KR20240093844A - Antagonist of GPR39 protein - Google Patents

Abstract

A novel compound that acts as an antagonist for the human GPR39 protein is disclosed. Pharmaceutical compositions and methods of use for antagonists against the human GPR39 protein are disclosed. In particular, methods of using this antagonist in the treatment of diseases or conditions including cardiovascular conditions, endocrine and hormonal disorders, cancer disorders, metabolic diseases, gastrointestinal and liver diseases, hematological disorders, neurological disorders, and respiratory diseases are disclosed. .

Description

Antagonist of GPR39 protein

Cross-reference to related applications

This application claims priority to U.S. Provisional Patent Application No. 63/272,076, filed October 26, 2021, the entire disclosure of which is incorporated herein by reference in its entirety.

field of invention

The present disclosure relates to novel compounds that act as antagonists for the human GPR39 protein. Additionally, the present disclosure relates to human GPR39 protein in the treatment of diseases or conditions including cardiovascular conditions, endocrine and hormonal disorders, cancer disorders, metabolic diseases, gastrointestinal and liver diseases, hematological disorders, neurological disorders, and respiratory diseases. It relates to pharmaceutical compositions and methods for using antagonists.

Background of the invention

The use of GPR39 antagonists for the treatment of pain sensitivity, including hyperalgesia, and methods for suppressing appetite has been described (US Patent Publication 2009/0298756 - Jin et al.).

The use of GPR39 agonists and/or antagonists in improving glucose control and treating impaired carbohydrate metabolism, including disorders such as diabetes and metabolic syndrome, is discussed in WO 2007/141322 - Moreaux et al. - Janssen Pharmaceutica N.V.

Paper Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor-Knockout Mouse, Gastroenterology, Moechars et al., Oct. 2006, Vol. 131, Issue 4, pp. 1131-1141 disclose the conclusion that GPR39 receptor antagonists may be useful in disorders affecting gastric motility and/or colorectal motility such as irritable bowel syndrome, diarrhea, or chronic constipation, including functional dyspepsia and diabetic gastroparesis. do.

The role of the obestatin/GPR39 system in human gastric adenocarcinomas, et al., Oncotarget 2016, 7:5957-5971 addresses the role of the obestatin/GPR39 system in regulating motility, EMT, and invasion of gastric adenocarcinoma cells.

GPR39 antagonists also demonstrate their potential in the treatment of breast cancer, especially ER-negative breast cancer, in the paper Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth, Ventura-Bixenshpaner et al., Scientific Reports (2018) 8:8119. Uses are discussed.

The use of GPR39 antagonists in the treatment of various cancers is discussed in the U.S. Pat. Discussed in 2004/0071708 (Claassen et al.).

Inge Depoortere discloses the use of GPR39 antagonists in the treatment of motility disorders such as functional dyspepsia, hypoparesis, and chronic constipation in her article GI functions of GPR39: novel biology , Current Opinion in Pharmacology, 2012, 12:647-652. do.

Thesis The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon, Cohen et al., Cell Death and Disease (2014) 5, e1307 is used in ulcerative colon diseases such as ulcerative colitis, and Potential uses of GPR antagonists in promoting or improving colonic epithelial function and tight junction barrier integrity, including treatment of diarrheal pathology, are discussed.

BRIEF SUMMARY OF THE INVENTION

Provided are compounds of formula (I-A):

here:

X ₁ is

is selected from the group consisting of:

n _a is an integer selected from the group of 0, 1, and 2;

n _b is an integer selected from the group of 0, 1, 2, 3, and 4;

However, the sum n _a + n _b is 2 or more and 4 or less;

or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;

X ₂ is

is selected from the group of;

wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;

Y ₁ is selected from the group of C and N;

Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;

However, one or less of Y ₁ and Y ₂ is C;

n _c is an integer selected from the group of 1, 2, and 3;

n _d is an integer selected from the group of 1, 2, and 3;

However, the sum n _c + n _d is 2 or more and 6 or less;

Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;

R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of -C ₁ -C ₆ alkyl substituted with;

n1 is an integer selected from the group of 0, 1, 2, and 3;

R ₂ is bonded through a carbocycle, and a carbon atom and 3, 4, 5, 6, 7, or 8 ring carbon atoms and 1, 2, 3 selected from the group of N, S, and O, or selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 4 ring heteroatoms, any of the preceding being C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C (=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl), -(CH ₂ ) _n1 -heterocyclyl (3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S , and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system containing 1, 2, 3, or 4 ring heteroatoms selected from the group of is substituted with 0, 1, 2, or 3 substituents selected from the group of, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents of choice; provided that R ₂ is not pyridinyl unless substituted at least once by -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl or phenyl;

R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;

R ₃ occurs one or more times and is independently selected from the group:

a) hydrogen, halogen, cyano, or OH;

b) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);

c) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;

d) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, where phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH;

e) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and

f) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;

R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl;

When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;

where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or heterocyclic rings having 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from the group N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ - is substituted with 0, 1, 2, or 3 substituents selected from the group of C ₃ alkyl;

R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;

R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;

n ₂ is in each case an integer selected from the group 0, 1, 2, and 3.

Further provided are compounds of formula (I-B):

here:

X ₁ is

is selected from the group of;

n _a is an integer selected from the group of 0, 1, and 2;

n _b is an integer selected from the group of 0, 1, 2, 3, and 4;

However, the sum n _a + n _b is 2 or more and 4 or less;

or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;

X ₂ is

is selected from the group of;

wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;

Y ₁ is selected from the group of C and N;

Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;

However, one or less of Y ₁ and Y ₂ is C;

n _c is an integer selected from the group of 1, 2, and 3;

n _d is an integer selected from the group of 1, 2, and 3;

However, the sum n _c + n _d is 2 or more and 6 or less;

Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;

R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of -C ₁ -C ₆ alkyl substituted with;

n1 is an integer selected from the group of 0, 1, 2, and 3;

R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl, provided that R ₂ is -(CH ₂ ) _n1 is not pyridinyl unless substituted at least once by -C ₃ -C ₆ cycloalkyl or phenyl;

R ₂ 'is selected from the group of OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;

R ₃ occurs one or more times and is independently selected from the group:

g) hydrogen, halogen, cyano, or OH;

h) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);

i) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;

j) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, where phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH;

k) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and

l) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;

R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;

When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;

where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl, and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or a heterocyclic ring having 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ is substituted with 0, 1, 2, or 3 substituents selected from the group of -C ₃ alkyl;

R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , -C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;

R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;

n ₂ is in each case an integer selected from the group 0, 1, 2, and 3.

Also provided are compounds of formula (I-C):

X ₁ is

is selected from the group of;

n _a is an integer selected from the group of 0, 1, and 2;

n _b is an integer selected from the group of 0, 1, 2, 3, and 4;

However, the sum n _a + n _b is 2 or more and 4 or less;

or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;

X ₂ is

is selected from the group of;

wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;

Y ₁ is selected from the group of C and N;

Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;

However, one or less of Y ₁ and Y ₂ is C;

n _c is an integer selected from the group of 1, 2, and 3;

n _d is an integer selected from the group of 1, 2, and 3;

provided that the sum n _c + n _d is 2, 3, 5, or 6;

Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;

R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;

n1 is an integer selected from the group of 0, 1, 2, and 3;

R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl, provided that R ₂ is -(CH ₂ ) _n1 is not pyridinyl unless substituted at least once by -C ₃ -C ₆ cycloalkyl or phenyl;

R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;

R ₃ occurs one or more times and is independently selected from the group:

m) hydrogen, halogen, cyano, or OH;

n) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);

o) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;

p) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;

q) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and

r) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;

R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl;

When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;

where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl, and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or a heterocyclic ring having 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ is substituted with 0, 1, 2, or 3 substituents selected from the group of -C ₃ alkyl;

R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , -C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;

R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;

n ₂ is in each case an integer selected from the group 0, 1, 2, and 3.

