg, 0.02 mmol), degassed dioxane (1 ml) and N , N -diisopropylethylamine (59.2 μl, 0.3 mmol). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes, and then tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol) was added to the vessel in one portion. The mixture was then degassed for an additional 5 minutes before being sealed. The mixture was then heated to 120° C. using microwave radiation and stirred for 1.5 h. At the end of this time, the reaction mixture was filtered through a Celite pad and concentrated to an orange oil. This oil was purified by column chromatography to give tert -butyl- N -[( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazolo[1,5-a ]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate as an orange oil with impurities, which was further transferred to the next stage without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₅ H ₃₃ ClN ₇ O ₃ S: 546.2; the found value is 546.5.

Stage 4

A 20 ml vessel was loaded with tert -butyl- N -[( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyrazin-4 -yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (62 mg, 0.1 mmol) and DCM (2 ml) to give an orange solution. TFA (0.5 ml) was added to the solution and the resulting mixture was stirred for 1 h. After this time, the reaction mixture was concentrated to obtain an orange–red residue, which was purified using preparative HPLC to obtain ( 3S,4S )–8– {7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan- 4-amine (23.4 mg, 46.2% yield) as formate salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.16 (s, 1H), 7.95 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.47 ( d, J=5.6 Hz, 1H), 7.11 (d, J=2.5 Hz, 1H), 5.67 (d, J=5.5 Hz, 1H), 4.58–4, 47 (m, 2H), 4.37-4.28 (m, 1H), 4.04 (d, J=9.2 Hz, 1H), 3.93 (d, J=9.3 Hz, 1H ), 3.52–3.44 (m, 2H), 3.40 (ddd, J=14.0, 11.3, 2.9 Hz, 1H), 2.00–1.90 (m, 3H ), 1.78 (d, J=13.3 Hz, 1H), 1.33 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₀ H ₂₅ ClN ₇ OS: 446.1; the found value is 446.2.

Example 26 Synthesis of ( 3S , 4S )-8-[7-(2,3-dichlorophenyl)pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro [4.5]decane-4-amine.

Stage 1

A 2 ml vessel was loaded with tert -butyl- N -[(3 S ,4 S )-8-{7-bromopyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa-8- azaspiro[4.5]decan-4-yl]carbamate (32mg, 0.07mmol), (2,3-dichlorophenyl)boronic acid (16mg, 0.08mmol), potassium carbonate (37mg, 0.27mmol) ) and degassed acetonitrile (677 μl). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes and then Pd(dppf)Cl ₂ (11 mg, 0.014 mmol) was added to the vessel. The mixture was then degassed for an additional 5 minutes. and heated to 105° C. for 2 hours. The resulting mixture was cooled and filtered through a celite pad. The filtrate was then concentrated under reduced pressure and purified by column chromatography to give tert -butyl- N -[( 3S , 4S )-8-[7-(2,3-dichlorophenyl)pyrazolo[1,5-a]pyrazine -4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (36 mg, 100% yield) as an orange foam, which was then carried to the next step without further purification. LC-MS (ESI): mass/charge: [M+H] calc. for C ₂₆ H ₃₁ Cl ₂ N ₅ O ₃ : 532.2; the found value is 532.1.

Stage 2

A 20 ml vessel was sequentially loaded with tert -butyl- N -[(3S,4S)-8-[7-(2,3-dichlorophenyl)pyrazolo[1,5-a]pyrazin-4-yl]-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (36 mg, 0.06 mmol), DCM (2 ml) and TFA (0.5 ml). After stirring for 1 h, the reaction mixture was concentrated under reduced pressure to give a thick red-orange oil, which was purified by preparative HPLC to give ( 3S , 4S )-8-[7-(2,3-dichlorophenyl)pyrazolo [1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (5.54 mg, 18.9% yield). ¹ H NMR (500 MHz, Methanol –d4 ) δ 7.94 (d, J=2.4 Hz, 1H), 7.74–7.69 (m, 1H), 7.47–7.44 (m , 2H), 7.38 (s, 1H), 7.04 (d, J=2.5 Hz, 1H), 4.46–4.29 (m, 3H), 4.04 (d, J= 9.2 Hz, 1H), 3.93 (d, J=9.1 Hz, 1H), 3.48 (d, J=4.1 Hz, 1H), 3.46–3.32 (m, 2H), 2.05–1.92 (m, 3H), 1.79 (d, J=13.1 Hz, 1H), 1.34 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₁ H ₂₄ Cl ₂ N ₅ O: 432.1; the found value is 432.3.

Example 27 Synthesis of [4-(4-amino-4-methylpiperidin-1-yl)-7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]methanol.

Stage 1

Ethyl-4-chloro-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (500 mg, 2.08 mmol), tert -butyl- N- (4-methylpiperidine-4- yl)carbamate (533 mg, 2.4 mmol), DMA (10 ml) and N , N -diisopropylethylamine (2 ml, 10.4 mmol). Then the flask was sealed and heated to 120°C. After stirring for 16 hours, the reaction mixture was cooled and diluted with ethyl acetate (40 ml) and water (10 ml). The layers were separated and the organic phase was washed successively with water (10 ml) and saturated aqueous sodium chloride solution (10 ml). The washed organic solution was then dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to an orange oil. This crude material was purified by column chromatography to give ethyl-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-6-methylpyrazolo[1,5-a]pyrazine- 2-carboxylate (836 mg, 96.3% yield) as a pale yellow oil. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₁ H ₃₂ N ₅ O ₄ : 418.2; the found value is 418.1.

Stage 2

Ethyl-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (200 mg, 0.4 mmol) and DMF (3 ml). The resulting pale yellowish brown solution was cooled to 0°C. After cooling, a solution of N -bromosuccinimide (76 mg, 0.43 mmol) in DMF (2.0 ml) was slowly added dropwise to the reaction mixture. The resulting solution was stirred for 1 hour at 0°C. After this time, the reaction mixture was diluted with water (10 ml) and ethyl acetate (10 ml) and the layers were separated. The aqueous phase was extracted with ethyl acetate (10 ml) and the combined organic extracts were washed successively with water (2×5 ml) and saturated aqueous sodium chloride (5 ml). The washed organic solution was then dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to give a rose oil, which was purified by column chromatography to give ethyl-7-bromo-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl) -6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (165.7 mg, 69.6% yield) as a white foam. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₁ H ₃₁ BrCl ₂ N ₅ O ₄ : 496.11; the found value is 496.0.

Stage 3

Ethyl-7-bromo-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-6-methylpyrazolo[1,5-a]pyrazine-2 -carboxylate (100 mg, 0.2 mmol), (2,3-dichlorophenyl)boronic acid (46 mg, 0.24 mmol), tripotassium phosphate (128 mg, 0.6 mmol), 4-(anthracen-9-yl )-3-tert-butyl-2,3-dihydro-1,3-benzoxaphosphol (15 mg, 0.04 mmol) and degassed dioxane (2 ml). Then the resulting suspension was degassed for 10 min. before adding palladium(II) acetate (4.51 mg, 0.02 mmol) and the orange mixture was degassed for an additional 5 min. After this time, the vessel was sealed and heated to 105°C. After 2 hours, the reaction mixture was cooled and filtered through a Celite pad. The filtrate was then concentrated and purified by column chromatography to give ethyl-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-7-(2,3-dichlorophenyl)-6 -methylpyrazolo[1,5-a]pyrazine-2-carboxylate (75.8 mg, 67% yield). LC-MS (ESI): mass/charge [M+H] calc. for C ₂₇ H ₃₄ Cl ₂ N ₅ O ₄ : 562.2; the found value is 562.2.

Stage 4

Ethyl-4-(4-{[( tert -butoxy)carbonyl]amino}-4-methylpiperidin-1-yl)-7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5 –a]pyrazine-2-carboxylate (76 mg, 0.13 mmol) and DCM (1.3 ml) before cooling it to –78°C. After cooling, DIBAL-H (1 M in DCM, 538 µl, 0.53 mmol) was added dropwise. After completion of the addition, the reaction mixture was stirred at –78°C for 30 min. before heating it to 0°C and stirring for an additional 30 min. After this time, the reaction mixture was again cooled to –78°C. At the same time, the reaction solution was poured into a saturated aqueous solution of Rochelle's salt (10 ml) pre-cooled to 0° C. and the reaction mixture was allowed to warm to room temperature and vigorously stirred overnight. The layers were then separated and the aqueous phase was extracted with DCM. The combined organic extracts were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under reduced pressure. The crude residue was then purified by column chromatography to give tert -butyl- N- {1-[7-(2,3-dichlorophenyl)-2-(hydroxymethyl)-6-methylpyrazolo[1,5-a]pyrazine-4- yl]-4-methylpiperidin-4-yl}carbamate as a clear, colorless glassy substance, which was used in the next reaction without further purification.

Stage 5

Tert -butyl- N- {1-[7-(2,3-dichlorophenyl)-2-(hydroxymethyl)-6-methylpyrazolo[1,5-a]pyrazin-4-yl]-4 -methylpiperidin-4-yl}carbamate (46 mg, 0.09 mmol), DCM (2 ml) and TFA (0.5 ml). The resulting pale yellow solution was stirred for 1 h. After this time, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to give [4-(4-amino-4-methylpiperidin-1-yl)-7 -(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]methanol (20.6 mg, 56% yield) as a fluffy white solid. [4-(4-Amino-4-methylpiperidin-1-yl)-7-(2,3-dichlorophenyl)-6-methylpyrazolo[1,5-a]pyrazin-2-yl]methanol was isolated as its formate salt . ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.50 (s, 1H), 7.70 (dd, J=8.1, 1.5 Hz, 1H), 7.46 (t, 1H), 7.35 (dd, J=7.6, 1.5Hz, 1H), 6.90 (s, 1H), 4.67 (s, 2H), 4.37-4.27 (m, 2H) , 3.63–3.51 (m, 2H), 2.12 ( s , 3H), 2.05–1.90 (m, 4H), 1.54 (s, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₀ H ₂₄ Cl 2 N ₅ O: 420.13; the found value is 420.1.

Example 28 Synthesis of {4-[( 3S,4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-7-(2,3-dichlorophenyl)-6 -methylpyrazolo[1,5-a]pyrazin-2-yl}methanol.

{4–[(3 S ,4 S )–4–amino–3–methyl–2–oxa–8–azaspiro[4.5]decan–8–yl]–7–(2,3–dichlorophenyl)–6–methylpyrazolo [1,5-a]pyrazin-2-yl}methanol was synthesized by a method similar to the method in example 27, except that tert-butyl-(4-methylpiperidin-4-yl)carbamate was replaced with ( 3S,4S )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.53 (s, 1H), 7.70 (dd, J=8.1, 1.6 Hz, 1H), 7.48–7.43 (m , 1H), 7.35 (dd, J=7.7, 1.5 Hz, 1H), 6.88 (s, 1H), 4.66 (s, 2H), 4.37–4.25 ( m, 3H), 3.97 (d, J=9.0 Hz, 1H), 3.85 (d, J=9.0 Hz, 1H), 3.49–3.34 (m, 2H), 3.27 (d, J=4.5 Hz, 1H), 2.11 (s, 3H), 2.02–1.90 (m, 2H), 1.90–1.82 (m, 1H) , 1.79–1.72 (m, 1H), 1.29 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₃ H ₂₈ Cl ₂ N ₅ O ₂ : 476.2; the found value is 476.4.

Example 29 Synthesis of {7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-4-[( 3S,4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5 ]decan-8-yl]-6-methylpyrazolo[1,5-a]pyrazin-2-yl}methanol.

Stage 1

Ethyl-7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-4-[(3 S ,4 S )-4-{[( tert -butoxy) carbonyl]amino}-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (200 mg, 0.36 mmol) , 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (86 mg, 0.4 mmol), Xantphos (42 mg, 0.07 mmol), degassed dioxane (3.6 ml) and N , N -diisopropylethylamine (187 µl, 1.08 mmol). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes and then tris(dibenzylideneacetone)dipalladium (33.1 mg, 0.0362 mmol) was added to the vessel in one portion. The mixture was then degassed for an additional 5 minutes before being sealed. The mixture was then heated to 120° C. using microwave radiation and stirred for 1.5 hours. At the end of this time, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to an orange oil. This oil was purified by column chromatography to give ethyl-7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-4-[( 3S , 4S )-4-{[( tert -butoxy) carbonyl]amino}-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (197 mg, 86% yield) in orange foam. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₉ H ₃₉ ClN ₇ O ₅ S: 632.2; the found value is 632.5.

Stage 2

Ethyl-7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-4-[( 3S , 4S )-4-{[( tert -butoxy)carbonyl]amino} was loaded into a 20 ml vessel -3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-methylpyrazolo[1,5-a]pyrazine-2-carboxylate (197 mg, 0.31 mmol) and DCM (3 ml). The resulting orange solution was then cooled to –78°C. After cooling, DIBAL-H (1 M in DCM, 1.2 mL, 1.2 mmol) was added dropwise to the solution, and the resulting mixture was stirred at –78°C for 30 min. After this time, the reaction mixture was warmed to 0° C. and stirred for an additional 30 minutes. Then the reaction mixture was again cooled to –78°C. Then the reaction mixture was poured into a saturated aqueous solution of Rochelle's salt (10 ml), pre-cooled to 0°C, and the biphasic mixture was vigorously stirred overnight while ensuring that the mixture warmed to room temperature. After this time, the biphasic mixture was transferred to a separating funnel and the layers were separated. The aqueous phase was then extracted with DCM and the combined organic extracts were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated under reduced pressure. Then, the crude residue thus obtained was purified by column chromatography to give tert -butyl- N -[( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]- 2–(hydroxymethyl)–6–methylpyrazolo[1,5–a]pyrazin–4–yl}–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–yl]carbamate (93 mg, yield 51 %) as a yellowish-brown solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₇ H ₃₇ ClN ₇ O ₄ S: 590.2; the found value is 590.6.