Also provided are compounds of formula (I-D):

here:

X ₁ is

is selected from the group of;

n _a is an integer selected from the group of 0, 1, and 2;

n _b is an integer selected from the group of 0, 1, 2, 3, and 4;

However, the sum n _a + n _b is 2 or more and 4 or less;

or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;

X ₂ is

is selected from the group of;

wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;

Y ₁ is selected from the group of C and N;

Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;

However, one or less of Y ₁ and Y ₂ is C;

n _c is an integer selected from the group of 1, 2, and 3;

n _d is an integer selected from the group of 1, 2, and 3;

However, the sum n _c + n _d is 2 or more and 6 or less;

Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;

R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;

n1 is an integer selected from the group of 0, 1, 2, and 3;

R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl, provided that R ₂ is -(CH ₂ ) _n1 is not pyridinyl unless substituted at least once by -C ₃ -C ₆ cycloalkyl or phenyl;

R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;

R ₃ occurs one or more times and is independently selected from the group:

s) hydrogen, halogen, cyano, or OH;

t) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);

u) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;

v) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Cycloalkyl each ring is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and OH -;

w) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents; and

x) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;

R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl;

When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;

where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl, and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or a heterocyclic ring having 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from the group N, O and S, substituted or unsubstituted phenyl, and -OC ₁ -C. ₃ is substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl;

R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;

R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;

n ₂ is in each case an integer selected from the group 0, 1, 2, and 3.

Further provided are compounds of formula (I-E):

here:

X ₁ is

is selected from the group of;

n _a is an integer selected from the group of 0, 1, and 2;

n _b is an integer selected from the group of 0, 1, 2, 3, and 4;

However, the sum n _a + n _b is 2 or more and 4 or less;

or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;

X ₂ is

is selected from the group of;

wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;

Y ₁ is selected from the group of C and N;

Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;

However, one or less of Y ₁ and Y ₂ is C;

n _c is an integer selected from the group of 1, 2, and 3;

n _d is an integer selected from the group of 1, 2, and 3;

However, the sum n _c + n _d is 2 or more and 6 or less;

Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;

R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;

n1 is an integer selected from the group of 0, 1, 2, and 3;

R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, provided that R ₂ is -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl or is not pyridinyl unless substituted at least once with phenyl;

R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;

R ₃ occurs one or more times and is independently selected from the group:

y) hydrogen, halogen, cyano, or OH;

z) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);

aa) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;

bb) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;

cc) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and

dd) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;

R ₄ occurs once or twice and is halogen;

R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;

R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from -OC ₁ -C ₃ alkyl;

n ₂ is in each case an integer selected from the group 0, 1, 2, and 3,

However, the compound is N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide; (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[3-(trifluoro methyl)pyrazol-1-yl]phenyl]methanone; [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoropy peridin-1-yl)methanone; (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(3-propane-2- Ilpyrazol-1-yl)phenyl]methanone; or N-[4-(4-fluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide.

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of compounds of formula (I-A), (I-B), (I-C), (I-D) and (I-E), or pharmaceutically acceptable salts thereof, compounds of formula (I'), or pharmaceutically acceptable salts thereof. , a compound of formula (I"), or a pharmaceutically acceptable salt thereof, and a compound of formula (I"'), or a pharmaceutically acceptable salt thereof, respectively:

wherein, _when present _{, in} each case _{X 1 ,} , or as defined for (IE).

Also, compounds of formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), and (I-7), or It is understood that there are separate, independent embodiments within the scope of Formula (I) based on the definitions of X ₁ and X ₂ above, each of which includes pharmaceutically acceptable salts:

_{where in each case , when they exist , ​ ​ ​ ​} All variables and provisos included are as defined above for formula (IA), (IB), (IC), (ID), or (IE).

In addition, compounds of the formulas (IA), (IB), (IC) based on _the definitions of X ₁ and ), (ID), and (IE).

where in each case when they exist R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , Z ₁ , Z ₂ , Z ₃ , n _a , n _b , n1 All variables and provisos, including , n2, are as defined above for formula (IA), (IB), (IC), (ID), or (IE).

Another separate embodiment is that in each embodiment Z ₁ , Z ₂ , and Z ₃ are each C, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and the proviso are as defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and each compound of formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof is provided.

Another separate embodiment is that in each embodiment Z ₁ , Z ₂ , and Z ₃ are each N, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and the proviso are as defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and each compound of formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof is provided.

A further separate embodiment is that in each embodiment Z ₁ and Z ₂ are each C, Z ₃ is N, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and proviso are defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-; ll) Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formula (I- 1) to (I-7), and compounds of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, are provided.

A further separate embodiment is that in each embodiment Z ₁ and Z ₃ are each C, Z ₂ is N, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and proviso are defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formula (I- 1) to (I-7), and compounds of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, are provided.

A further separate embodiment is that in each embodiment Z ₁ and Z ₃ are each N, Z ₂ is C, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and proviso are defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formula (I- 1) to (I-7), and compounds of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, are provided.

A further separate embodiment is that in each embodiment Z ₁ and Z ₂ are each N, Z ₃ is C, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and proviso are defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formula (I- 1) to (I-7), and compounds of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, are provided.

A further separate embodiment is that in each embodiment Z ₂ and Z ₃ are each N, Z ₁ is C, and R _a , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, and proviso are defined above for the corresponding formulas (IA), (IB), (IC), (ID), or (IE) to (I-ll). Formulas (IA), (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formula (I- 1) to (I-7), and compounds of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, are provided.

Formula (IA), Formula (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Formulas (Ia) to (I-jj), or Within each embodiment of the pharmaceutically acceptable salt thereof, R ₂ is

is selected from the group of;

Here, R ₇ occurs once or twice and is independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, where n1 is 0, 1, 2, and There is a further embodiment wherein it is an integer selected from the group of 3.

Formula (IA), Formula (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Formulas (Ia) to (I-jj), or Within each embodiment of the pharmaceutically acceptable salt thereof, R ₂ is

is selected from the group of;

Here, R ₇ occurs once or twice and is independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, where n1 is 0, 1, 2, and There is a further embodiment wherein it is an integer selected from the group of 3.

Formula (IA), Formula (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Formulas (Ia) to (I-jj), or In each embodiment of the present application of a pharmaceutically acceptable salt thereof, R ₂ is

There are further embodiments that are selected from the group of:

Formulas (IB), (IC), (ID), and (IE), formulas (I'), (I"), and (I"'), formulas (I-1) to (I-7), and in each embodiment herein of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, R ₂ is

is selected from the group of:

wherein R ₇ and R ₈ at each occurrence are independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -CF ₃ , and phenyl, provided that only one of R ₇ and R ₈ There are additional embodiments that may be phenyl. In embodiments herein when the R ₂ group is a bicyclic or spirocyclic ring, R ₇ and R ₈ may be bonded to any available ring carbon or nitrogen atom of either ring and R ₇ and R It is understood that ₈ may be bonded to ring atoms of the same or different rings.

Formulas (IB), (IC), (ID), and (IE), formulas (I'), (I"), and (I"'), formulas (I-1) to (I-7), and in each embodiment herein of formulas (Ia) to (I-ll), or pharmaceutically acceptable salts thereof, R ₂ is

is selected from the group of;

wherein R ₇ and R ₈ at each occurrence are independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -CF ₃ , and phenyl, provided that only one of R ₇ and R ₈ There are additional embodiments that may be phenyl.

Also, Formulas (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7) , and each compound of formulas (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof, wherein R ₂ is as defined above. phosphorus contains compounds of each chemical formula. For example, a compound of formula (IB), (IC), (ID), or (IE) wherein R ₂ is an azepane ring of group a) substituted by variable groups R ₇ and R ₈ , or pharmaceutically thereof. Acceptable salts are provided. Another embodiment is of formula (IB), (IC), (ID), or (IE) wherein R ₂ is an azabicyclo[3.10.0]hexanyl ring of group b) substituted by variable groups R ₇ and R ₈ ) includes compounds. This pattern continues to define the remaining embodiments, each with a separately mentioned R ₂ group from the list above.

Formulas (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ in each of the above embodiments of each compound of formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof. , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2 each variable and proviso has the corresponding formula (IB), (IC), (ID), and (IE), formula (I) '), (I"), and (I"'), as defined above for formulas (I-1) to (I-7), and formulas (Ia) to (I-ll), and R ₂ go

is selected from the group of:

There is a further embodiment wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, halogen, and -CF ₃ .

Formulas (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ in each of the above embodiments of each compound of formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof. , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2 and the corresponding formulas (I), (I-1) to (I-7), and (Ia). to (I-ll) as defined above, and R ₂

is selected from the group of;

There is a further embodiment wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, and -CF ₃ .

Formulas (IB), (IC), (ID), and (IE), Formulas (I'), (I"), and (I"'), Formulas (I-1) to (I-7), and Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ in each of the above embodiments of each compound of formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof. , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, each variable and proviso is represented by the corresponding formula (I), formula (I-1) to (I-7), and formula ( Ia) to (I-ll) as defined above, and R ₂

is selected from the group of;

There is a further embodiment wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, and -CF ₃ .

Z ₁ , Z in each of the above embodiments of each compound of Formula (I), Formula (I-1) to (I-7), and Formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof. Each variable and proviso, including ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, has the corresponding chemical formula ( I), formulas (I-1) to (I-7), and formulas (Ia) to (I-ll), and R ₂ is

is selected from the group of;

There is a further embodiment wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, and -CF ₃ .

Z ₁ , Z in each of the above embodiments of each compound of Formula (I), Formula (I-1) to (I-7), and Formula (Ia) to (I-ll), or a pharmaceutically acceptable salt thereof. Each variable and proviso, including ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , n _a , n _b , n1, n2, has the corresponding chemical formula ( I), formulas (I-1) to (I-7), and formulas (Ia) to (I-ll), and R ₂ is

is selected from the group of;

There is a further embodiment wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, and -CF ₃ .

In some embodiments herein, R ₇ and R ₈ are selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy. In other embodiments, R ₇ and R ₈ are selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy. In yet other embodiments, hydrogen, F, Cl, -CF ₃ , C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy.

There are further embodiments of the same scope except that within each embodiment of the compounds and salts herein comprising an R ₃ moiety, R ₃ is present 1 to 3 times. There are further embodiments of the same scope except that within each embodiment of the compounds and salts herein comprising an R ₃ moiety, R ₃ is present 1 to 2 times. There are further embodiments of the same scope except that within each embodiment of the compounds and salts herein comprising an R ₃ moiety, R ₃ occurs only once. Within each embodiment of the compounds and salts herein comprising an R ₃ moiety, R ₃ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -C ₁ -C ₄ alkyl-0H, selected from the group of phenyl, pyrazolyl, and thiophenyl, wherein the phenyl, pyrazolyl, and thiophenyl rings are selected from the group of halogen, OH, -CF ₃ , C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy. There are further embodiments of the same scope except that the substituents are substituted with 0, 1, 2, or 3 substituents of choice.

Within each embodiment of the compounds and salts herein comprising an R ₃ moiety, R ₃ is 0, 1, selected from the group of halogen, OH, -CF ₃ , C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy. There are further embodiments of the same scope except that it is selected from the group of phenyl, pyrazolyl, and thiophenyl substituted with 2 or 3 substituents.

Additionally, each compound of the formulas (I-A), (I-B), (I-C), (I-D), and (I-E) and all other formulas and the compounds specifically named herein include pharmaceutically acceptable salts of such compounds, pharmaceutically acceptable salts, and pharmaceutically acceptable salts of such compounds. acceptable co-crystals, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, and polymorphs. , and pharmaceutically acceptable prodrugs are also included.

Compounds of the present disclosure may have asymmetric centers and may occur as racemic mixtures or as individual enantiomers. The individual enantiomers can be obtained by asymmetric synthesis or by resolution of the racemic or non-racemic mixture of the intermediates at some suitable stage of the synthesis. Individual enantiomers can also be obtained by conventional means, such as crystallization in the presence of resolving agents, or resolution of the compounds by chromatography, for example using a chiral high pressure liquid chromatography (HPLC) column. Individual enantiomers, as well as racemic and non-racemic mixtures of enantiomers, are within the scope of this disclosure and, unless specifically indicated otherwise, all are intended to be included within structures depicted herein.

How to use

Hypertension is the most common chronic disease, affecting 1.13 billion people worldwide and causing 10 million deaths each year. Despite the availability of antihypertensive drugs that successfully lower blood pressure (BP) in millions of patients, a significant unmet need remains. Only half of hypertensive patients control their BP, and current antihypertensive medications do not restore normal BP in a large proportion of patients. Treatment-resistant hypertension (TRH), also known as resistant hypertension, is on the rise due to rising rates of diabetes and obesity, which contribute up to 75% of the risk of hypertension and most cases of TRH. Identifying new targets and developing new strategies to prevent and treat hypertension and its complications remain high public health and medical priorities.

A method of inhibiting the activity of a GPR39 protein in a subject, comprising administering to the subject in need of inhibiting the activity of the GPR39 protein a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E). , or a pharmaceutically acceptable salt thereof is provided.

Nonetheless, in certain embodiments, the method provides to a subject in need thereof a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), or formula (I-A), administering a compound of any subformula of (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. Includes steps.

1. A method of treating hypertension in a human in need of treatment for hypertension, comprising administering to the human in need of treatment a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E). , or a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any of the compounds specifically named herein, or any of the foregoing compounds. A method comprising administering an acceptable salt is provided. In one embodiment, the hypertension being treated is primary hypertension, also called essential hypertension.

In another embodiment, the hypertension being treated is caused by sleep apnea, renal artery blockage, abnormal levels of hormones, enzymes, growth factors, or other agents that control systemic or local blood pressure (renin, angiotensin I and II, and aldosterone, angiotensin converting Enzymes, catecholamines, thrombin, prostaglandins, natriuretic peptides, vasopressin, adreomedullin, substance P, calcitonin gene-related peptide, kallikrein, kininogen, kinin, kinin-degrading enzyme, phosducin, adipokine, and leptin. secondary hypertension, including but not limited to), adrenal disease, thyroid abnormalities (including hyperthyroidism, hypothyroidism, Cushing's disease, pheochromocytoma, and excess growth hormone), and aortic constriction, including stenosis. am.

In one embodiment, the hypertension being treated is treatment-resistant or refractory hypertension.

In another embodiment, the hypertension being treated is hypertensive urgency.

In another embodiment, the hypertension being treated is malignant hypertension, which may also be called a hypertensive emergency or hypertensive crisis.

In a further embodiment, the hypertension being treated is isolated systolic hypertension.

In a further embodiment, the hypertension being treated is salt-sensitive hypertension.

In another embodiment, the hypertension being treated is pulmonary hypertension.

Current stroke therapy involves dissolving or removing the blood clot that causes a blood vessel blockage. However, despite opening of large vessels, in a significant proportion of patients, up to 30-50%, small blood vessels are still damaged, resulting in ineffective therapy. Compounds as described herein can be combined with current stroke therapies to improve outcomes in a large proportion of patients.

Accordingly, as a method of treating stroke in a human in need of stroke treatment, a pharmaceutically effective amount of formula (I-A), (I-B), (I-C), (I-D), or (I-E) is administered to the human in need of stroke treatment. , a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutical of any of the foregoing compounds. A method comprising the step of administering a scientifically acceptable salt is provided.

Vascular dementia is a small blood vessel disease of the brain that impairs blood flow and oxygen delivery to brain cells, resulting in neuronal dysfunction. Dementia due to small vessel disease is the second leading cause of dementia after Alzheimer's disease and is the predominant cause in individuals over 70 years of age and in developing countries. As a method of treating dementia caused by small vessel disease in humans in need of treatment for dementia caused by small vessel disease, the chemical formula (I-A) is administered in a pharmaceutically effective amount to humans in need of treatment of dementia caused by small vessel disease. Compounds of formula (I-B), (I-C), (I-D), or (I-E), compounds of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), as specified herein. A method is provided comprising administering any of the compounds named, or a pharmaceutically acceptable salt of any of the foregoing compounds.

In light of their effects on relaxation and protection of microvessels, the compounds and compositions herein can also be used in methods of treating conditions associated with microvascular dysfunction and microvascular diseases, each of which can be used to treat microvascular dysfunction and microvascular diseases. To a subject in need of treatment of a disease-related condition, administer a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula (I-A), (I-B), ( administering a compound of any subformula (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. This includes methods of treating microvascular complications associated with or resulting from diabetes. In one embodiment, the diabetes in question is type I diabetes mellitus. In another embodiment, the diabetes in question is type 2 diabetes mellitus. This also includes methods of treating microvascular complications associated with or resulting from pre-diabetic conditions, also known as pre-diabetes.

Also, as a method of treating heart failure in humans, a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E) is administered to a human in need of heart failure treatment. ), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. A method comprising the step of administering is provided.

Methods for treating microvascular angina, cerebral small vessel disease (cSVD), vascular cognitive impairment (VCI), systemic microvascular endothelial dysfunction (alone or with infective endocarditis), and chronic kidney disease are included.

Peripheral artery disease is mostly small vessel disease and is generally not helped by surgical and stenting techniques that target large vessels and do not treat small vessel disease.