Stage 3

tert -Butyl- N -[(3S,4S)-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-2-(hydroxymethyl)- 6-methylpyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (93 mg, 0.158 mmol), DCM (2 ml ) and TFA (0.5 ml). The resulting yellow solution was allowed to stir for 1 h before concentrating the reaction mixture under reduced pressure to give a thick golden oil which was purified by preparative HPLC to give {7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]- 4–[(3S,4S)–4–amino–3–methyl–2–oxa–8–azaspiro[4.5]decan–8–yl]–6–methylpyrazolo[1,5–a]pyrazin–2–yl} methanol (40.2 mg, 52% yield) as its formate salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.11 (s, 1H), 7.47 (d, J=5.6 Hz, 1H), 6.99 (s, 1H), 5.65 ( d, J=5.6 Hz, 1H), 4.70 (s, 2H), 4.58 (ddt, J=13.5, 5.4, 2.6 Hz, 1H), 4.55–4 .48 (m, 1H), 4.33 (qd, J=6.5, 4.1 Hz, 1H), 4.04 (d, J=9.2 Hz, 1H), 3.93 (d, J=9.2, 0.8 Hz, 1H), 3.48–3.42 (m, 2H), 3.37 (ddd, J=14.0, 11.3, 2.9 Hz, 1H) , 2.51 (s, 3H), 1.99–1.89 (m, J=4.2 Hz, 3H), 1.82–1.74 (m, 1H), 1.33 (d, J =6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₂ H ₂₉ ClN ₇ O ₂ S: 490.2; the found value is 490.4.

Example 30 Synthesis of ( 3S,4S )–8–{7–[(2–amino–3–chloropyridin–4–yl)sulfanyl]–6–methylpyrazolo[1,5–a]pyrazin–4–yl}–3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

tert -butyl- N -[( 3S,4S )-8-{7-bromo-6-methylpyrazolo[1,5-a]pyrazin-4-yl}-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (200 mg, 0.4163 mmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (99.2 mg, 0.49 mmol), Xantphos (48 mg, 0.08 mmol), degassed dioxane (4.16 ml) and N , N -diisopropylethylamine (215 µl, 1.24 mmol). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes. and then tris(dibenzylideneacetone)dipalladium (38.1 mg, 0.04163 mmol) was added to the vessel in one portion. The mixture was then degassed for an additional 5 minutes before being sealed. The mixture was then heated to 120° C. using microwave radiation and stirred for 1.5 hours. At the end of this time, the reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to an orange oil. Purification by column chromatography provided tert -butyl- N -[( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-methylpyrazolo[1,5- a]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (233 mg, 100% yield) as an orange oil. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₆ H ₃₄ ClN ₇ O ₃ S: 560.2; the found value is 560.3.

Stage 2

tert -butyl- N -[( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-methylpyrazolo[1, 5-a]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (233 mg, 0.41 mmol), DCM (2 ml) and TFA ( 1 ml). The resulting red-orange solution was allowed to stir for 1 h before concentrating the reaction mixture under reduced pressure to give a thick red oil, which was purified by preparative HPLC to give ( 3S,4S )-8-{7-[(2-amino-3 -chloropyridin-4-yl)sulfanyl]-6-methylpyrazolo[1,5-a]pyrazin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (54 mg, yield 26%) as formate salt. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.21 (s, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.46 (d, J=5.5 Hz, 1H), 7.03 (d, J=2.5 Hz, 1H), 5.61 (d, J=5.6 Hz, 1H), 4.62–4.56 (m, 1H), 4, 56–4.49 (m, 1H), 4.32 (qd, J=6.5, 4.2 Hz, 1H), 4.04 (d, J=9.2 Hz, 1H), 3.93 (d, J=9.3, 0.9 Hz, 1H), 3.50–3.42 (m, 2H), 3.38 (ddd, J=14.0, 11.3, 2.9 Hz , 1H), 2.53 (s, 3H), 1.99–1.91 (m, J=4.2 Hz, 4H), 1.81–1.75 (m, 1H), 1.33 ( d, J=6.6 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₁ H ₂₇ ClN ₇ OS: 460.2; the found value is 460.4.

Example 31 Synthesis of ( 3S,4S )-8-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-[1,2,4]triazolo[1,5-a]pyrazine-8 –yl}–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–amine.

Stage 1

tert -Butyl- N -[( 3S,4S )-8-{5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate (50 mg, 106 µmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (31.5 mg, 159 µmol), [5-(diphenylphosphanyl )-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane (known as XantPhos) (12.2 mg, 21.2 µmol), tris(dibenzylideneacetone) dipalladium (10 mg, 10.6 µmol) and coated with Teflon, a magnetic stirrer was added sequentially to a 2.5 ml microwave treatment vessel. The vial was closed and then purged with nitrogen gas for 3 minutes. Dioxane (1.1 ml) was then added to this vessel, which was purged with nitrogen gas for 30 minutes, followed by the addition of N , N -diisopropylethylamine (36.7 μl, 212 μmol). This heterogeneous mixture was then heated in a microwave oven to 120° C. for 1.5 h. The reaction mixture was filtered through a celite pad, washed with EtOAc. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography. LCMS (ESI): mass/charge: [Μ+H] calc. for C ₂₄ H ₃₂ ClN ₈ O ₃ S: 547.2; the found value is 547.2.

Stage 2

To a solution of tert -butyl-N-[( 3S,4S )-8-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-[1,2,4]triazolo[1,5- a]pyrazin-8-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (58 mg, 106 µmol) in DCM (3 ml) was added with TFA (706 µl). The reaction mixture was stirred at 25°C for 1 h. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to give ( 3S,4S )–8–{5–[(2–amino–3–chloropyridine–4– yl)sulfanyl]-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (20 mg, 38.6%) as formic acid salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.38 (s, 1H), 7.99 (s, 1H), 7.52 (d, J=5.5 Hz, 1H), 5.79 ( d, J=5.5 Hz, 1H), 5.39–5.20 (m, 2H), 4.35 (qd, J=6.5, 4.2 Hz, 1H), 4.06 (d , J=9.2 Hz, 1H), 3.95 (d, J=9.2 Hz, 1H), 3.70–3.51 (m, 2H), 3.46 (d, J=4, 2 Hz, 1H), 2.00–1.89 (m, 3H), 1.81 (dt, J=14.1, 3.6 Hz, 2H), 1.35 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₉ H ₂₄ ClN ₈ OS: 447.1; the found value is 447.4.

Example 32 Synthesis of ( 3S,4S )-8-[5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

tert -Butyl-N-[( 3S,4S )-8-{5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (100 mg, 213 µmol), (2,3-dichlorophenyl)boronic acid (60.8 mg, 319 µmol), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (34.7 mg, 42.6 µmol) and K ₂ CO ₃ (117 mg, 852 µmol). The mixture was sparged with N ₂ for 10 minutes before being added to ACN (2.1 ml). The reaction mixture was stirred at 100° C. for 1 hour. The resulting mixture was filtered through a Celite pad and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by column chromatography to give the desired product. LCMS (ESI): mass/charge [M +H] calc. for C ₂₅ H ₃₁ Cl ₂ N ₆ O ₃ : 533.2; the found value is 533.5.

Stage 2

To a solution of tert -butyl-N-[( 3S,4S )-8-[5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl]- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (56 mg, 104 µmol) in DCM (1 ml) was added with TFA (260 µl). The reaction mixture was stirred at 25°C for 1.5 h. The resulting solution was concentrated under reduced pressure and the residue was purified by preparative HPLC to give ( 3S,4S )–8–[5–(2,3–dichlorophenyl)–[1 ,2,4]triazolo[1,5-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (18.5 mg, 38.5 µmol, 37%) as a salt of formic acid. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.36 (s, 1H), 7.74 (dd, J=7.7, 2.0 Hz, 1H), 7.65 (s, 1H), 7.54–7.44 (m, 2H), 5.15 (ddt, J=28.2, 13.7, 3.2 Hz, 2H), 4.33 (qd, J=6.5, 4 .4 Hz, 1H), 4.04 (d, J=9.1 Hz, 1H), 3.92 (d, J=9.1 Hz, 1H), 3.62 (ddd, J=14.1 , 9.9, 4.3 Hz, 1H), 3.55 (ddd, J=13.8, 11.0, 2.9 Hz, 1H), 3.38 (d, J=4.4 Hz, 1H), 2.00–1.89 (m, 3H), 1.83–1.75 (m, 1H), 1.33 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₀ H ₂₃ Cl ₂ N ₆ O: 433.1; the found value is 433.2.

Example 33 Synthesis of ( 3S , 4S )–8–{7–[(2–amino–3–chloropyridin–4–yl)sulfanyl]–[1,2,5]thiadiazolo[3,4–c]pyridine -4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a solution of 4-chloro-[1,2,5]thiadiazolo[3,4-c]pyridine (230 mg, 1.34 mmol) and N-[(3S,4S)-8-chloro-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-yl]chloranamine (454 mg, 1.87 mmol) in DMA (7 ml) DIPEA (1 ml, 6.70 mmol) was added at 25°C. The mixture was covered and heated to 110° C. for 2 hours. After this time, the reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The crude product was used in the next step without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₄ H ₂₀ N ₅ OS: 306.14; the found value is 306.1.

Stage 2

To a solution of (3 S ,4 S )–3–methyl–8–{[1,2,5]thiadiazolo[3,4–c]pyridin–7–yl}–2–oxa–8–azaspiro[4.5]decane -4-amine (409 mg, 1.34 mmol) in ACN (3.94 ml) was added N-bromosuccinimide (261 mg, 1.47 mmol) and the reaction mixture was stirred at room temperature for 1 h, concentrated under reduced pressure. The residue was diluted with EtOAc (6 ml), washed with saturated NaHCO ₃ (2×3 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was used in the next step without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₄ H ₁₉ BrN ₅ OS: 384.04; the found value is 384.2.

Stage 3

( 3S,4S )–8–{7–bromo–[1,2,5]thiadiazolo[3,4–c]pyridin–4–yl}–3–methyl–2–oxa–8 -azaspiro[4.5]decan-4-amine (80 mg, 208 µmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (82.6 mg, 416 µmol), Pd ₂ dba ₃ (19.0 mg, 20.8 µmol), Xantphos (24 mg, 41.6 µmol), and DIEPA (53 mg, 416 µmol), and degassed dioxane (1 ml). The mixture was purged with N ₂ and evacuated three times. The reaction mixture was stirred under microwave conditions at 130° C. for 2 hours. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give ( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-[1,2,5]thiadiazolo[3,4-c ]pyridin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (78.0 mg, 168 µmol, 80.8%) as a yellow solid. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.41 (s, 1H), 8.22 (s, 1H), 7.42 (d, J=5.6 Hz, 1H), 5.78 ( d, J=5.6 Hz, 1H), 4.33 (dd, J=6.6, 4.2 Hz, 1H), 4.06 (d, J=9.2 Hz, 1H), 3, 94 (dd, J=9.2, 0.8 Hz, 1H), δ 3.73–3.56 (m, 2H), 3.45 (d, J=4.2 Hz, 1H), 2, 01–1.91 (m, 3H), 1.85–1.78 (m, 1H), 1.33 (d, J=6.5 Hz, 3H). LC-MS (ESI): mass/charge [M+H] calc. for C ₁₉ H ₂₃ ClN ₇ OS ₂ : 464.10; the found value is 464.3.

Example 34 Synthesis of 4–{[4–(4–amino–4–methylpiperidin–1–yl)–[1,2,5]oxadiazolo[3,4–c]pyridin–7–yl]sulfanyl}–3– chloropyridine-2-amine.

Stage 1

To a solution of 5-bromo-2-chloro-3-nitropyridine-4-amine (0.50 g, 1.98 mmol) in DMA (9.90 ml) was added tert -butyl- N- (4-methylpiperidine-4- yl)carbamate (0.63 g, 2.96 mmol) and N , N -diisopropylethylamine (1.7 ml, 9.89 mmol) at room temperature. The reaction mixture was heated to 100° C. for 1 hour, concentrated under reduced pressure, and the resulting residue was used in the next step without purification. LC-MS (ESI): mass/charge [M+H] ⁺ calc. for C ₁₆ H ₂₅ BrN ₅ O ₄ : 430.1; the found value is 430.1.

Stage 2

tert -Butyl- N- [1-(4-amino-5-bromo-3-nitropyridin-2-yl)-4-methylpiperidin-4-yl]carbamate (650 mg, 1.51 µmol) was in benzene (7 .55 ml, 0.2 M). (Acetyloxy)(phenyl)-λ³-iodanyl acetate (0.53 g, 1.66 mmol) was added. The resulting mixture was stirred at 85° C. for 4 hours. The mixture was concentrated under reduced pressure and diluted with DCM, washed with NaHCO ₃ until pH 8 was reached and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was subjected to the next step. LC-MS (ESI): mass/charge [M+H] ⁺ calc. for C ₁₆ H ₂₃ BrN ₅ O ₄ : 428.1; the found value is 427.9.

Stage 3

A solution of triphenylphosphine (0.12 g, 0.46 mmol) in PhMe (0.5 ml) was added to a solution of tert -butyl-7-bromo-4-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidine- 1-yl)-[1,2,5]oxadiazolo[3,4-c]pyridine-3-oxide (0.15 g, 0.35 mmol) in PhMe (1.24 ml). The reaction mixture was stirred for 4 hours at 110 ^° C., filtered through a pad of silica gel, and the filtrate was concentrated under reduced pressure. The resulting product was subjected to the next step without further purification. LC-MS (ESI): mass/charge: [M+H] calc. for C ₁₆ H ₂₃ BrN ₅ O ₃ : 412.1; the found value is 412.0.