Disclosed herein is a method of treating peripheral arterial disease in a human, comprising administering to a mammal in need thereof a pharmaceutically effective amount of formula (I-A), (I-B), (I-C), (I-D), or (I-E) , a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutical of any of the foregoing compounds. A method comprising the step of administering a scientifically acceptable salt is provided.

The compounds herein may also be used in the treatment of preeclampsia, a pregnancy complication characterized by high blood pressure and signs of damage to other organ systems, most commonly the liver and kidneys. Disclosed herein is a method of treating preeclampsia in humans, comprising administering to a mammal in need of preeclampsia treatment a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula ( A compound of any of the subformulas I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. A method comprising the step of administering is provided.

The compounds herein are also useful in the treatment of myocardial infarction, especially when a no-reflow phenomenon exists. The no-reflow phenomenon exists when destruction or occlusion of the coronary microvasculature can significantly reduce blood flow to the infarcted area despite restoration of coronary blood flow to the myocardium. In these cases, flow into the microcirculation may occur in one third of patients with myocardial infarction.

Accordingly, as a method of treating myocardial infarction in humans, a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E) is administered to a mammal in need of treatment for myocardial infarction, Pharmaceutically acceptable compounds of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or any of the foregoing compounds. A method comprising the step of administering a salt is provided.

Also, as a method of treating myocardial infarction in which a no-reflow phenomenon exists in humans, a pharmaceutically effective amount of Formulas (I-A) and (I-B) is administered to mammals in need of treatment for myocardial infarction in which a no-reflow phenomenon exists. , (I-C), (I-D), or (I-E), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), specifically named herein A method is provided comprising administering any of the compounds described above, or a pharmaceutically acceptable salt of any of the foregoing compounds.

The compounds of the invention have also been used to bypass or stent the aorta; It can also be used in the setting of chronic coronary artery disease, in which approximately one-third of patients continue to suffer from angina pectoris due to microvascular dysfunction.

Accordingly, as a method of treating chronic coronary artery disease in humans, a pharmaceutically effective amount of formula (I-A), (I-B), (I-C), (I-D), or ( A compound of formula (I-E), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or any of the preceding compounds. A method comprising the step of administering a pharmaceutically acceptable salt of is provided.

Additionally, as a method of treating microvascular dysfunction associated with chronic coronary artery disease in humans, a pharmaceutically effective amount of formula (I-A), (I-B) is administered to a mammal in need of treatment for microvascular dysfunction associated with chronic coronary artery disease. , (I-C), (I-D), or (I-E), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), specifically named herein A method is provided comprising administering any of the compounds described above, or a pharmaceutically acceptable salt of any of the foregoing compounds.

Compounds of the invention may also be used for a condition called Syndrome Accordingly, as a method of treating Syndrome , a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or pharmaceutically of any of the foregoing compounds. A method is provided comprising administering an acceptable salt.

1. A method of treating breast cancer in a human in need of breast cancer treatment, comprising administering to the human in need of breast cancer treatment a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E). , a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or pharmaceutically of any of the foregoing compounds. A method is provided comprising administering an acceptable salt. In some embodiments, the breast cancer treated by this method is ER negative breast cancer.

Also, as a method of treating gastric adenocarcinoma in humans, the method includes administering to a human in need of gastric adenocarcinoma treatment a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula ( A compound of any of the subformulas I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. A method comprising the step of administering is provided.

Also provided is a method of promoting or improving colonic epithelial function and tight junction barrier integrity in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of formula (I-A), (I-B). ), (I-C), (I-D), or (I-E), compounds of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), as specifically described herein. A method is provided comprising administering any of the named compounds, or a pharmaceutically acceptable salt of any of the foregoing compounds.

Likewise, a method of treating ulcerative colon disease in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of formula (I-A), (I-B), (I-C), (I-D), or (I-E) , a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutical of any of the foregoing compounds. A method comprising the step of administering a scientifically acceptable salt is provided. In one embodiment, the ulcerative colon disease being treated is ulcerative colitis. In another embodiment, the ulcerative colon disease being treated is Crohn Disease or Crohn's Disease. In another embodiment, the ulcerative colon disease being treated is irritable bowel syndrome (IBS), which may also be called colitis, enteritis, ileitis, or proctitis.

Also, a method of treating inflammatory bowel disease (IBD) in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of formula (I-A), (I-B), (I-C), (I-D), or (I-E). ), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or any of the foregoing compounds. A method comprising administering a pharmaceutically acceptable salt is provided.

Also, as a method of treating diarrhea in humans, the method includes administering to a human in need of diarrhea treatment a pharmaceutically effective amount of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula (I-A) ), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. A method comprising the step of administering is provided.

Because microvascular complications can inhibit uniform delivery of an anesthetic, in some embodiments the compounds herein may be used in methods to distribute and improve the effectiveness of local, regional, or systemic delivery of an anesthetic. Accordingly, as a method of improving the delivery of an anesthetic to a human experiencing microvascular complications, a pharmaceutically effective amount of formula (I-A), (I-B), (I-C) is administered to a human experiencing microvascular complications in need of improved delivery of an anesthetic. ), (I-D), or (I-E), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any of the compounds specifically named herein A method is provided comprising administering a compound, or a pharmaceutically acceptable salt of any of the foregoing compounds, and a pharmaceutically effective amount of an anesthetic agent. In some embodiments, a compound of Formula (I-A), (I-B), (I-C), (I-D), or (I-E), Formula (I-A), (I-B), (I-C), (I-D), or (I-E) A compound of any subformula, any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds is administered to the human prior to administration of an anesthetic agent.

pharmaceutical composition

Also provided herein are pharmaceutically effective amounts of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula (I-A), (I-B), (I-C), (I-D), or Comprising a compound of any subformula of (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal of any of the foregoing compounds, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition is provided. Additional pharmaceutical compositions include a pharmaceutically effective amount of formula (I'), (I"), (I"'), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), and (I-7), and compounds of each formula (I-a)-(I-ll), and a pharmaceutically acceptable carrier or excipient, respectively. do.

Additionally, herein, in the manufacture of pharmaceuticals, compounds of formula (I-A), (I-B), (I-C), (I-D), or (I-E), formula (I-A), (I-B), (I-C), (I-D), or Provided is the use of a compound of any subformula (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal of any of the foregoing compounds. Additional uses include pharmaceutically effective amounts of formulas (I'), (I"), (I"'), (I-1), (I-2), (I-3), ( Compounds selected from I-4), (I-5), (I-6), and (I-7), and compounds of the respective formulas (I-a)-(I-ll), as well as specifically named herein Includes compounds each containing the above-mentioned compounds.

The term “carrier” refers to an excipient or vehicle, including but not limited to diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, etc., with which the compound is administered. Pharmaceutically acceptable carriers are generally described herein and also in "Remington's Pharmaceutical Sciences" by E. W. Martin. Examples of carriers include aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl. Cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, Poloxamer 182, Poloxamer 188, Poloxamer 237, Poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. However, it should be understood that the carrier selected for the pharmaceutical composition, and the amount of such carrier in the composition, may vary depending on the formulation method (e.g., dry granulation formulation, solid dispersion formulation).

Some examples of suitable excipients in oral formulations include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone. , cellulose, sterilized water, syrup, and methyl cellulose. The formulation may contain lubricating agents such as talc, magnesium stearate, and mineral oil; humectant; Emulsifiers and suspending agents; Preservatives such as methyl and propylhydroxy-benzoate; sweetener; And it may further include a fragrance.

As used herein, “pharmaceutically acceptable excipient” refers to pharmaceutically acceptable excipients, including without limitation any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. This is an acceptable vehicle. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional medium or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients may also be included in the composition.

The pharmaceutical compositions may be administered by the rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or as an impregnated or coated device such as a stent, e.g. For example, single or multiple doses may be administered by any approved mode of administration of agents with similar utility as described in, for example, patents and patent applications, which are incorporated by reference, including via arterially inserted cylindrical polymers. .

One mode of administration is parenterally, especially by injection. A compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E) Forms in which the compound, any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof may be included for administration by injection include sesame oil, corn oil, cottonseed oil, or peanut oil, as well as as well as aqueous or oil suspensions, or emulsions using elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles. Aqueous solutions in saline can also be routinely used for injections. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be used. Adequate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions and by the use of surfactants. Prevention of microbial action can be caused by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

Sterile injectable solutions are prepared by incorporating a compound according to the disclosure in the required amount in an appropriate solvent with various other ingredients enumerated above as required followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those enumerated above. For sterile powders for the preparation of sterile injectable solutions, the preferred preparation methods are vacuum drying and freeze-drying techniques, which produce powders of the active ingredient as well as any additional desired ingredients from pre-sterile filtered solutions. In some embodiments, for parenteral administration, a therapeutically effective amount, e.g., 0.1 to 1000 mg, of a compound of Formula (I-A), (I-B), (I-C), (I-D), or (I-E), Formula (I-A) ), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof. A sterile injectable solution is prepared. However, the amount of compound actually administered is usually determined by the physician in light of relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, etc. You will understand that it will be decided by .

Oral administration involves a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any of formula (I-A), (I-B), (I-C), (I-D), or (I-E). is another route for administration of a compound of a subformula, any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof. Administration can be through capsules or enteric-coated tablets. A compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E) In the manufacture of pharmaceutical compositions comprising a compound of, any of the compounds specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof, the active ingredient is usually diluted by excipients and/or placed in capsules, sachets, paper or Encapsulated within this carrier, which may be in the form of another container. When an excipient acts as a diluent, it may be in the form of a solid, semi-solid or liquid substance (as above) that acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, containing up to 10% by weight of the active compound. It may be in the form of ointments, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

In some embodiments, for parenteral administration, each dosage unit is 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of Formula (I-A), (I-B), (I-C), (I-D) ), or a compound of (I-E), a compound of any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any compound specifically named herein, or pharmaceutical Contains a scientifically acceptable salt or co-crystal thereof. In some embodiments, a compound of Formula (I-A), (I-B), (I-C), (I-D), or (I-E), Formula (I-A), (I-B), (I-C), (I-D), or (I-E) A therapeutically effective or pharmaceutically effective amount of a compound of any subformula, any compound specifically named herein, or a pharmaceutically acceptable salt thereof includes from about 0.1 mg to about 500 mg per dose, once per day. Given once or twice. In some embodiments, the individual doses are 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg per dose. mg, 350 mg, 400 mg, and 500 mg.

However, for any of the dosage units described herein, the amount of compound actually administered will usually depend on the condition being treated, the route of administration chosen, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, and the subject's symptoms. It will be understood that the decision will be made by the physician in light of the relevant circumstances, including severity.

Manufacturing supplies and kits

A compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any subformula of formula (I-A), (I-B), (I-C), (I-D), or (I-E) Compositions (including, e.g., formulations and unit doses) comprising a compound, any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof are prepared and placed in a suitable container and used for the treatment of an indicated condition. It can be labeled as a dragon. Accordingly, also a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), any of formula (I-A), (I-B), (I-C), (I-D), or (I-E) An article of manufacture comprising a unit dosage form of a compound of a subformula, any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof, and a label containing instructions regarding the use of the compound, For example, a container is provided. In some embodiments, the article of manufacture is a compound of Formula (I-A), (I-B), (I-C), (I-D), or (I-E), Formula (I-A), (I-B), (I-C), (I-D), or A unit dosage form of a compound of any subformula of (I-E), any compound specifically named herein, or a pharmaceutically acceptable salt or co-crystal thereof, and at least one pharmaceutically acceptable vehicle. It is the courage to do it. The article of manufacture may be a bottle, vial, ampoule, single-use disposable applicator, etc. containing the pharmaceutical composition provided in this disclosure. The container may be formed from a variety of materials, such as glass or plastic, and on one side also contains a label on or associated with the container indicating instructions for use in the treatment of cancer or inflammatory conditions. It should be understood that the active ingredients may be packaged in any material capable of improving chemical and physical stability, such as aluminum foil bags. In some embodiments, the disease or condition indicated in the label may include, for example, cancer treatment.

Justice

Terms such as “microvascular tone,” “microcirculatory tone,” “microcirculatory vascular tone,” and “arteriolar tone” refer to the degree of constriction experienced by microcirculatory vessels compared to their maximally dilated state. Microcirculation can be anatomically defined as blood vessels with a diameter of about 250 μm to about 100 μm, including especially blood vessels with a diameter of about 200 μm to about 150 μm, and include arterioles, capillaries, and venules (postcapillary). venules). Collectively, these blood vessels may be referred to as “microvessels”, “microcirculatory vessels”, etc. In embodiments herein, it relaxes microvessels in a subject, reduces vascular resistance and protects the microvessels themselves, and prevents end-organ damage associated with microvascular resistance, particularly that seen in the eyes, kidneys, and heart, as well as microvasculature. The goal is to provide compounds, compositions, and methods for reducing or eliminating nerve sheath damage associated with. In some embodiments, microcirculation is defined as blood vessels <200 μm in diameter. Approximately 90% of the blood volume in the human body resides in these blood vessels, which include arterioles, capillaries, and venules. The diameter of arterioles ranges from approximately 50-200 μm. Some venules contain vascular smooth muscle, and some capillaries are surrounded by pericytes, both of which are contractile cells that allow these blood vessels to contract and relax, thus allowing blood and oxygen to pass to the cells to some extent. Allows, and cellular waste is removed. The size of these arterioles is tightly regulated to meet the oxygen needs of the cells they supply.

“Coronary microvascular disease” is a heart disease that affects the walls and inner lining of very small blood vessels that branch off from larger coronary arteries. Coronary microvascular disease may also be called “cardiac X syndrome” or “non-obstructive coronary heart disease”. In the heart or elsewhere it may also be called "small artery disease", "small vessel disease", or "arteriosclerosis".

This small vessel disease is commonly seen in primary hypertension, stroke, and hypertensive kidney disease. Findings as renal lesions typically involve the auricular and interlobular arteries and may include intimal thickening that increases the media-to-lumen ratio, vascular smooth muscle cell proliferation, and extracellular matrix deposition. So areas of vascular smooth muscle cells can be replaced with fibrosis and cell loss.

“Microvascular angina” refers to a form of chest pain caused by abnormalities in the microvasculature of the heart, including but not limited to malrelaxation or spasms of the heart.

As used herein, “heterocycle” or “heterocyclic group” refers to a chemical ring containing carbon atoms and at least one ring heteroatom selected from O, S, and N, including saturated, unsaturated, partially saturated, and aromatic rings. refers to

Examples of 3-membered heterocycles as seen from the definitions of R ₃ and R ₄ herein include, by way of example and without limitation, aziridinyl, azirinyl, oxiranyl, and thiranyl groups.

Examples of four-membered heterocycles as can be seen from the definitions of R ₃ and R ₄ herein include, by way of example and without limitation, azetidinyl, dihydro-1λ ⁴ -azetyl, azetyl, 1,3-diazetidinyl. and oxetanyl groups.

Examples of five-membered heterocycles as seen from the definitions of R ₃ and R ₄ herein include, by way of example and without limitation, thiazolyl, tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, furanyl, thienyl, p. Rollyl, dihydropyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, pyrrolidinyl, 2-pyrrolidonyl, dihydropyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, thienyl, 2H -pyrrolyl, isothiazolyl, isoxazolyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl and oxazolidinyl groups.

Examples of 6-membered heterocycles as seen in the definitions of R ₃ and R ₄ herein include, by way of example and without limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), pyrimidinyl, piperidyl; Ridinyl, thiadiazinyl, thiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, pyrazinyl, pyridazinyl, piperazinyl, thienyl, thiopyran, ditanyl, morpholinyl , contains a thiomorpholinyl group.

Examples of 7-membered heterocycles herein include, by way of example and without limitation, borepinyl, azepanil, azepinyl, oxepanil, oxefinyl, teipanyl, thiephanyl, diazepanil, diazepinyl, and thiazepinyl. Includes flag.

Examples of 8-membered heterocycles herein include, by way of example and without limitation, azocinyl, azocinyl, oxocanyl, oxocynyl, thiochanyl, and thiocinyl groups.

Examples of nine-membered heterocycles herein include, by way of example and without limitation, monocyclic heterocycles such as azonanyl, azoninyl, oxonanyl, oxoninyl, thionanyl, and thioninyl groups and fused heterocycles such as indolyl. , indolinyl, isoindolyl, indolizinyl, indazolyl, azaindolyl, benzimidazolyl, azaindazolyl, pyrazolopyrimidinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, Benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]thiazolyl, benzisothiazolyl, It includes adeninyl, and guaninyl groups.