Stage 4

Loaded into a microwave treatment vesseltert-butyl-N–(1–{7–bromo–[1,2,5]oxadiazolo[3,4–c]pyridin–4–yl}–4–methylpiperidin–4–yl)carbamate (0.075 g, 0.181 mmol), 3– chloro-4-(potassiumsulfanyl)pyridine-2-amine (0.072 g, 0.362 mmol), tris(dibenzylideneacetone) dipalladium (0.016 g, 0.0181 mmol), Xantphos (0.02 g, 0.0362 mmol) andN,N-diisopropylethylamine (0.0944 ml, 0.543 mmol). The mixture was degassed before being added to degassed dioxane (1.80 ml 0.1M). The reaction vessel was evacuated and purged with N₂ three times before stirring under microwave conditions at 130° C. for 2 hours. After 1.5 hours, LCMS showed complete conversion. The reaction mixture was filtered through a Celite pad and then concentrated under reduced pressure. The residue was dissolved in DCM (3 ml) and added TFA (1 ml) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 hour at this temperature. The reaction mixture was concentrated under reduced pressure and loaded onto a column. Purification by reverse phase column chromatography provided 4-{[4-(4-amino-4-methylpiperidin-1-yl)-[1,2,5]oxadiazolo[3,4-c]pyridin-7-yl ]sulfanyl}-3-chloropyridine-2-amine (52.7 mg, 61% yield).^oneH NMR (500 MHz, DMSO–d6) δ 8.11 (s, 1H), 7.59 (d, J=5.4 Hz, 1H), 6.37 (s, 2H), 5.97 (d, J=5.4 Hz, 1H ), 3.33 (s, 4H), 1.89 (s, 4H), 1.42 (s, 3H). LC-MS (ESI): mass/charge [M+H]+ calc. for C₁₆H₁₉ClN₇OS: 392.1; the found value is 392.3.

Example 35 Synthesis of ( 3S,4S )-8-{5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-6-methyl-[1,2,4]triazolo[4,3-a ]pyrazin-8-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a mixture of 5-methylpyrazine-2-amine (10 g, 92 mmol) in DCM (300 ml) was added NBS (16 g, 91.63 mmol) in one portion at 0°C under N ₂ atmosphere. The mixture was stirred at 30° C. for 1 hour. The resulting mixture was poured into saturated aq. Na ₂ SO ₃ (100 ml) and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 3-bromo-5-methylpyrazine-2-amine (12 g, 69% yield) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ –d) δ ppm 7.82 (s, 1 H) 4.79–5.03 (m, 2 H) 2.39 (s, 3 H).

Stage 2

To a mixture of 3-bromo-5-methylpyrazine-2-amine (31 g, 164.87 mmol) in MeOH (150 ml) was added NaOMe (14 g, 263.79 mmol) in one portion at 30°C under N ₂ atmosphere. The mixture was stirred at 100° C. for 6 hours. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (100 ml). The mixture was extracted with EtOAc and the combined organic layers were washed with brine (20 ml), dried with Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 3-methoxy-5-methylpyrazine-2-amine (21 g, 92% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ –d) δ ppm 7.39 (s, 1 H) 4.59 (br s, 2 H) 3.97 (s, 3 H) 2.29 (s, 3 H )

Stage 3

To a solution of 3-methoxy-5-methylpyrazin-2-amine (21 g, 150.91 mmol) in CH ₂ I ₂ (40 ml) was added isopentyl nitrite (35.36 g, 301.82 mmol, 40.64 ml) and I ₂ (45.96 g, 181.09 mmol, 36.48 ml) at 0°C. The mixture was heated to 30° C. and stirred at 30° C. for 3 hours. The reaction mixture was poured into 300 ml of saturated aq. Na ₂ SO ₃ and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 2-iodo-3-methoxy-5-methylpyrazine (21 g, 55.65% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ –d) δ ppm 7.81 (s, 1 H) 3.99 (s, 3 H) 2.40 (s, 3 H)

Stage 4

To a mixture of ₂ -iodine-3-methoxy-5-methylpyrazine (5 g, 20 mmol) in EtOH (50 ml) at 70°C under N 9 ml). The mixture was stirred at 70°C for 48 hours. The mixture was concentrated under reduced pressure and purified by column chromatography to give (3-methoxy-5-methylpyrazin-2-yl)hydrazine (2.16 g, 14.01 mmol, yield 70%) as a light yellow solid. LCMS (ESI): mass/charge [M +H] calc. for C ₆ H ₁₁ N ₄ O: 155.1; the found value is 155.2.

Stage 5

A mixture of (3-methoxy-5-methylpyrazin-2-yl)hydrazine (2 g, 12.97 mmol) and triethylorthoformate (17.8 g, 120.24 mmol, 20 ml) was heated at 140°C under N ₂ in for 1 h. The reaction solution was filtered and the filter cake was dried under reduced pressure to give 8-methoxy-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine (1.5 g, yield 70, 4%) as a light yellow solid. LCMS (ESI): mass/charge [M +H] calc. for C ₇ H ₉ N ₄ O: 165.1; the found value is 165.1.

Stage 6

HCl ( ₁ N , 6 ml). The mixture was stirred at 105°C for 1 h. The resulting mixture was concentrated under reduced pressure to give 6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-ol (740 mg) as a brown solid. LCMS (ESI): mass/charge [M +H] calc. for C ₆ H ₇ N ₄ O: 151.1; the found value is 151.1.

Stage 7

A mixture of 6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-ol (900 mg, 5.99 mmol) in POCl ₃ (29.70 g, 193.70 mmol, 18, 00 ml) was heated at 120°C for 1 h Excess POCl ₃ was removed under reduced pressure. The mixture was then quenched with saturated aq. NaHCO ₃ (100 ml) with the removal of all remaining POCl ₃ . The resulting mixture was poured into water (300 ml) and stirred for 2 minutes. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 8-chloro-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine (900 mg, 84.61% yield) as a black-brown solid .

Stage 8

To a mixture of 8-chloro-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine (400 mg, 2.37 mmol) and ( 3S , 4S )-3-methyl-2-oxa 8-azaspiro[4.5]decan-4-amine (403.49 mg, 2.37 mmol) in i-PrOH (20 ml) was added DIEA (1.53 g, 11.85 mmol, 2.06 ml). The mixture was heated to 80°C and stirred for 1 h. After 1 h, Boc ₂ O (517.25 mg, 2.37 mmol, 544.47 μl) was added and the reaction mixture was stirred at 20°C for 2 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0:1) to give tert -butyl-N-[( 3S,4S )-3-methyl-8 -(6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (800 mg, 1 .95 mmol, 82.1% yield as a white solid. ¹ H NMR (400 MHz, CDCl3–d) δ ppm 8.61 (s, 1 H) 7.23 (s, 1 H) 4.63 (br d, J =10.80 Hz, 2 H) 4, 17–4.24 (m, 1 H) 4.01 (br dd, J =10.69, 4.30 Hz, 1 H) 3.68–3.77 (m, 2 H) 2.26 (s , 2 H) 1.82–1.96 (m, 2 H) 1.53–1.59 (m, 4 H) 1.52 (s, 1 H) 1.49 (s, 1 H) 1, 45 (s, 9H) 1.18–1.25 (m, 4H).

Stage 9

To a mixture of tert-butyl-N-[( 3S,4S )-3-methyl-8-(6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-2- oxa-8-azaspiro[4.5]decan-4-yl]carbamate (700 mg, 1.74 mmol) in DMF (7 ml) was added NBS (309 mg, 1.74 mmol). The mixture was stirred at 0°C for 5 min. The resulting mixture was quenched by adding saturated aq. Na ₂ SO ₃ (10 ml) and concentrated under reduced pressure. The remaining residue was purified by column chromatography to give tert -butyl-N-[(3S,4S)-8-(5-bromo-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine- 8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (500 mg, 59.7% yield) as a red solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₀ H ₃₀ BrN ₆ O ₃ : 481.15; the found value is 481.3.

Stage 10

To a solution of tert -butyl-N-[(3S,4S)-8-(5-bromo-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-3- methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (200 mg, 415 μmol) in dioxane (3 ml) was added 2-amino-3-chloropyridine-4-thiol (166 mg, 1. 04 mmol), K ₃ PO ₄ (176 mg, 830 µmol), 1,10-phenanthroline (14.9 mg, 83.1 µmol) and CuI (7.91 mg, 41.5 µmol). The reaction mixture was stirred at 130° C. for 4 hours. The reaction was monitored by LCMS. The reaction mixture was filtered and concentrated, the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=5:1, 0:1) to give tert -butyl-N-[( 3S , 4S )-8-[5-[ (2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-3-methyl-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate (80 mg, 32.7% yield) as a white solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₅ H ₃₄ ClN ₈ O ₃ S: 561.2; the found value is 561.3.

Stage 11 .

A mixture of tert -butyl-N-[(3 S ,4 S )-8-[5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-[1,2,4]triazolo [4,3-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (20 mg, 35.6 µmol) in HCl/MeOH (1 ml) was stirred at 25°C for 2 hours. The reaction was monitored by LCMS and HPLC. The reaction mixture was concentrated to dryness and adjusted to pH=7 with NaOH in MeOH at –78°C, then filtered and concentrated. The residue was purified by preparative HPLC to give ( 3S , 4S )-8-[5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-[1,2,4]triazolo [4,3-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (10 mg, 60% yield) as a white solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₀ H ₂₆ ClN ₈ OS: 461.16; the found value is 461.2. ¹ H NMR (400 MHz, Methanol –d4 ) δ ppm 8.99 (s, 1 H) 7.60 (d, J=5.50 Hz, 1 H) 5.88 (d, J=5.50 Hz , 1 H) 5.26–4.96 (m, 1 H) 4.57 (s, 1 H) 4.34–4.21 (m, 1 H) 4.05–3.71 (m, 4 H) 3.07 (d, J=5.01 Hz, 1 H) 2.48 (s, 3 H) 2.03-1.67 (m, 4 H) 1.25 (d, J=6, 48 Hz, 3H).

Example 36 Synthesis of 4-[[8-(4-amino-4-methyl-1-piperidyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-5-yl]sulfanyl ]–3–chloropyridine–2–amine.

Stage 1

Tert -butyl-N-[1-(5-bromo-6-methyl-[1.2, 4]triazolo[4,3-a]pyrazin-8-yl)-4-methyl-4-piperidyl]carbamate (130 mg, 305 µmol), K ₃ PO ₄ (129 mg, 611 µmol), 1.10– phenanthroline (11.0 mg, 61.1 µmol) and CuI (6 mg, 30.5 µmol). The reaction mixture was stirred at 130° C. for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure. The remaining residue was purified by column chromatography to give tert -butyl-N-[1-[5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-[1,2,4]triazolo [4,3-a]pyrazin-8-yl]-4-methyl-4-piperidyl]carbamate (60 mg, 37% yield) as a white solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₂ H ₃₀ ClN ₈ O ₂ S: 505.18; the found value is 505.3.

Stage 2

A mixture of tert -butyl-N-[1-[5-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine -8-yl]-4-methyl-4-piperidyl]carbamate (30 mg, 59 μmol) in HCl/MeOH (2 ml) was stirred at 25°C for 2 h. The reaction mixture was concentrated under reduced pressure. The remaining residue was dissolved in MeOH (2 ml) and the pH of the solution was adjusted to pH 7 by adding NaOH in MeOH at –78°C. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 4-[[8-(4-amino-4-methyl-1-piperidyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine -5-yl]sulfanyl]-3-chloropyridine-2-amine (10 mg, 40% yield) as a white solid; the found value is 405.3. ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.96 (s, 1 H) 7.57 (d, J=5.50 Hz, 1 H) 5.85 (d, J=5.50 Hz , 1 H) 4.47 (s, 2 H) 3.34 (s, 2 H) 2.45 (s, 3 H) 1.79–1.59 (m, 4 H) 1.25 (s, 2H); LCMS (ESI): mass/charge [M +H] calc. for C ₁₇ H ₂₂ ClN ₈ S: 405.1; the found value is 405.1.

Example 37 Synthesis of 1-[5-(2,3-dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-4-methylpiperidin-4-amine .

Stage 1

A mixture of 6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-ol (120 mg, 799.27 µmol) and POCl ₃ (3.30 g, 21.52 mmol, 2, 00 ml) was heated to 120°C and stirred for 1 h Excess POCl ₃ was removed under reduced pressure. The mixture was then quenched with saturated aq. NaHCO ₃ (100 ml) with the removal of all remaining POCl ₃ . The resulting mixture was poured into water (300 ml) and stirred for 2 minutes. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 8-chloro-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine (120 mg, 80.2% yield) as a black-brown solid . ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 9.05 (s, 1 H) 7.32 (s, 1 H) 2.09 (s, 3 H).

Stage 2

To a mixture of 8-chloro-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine (120 mg, 711.81 µmol) and tert -butyl-N-(4-methyl-4-piperidyl )carbamate (198 mg, 925.36 µmol) in i -PrOH (2 ml) was added DIEA (460 mg, 3.56 mmol, 619.93 µl). The mixture was heated to 80°C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified using column chromatography to obtain tert -butyl-N-[4-methyl-1-(6-methyl-[1, 2,4]triazolo[4,3-a]pyrazin-8-yl)-4-piperidyl]carbamate (160 mg, 55% yield) as a red solid. ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.99 (s, 1 H) 7.55 (d, J = 0.98 Hz, 1 H) 3.68 (br t, J = 11.13 Hz, 2 H) 2.26 (d, J =0.98 Hz, 3 H) 2.21 (br d, J =13.08 Hz, 2 H) 2.02 (s, 1 H) 1.58 –1.67 (m, 2 H) 1.43–1.51 (m, 9 H) 1.37 (s, 3 H).

Stage 3

To a mixture of tert -butyl-N-[4-methyl-1-(6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-4-piperidyl]carbamate (160 mg , 461.86 µmol) in DMF (2 ml) NBS (82.20 mg, 461.86 µmol) was added in one portion at 0°C. The mixture was stirred at 0°C for 10 min. The mixture was quenched by adding sat. aq. Na ₂ SO ₃ (10 ml) and concentrated under reduced pressure. The remaining residue was purified by column chromatography to give tert -butyl-N-[1-(5-bromo-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-4 -methyl-4-piperidyl]carbamate (180 mg, 91.6% yield) as a red solid. ¹ H NMR (400 MHz, CDCl3–d) δ ppm 8.82 (s, 1 H) 4.83 (br s, 2 H) 4.46 (br s, 1 H) 3.82 (br s, 2 H) 2.41 (s, 3 H) 2.16 (br d, J = 15.21 Hz, 2 H) 2.06 (s, 1 H) 1.70 (ddd, J = 14.22, 10 .47, 3.97Hz, 2H) 1.46(s, 9H) 1.42(s, 3H)

Stage 4

To a mixture of tert -butyl-N-[1-(5-bromo-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-4-methyl-4-piperidyl] carbamate (180 mg, 423.21 µmol) and (2,3-dichlorophenyl)boronic acid (121 mg, 634.81 µmol) in DME (2 ml) and H ₂ O (1 ml) was added Pd(PPh ₃ ) ₄ (63.58 mg, 55.02 µmol) and Na ₂ CO ₃ (112 mg, 1.06 mmol). The reaction mixture was heated to 80°C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by column chromatography to give tert -butyl-N-[1-[5-(2,3-dichlorophenyl)- 6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-4-methyl-4-piperidyl]carbamate (100 mg, 47.6% yield) as light yellow solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₃ H ₂₉ Cl ₂ N ₆ O ₂ : 491.2; the found value is 491.2.