Examples of 10-membered heterocycles herein include, by way of example and without limitation, decahydroisoquinolinyl, decahydroquinolinyl, tetrahydroquinolinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinoxali. Nyl, quinolizinyl, phthalazinyl, quinazolinyl, cinnolinyl, chromenyl, isochromenyl, naphthyridinyl, pyrido [3,2-d] pyrimidinyl, pyrido [4,3-d ]Pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, benzo[e][1,2]oxazinyl, benzo[e][ 1,3]oxazinyl, benzo[b][1,4]oxazinyl, quinolinonyl, thienopyrimidinyl (including thieno[3,2-d]pyrimidinyl), and isoquinolinonyl groups Includes.

The general term for heterocycles referred to herein includes each isomeric form of the heterocycle, for example the term "dithianyl" includes the groups 1,2 dithianyl, 1,3-dithianyl and 1,4-dithianyl, The term "thiadiazinyl" includes the groups 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl, and the term "azaindolyl" includes 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, -azaindolyl, and 7-azaindolyl, and "benzothiophenyl" is understood to include benzo[b]thiophenyl and benzo[c]thiophenyl groups.

Likewise, the general heterocycle name includes each change at one or more points of unsaturation. For example, the term “dihydropyrrolyl” refers to the groups “2,3-dihydro-1H-pyrrolyl” and “2,5-dihydro-1H-pyrrolyl”.

The term “alkyl” refers to a straight or branched chain hydrocarbon. For example, an alkyl group can have a specified number of chain carbons, such as 1 to 6 carbon atoms (ie, C ₁ -C ₆ alkyl or C _1-6 alkyl). Examples of suitable alkyl groups are methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl. (i-Pr, i-propyl, --CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, --CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, --CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, --CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl- 2-propyl (t-Bu, t-butyl, --C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, --CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-- CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (--CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (--CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl(--CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1 -Butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (--CH ₂ CH ₂ CH2CH ₂ CH ₂ CH ₃ ), 2-hexyl (--CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl(-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl(-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) , 3-methyl-2-pentyl(-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl(-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl(--C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl(-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2, 3-dimethyl-2-butyl(--C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), and 3,3-dimethyl-2-butyl(-CH(CH ₃ )C(CH ₃ ) ₃ It is not limited to this.

The term “alkoxy” refers to a group with the formula “-O-alkyl” wherein an alkyl group as defined above is attached to the parent molecule through an oxygen atom. The alkyl portion of an alkoxy group may have the specified number of carbon chain atoms, such as 1 to 6 carbon atoms (i.e., C ₁ -C ₆ alkoxy or C _1-6 alkoxy). Examples of suitable alkoxy groups are methoxy (-O-CH ₃ or --OMe), ethoxy (-OCH ₂ CH ₃ or --OEt), t-butoxy (--O--C(CH ₃ ) ₃ or --OtBu), etc.

The term “carbocycle” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings.

The term “cycloalkyl” refers to a saturated ring having 3 to 6 carbon atoms as a monocycle, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The term “halogen” refers to an atom selected from the group of elements chlorine, fluorine, bromine and iodine.

The term “oxo” refers to the double bond oxygen “=O”.

The terms “therapeutically effective amount” and “pharmaceutically effective amount” refer to an amount sufficient to effect treatment as defined below when administered to a subject (e.g., a mammal, such as a human) in need of treatment. . The therapeutic or pharmaceutically effective amount will vary depending on the subject and disease condition to be treated, the subject's weight and age, the severity of the disease condition, the mode of administration, etc., and can be easily determined by a person of ordinary skill in the relevant field. For example, a “therapeutically effective amount” or “pharmaceutically effective amount” of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), or a pharmaceutically acceptable salt or co-crystal thereof. An “effective amount” is an amount sufficient to treat a subject (e.g., a human) suffering from an indication or to improve or alleviate the existing symptoms of the indication by antagonizing GPR39 expression or activity. For example, a therapeutically or pharmaceutically effective amount may be an amount sufficient to reduce symptoms of a disease or condition that responds to inhibition of GPR39 activity.

“Treatment” or “treating” is an approach to achieve beneficial or desired results, including clinical outcomes. The beneficial or desired clinical outcome may include one or more of the following: (i) inhibition of the disease or condition (e.g., reduction of one or more symptoms due to the disease or condition and/or attenuation of the severity of the disease or condition) ; (ii) slowing or halting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or spreading the disease or condition ( For example, preventing or delaying metastasis); and/or (iii) alleviating the disease, i.e. causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete relief of the disease or condition, enhancing the effectiveness of another agent, delaying disease progression, quality of life). increase and/or prolong survival).

The term “inhibiting” or “inhibition” refers to a decrease, such as a significant decrease, in the baseline activity of a biological activity or process. “Inhibition of GPR39 activity” refers to a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E) compared to the activity of GPR39 in the absence of such compound, or a pharmaceutically acceptable salt or co-crystal thereof. ) refers to a decrease in GPR39 activity as a direct or indirect response to the presence of a compound, or a pharmaceutically acceptable salt or co-crystal thereof. The decrease in activity may be due to a direct interaction of the compound with GPR39, or may be due to an interaction of the compound(s) described herein with one or more other factors that consequently affect GPR39 expression and/or activity. You can. For example, the presence of compound(s) may be present by directly binding to GPR39, by causing another factor (directly or indirectly) to reduce GPR39 expression or activity, or by decreasing the amount of GPR39 protein present in a cell or organism ( GPR39 activity can be reduced by reducing (directly or indirectly). In some embodiments, inhibition of GPR39 activity can be compared in the same subject before treatment, or in different subjects who have not received treatment. The term “inhibitor” is understood to refer to a compound or agent that provides the desired inhibitory activity when administered in a pharmaceutically or therapeutically effective dose to a human in need thereof.

To “delay” the development of a disease or condition means to slow, arrest, slow down, retard, stabilize and/or postpone the development of a disease or condition. This delay may vary in length of time depending on the history of the disease or condition and/or the subject being treated. A method of “delaying” the development of a disease or condition reduces the likelihood of the disease or condition developing within a given time frame and/or reduces the severity of the disease or condition within a given time frame compared to not using the method. This is the way to do it. These comparisons are typically based on clinical studies using statistically significant numbers of subjects. The development of a disease or condition can be detected using standard methods, such as routine physical examination, mammography, imaging, or biopsy. Development can also refer to the progression of a disease or condition beyond initially detectability and includes occurrence, recurrence, and onset.

As used herein, the singular terms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Likewise, the word “or” is intended to include “and” unless the context clearly dictates otherwise. Additionally, as used herein, the term “comprises” means “includes.” Accordingly, “comprising A or B” means including A, B, or A and B.

Numerical values in the specification and claims of this application, when converted to the same number of significant figures, differ from the stated values and the same numerical value by less than the experimental error of conventional measurement techniques of the type described in this application for determining that value. It should be understood that it includes numeric values that differ from .

All ranges disclosed and/or claimed herein include the recited endpoints and are independently combinable (e.g., the ranges “2 to 10” and “2-10” include endpoints 2 and 10, and all intermediate values includes 3, 4, 5, 6, 7, 8 and 9).

“Significant” means any detectable change that is statistically significant in a standard parametric test of statistical significance, such as Student's T-test, in which case p<0.05.

“Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with organic acids. Examples of salts are hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate ( mesylate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (e.g. acetate, HOOC- -(CH ₂ ) _n --COOH, where n is 0-4). Additionally, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying the acid salt solution. Conversely, if the product is a free base, acid addition salts, especially pharmaceutically acceptable addition salts, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid, following the usual procedure for preparing acid addition salts from base compounds. It can be created by doing Those skilled in the art will recognize a variety of synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable addition salts.

As used herein, the term “crystal form” and related terms include polymorphs, solvates, hydrates, co-crystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. However, it refers to various crystalline variants of a given material, but is not limited thereto. The crystalline form of the material can be obtained by many methods as known in the art. These methods include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces, such as in nanopores or capillaries, recrystallization on surfaces or templates, such as on polymers, additives such as, for example, Examples include, but are not limited to, recrystallization in the presence of counter-cocrystal molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent drop grinding.