Stage 5

A mixture of tert -butyl-N-[1-[5-(2,3-dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-4-methyl -4-piperidyl]carbamate (100 mg, 203.5 µmol) in HCl/MeOH (6 ml) was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to give 1-[5-(2.3 -dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-4-methylpiperidin-4-amine (66 mg, 160.24 µmol, 78% yield) as a light yellow solid. ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.86 (s, 1 H) 7.84 (dd, J = 7.89, 1.75 Hz, 1 H) 7.55–7.60 ( m, 1 H) 7.50–7.55 (m, 1 H) 5.10 (br s, 2 H) 3.99 (br s, 2 H) 2.17 (s, 3 H) 2.05 (br t, J =5.26 Hz, 5 H) 1.59 (s, 3 H). LCMS (ESI): mass/charge [M +H] calc. for C ₁₈ H ₂₁ Cl ₂ N ₆ : 391.11; the found value is 391.1.

Example 38 Synthesis of ( 3S,4S )-8-[5-(2,3-dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a mixture of tert -butyl-N-[( 3S,4S )-8-(5-bromo-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)-3- methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (150 mg, 311.60 mmol) and (2,3-dichlorophenyl)boronic acid (89.19 mg, 467.40 mmol) in DME (2 ml) was added with Pd(PPh ₃ ) ₄ (46.81 mg, 40.51 µmol) and Na ₂ CO ₃ (82.57 mg, 779.00 µmol). The mixture was heated and stirred at 80°C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give tert -butyl-N-[( 3S,4S )-8-[5-(2,3 -dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl] carbamate (90 mg, 51.70% yield) as a white solid. LCMS (ESI): mass/charge [M +H] calc. for C ₂₆ H ₃₂ Cl ₂ N ₆ O ₃ : 547.19; the found value is 547.3.

Stage 2

A solution of tert -butyl-N-[( 3S,4S )-8-[5-(2,3-dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine-8- yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (40 mg, 73.06 µmol) in HCl/MeOH (3 ml) was stirred at 25°C for 1, 5 h. The reaction mixture was concentrated under reduced pressure to give ( 3S,4S )-8-[5-(2,3-dichlorophenyl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrazine -8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (29 mg, HCl salt in 77.94% yield) as a white solid. ¹ H NMR (400 MHz, Methanol –d4 ) δ ppm 8.92 (s, 1 H) 7.86 (dd, J = 7.64, 1.65 Hz, 1 H) 7.57–7.61 ( m, 1 H) 7.56 (d, J =3.30 Hz, 1 H) 5.36 (br s, 1 H) 5.17 (br s, 1 H) 4.36 (dd, J = 6 .42, 4.10 Hz, 1 H) 4.08 (d, J = 9.29 Hz, 1 H) 3.96 (d, J = 9.17 Hz, 1 H) 3.80 (br s, 2 H) 3.55 (d, J =4.16 Hz, 1 H) 2.20 (s, 3 H) 2.07–2.17 (m, 3 H) 1.91 (br d, J= 12.47 Hz, 1 H) 1.32-1.39 (m, 3 H). LMS (ESI): mass/charge [M +H] calc. for C ₂₁ H ₂₅ Cl ₂ N ₆ O: 447.1; the found value is 447.1.

Example 39 Synthesis of 1-[7-(2,3-dichlorophenyl)-6-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl]-4-methylpiperidin-4-amine.

Stage 1

To a solution of 4-chloro-6-methyl-1H-pyrazolo[4,3-c]pyridine (0.5 g, 2.98 mmol) in DCM (3 ml) was added SEM-Cl (1.24 g, 7. 46 mmol, 1.32 ml) and DIEA (3.86 g, 29.8 mmol, 5.20 ml) at 0°C and the mixture was stirred at 0°C for 4 hours. The reaction mixture was poured into ice water and stirred within 5 min. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-[(4-chloro-6-methylpyrazolo[4,3-c]pyridin-1-yl)methoxy]ethyltrimethylsilane (365 mg, 41.1% yield). ¹ H NMR (400 MHz, CDCl3–d) δ ppm 8.22 (s, 1 H), 7.24 (s, 1 H), 5.69 (s, 2 H) 3.66–3.60 ( m, 2 H), 2.57 (s, 3 H), 0.98–0.91 (m, 2 H), 0.01–0.05 (m, 9 H); LCMS (ESI): mass/charge [M +H] calc. for C ₁₃ H ₂₁ ClN ₃ OSi: 298.1; found value 298.3;

Stage 2

DIEA (911 mg, 7.05 mmol, 1.23 ml) and tert -butyl-N-(4-methyl-4-piperidyl)carbamate (755 mg, 3.53 mmol) and the mixture was stirred at 90°C for 24 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert -butyl-N-[4-methyl-1-[6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-4 -piperidyl]carbamate (384 mg, 68.7% yield). ¹ H NMR (400 MHz, Methanol –d4 ) δ ppm 8.52 (s, 1 H) 6.51 (s, 1 H) 5.54–5.49 (m, 2 H) 4.01–3, 96 (m, 1 H) 3.53 ( t, J=8.11 Hz, 1 H) 3.48–3.30 (m, 3 H) 2.25 (s, 2 H) 2.09 ( d , J=12.72 Hz, 2 H) 1.91 (s, 1 H) 1.59–1.49 (m, 2 H) 1.34 (s, 9 H) 1.26 (s, 3 H ) 0.85–0.72 (m, 2 H) –0.12 (s, 9 H); LCMS (ESI): mass/charge [M +H] calc. for: C ₂₄ H ₄₂ N ₅ O ₃ Si 476.3; the found value is 476.3.

Stage 3

To a solution of tert -butyl-N-[4-methyl-1-[6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-4-piperidyl]carbamate (250 mg , 525 µmol) in DMF (3 ml) was added NBS (112 mg, 630 µmol) at 0°C and the mixture was stirred at 0°C for 0.5 h, and then poured into sat. aq. Na ₂ SO ₃ (9 ml) and filtered. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give tert -butyl-N-[1-[7-bromo-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]- 4-methyl-4-piperidyl]carbamate (160 mg, 54.9% yield). ¹ H NMR (400 MHz, CDCl3–d) δ ppm 8.19 (s, 1 H) 5.68 (s, 2 H) 4.43 ( s, 1 H) 4.04 ( d, J=12, 96 Hz, 2 H) 3.71-3.63 (m, 2 H) 3.45-3.55 (m, 2 H) 2.51 (s, 3 H) 2.19-2.07 (m , 2 H) 1.78–1.66 (m, 2 H) 1.44 (s, 9 H) 1.41 (s, 3 H) 0.99–0.80 (m, 2 H) 0, 09–0.01 (m, 9H); LCMS (ESI): mass/charge [M +H] calc. for C ₂₄ H ₄₁ BrN ₅ O ₃ Si: 556.2; the found value is 556.0.

Stage 4

To a solution of tert -butyl-N-[1-[7-bromo-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-4-methyl-4-piperidyl] carbamate (50 mg, 90.2 µmol) in H ₂ O (0.2 ml) and DME (1 ml) was added (2,3-dichlorophenyl)boronic acid (18.9 mg, 99.2 µmol), Na ₂ CO ₃ (19.1 mg, 180 µmol) and Pd(PPh ₃ ) ₄ (10.4 mg, 9.02 µmol). The mixture was stirred under N ₂ at 80°C for 6 hours, cooled to room temperature and filtered. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give tert -butyl-N-[1-[7-(2,3-dichlorophenyl)-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4, 3-c]pyridin-4-yl]-4-methyl-4-piperidyl]carbamate (20.0 mg, 32.2 µmol, 35.7% yield). LCMS (ESI): mass/charge [M +H] calc. for C ₃₀ H ₄₃ Cl ₂ N ₅ O ₃ Si: 620.3; the found value is 620.3.

Stage 5

A mixture of tert -butyl-N-[1-[7-(2,3-dichlorophenyl)-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-4-methyl -4-piperidyl]carbamate (40 mg, 64.5 µmol) in HCl/MeOH (2 ml each) was stirred at 25°C for 0.5 h. The mixture was concentrated under reduced pressure and the crude residue was purified by preparative HPLC to give 1-[7-(2,3-dichlorophenyl)-6-methyl-1H-pyrazolo[4,3-c]pyridin-4-yl]-4-methylpiperidin-4-amine (2.7 mg, yield 10.70%). ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.37 ( s, 1 H) 8.10 (s, 1 H) 7.53 ( J = 8.07, 1.34 Hz, 1 H) 7 .30 (t, J=7.89 Hz, 1 H) 7.16 ( J=7.58, 1.47 Hz, 1 H) 4.31 (t, J=14.12 Hz, 2 H) 3 .58–3.33 (m, 2 H) 2.06 (s, 3 H) 1.92–1.75 (m, 4 H) 1.42 (s, 3 H); LCMS (ESI): mass/charge [M +H] calc. for C ₁₉ H ₂₂ Cl ₂ N ₅ : 390.1; the found value is 390.3.

Example 40 Synthesis of ( 3S,4S )-8-[7-(2,3-dichlorophenyl)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl]-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-amine.

Стадия 1.

Stage 1

To a solution of 4-chloro-[1,2,5]thiadiazolo[3,4-c]pyridine (230 mg, 1.34 mmol) and ( 3S,4S )-3-methyl-2-oxa-8-azaspiro[ 4.5]decane-4-amine (454 mg, 1.87 mmol) in DMA (6.7 ml) DIPEA (1.19 ml, 6.70 mmol) was added at 25°C. The mixture was covered and heated to 110°C for 2 hours, cooled to 25°C and concentrated under reduced pressure. The crude product was used in the next step without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₄ H ₂₀ N ₅ OS: 306.14; the found value is 306.1.

Stage 2

To a solution of ( 3S,4S )–3–methyl–8–{[1,2,5]thiadiazolo[3,4–c]pyridin–7–yl}–2–oxa–8–azaspiro[4.5]decan–4 -amine (409 mg, 1.34 mmol) in acetonitrile (3.94 ml) was added N-bromosuccinimide (261 mg, 1.47 mmol) and the reaction mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, the crude the residue was diluted with EtOAc (6 ml), washed with saturated NaHCO ₃ (2×3 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material thus obtained was used in the next step without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₁₄ H ₁₉ BrN ₅ OS: 384.04; the found value is 384.2.

Stage 3

In a 20 ml vial containing ( 3S , 4S )-8-{7-bromo-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl}-3-methyl-2-oxa -8-azaspiro[4.5]decan-4-amine (166 mg, 431 µmol), (2,3-dichlorophenyl)boronic acid (123 mg, 646 µmol), bis(cyclopenta-1,3-diene-1- yldiphenylphosphane) palladium (2+) - methylene chloride - iron dichloride (70.3 mg, 86.2 mmol) and potassium carbonate (237 mg, 1.72 mmol). The vessel was purged with N ₂ , ACN (4.31 ml) was added and the vessel was sealed and heated to 100°C. After 1 hour, the reaction mixture was cooled to 25°C, filtered through Celite, eluted with EtOAc and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give ( 3S,4S )-8-[7-(2,3-dichlorophenyl)-[1,2,5]thiadiazolo[3,4-c]pyridin-4-yl]- 3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (12.1 mg, 5.7% yield) as a white solid. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.55 (s, 1H), 7.97 (s, 1H), 7.62 (dd, J=7.6, 2.0 Hz, 1H), 7.51-7.33 (m, 2H), 5.19-5.08 (m, 2H), 4.38-4.25 (m, 1H), 4.03 (d, J=8.9 Hz, 1H), 3.90 (d, J=9.0 Hz, 1H), 3.77 (ddd, J=13.9, 10.4, 3.4 Hz, 1H), 3.69 (ddd , J=13.9, 10.5, 2.9 Hz, 1H), 3.29 (d, J=4.6 Hz, 1H), 2.68 (s, 3H), 2.06–1, 86 (m, 3H), 1.80 (d, J=13.8 Hz, 1H), 1.31 (d, J=6.5 Hz, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₂₀ H ₂₂ Cl ₂ N ₅ OS: 450.1; the found value is 450.3.

Example 41 Synthesis of 4-{[4-(4-amino-4-methylpiperidin-1-yl)-3H-[1,2,3]triazolo[4,5-c]pyridin-7-yl]sulfanyl}- 3-chloropyridine-2-amines.

Stage 1

In a suspension of 2,5-dibromopyridine-3,4-diamine (2.5 g, 9.36 mmol) in aqueous 2 N. HCl (12.4 ml) at 0°C was added an aqueous solution of sodium nitrite (3.7 ml of water, 965 mg). After completion of the addition, the solution was vigorously stirred for 2 hours while maintaining the reaction temperature at 0°C. At the end of this time, the reaction mixture was filtered and the collected solid was washed with ice water and dried under reduced pressure to give 4,7-dibromo-3H-[1,2,3]triazolo[4,5-c]pyridine (2.38 g , 91% yield) as a light tan solid. LC-MS (ESI): mass/charge [M+H] calc. for C ₅ H ₂ Br ₂ N ₄ : 276.9; the found value is 277.0.

Stage 2

4,7-dibromo-3H-[1,2,3]triazolo[4,5-c]pyridine (753 mg, 2.70 mmol), tert -butyl- N- (4-methylpiperidine-4 -yl) carbamate (867 mg, 4.05 mmol), copper iodide (51.4 mg, 0.27 mmol), tripotassium phosphate (573 mg, 2.70 mmol), N , N -bis (2.4.6 -trimethoxyphenyl)oxalamide (BTMPO, 113 mg, 0.27 mmol) and degassed DMSO (5 ml). The vessel was then sealed and the headspace above the reaction mixture was evacuated and filled with N ₂ . This procedure was repeated twice and then the vessel was placed in a reaction block preheated to 120°C. After stirring for 16 hours, the reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The filtrate was further diluted with ethyl acetate and washed successively with water (4×50 ml) and saturated aqueous sodium chloride solution (1×25 ml). The washed solution was dried over magnesium sulfate. The dried solution was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert -butyl-(1-(7-bromo-3H-[1,2,3]triazolo[4,5-c]pyridin-4-yl)-4-methylpiperidin-4-yl )carbamate (213 mg, 19% yield) as a yellow solid. LC-MS (ESI): mass/charge: [M+H] calc. for C ₁₆ H ₂₃ BrN ₆ O ₂ : 411.1; the found value is 410.9.

Stage 3

A 5 ml microwave treatment vessel was charged sequentially with tert -butyl- N- (1-{7-bromopyrazolo[1,5-a]pyrazin-4-yl}-4-methylpiperidin-4-yl)carbamate (37.3 mg , 0.09 mmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (21.6 mg, 0.10 mmol), Xantphos (10.5 mg, 0.018 mmol), degassed dioxane (909 µl) and N , N -diisopropylethylamine (47.4 µl, 0.27 mmol). The resulting mixture was degassed by bubbling nitrogen gas through the solution for 10 minutes. and then tris(dibenzylideneacetone)dipalladium (8.32 mg, 0.01 mmol) was added to the vessel in one portion. The mixture was then degassed for an additional 5 minutes before being sealed, and the mixture was heated to 120° C. by microwave irradiation and stirred for 1.5 hours. At the end of this time, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure until an orange oil is obtained. This oil was purified by column chromatography to give tert -butyl- N- (1-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3H-[1,2,3]triazolo[4 ,5-c]pyridin-4-yl}-4-methylpiperidin-4-yl)carbamate as an orange oil with impurities, which was used in the next step without further purification. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₁ H ₂₇ ClN ₈ O ₂ S: 491.2; the found value is 491.4.

Stage 4

A 20 ml vessel was sequentially loaded with tert -butyl- N- (1-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3H-[1,2,3]triazolo[4,5- c]pyridin-4-yl}-4-methylpiperidin-4-yl)carbamate (33 mg, 0.07 mmol), DCM (2 ml) and TFA (0.5 ml) at room temperature. The resulting yellow solution was allowed to stir for 1 hour. After this time, the reaction mixture was concentrated under reduced pressure to give an orange residue. This crude residue was purified by preparative HPLC to give 4-{[4-(4-amino-4-methylpiperidin-1-yl)-3H-[1,2,3]triazolo[4,5-c]pyridine-7 -yl]sulfanyl}-3-chloropyridine-2-amine (7.7 mg, 29% yield) as a fluffy white solid. 4–{[4–(4–Amino–4–methylpiperidin–1–yl)–3H–[1,2,3]triazolo[4,5–c]pyridin–7–yl]sulfanyl}–3–chloropyridine– 2-amine was isolated as its formate salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.34 (s, 1H), 8.08 (s, 1H), 7.50 (d, J=5.5 Hz, 1H), 5.70 ( d, J=5.6 Hz, 1H), 5.13 (d, J=14.1 Hz, 2H), 3.88 (ddd, J=14.0, 9.5, 4.0 Hz, 2H ), 2.01–1.88 (m, 4H), 1.57 (s, 3H); LC-MS (ESI): mass/charge [M+H] calc. for C ₁₆ H ₂₀ ClN ₈ S: 391.1; the found value is 391.2.

Example 42 Synthesis of 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl]-4-methylpiperidin-4-amine.

Stage 1

To a solution of 5-bromo-8-chloro-6-methylimidazo[1,2-a]pyrazine (800 mg, 3.24 mmol) in DMA (16.2 ml) was added tert -butyl-N-(4-methylpiperidine- 4-yl)carbamate (762 mg, 3.56 mmol) and DIPEA (16.2 mmol). The reaction mixture was stirred in a closed vessel at 100° C. for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to remove as much DMA as possible. The residue was purified by column chromatography to give tert -butyl-N-(1-{5-bromo-6-methylimidazo[1,2-a]pyrazin-8-yl}-4-methylpiperidin-4-yl)carbamate (1 .10 g, 80%). LCMS (ESI): mass/charge [M +H] calc. for C ₁₈ H ₂₇ BrN ₅ O ₂ : 424.13; the found value is 424.4.

Stage 2

Tert -butyl-N-(1-{5-bromo-6-methylimidazo[1,2-a]pyrazin-8-yl}-4-methylpiperidin-4-yl)carbamate (100 mg, 235 µmol) was added to the vessel , (2,3-dichlorophenyl)boronic acid (53.8 mg, 282 µmol), Antphos (17.4 mg, 47.0 µmol), K ₃ PO ₄ (149 mg, 705 µmol) and Pd(OAc) ₂ (5.27 mg, 23.5 µmol). The mixture was evacuated in a centralized vacuum system for 10 min. before adding to degassed dioxane (2.34 ml). The resulting mixture was filled with N ₂ and degassed three times before stirring at 105° C. for 2 hours. The resulting reaction mixture was filtered through a celite pad, washing with DCM and MeOH. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give tert -butyl-N-{1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl] -4-methylpiperidin-4-yl}carbamate (95.0 mg, 82.6%). LCMS (ESI): mass/charge [M+H] calc. for C ₂₄ H ₃₀ Cl ₂ N ₅ O ₂ : 490.2; the found value is 490.4.

Stage 3

To a solution of tert -butyl-N-{1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl]-4-methylpiperidin-4-yl}carbamate (115 mg, 234 µmol) in methanol (1.9 ml) was added 4 M hydrogen chloride in dioxane (482 µl, 1.93 mmol). The reaction mixture was stirred in a closed vessel for 4 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (Biotage) to give the desired product, which is 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,2-a]pyrazin-8-yl]-4- methylpiperidine-4-amine (10.0 mg, 25.6 µmol, 13.2%), as formic acid salt. ¹ H NMR (500 MHz, methanol -d4 ) δ 8.56 (s, 1H), 7.79 (dd, J=8.1, 1.5 Hz, 1H), 7.54 (t, J=7 .9 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 7.44 (dd, J=7.7, 1.6 Hz, 1H), 7.04 (d, J =1.3 Hz, 1H), 3.92-3.77 (m, 2H), 2.11 (s, 3H), 1.90 (dt, J=11.7, 4.8 Hz, 6H) , 1.49 (s, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₁₉ H ₂₂ Cl ₂ N ₅ : 390.1; the found value is 390.1.

Example 43 Synthesis of ( 3S,4S )-8-[7-(2,3-dichlorophenyl)-3H-imidazo[4,5-c]pyridin-4-yl]-3-methyl-2-oxa-8- azaspiro[4.5]decane-4-amine.

Stage 1

7-bromo-4-chloro-1H-imidazo[4,5-c]pyridine (130 mg, 559 µmol), 2-methyl-N-[( 3S,4S )-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-yl]propan-2-sulfinamide (153 mg, 559 µmol), CuI (106 mg, 559 µmol), K ₃ PO ₄ (118 mg, 559 µmol) and BTMPO ( 235 mg, 559 µmol). The contents of the vessel were evacuated and filled with N ₂ three times before being added to dimethyl sulfoxide (1 ml). The reaction mixture was stirred in a closed vessel at 120° C. for 24 hours. The resulting reaction mixture was diluted with EtOAc and H ₂ O. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine. The resulting organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired product, which is N–[( 3S,4S )–8–{7–bromo–1H–imidazo[4,5–c]pyridin–4–yl}–3–methyl– 2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropan-2-sulfinamide (60 mg, 22.9%). LCMS (ESI): mass/charge [M +H] calc. for C ₁₉ H ₂₉ BrN ₅ O ₂ S: 470.1; the found value is 470.2.

Stage 2

N–[( 3S,4S )–8–{7–bromo–1H–imidazo[4,5–c]pyridin–4–yl}–3–methyl–2–oxa–8–azaspiro[4.5 ]decan-4-yl]-2-methylpropan-2-sulfinamide (50 mg, 106 µmol), (2,3-dichlorophenyl)boronic acid (30.3 mg, 159 µmol), Pd(dppf)Cl ₂ DCM (17.3 mg, 21.2 µmol) and K ₂ CO ₃ (43.9 mg, 318 µmol). The mixture was evacuated and filled with N ₂ three times before being added to acetonitrile (1.05 ml). The reaction mixture was stirred at 100° C. for 2 hours. The resulting reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give N–[( 3S,4S )–8–[7–(2,3–dichlorophenyl)–1H–imidazo[4,5–c]pyridine–4– yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropan-2-sulfinamide (25.0 mg, 44.0%). LCMS (ESI): mass/charge [M +H] calc. for C ₂₅ H ₃₂ Cl ₂ N ₅ O ₂ S: 536.1; the found value is 536.3.

Stage 3

To a solution of N–(( 3S,4S )–8–(7–(2,3–dichlorophenyl)–1H–imidazo[4,5–c]pyridin–4–yl)–3–methyl–2–oxa–8 -azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (25 mg, 46.5 µmol) in methanol (1 ml) was added 4 M hydrogen chloride solution (34.7 µl, 139 µmol) in dioxane. The reaction mixture was stirred in a closed vessel at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give ( 3S,4S )-8-[7-(2,3-dichlorophenyl)-3H-imidazo[4,5-c]pyridin-4-yl]-3-methyl- 2-oxa-8-azaspiro[4.5]decan-4-amine (5.00 mg, 24.8%). ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.57 (s, 1H), 8.05 (s, 1H), 7.75 (s, 1H), 7.64 (dd, J=7.6 , 2.0 Hz, 1H), 7.50–7.32 (m, 2H), 4.30 (dd, J=6.5, 4.8 Hz, 1H), 3.96 (d, J= 8.7 Hz, 1H), 3.83 (d, J=8.8 Hz, 1H), 3.54 (d, J=41.6 Hz, 2H), 3.16 (d, J=4, 9 Hz, 2H), 1.96 (dd, J=16.0, 10.6 Hz, 2H), 1.82 (s, 1H), 1.76 (s, 1H), 1.28 (d, J=6.5Hz, 4H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₁ H ₂₄ Cl ₂ N ₅ O: 432.1; the found value is 432.2.

Example 44 Synthesis of ( 3S,4S )-8-{5-[(2,3-dichlorophenyl)sulfanyl]imidazo[1,5-a]pyrazin-8-yl}-3-methyl-2-oxa-8- azaspiro[4.5]decane-4-amine.

Stage 1

To a solution of 5-bromo-8-chloroimidazo[1,5-a]pyrazine (30 mg, 129 µmol) in DMA (1 ml) was added 2-methyl-N-(( 3S,4S )-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-yl)propan-2-sulfinamide (38.6 mg, 141 µmol) and DIPEA (112 µl, 645 µmol). The mixture was covered and stirred at 80°C for 2 h. The resulting mixture was diluted with EtOAc and H ₂ O. The organic layer was separated and then washed 3 more times with H ₂ O. The combined organic layer was separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give N–(( 3S,4S )–8–(5–bromimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5 ]decan-4-yl)-2-methylpropan-2-sulfinamide (30.0 mg, 49.5%). LCMS (ESI): mass/charge [M +H] calc. for C ₁₉ H ₂₉ BrN ₅ O ₂ S: 470.1; the found value is 470.3.

Stage 2

N–(( 3S,4S )–8–(5–bromimidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8–azaspiro[4.5]decane -4-yl)-2-methylpropan-2-sulfinamide (30 mg, 63.7 µmol), 2,3-dichlorobenzenethiol (22.7 mg, 127 µmol), Xantphos (7.34 mg, 12.7 µmol) , Pd ₂ (dba) ₃ (2.84 mg, 6.37 µmol) and DIPEA (16.4 mg, 127 µmol). The contents of the vessel were evacuated for 10 min. before adding to degassed dioxane (637 µl). The mixture was purged and evacuated with gaseous N ₂ three times. The reaction mixture was subjected to microwave radiation for 2 hours at 110°C. The resulting reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give N–(( 3S,4S )–8–(5–((2,3–dichlorophenyl)thio)imidazo[1,5–a]pyrazine–8– yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (23.0 mg, 63.5%). LCMS (ESI): mass/charge [M +H] calc. for C ₂₅ H ₃₂ Cl ₂ N ₅ O ₂ S ₂ : 568.1; the found value is 568.3.

Stage 3

To a solution of N–(( 3S,4S )–8–(5–((2,3–dichlorophenyl)thio)imidazo[1,5–a]pyrazin–8–yl)–3–methyl–2–oxa–8 -azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (23 mg, 40.4 µmol) in methanol (2 ml) was added 4 M HCl in dioxane (1 ml, 4.00 mmol). The reaction mixture was stirred in a closed vessel at room temperature for 1 h. The resulting reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC to give ( 3S,4S )-8-{5-[(2,3-dichlorophenyl )sulfanyl]imidazo[1,5-a]pyrazin-8-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (7.00 mg, 37.4%). ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.53 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H), 7, 40 (dd, J=8.0, 1.4Hz, 1H), 7.11 (t, J=8.1Hz, 1H), 6.69 (dd, J=8.1, 1.4Hz , 1H), 4.53–4.41 (m, 2H), 4.37–4.25 (m, 1H), 3.99 (d, J=9.0 Hz, 1H), 3.86 ( d, J=8.9 Hz, 1H), 3.70–3.50 (m, 2H), 2.04–1.84 (m, 4H), 1.78 (d, J=13.2 Hz , 1H), 1.30 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₁ H ₂₄ Cl ₂ N ₅ OS: 464.1; the found value is 464.2.

Example 45 Synthesis of ( 3S,4S )-8-[5-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazin-8-yl]-3-methyl-2-oxa-8-azaspiro[4.5 ]decane-4-amine.

Stage 1

( 3S,4S )-3-methyl-2-oxa-8-azaspiro[4.5 ]decane-4-amine (135 mg, 567 µmol) and DIPEA (447 µl, 2.57 mmol). The mixture was covered and stirred at 80° C. for 2 hours. The resulting reaction mixture was diluted with EtOAc and NH ₄ OH. The organic layer was separated and then washed three more times with H ₂ O. The resulting organic layer was separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 4-amines (113 mg, 60.1%). LCMS (ESI): mass/charge [Μ+H] calc. for C ₁₅ H ₂₁ BrN ₅ O: 366.09; the found value is 366.2.