As used herein, the term "co-crystal" or "co-crystal salt" means a crystalline material composed of two or more distinct solids at room temperature, each solid having unique physical characteristics such as structure, melting point, and heat of fusion, and hygroscopicity. , solubility, and stability. Co-crystals or co-crystal salts can be produced according to co-crystallization methods known per se. The term co-crystal (or co-crystal) or co-crystal salt also refers to a host API (active pharmaceutical ingredient) molecule or molecules such as formula (I-A), (I-B), (I-C), (I-D), or ( I-E), and a multicomponent system in which guest (or co-former) molecules or molecules are present. In certain embodiments, the pharmaceutically acceptable co-crystal of a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E) with a co-former molecule is a malonic acid co-crystal, It is a crystalline form selected from succinic acid co-crystal, decanoic acid co-crystal, salicylic acid co-crystal, vanillic acid co-crystal, maltol co-crystal, or glycolic acid co-crystal. The co-crystal may have improved properties compared to the parent form (i.e., free molecule, zwitterion, etc.) or salt of the parent compound. The improved properties include increased solubility, increased dissolution, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline forms of normally amorphous compounds, crystalline forms of compounds that are difficult or cannot be salted, and reduced Includes improved form diversity, more desired morphologies, etc.

As used herein, the terms “isotope” and “isotopic” with respect to a compound as disclosed herein mean that one or more atoms of the compound are replaced with an isotope of such one or more atoms. “Isotope” refers to any two or more forms of a chemical element having the same number of protons in the nucleus but different numbers of neutrons in the nucleus. For example, isotopic compounds include compounds in which one or more hydrogen atoms (H) have been replaced by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) causes the resulting compound to be an isotope compound. For example, and with respect to formulas (IA), (IB), (IC), (ID), or (IE), two methyl groups of the isopropyl moiety (-CH(CH ₃ ) ₂ ) are completely deuterated. Replacement of the digested methyl group (-CH(CD ₃ ) ₂ ) will result in an isotopic compound of formula (IA), (IB), (IC), (ID), or (IE). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotopic substitutions include replacing carbon 12 with carbon 13, while unstable (radioactive) isotopic substitution includes replacing hydrogen with tritium, carbon 12 It includes replacing with carbon 14, replacing iodine 127 with iodine 123 or iodine 125, etc. Accordingly, all references herein to isotopic compounds of formula (IA), (IB), (IC), (ID), or (IE), as well as various embodiments thereof, refer to one or more deuterium atoms in the compound. Refers to a compound that has one or more isotopic substitutions, including but not limited to substitution of one or more hydrogen atoms and any occurrence(s). To this end, the isotopic compounds disclosed herein offer improved advantages over their non-isotopic forms. To this end, isotopic modifications provide a means to improve existing drugs and/or a tool to design new drugs. For example, isotopic drug design has proven successful with respect to deuterium (D) kinetic isotope effects. Because of the twice higher mass of D compared to H, the CD bond is much more resistant to oxidation processes (e.g. its ability to be catalyzed by CYP450 or other enzymes involved in metabolism) while retaining very similar steric properties. Therefore, HD isosteric replacement usually improves pharmacokinetics by affecting half-life and/or area under the curve values, and ultimately, dose and/or dosing regimen, while retaining the pharmacodynamics of the compound. For example, drug exposure may be enhanced through isotopic modification and/or reduced clearance. These benefits are provided by isotopic derivation of the compounds disclosed herein.

Terms such as “subject” and “patient” refer to an animal, such as a mammal, that has been or will be the subject of treatment, observation, or experimentation. The methods described herein may be useful for both human therapy and veterinary applications. In some embodiments, the subject is a mammal; In some embodiments the subject is a human; In some embodiments the subject is selected from cats and dogs. “Subject in need” or “Human in need” refers to a specific treatment; Benefit from treatment with a compound of formula (I-A), (I-B), (I-C), (I-D), or (I-E), or a pharmaceutically acceptable salt or co-crystal thereof, for example as described herein. refers to a subject, such as a human, who may have or is suspected of having a disease or condition that may result in . This includes subjects who have been determined to be at risk for, or susceptible to, such disease or condition and for whom treatment would prevent the disease or condition from developing.

The term “prediabetes” or “prediabetic condition” refers to a condition in which a subject's blood sugar levels are not high enough to be considered diabetes, but may be a precursor to type 2 diabetes. A pre-diabetic condition can be defined in a subject having a fasting blood sugar level of 100 mg/dl or more but less than 126 mg/dl (the level at which diabetes is diagnosed). Hemoglobin A1c (HbA1c) level is another laboratory test for diabetes. HbA1c levels above 6.5% are characteristic of diabetes, and levels between 5.7% and 6.4% are suggestive of pre-diabetes.

Example

Measurement of intracellular calcium responses in PC3 cells expressing endogenous human GPR39 receptor

Human prostate adenocarcinoma (PC3) cells endogenously expressing the human GPR39 receptor were grown at a density of 7,500 cells per well in DMEM (low glucose) supplemented with 10% heat-inactivated fetal bovine serum and 1% Pen/Strep, with black walls and clear bottoms 384 -Seed in well plates and grow overnight at 37°C, 5% CO2. After washing with assay buffer (20mM HEPES, 137mM NaCl, 5.4mM KCl, 10mM Glucose, 0.8mMgSO4, 1.3mM CaCl2, 0.3mM Na2HPO4, 0.4mMKH2PO4, 4.2mM NaHCO3, pH 7.4), cells were incubated with Calcium. Incubation with -6 probe (Molecular Devices) at 37°C for 2 h and then equilibrated on a metal block for 30 min at RT. Fluorescence was measured in real time by a Fluorometric Imaging Plate Reader (FLIPR TETRA, Molecular Devices) (excitation wavelength of 470-495 nm, emission wavelength of 515-575 nm).

Compounds of the invention were serially diluted to 1000-fold concentration in neat DMSO, plated in 384-well plates, and assayed containing 150 μM ZnCl2 (30 μM final concentration) and 1.1% DMSO (0.32% final concentration). It was diluted 200 times in buffer.

Compounds diluted 200 times in assay buffer containing 150 μM ZnCl2 and 1.1% DMSO were added first, followed by submaximal concentration after 10 min at an EC90 of 1.5 μM (the concentration that produced 90% of the maximum response). A double addition FLIPR protocol was used, including a second addition of the hGPR39 receptor agonist C3 (Tocris, TC-G 1008).

Fluorescence was monitored throughout the run assay. The peak of Ca2+ stimulation (baseline subtracted) was expressed as a percentage of maximal inhibition of the EC90 C3 response and plotted against the concentration of test compound. Curve fitting and IC50 estimation are performed using a four-parameter logistic model using XLfit software.

The potency of the compound was reported as functional pKi (-Log10Ki) obtained using the modified Cheng-Prusoff relationship (Cheng, Y., Prusoff, W.H. 1973.)

fKi =IC50/(1+[L]/EC50) where IC50 is the concentration of antagonist required for 50% inhibition of the maximal response, [L] is the concentration of agonist used (EC90), and EC50 is the maximal response (each is the concentration of agonist required to induce 50% of the dose (obtained from the experimental plate).

The fpKi data is shown in Table 1 below. fpKi less than 5.2 is reported as "+/-". fpKi ranging from 5.2 to 5.9 is reported as “+”. An fpKi of 6.0 to 6.5 is reported as “++”. An fpKi of 6.6 to 7.2 is reported as “+++”. fpKi above 7.3 is reported as "++++".

synthesis

The compounds described herein can be prepared by methods known in the art and are exemplified by the following non-limiting description.

Unless otherwise stated, all reactions are typically performed under an inert atmosphere (e.g. under nitrogen). The following abbreviations are used in the document:

EtOAc, AcOEt, EA = ethyl acetate

Et ₂ O = diethyl ether

CH ₃ CN = acetonitrile

MeOH = methanol

THF = tetrahydrofuran

r.t.(RT) = room temperature

DMSO = dimethyl sulfoxide

DMF = N,N'-dimethylformamide

DCM = dichloromethane

EtOH = Ethanol

RP = reverse phase

FA = formic acid

Cy, cHex = cyclohexane

TEA = triethylamine

DIPEA = N,N-diisopropylethylamine

Boc ₂ O = di- tert -butyl dicarbonate

TFA = trifluoroacetic acid

HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

AcOH = acetic acid

SCX cartridge = powerful cation exchange cartridge

FC = flash chromatography

s.s. = saturated solution

ON = overnight

Scheme 1

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Enamine) by SNAr substitution with pyrrolidine, typically at 80° C., in a suitable aprotic solvent, such as CH ₃ CN. The reaction takes approximately 1 hour to complete.

Step 2

Compounds of formula (III) can be obtained by nitro reduction of compounds of formula (II) under catalytic hydrogenation conditions using, for example, Pd/C in a suitable solvent such as acetic acid, typically at room temperature. The reaction takes approximately 4 hours to complete.