Stage 2

( 3S,4S )-8-(5-bromimidazo[1,5-a]pyrazin-8-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (113 mg, 308 µmol), (2,3-dichlorophenyl)boronic acid (88.1 mg, 462 µmol), tetrakis (21.2 mg, 18.4 µmol) and potassium carbonate (127 mg, 924 µmol) were added to the microwave treatment vessel . The vessel was purged with N ₂ before adding the mixture to degassed EtOH (3.94 ml). The mixture was purged and evacuated with N ₂ three times. The reaction mixture was heated under microwave radiation for 2 hours at 110°C. The resulting reaction mixture was filtered through a celite pad, concentrated under reduced pressure, and the residue was purified by reverse phase to give ( 3S,4S )-8-[5-(2,3-dichlorophenyl)imidazo[1,5-a]pyrazine- 8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (35.0 mg, 26.3%) as formic acid salt. ¹ H NMR (500 MHz, Methanol –d4 ) δ 8.40 (s, 2H), 7.91 (s, 1H), 7.83 (s, 1H), 7.81–7.74 (m, 1H ), 7.56–7.49 (m, 2H), 7.12 (s, 1H), 4.58–4.39 (m, 2H), 4.33 (qd, J=6.5, 4 .1 Hz, 1H), 4.04 (d, J=9.2 Hz, 1H), 3.99–3.87 (m, 1H), 3.49–3.45 (m, 2H), 1 .95 (s, 4H), 1.79 (d, J=13.5 Hz, 1H), 1.34 (d, J=6.5 Hz, 3H). LCMS (ESI): mass/charge [M +H] calc. for C ₂₁ H ₂₄ Cl ₂ N ₅ O: 432.1; the found value is 432.2.

Example 46 Synthesis of ( 3S,4S )–8–{7–[(2–amino–3–chloropyridin–4–yl)sulfanyl]furo[3,2–c]pyridin–4–yl}–3–methyl– 2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a solution of 7-bromo-4-chlorofuro[3,2-c]pyridine (250 mg, 1.07 mmol) and (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4 -amine (311 mg, 1.28 mmol, HCl salt) in dimethylacetamide (5.35 ml) was added N , N -diisopropylethylamine (931 μl, 5.35 mmol) at room temperature. Then the solution was heated at 140°C for 18 h. The resulting solution was concentrated under reduced pressure and purified by flash column chromatography to obtain ( 3S,4S )-8-{7-bromofuro[3,2-c]pyridine-4- yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (390 mg, 100%) as a viscous yellow oil. LC-MS (ESI): mass/charge [M+H]+ calc. for C ₁₆ H ₂₁ BrN ₃ O ₂ : 366.1; the found value is 366.2.

Stage 2

( 3S,4S )–8–{7–bromofuro[3,2–c]pyridin–4–yl}–3–methyl–2–oxa–8–azaspiro[4.5]decan– 4-amine (100 mg, 273 µmol), 3-chloro-4-(potassiumsulfanyl)pyridine-2-amine (81 mg, 409 µmol), XantPhos (32 mg, 54.6 µmol) and tris(dibenzylideneacetone) dipalladium ( 25 mg, 27.3 µmol). The vessel was then closed and purged with N ₂ followed by the addition of degassed dioxane (3 ml) and DIPEA (95 μl, 546 μmol). The mixture was heated to 120°C for 2 hours under the influence of microwave radiation. The resulting mixture was filtered through a Celite pad, washed with 20% MeOH/DCM and concentrated under reduced pressure. Purification by silica gel chromatography followed by preparative HPLC purification provided ( 3S,4S )-8-{7-[(2-amino-3-chloropyridin-4-yl)sulfanyl]furo[3,2-c] pyridin-4-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (7.9 mg, 7% yield) as formic acid salt. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.49 (s, 1H), 8.08 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.49 ( d, J=5.6 Hz, 1H), 7.13 (d, J=2.3 Hz, 1H), 5.71 (d, J=5.6 Hz, 1H), 4.39 (dt, J=14.2, 4.5 Hz, 1H), 4.36–4.26 (m, 2H), 4.00 (d, J=9.1 Hz, 1H), 3.88 (d, J =9.0 Hz, 1H), 3.44 (ddd, J=14.0, 10.0, 4.1 Hz, 1H), 3.41–3.33 (m, 2H), 2.02– 1.87 (m, 3H), 1.75 (d, J=13.3 Hz, 1H), 1.31 (d, J=6.5 Hz, 3H). LC-MS (ESI): mass/charge [M+H]+ calc. for C ₂₁ H ₂₅ ClN ₅ O ₂ S: 446.1; the found value is 446.3.

Example 47 Synthesis of ( 3S,4S )–8–[5–(2H–indazol–6–yl)–6–methylimidazo[1,5–a]pyrazin–8–yl]–3–methyl–2–oxa– 8-azaspiro[4.5]decan-4-amine.

( 3S,4S )–8–{5–bromo–6–methylimidazo[1,5–a]pyrazin–8–yl}–3–methyl–2–oxa–8–azaspiro[4.5] was added to a 40 ml scintillation vessel decan-4-amine (0.1 g, 262 µmol), (1H-indazol-6-yl)boronic acid (50.8 mg, 314 µmol), Pd(dppf)Cl ₂ DCM (21.3 mg, 26.2 µmol) and potassium carbonate (143 mg, 1.04 mmol). The vial was closed and then the headspace was purged with nitrogen gas for 3 minutes. ACN (3.61 ml) was then added to the solids mixture, which was sparged with nitrogen gas for 45 minutes. Then the heterogeneous solution was heated to 100°C for 1 h. Dimethylacetamide (0.5 ml), ACN (0.5 ml), Pd(dppf)Cl ₂ DCM (21.3 mg, 26.2 μmol ) and (1H-indazol-6-yl)boronic acid (20 mg, 123 µmol). The solution was then sparged with nitrogen gas for 10 minutes. The reaction mixture was then allowed to stir at 115° C. for an additional 16 hours. The resulting mixture was filtered through a Celite pad, which was washed with 20% MeOH/DCM, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give ( 3S,4S )-8-[5-(1H-indazol-6-yl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-3-methyl-2 -oxa-8-azaspiro[4.5]decan-4-amine (8.0 mg, 7% yield) as formic acid salt. ¹ H NMR (500 MHz, methanol –d4 ) δ 8.55 (s, 2H), 8.17 (s, 1H), 8.00 (dt, J=8.3, 0.9 Hz, 1H), 7.79 (d, J=0.9 Hz, 1H), 7.65 (dd, J=2.7, 1.0 Hz, 2H), 7.19 (dt, J=8.3, 1, 2 Hz, 1H), 4.43-4.21 (m, 3H), 3.95 (d, J=8.7 Hz, 1H), 3.81 (d, J=8.8 Hz, 1H) , 3.54 (dd, J=14.4, 9.3 Hz, 1H), 3.50–3.38 (m, 1H), 3.24–3.09 (m, 1H), 2.13 (d, J=0.8 Hz, 3H), 2.06–1.87 (m, 2H), 1.86–1.79 (m, 1H), 1.78–1.70 (m, 1H ), 1.27 (d, J=6.5 Hz, 3H). LC-MS (ESI): mass/charge [M+H] calc. for C ₂₃ H ₂₈ N ₇ O: 418.2; the found value is 418.4.

Example 48 Synthesis of 4-((7-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-c]pyridin-4-yl)thio)-3-chloropyridine-2-amine .

Stage 1

In a vessel filled with 4-bromo-7-chloro-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.860 mmol), tert -butyl-N-(4-methylpiperidin-4-yl)carbamate (276 mg , 1.29 mmol), copper iodide (16.3 mg, 0.08603 mmol), tripotassium phosphate (182 mg, 0.860 mmol) and N , N -bis(2,4,6-trimethoxyphenyl)oxalamide (BTMPO) (36 .1 mg, 0.08603 mmol), degassed DMSO (860 µl) was added. The vessel was closed, the headspace above the reaction mixture was evacuated and filled with N ₂ and the mixture was allowed to stir at 120° C. overnight. The resulting mixture was diluted with ethyl acetate, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography to give tert -butyl-(1-(4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)-4-methylpiperidin-4-yl)carbamate (240 mg , 68%). LC-MS (ESI): mass/charge [M+H] calc. for C ₁₇ H ₂₄ BrN ₅ O ₂ : 410.1; the found value is 409.9.

Stage 2

To a microwave vessel filled with tert -butyl-(1-(4-bromo-1H-pyrazolo[3,4-c]pyridin-7-yl)-4-methylpiperidin-4-yl)carbamate (47 mg, 0.115 mmol), 2-amino-3-chloropyridine-4-potassium thiolate (34.1 mg, 0.1717 mmol), Pd ₂ (dba) ₃ (6.29 mg, 0.0069 mmol) and Xantphos (6.62 mg, 0.0115 mmol), degassed dioxane (1.14 ml) was added followed by DIPEA (60 μl, 0.343 mmol). The vessel was closed and the headspace above the reaction mixture was evacuated and filled with N ₂ . The vessel was closed, the headspace of the reaction mixture was evacuated and filled with N ₂ and the mixture was allowed to stir at 125°C for 1.5 h. The resulting mixture was then diluted with ethyl acetate, filtered through a celite pad and concentrated under reduced pressure. The crude product was purified by column chromatography to give tert -butyl-(1-(4-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-c]pyridine-7- yl)-4-methylpiperidin-4-yl)carbamate, 19 mg (33%), in the form of a light yellow film. LC-MS (ESI): mass/charge [M+H] calc. for C ₂₂ H ₂₈ ClN ₇ O ₂ S: 490.2; the found value is 490.5.

Stage 3

To a solution of dichloromethane (3 ml) andtert-butyl-(1-(4-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[3,4-c]pyridin-7-yl)-4-methylpiperidin-4-yl )carbamate (19 mg, 0.038 mmol) trifluoroacetic acid (500 μl) was added. The resulting homogeneous solution was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give 4-((7-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo [3,4-c]pyridin-4-yl)thio)-3-chloropyridin-2-amine (10.7 mg, 71%) in the form of formate salt.^oneH NMR (500 MHz, methanol-d4) δ 8.26 (br s, 1H), 7.83 (br s, 1H), 7.48 (d, J=5.6 Hz, 1H), 5.83 (d, J=5.6 Hz , 1H), 5.06 (br s, 1H), 3.77 (m, 2H), 1.96 (m, 4H), 1.58 (s, 3H). LC-MS (ESI): mass/charge [M+H] calc. for C₁₇H₂₁ClN₇S: 390.1; the found value is 390.4.

Example 49 Synthesis of ( 3S , 4S )-8-[6-amino-5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl] -3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a mixture of methyl-4H-1,2,4-triazole-3-carboxylate (15 g, 118.02 mmol) and 2-chloroacetonitrile (13 g, 177.02 mmol, 11.23 ml) in ACN (200 ml) K ₂ CO ₃ (32 g, 236 mmol) was added. The mixture was heated to 80° C. for 24 hours. After cooling to room temperature, the mixture was filtered and the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography to give methyl 2-(cyanomethyl)-1,2,4-triazole-3-carboxylate (5 g, 25.50% yield). LCMS (ESI): mass/charge [M +H] calc. for C ₆ H ₇ N ₄ O ₂ : 167.1; the found value is 167.0. ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 8.30 (s, 1 H) 5.79 (s, 2 H) 3.94 (s, 3 H).

Stage 2

A mixture of methyl-2-(cyanomethyl)-1,2,4-triazole-3-carboxylate (5 g, 30.10 mmol) in NH ₃ /MeOH (100 ml, 30%) was stirred at 25°C for 24 h MTBE (100 mL) was added dropwise to the reaction mixture and the resulting precipitate was isolated by filtration to give 6-amino-[1,2,4]triazolo[1,5-a]pyrazin-8-ol (3.4 g, 22.5 mmol, 74% yield. LCMS (ESI): mass/charge: [M +H] calc. for C ₅ H ₆ N ₅ O: 152.1; the found value is 152.3. ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 11.24 (br s, 1 H) 8.17 (s, 1 H) 6.94 (s, 1 H) 5.35 (s, 2 H) .

Stage 3

TEA (6.03 g, 59 .55 mmol, 8.3 ml), Boc ₂ O (13.00 g, 59.55 mmol, 13.68 ml) and DMAP (242.52 mg, 1.99 mmol). The mixture was stirred at 30° C. for 3 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give tert -butyl-N- tert -butoxycarbonyl-N-(8-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)carbamate ( 700 mg, 10.04% yield. LCMS (ESI): mass/charge [M +H] calc. for C ₁₅ H ₂₂ N ₅ O ₅ : 352.1; found value 352.2; ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 12.51 (br s, 1 H) 8.55 (s, 1 H) 8.34 (s, 1 H) 1.41 (s, 18 H) .

Stage 4

To a mixture of tert -butyl-N- tert -butoxycarbonyl-N-(8-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)carbamate (400 mg, 1.14 mmol) NBS (222.88 mg, 1.25 mmol) was added to DMF (4 ml) at 0° C. under N ₂ atmosphere. The mixture was stirred at 0°C for 5 min. and then quenched with Na ₂ SO ₃ (aq., sat.). A yellow precipitate formed and was separated by filtration to give tert -butyl-N-(5-bromo-8-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-N- tert-butoxycarbonyl-carbamate (430 mg, 83.40% yield). ¹ H NMR (400 MHz, DMSO– d6 ) δ ppm 13.01 (br s, 1 H) 8.64 (s, 1 H) 1.41 (s, 18 H).

Stage 5

To a mixture of tert -butyl-N-(5-bromo-8-hydroxy-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-N-tert-butoxycarbonyl-carbamate (430 mg, 999.41 µmol) in dioxane (17 ml) was added PPh ₃ (521.65 mg, 1.99 mmol) and NCS (272.25 mg, 2.04 mmol). The mixture was stirred at 100°C for 8 hours and then cooled to room temperature. TEA (5 ml) was added over 15 minutes. followed by the addition of MTBE (10 ml). The resulting precipitate was isolated by filtration and purified by column chromatography to give tert -butyl-N-(5-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)carbamate (100 mg, 28.70% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d6 ) δ ppm 8.99-9.04 (m, 1 H) 1.40 (s, 9 H).

Stage 6

To a mixture of tert -butyl-N-(5-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)carbamate (50 mg, 143.44 µmol) and hydrochloride (3 S ,4 S )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (29 mg, 143.4 µmol, HCl) in i -PrOH (3 ml) was added DIEA (92 mg, 717 µmol, 124 µl). The mixture was stirred at 80°C for 2 hours and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give tert -butyl-N-[8-[( 3S , 4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl ]–5–bromo–[1,2,4]triazolo[1,5–a]pyrazin–6–yl]carbamate (20 mg, 28.91% yield). LCMS (ESI): mass/charge [M +H] calc. for C ₁₉ H ₂₉ BrN ₇ O ₃ : 482.1, found value 482.2.

Stage 7

To a solution of tert -butyl-N-[8-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-bromo-[1, 2,4]triazolo[1,5-a]pyrazin-6-yl]carbamate (22 mg, 45.6 µmol) in DME (1 ml) was added (2,3-dichlorophenyl)boronic acid (13.0 mg, 68.4 µmol), Na ₂ CO ₃ (9.67 mg, 91.2 µmol, 3.11 µl) in H ₂ O (0.2 ml) and Pd(PPh ₃ ) ₄ (5.27 mg, 4 .56 µmol). The reaction mixture was stirred at 85° C. for 0.5 h. The reaction mixture was cooled to room temperature and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give tert -butyl-N-[8-[( 3S,4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan- 8-yl]-5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]carbamate (12 mg, 47.9% yield). LCMS (ESI): mass/charge [M +H] calc. for C ₂₅ H ₃₂ Cl ₂ N ₇ O ₃ : 548.2; the found value is 548.2.

Stage 8

To a solution of tert -butyl-N-[8-[( 3S,4S )-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-(2,3- dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl]carbamate (10 mg, 18.2 µmol) in DCM (2 ml) was added with TFA (1 ml). The reaction mixture was stirred at 25° C. for 48 hours. The reaction mixture was then concentrated to dryness and redissolved in MeOH. The solution was adjusted to pH 7 with NaOH/MeOH (0.5N) at –78°C. The mixture was then concentrated and all solids were removed by filtration. The final filtrate was dissolved with MeOH and stirred with the anion exchange resin for 4 hours. The resin was then filtered and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC to give ( 3S , 4S )-8-[6-amino-5-(2,3-dichlorophenyl)-[1,2,4]triazolo[1,5-a]pyrazine- 8-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1 mg, 12.2% yield). ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.66–8.36 (m, 1 H) 8.07 (s, 1 H) 7.68 ( d, J=7.02 Hz, 1 H ) 7.51–7.37 (m, 1 H) 5.23–5.00 (m, 1 H) 4.61 (s, 1 H) 4.35–4.24 (m, 1 H) 4 .04–3.99 (m, 1 H) 3.89 (d, J=9.65 Hz, 1 H) 3.60–3.53 (m, 2 H) 1.93–1.88 (m , 2 H) 1.74 –1.71 (m, 1 H) 1.30 (d, J=6.14 Hz, 3 H); LCMS (ESI): mass/charge [M +H] calc. for: C ₂₀ H ₂₄ Cl ₂ N ₇ O: 448.1; the found value is 448.2.

Example 50 Synthesis of 4-[[4-(4-amino-4-methyl-1-piperidyl)-6-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl]sulfanyl]-3-chloropyridine -2-amines.

Stage 1

Degassed dioxane (4.00 ml) was added to a mixture of tert -butyl-N-[1-[7-bromo-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl] -4-methyl-4-piperidyl] carbamate (60 mg, 108 µmol), 2-amino-3-chloropyridine-4-thiol (34.8 mg, 216 µmol), 1,10-phenanthroline (5.85 mg, 32.5 µmol), K ₃ PO ₄ (45.9 mg, 216 µmol) and CuI (4.12 mg, 21.6 µmol) under N ₂ and the mixture was stirred at 130°C for 12 h. The solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to give tert -butyl-N-[1-[7-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-1-(2 -trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-4-methyl-4-piperidyl]carbamate (15.0 mg, 15.8 µmol, 21.9% yield). LCMS (ESI): mass/charge: [M +H] calc. for C ₂₉ H ₄₅ ClN ₇ O ₃ SSi 634.27; the found value is 634.4.

Stage 2

A solution of tert -butyl-N-[1-[7-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-6-methyl-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridine -4-yl]-4-methyl-4-piperidyl]carbamate (15 mg, 23.7 μmol) in HCl/MeOH (2 ml) was stirred at 25°C for 1 h. The solvent was removed under reduced pressure, the residue was dissolved in MeOH (0.5 ml). The resulting mixture was adjusted to pH ~8 with NaOH/MeOH (0.5 M). The solvent was removed under reduced pressure and the residue was suspended in DCM/MeOH (2 ml). The mixture was filtered and the filtrate was 4-[[4-(4-Amino-4-methyl-1-piperidyl)-6-methyl-1H-pyrazolo[4,3-c]pyridin-7-yl]sulfanyl] -3-chloropyridine-2-amine (3.30 mg, 7.86 µmol, 33.2% yield). ¹ H NMR (400 MHz, methanol –d4 ) δ ppm 8.25 (s, 1 H) 7.49 (d, J=5.26 Hz, 1 H) 5.68 (d, J =5.70 Hz , 1 H) 4.40 ( d, J=13.15 Hz, 2 H) 3.75 ( s, 2 H) 2.51 (s, 3 H) 1.87 ( s, 4 H) 1.46 (s, 3H); LCMS (ESI): mass/charge [M +H] calc. for C ₁₈ H ₂₃ ClN ₇ S 404.13; the found value is 404.3.

Example 51 Synthesis of ( 3S,4S )-8-(7-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[4,3-c]pyridin-4-yl)-3 -methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

Stage 1

To a solution of 4-chloro-1H-pyrazolo[4,3-c]pyridine (2 g, 13.02 mmol) in anhydrous THF (25 ml) was added NaH (625 mg, 15.6 mmol, 60%) at 0° C. After stirring at 25°C for 20 min. SEM-Cl (2.82 g, 16.93 mmol, 3 ml) was added dropwise at 0°C. The reaction mixture was stirred at 25° C. for 2 hours and then quenched with slow addition of H ₂ O. After extraction with EtOAc, the combined organic phases were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (1.7 g, 5.99 mmol, yield 46%). LCMS (ESI): mass/charge [M +H] calc. for C ₁₂ H ₁₉ ClN ₃ OSi: 284.1; the found value is 284.1.

Stage 2

To a solution of 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (400 mg, 1.41 mmol) in i -PrOH (8 ml) was added ( 3S,4S )-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine-bis-hydrochloride (377 mg, 1.55 mmol) and DIEA (1.27 g, 9.87 mmol, 1.72 ml). The reaction mixture was stirred at 85°C for 16 h and then concentrated to give ( 3S,4S )-3-methyl-8-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4, 3-c]pyridin-4-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine (600 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS (ESI): mass/charge [M +H] calc. for C ₂₁ H ₃₆ N ₅ O ₂ Si: 418.3; the found value is 418.3.

Stage 3

To solution (3S,fourS)-3-methyl-8-[1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine (600 mg, 1.44 mmol) in DCM (10 ml) was added TEA (290 mg, 2.87 mmol, 399 μl) and Boc₂O (627 mg, 2.87 mmol, 660 µl). The reaction mixture was stirred at 40°C for 1 hour and then concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to givetert-butyl-((3S,4S)–3–methyl–8–(1–((2–(trimethylsilyl)ethoxy)methyl)–1H–pyrazolo[4,3–c]pyridin–4–yl)–2–oxa–8–azaspiro[4.5] decan-4-yl) carbamate (300 mg, 40% yield).^oneH NMR (400 MHz, CDCl3–d) δ ppm 8.06 (s, 1 H) 8.01 (d, J=5.99 Hz, 1 H) 6.86 (d, J=5.87 Hz, 1 H) 5.69 (s, 2 H) 4.67 (d, J=10.64 Hz, 1 H) 4.20–4.04 (m, 3 H) 3.81–3.74 (m , 3 H) 3.70–3.56 (m, 3 H) 2.22 (s, 1 H) 2.03–1.82 (m, 3 H) 1.77–1.68 (m, 1 H) 1.50 (s, 9 H) 1.26 (d, J=6.36 Hz, 3 H) 0.00 (s, 9 H); LCMS (ESI): mass/charge: [M +H] calc. for C₂₆H₄₄N₅O_fourSi: 518.3; the found value is 518.4.

Stage 4

To a solution of tert -butyl-N-[(3 S ,4 S )-3-methyl-8-[1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-2-oxa- 8-azaspiro[4.5]decan-4-yl]carbamate (300 mg, 579 µmol) in DMF (5 mL) was added NBS (123 mg, 695 µmol) at –20°C. The reaction mixture was stirred at –20°C for 30 min. and then quenched by adding Na ₂ SO ₃ (sat. aq.). The mixture was filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give tert -butyl-N-[( 3S,4S )-8-[7-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl ]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (250 mg, 72% yield). ¹ H NMR (400 MHz, CDCl3–d) δ ppm 8.06 (d, J=1.34 Hz, 1 H) 6.05 (s, 1 H) 4.66 (d, J=10.64 Hz , 1 H) 4.27–4.20 (m, 1 H) 4.09–3.94 (m, 3 H) 3.79–3.71 (m, 3 H) 3.69–3.61 (m, 3 H) 2.01–1.81 (m, 3 H) 1.76–1.67(m, 1 H) 1.50 (s, 9 H) 1.26 (d, J=6 .36 Hz, 3 H) 1.02–0.892 (m, 2 H) –0.02–0.05 (m, 8 H); LCMS (ESI): mass/charge [M +H] calc. for C ₂₆ H ₄₃ BrN ₅ O ₄ Si: 598.2; the found value is 598.4.

Stage 5

To a solution of tert -butyl-N-[( 3S,4S )-8-[7-bromo-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c]pyridin-4-yl]-3-methyl-2- oxa-8-azaspiro[4.5]decan-4-yl]carbamate (250 mg, 419 µmol) in dioxane (3.5 ml) was added 2-amino-3-chloropyridine-4-thiol (134 mg, 838 µmol), K ₃ PO ₄ (177 mg, 838 µmol), 1,10-phenanthroline (15.1 mg, 83.8 µmol) and CuI (7.98 mg, 41.9 µmol). The reaction mixture was stirred at 130° C. for 48 hours under N ₂ atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by preparative TLC to give tert -butyl-N-[( 3S,4S )-8-[7-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-1-(2-trimethylsilylethoxymethyl )pyrazolo[4,3-c]pyridin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (50 mg, 73.9 µmol, 17% yield) . LCMS (ESI): mass/charge [M +H] calc. for C ₃₁ H ₄₇ ClN ₇ O ₄ SSi: 676.3; the found value is 676.1.

Stage 6

A solution of tert -butyl-N-[( 3S,4S )-8-[7-[(2-amino-3-chloro-4-pyridyl)sulfanyl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[4,3-c ]pyridin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (40 mg, 59.1 µmol) in HCl/MeOH (2 ml) was stirred at 25° C for 1 hour and then concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give ( 3S,4S )-8-(7-((2-amino-3-chloropyridin-4-yl)thio)-1H-pyrazolo[4,3-c]pyridine-4 –yl)–3–methyl–2–oxa–8–azaspiro[4.5]decan–4–amine (16 mg, 60% yield). ¹ H NMR (400 MHz, Methanol –d4 ) δ ppm 8.61–8.42 (m, 1 H) 8.33 (s, 1 H) 7.97 (s, 1 H) 7.48 (d, J=5.50 Hz, 1 H) 5.72 (d, J=5.62 Hz, 1 H) 4.61-4.42 (m, 2 H) 4.36-4.25 (m, 1 H) 4.00 (d, J=9.05 Hz, 1 H) 3.88 (d, J=9.05 Hz, 1 H) 3.60-3.37 (m, 2 H) 3.34 (d, J=4.40 Hz, 1 H) 1.97-1.84 (m, 3 H) 1.76 (d, J=13.08 Hz, 1 H) 1.30 (d, J= 6.48 Hz, 3H); LCMS (ESI): mass/charge [M +H] calc. for C ₂₀ H ₂₅ ClN ₇ OS: 446.2; the found value is 446.0.

Example 52 Synthesis of 3-{4-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-methylpyrazolo[1,5-a ]pyrazin-7-yl}-2-chlorobenzonitrile.

3–{4–[(3S,4S)–4–amino–3–methyl–2–oxa–8–azaspiro[4.5]decan–8–yl]–6–methylpyrazolo[1,5–a]pyrazin–7 -yl}-2-chlorobenzonitrile was synthesized by a method similar to the method in example 22, except that (2-chloro-3-cyanophenyl)boronic acid was used instead of (2,3-dichlorophenyl)boronic acid.^oneH NMR (500 MHz, Methanol–d4) δ 7.99 (dd,J=7.8, 1.7 Hz, 1H), 7.82 (d,J=2.5Hz, 1H), 7.76(dd,J=7.8, 1.6 Hz, 1H), 7.67 (t,J=7.7 Hz, 1H), 6.96 (d,J=2.5 Hz, 1H), 4.37–4.20 (m, 1H), 3.94 (d,J=8.7 Hz, 1H), 3.81 (d,J=8.7 Hz, 1H), 3.63–3.42 (m, 2H), 3.12 (d,J=4.8Hz, 1H), 2.14(s, 3H), 1.95(dtd,J=28.8, 9.9, 5.0 Hz, 2H), 1.79 (dd,J=27.2, 13.3 Hz, 2H), 1.27 (d,J=6.5 Hz, 3H). LC-MS (ESI): mass/charge [M+H] calc. for C₂₃H₂₆ClN₆O: 437.2; the found value is 437.4.

Biological Examples - SHP2 Allosteric Inhibition Assay

Without being limited by theory, it is believed that SHP is allosterically activated by the binding of bis-tyrosyl-phosphorylated peptides to its Src-homologous 2 (SH2) domains. The last activation step results in the release of the autoinhibitory surface of SHP2, which in turn makes the protein tyrosine phosphatase (PTP) of SHP2 active and available for substrate recognition and reaction catalysis. SHP2 catalytic activity was monitored using a DiFMUP surrogate substrate in a fast fluorescence assay format.

Phosphatase reactions were performed at room temperature in a 96-well flat-bottom black polystyrene plate with a non-binding surface (Corning, Cat # 3650) using a final reaction volume of 100 µl and the following assay conditions in buffer: 50 mM HEPES, pH 7, 2, 100 mM NaCl, 0.5 mM EDTA, 0.05% P-20, 1 mM DTT.

Monitoring of SHP2 inhibition by the compounds of the present invention (with concentrations ranging from 0.00005-10 μM) was performed using an assay in which 0.2 nM SHP2 was incubated with 0.5 μM activating peptide 1 (sequence: H ₂ N-LN (pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide) or activating peptide ₂ (sequence: H2N-LN(pY)AQLWHA(dPEG8)LTI(pY)ATIRRF-amide). After incubation for 30-60 minutes at 25°C, DiFMUP surrogate substrate (Invitrogen, Cat # D6567) was added to the reaction mixture and activity was determined by kinetic reading using a microplate reader (Envision, Perkin-Elmer, or Spectramax M5, Molecular devices). The excitation and emission wavelengths were 340 nm and 450 nm, respectively. Baseline values were determined from a linear fit of the data, and inhibitor dose-response curves were analyzed using a normalized IC ₅₀ regression curve fit with control-based normalization.

Using the protocol described above, the SHP2 inhibition shown in Table 1 was measured.

Table 1 Inhibition of SHP2 by Test Compounds

Compound IC ₅₀ SHP2, nM Compound 2 (example 2) 190 Compound 3 (example 3) 34 Compound 6 (example 6) 1100 Compound 15 (example 15) 340 Compound 16 (Example 16) 83

In some embodiments, the compounds of the present invention may have an activity of less than 1000 nM. In some embodiments, the compounds of the present invention may have an activity of from about 1 nM to about 10 nM. In some embodiments, the compounds of the present invention may have an activity of less than about 1 nM. In some embodiments, the compounds of the present invention may have an activity of from about 10 nM to about 100 nM. In some embodiments, the compounds of the present invention may have an activity of from about 100 nM to about 10 μM.

Equivalents

While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (104)

1. Compound of formula IV

, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁴ is

; A is a 5-12 membered monocyclic or polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl, provided that heteroaryl is not

or

; R ¹ independently at each occurrence is -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -C ₃ - C ₈ cycloalkyl, -OH, -OR ⁵ , halogen, -NO ₂ , -CN, -NR ⁵ R ⁶ , -SR ⁵ , -S (O) ₂ NR ⁵ R ⁶ , -S (O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , -NR ⁵ S(O)R ⁶ , -C(O)R ⁵ or -CO ₂ R ⁵ , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl or cycloalkyl is optionally substituted with one or more of -OH, halogen , –NO ₂ , oxo, –CN, –R ⁵ , –OR ⁵ , –NR ⁵ R ⁶ , –SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O)NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; Y ¹ is –S–, direct bond, –NH–, –S(O) ₂ –, –S(O) ₂ –NH–, –C(=CH ₂ )–, –CH– or –S(O )–; X ¹ is N; X ² is N; B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F; R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, -NH ₂ , halogen, -C ₃ -C ₈ cycloalkyl or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O; wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocyclyl is optionally substituted with one or more of -OH, halogen, -NO ₂ , oxo, -CN, -R ⁵ , -OR ⁵ , -NR ⁵ R ⁶ , -SR ⁵ , –S(O) ₂ NR ⁵ R ⁶ , –S(O) ₂ R ⁵ , –NR ⁵ S(O) ₂ NR ⁵ R ⁶ , –NR ⁵ S(O) ₂ R ⁶ , –S(O )NR ⁵ R ⁶ , –S(O)R ⁵ , –NR ⁵ S(O)NR ⁵ R ⁶ , –NR ⁵ S(O)R ⁶ , heterocycle, aryl or heteroaryl; and while heterocyclyl is not attached through a nitrogen atom; Y ² is -NR ^a -; wherein the link on the left side of Y ² as shown is a link to the ring, and the link on the right side of the fragment Y ² as shown is a link to R ³ ; R³ can be combined with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, oxo, heteroaryl, heterocyclyl, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl; R ⁵ and R ⁶ are independently in each occurrence -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, - C ₃ -C ₈ cycloalkyl, monocyclic or polycyclic 3-12-membered heterocycle, -OR ⁷ , -SR ⁷ , halogen, -NR ⁷ R ⁸ , -NO ₂ or -CN; R ⁷ and R ⁸ independently in each case are -H, -D, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₄ -C ₈ cycloalkenyl, -C ₂ -C ₆ alkynyl, - C ₃ -C ₈ cycloalkyl or monocyclic or polycyclic 3-12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more of -OH, -SH, -NH ₂ , -NO ₂ or -CN; and n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 2. The compound according to p. 1 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atom to which they are attached are combined to form a 3–12-membered monocyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 3. The compound according to p. 1 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atoms to which they are attached are combined to form a 3–12-membered polycyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 4. The compound according to p. 1 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atoms to which they are attached are combined to form a 5–12-membered spiro heterocycle, with the spiro heterocycle optionally substituted by one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 5. A compound according to claim 2 or 3, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyl. 6. The connection according to any one of paragraphs. 2, 3 or 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -(CH ₂ ) _n NH ₂ where n is 1. 7. Connection according to any one of paragraphs. 2, 3, 5 or 6 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -NH ₂ . 8. The compound of claim 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the spiro heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyls. 9. A compound according to claim 4 or 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the spiro heterocycle is optionally substituted with one or more –(CH ₂ ) _n NH ₂ , where n is 1. 10. Connection according to any one of paragraphs. 4, 8 or 9 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the spiro heterocycle is optionally substituted with one or more -NH ₂ . 11. A compound according to claim 1, wherein the compound of formula IV is a compound of formula IV-Q

, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁴ is

; A is a 5-12 membered monocyclic or polycyclic aryl or heteroaryl, provided that the heteroaryl is not

or

; R ¹ is independently at each occurrence -H, -OR ⁵ , halogen, -C ₁ -C ₆ alkyl, -CN or -NR ⁵ R ⁶ ; Y ¹ is -S- or a direct link; X ¹ is N; X ² is N; B, including the atoms at the points of attachment, is a monocyclic or polycyclic 5-12 membered heterocycle or a monocyclic or polycyclic 5-12 membered heteroaryl, with each heterocycle or heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F; R ² is -H, -OH, -NR ⁵ R ⁶ , -C ₁ -C ₆ alkyl or -NH ₂ ; wherein each alkyl is optionally substituted with one or more of -OH, halo, -OR ⁵ or -NR ⁵ R ⁶ ; Y ² is -NR ^a - where the bond on the left side of Y ² as shown is a ring bond and the bond on the right side of the Y ² moiety as shown is a bond to R ³ ; R³ merged with R^a to form a 3–12 membered monocyclic or polycyclic heterocycle or a 5–12 membered spiroheterocycle, with each heterocycle or spiroheterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F, provided that the heterocycle formed by combining R³ and R^a, is not an optionally substituted piperazinyl; R ⁵ and R ⁶ are independently at each occurrence -H or -C ₁ -C ₆ alkyl; and n is independently at each occurrence 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 12. The compound according to p. 11 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atom to which they are attached are combined to form a 3–12-membered monocyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂. 13. The compound according to p. 11 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atoms to which they are attached are combined to form a 3–12-membered polycyclic heterocycle, with the heterocycle optionally substituted with one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 14. The compound according to p. 11 or its pharmaceutically acceptable salt or stereoisomer, where R³ and R^a together with the atoms to which they are attached are combined to form a 5–12-membered spiro heterocycle, with the spiro heterocycle optionally substituted by one or more of –C_one-C₆alkyl, –OH, –NH₂, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 15. A compound according to claim 12 or 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyl. 16. Connection according to any one of paragraphs. 12, 13 or 15 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -(CH ₂ ) _n NH ₂ where n is 1. 17. Connection according to any one of paragraphs. 12, 13, 15 or 16 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heterocycle is optionally substituted with one or more -NH ₂ . 18. The compound of claim 14, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the spiro heterocycle is optionally substituted with one or more -C ₁ -C ₆ alkyls. 19. A compound according to claim 14 or 18, or a pharmaceutically acceptable salt or stereoisomer thereof, where the spiro heterocycle is optionally substituted with one or more -(CH ₂ ) _n NH ₂ , where n is 1. 20. Connection according to any one of paragraphs. 14, 18 or 19 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the spiro heterocycle is optionally substituted with one or more -NH ₂ . 21. Connection according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is a monocyclic or polycyclic aryl. 22. The compound of claim 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is phenyl. 23. Connection according to any one of paragraphs. 1-20 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is a monocyclic or polycyclic heteroaryl. 24. The compound of claim 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein A is pyridinyl. 25. Connection according to any one of paragraphs. 1-24 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y ¹ is -S-. 26. Connection according to any one of paragraphs. 1-24 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Y ¹ is a direct bond. 27. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H, -OR ⁵ or halogen. 28. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H, -OR ⁵ or -NR ⁵ R ⁶ . 29. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H, halogen, or -NR ⁵ R ⁶ . 30. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H or -OR ⁵ . 31. A compound according to claim 27 or 30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ is -H or -C ₁ -C ₆ alkyl. 32. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H or halogen. 33. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H or -NR ⁵ R ⁶ . 34. Connection according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ¹ is independently at each occurrence -H, methyl, fluorine, chlorine, or -NH ₂ . 35. Connection according to any one of paragraphs. 28, 29 or 33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ and R ⁶ are each independently -H or -C ₁ -C ₆ alkyl. 36. A compound according to claim 35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ and R ⁶ are each independently -H. 37. A compound according to claim 35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ and R ⁶ are independently in each occurrence -C ₁ -C ₆ alkyl. 38. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is -OH. 39. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is -C ₁ -C ₆ alkyl, where the alkyl is optionally substituted with one or more of -OH, halogen, -OR ⁵ or -NR ⁵ R ⁶ . 40. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is methyl. 41. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is -NR ⁵ R ⁶ . 42. The compound of claim 41, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ and R ⁶ are each independently -H. 43. The compound of claim 41, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ⁵ and R ⁶ are independently in each occurrence -C ₁ -C ₆ alkyl. 44. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is -H. 45. Connection according to any one of paragraphs. 1-37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ² is -NH ₂ . 46. Connection according to any one of paragraphs. 1-45 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B, including atoms at the points of attachment, is a monocyclic 5-12 membered heterocycle, with each heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 47. Connection according to any one of paragraphs. 1-45 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B, including atoms at the points of attachment, is a polycyclic 5-12 membered heterocycle, with each heterocycle optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 48. A compound according to claim 46 or 47, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein heterocycle B is substituted with one or more oxo. 49. Connection according to any one of paragraphs. 1-45 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B, including the atoms at the points of attachment, is a monocyclic 5-12 membered heteroaryl, with each heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 50. Connection according to any one of paragraphs. 1-45 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B, including atoms at the points of attachment, is a polycyclic 5-12 membered heteroaryl, with each heteroaryl optionally substituted with one or more of -C_one-C₆alkyl, –OH, –NH₂, oxo, –(CH₂)_nNH₂, –(CH₂)_nOh, –CF₃, –CHF₂ or -CH₂F. 51. A compound according to claim 49 or 50, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -C ₁ -C ₆ alkyls. 52. Connection according to any one of paragraphs. 49-51 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -OH. 53. Connection according to any one of paragraphs. 49-51 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -NH ₂ . 54. Connection according to any one of paragraphs. 49-53 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -(CH ₂ ) _n NH ₂ . 55. Connection according to any one of paragraphs. 49-54 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -(CH ₂ ) _n OH. 56. A compound according to claim 54 or 55, or a pharmaceutically acceptable salt or stereoisomer thereof, where n is 1. 57. Connection according to any one of paragraphs. 49-56 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -CF ₃ . 58. Connection according to any one of paragraphs. 49-57 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -CHF ₂ . 59. Connection according to any one of paragraphs. 49-58 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the heteroaryl B is substituted with one or more -CH ₂ F. 60. A compound selected from the group consisting of: one

, 2

, 3

, four

, 5

, 6

, 7

, eight

, 9

, ten

, eleven

, 12

, 13

, fourteen

, fifteen

, 16

, 17

, eighteen

, 19

, twenty

, 21

, 22

, 23

, 24

, 25

, 26

, 27

, 28

, 29

, thirty

, 31

, 32

, 33

, 34

, 35

, 36

, 37

, 38

, 39

, 40

, 41

, 42

, 43

, 44

, 45

, 46

, 47

, 48

, 49

, fifty

, 51

and 52

, or a pharmaceutically acceptable salt or stereoisomer of any of the above compounds. 61. A compound according to claim 60, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the group consisting of: 2

, 3

, 6

, fifteen

, 16

, 22

, 25

, 28

, 29

, and thirty

. 62. Pharmaceutical composition for the treatment of a disease associated with SHP2 modulation, containing an effective amount of a compound according to any one of paragraphs. 1-61 or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier. 63. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of paragraphs. 1-61 or a pharmaceutically acceptable salt or stereoisomer thereof. 64. The method of claim 63, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers. 65. Connection according to any one of paragraphs. 1-61 or a pharmaceutically acceptable salt or stereoisomer thereof for use as a drug. 66. Connection according to any one of paragraphs. 1-61 or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment or prevention of a disease associated with SHP2 modulation. 67. The use of a compound according to any one of paragraphs. 1-61 or a pharmaceutically acceptable salt or stereoisomer thereof for the preparation of a medicament for the treatment or prevention of a disease associated with SHP2 modulation. 68. A method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition according to claim 62. 69. The method of claim 68, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and rectal cancers. 70. Pharmaceutical composition according to claim 62 for use as a medicine. 71. A pharmaceutical composition according to claim 62 for use in the treatment or prevention of a disease associated with SHP2 modulation. 72. The use of a pharmaceutical composition according to claim 62 in the manufacture of a medicinal product intended for the treatment or prevention of a disease associated with SHP2 modulation.