Step 3

Compounds of formula IV can be obtained by a coupling reaction between a compound of formula III and a suitable commercially available acyl chloride, for example cyclopropanecarbonyl chloride, in the presence of an organic base, for example TEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained from compounds of formula (IV) by hydrolysis using, for example, LiOH at 50° C. in a suitable solvent mixture such as MeOH/THF/H ₂ O. The reaction takes approximately 36 hours to complete.

Step 5

Compounds of formula VI can be obtained from compounds of formula V by coupling with an appropriate amine in the presence of a coupling agent, such as HATU, and an organic base, such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete.

Scheme 1, Preparation of Cpd II : Methyl 4-nitro-2-pyrrolidin-1-ylbenzoate

To a solution of methyl 2-fluoro-4-nitrobenzoatoe (5.0 g, 25.11 mmol) in MeCN (50 mL) was added pyrrolidine (5.36 g, 75.32 mmol) and the reaction was stirred at 80 °C for 1 h. did. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was taken together with water and filtered. The solid was dried under vacuum to give the product methyl 4-nitro-2-pyrrolidin-1-ylbenzoate, which was used in the next step without further purification.

Yield: 6 g

1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.49 (d, 1H), 7.44 (dd, 1H), 3.86 (s, 3H), 3.26 - 3.20 (m, 4H), 1.95 - 1.90 (m, 4H); LC-MS: 251.05 (MH+).

Scheme 1, Preparation of Cpd III : Methyl 4-amino-2-pyrrolidin-1-ylbenzoate

To a solution of methyl 4-nitro-2-pyrrolidin-1-ylbenzoate (4.75 g, 18.98 mmol) in acetic acid (190 mL) was added Pd-C 10% (2.02 g, 1.9 mmol). The reaction was stirred at room temperature under H ₂ atmosphere for 4 hours. After this time, the mixture was filtered through a pad of Celite, washed with MeOH and the solvent was evaporated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product methyl 4-amino-2-pyrrolidin-1-ylbenzoate, which was added It was used in the next step without purification.

Yield: 3.95 g

1H NMR (400 MHz, DMSO-d6) δ 7.29 (d, 1H), 6.02 - 5.88 (m, 2H), 5.47 (s, 2H), 3.67 (s, 3H), 3.16 - 2.99 (m, 4H), 2.00 - 1.71 (m, 4H); LC-MS: m/z 221.39 (MH+).

Scheme 1, Preparation of Cpd IV : Methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate

A solution of methyl 4-amino-2-pyrrolidin-1-ylbenzoate (5.75 g, 26.1 mmol) and N,N-diisopropylethylamine (9.09 mL, 52.21 mmol) in dry DCM (145.57 mL) Cooled to 0 °C and stirred for 10 min. After this time, cyclopropanecarbonyl chloride (3.08 mL, 33.94 mmol) was added dropwise, and the reaction mixture was allowed to reach room temperature and stirred overnight. The next day the reaction was diluted with DCM and washed with saturated NaHCO ₃ solution. The organic phase was washed with brine, dried in a phase separator and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with cHex/AcOEt 9:1 to cHex/AcOEt 9:1) to obtain the product of the above formula: methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzo. Eight were provided.

Yield: 5.6 g

1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 6.92 (dd, 1H), 3.75 (s, 3H), 3.11 (q, 4H), 1.92 - 1.83 (m, 4H), 1.83 - 1.75 (m, 1H), 0.83 - 0.76 (m, 4H); LC-MS: m/z 289.12 (MH+).

Scheme 1, Preparation of Cpd V : 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid

To a solution of methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate (5.0 g, 17.34 mmol) in THF (150 mL)/MeOH (20 mL) was added 6N NaOH solution (5.78 mL). , 34.68 mmol) was added. The reaction was stirred at 50°C overnight.

The next day additional 6N sodium hydroxide solution (5.78 mL, 34.68 mmol) was added followed by 10 mL of MeOH and the reaction was stirred at 50°C for 1 day. After this time, the reaction was cooled to RT and concentrated under vacuum. The aqueous solution was washed with DCM (3 times), acidified with 12N HCl until pH = 1, and extracted with AcOEt 5 times. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was taken with Et ₂ O, filtered and the solid washed with Et ₂ O and dried under vacuum to give the product 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid of the formula: This was used in the next step without further purification.

Yield: 2.5 g

1H NMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 10.25 (s, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 6.99 (dd, 1H), 3.21 - 3.04 ( m, 4H), 2.01 - 1.78 (m, 4H), 1.79 (tt, 1H), 0.86 - 0.73 (m, 4H); LC-MS: m/z 275.08 (MH+).

Manufactured by: N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 1

4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-yl benzoic acid (46.58 mg, 0.170 mmol) and (HATU) [dimethylamino(3-triazolo[4,5-) in DMF (2 mL) b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (96.85 mg, 0.250 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.510 mmol) in DMF (1 mL). A solution of -phenylpyrrolidine (25.0 mg, 0.170 mmol) was added. The reaction mixture was stirred RT/ON. After the reaction was completed, the mixture was diluted with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with cHex/AcOEt 8:2 to cHex/AcOEt 2:8) to obtain the product N-[4-(2-phenylpyrrolidine-1-carbonyl)-3 of the above formula. -pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was provided (see Example 1 ).

Yield: 34.2 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.14 - 9.87 (m, 1H), 7.38 - 7.27 (m, 3H), 7.26 - 7.12 (m, 2H), 7.09 - 6.92 (m, 3H), 5.17 - 4.78 (m, 1H), 3.61 (d, 2H), 3.08 (d, 4H), 2.39 - 2.17 (m, 1H), 2.04 - 1.62 (m, 8H), 0.84 - 0.62 (m, 4H); LC-MS: m/z 404.3 (MH+).

Manufactured by: N-[4-(3-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 2

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 3-phenylpyrrolidine was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 38% (26 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, 1H), 7.39 - 7.18 (m, 5H), 7.10 - 6.97 (m, 2H), 6.96 - 6.85 (m, 1H), 3.99 - 3.65 (m) , 2H), 3.38 (d, 3H), 3.26 - 2.99 (m, 4H), 2.25 (d, 1H), 2.08 - 1.70 (m, 6H), 0.77 (dtd, 4H); LC-MS: m/z 404.3 (MH+).

Manufactured by: N-[4-(2-oxa-7-azaspiro[3.4]octane-7-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 3

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 2-oxa-6-azaspiro[3.4]octane was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 61% (40 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.10 - 7.02 (m, 1H), 6.99 - 6.86 (m, 2H), 4.57 (d, 1H), 4.49 - 4.38 (m, 3H) ), 3.65 (s, 1H), 3.41 (s, 2H), 3.11 (d, 5H), 2.12 (dt, 2H), 1.89 - 1.81 (m, 4H), 1.77 (qd, 1H), 0.77 (dt, 4H); LC-MS: m/z 370.2 (MH+).

Manufactured by: N-[4-[(trans)-2,6-dimethylmorpholine-4-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 4

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where trans-2,6-dimethylmorpholine was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 50% (33 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1H), 7.06 (s, 1H), 6.99 - 6.88 (m, 2H), 4.11 - 3.67 (m, 3H), 3.41 - 2.72 (m, 7H), 1.95 - 1.80 (m, 4H), 1.80 - 1.70 (m, 1H), 1.32 - 1.09 (m, 3H), 0.99 (dd, 3H), 0.82 - 0.69 (m, 4H); LC-MS: m/z 372.23 (MH+).

Manufactured by: N-[4-(2,6-dimethyl-1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 5

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 2,6-dimethyl-1,4-thiazinane 1,1-dioxide hydrochloride was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 44% (34 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, 1H), 7.28 - 6.72 (m, 3H), 4.79 (d, 1H), 3.83 (dd, 1H), 3.48 - 3.38 (m, 1H), 3.25 - 2.76 (m, 7H), 1.97 - 1.65 (m, 5H), 1.25 (t, 3H), 1.06 (dd, 3H), 0.81 - 0.74 (m, 4H); LC-MS: m/z 420.2 (MH+).

Manufactured by: N-[4-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 6

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 44% (34 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.06 (dd, 1H), 7.00 - 6.82 (m, 2H), 4.47 - 4.00 (m, 3H), 3.24 - 2.82 (m, 7H) ), 1.98 - 1.44 (m, 9H), 0.77 (dt, 4H); LC-MS: m/z 370.2 (MH+).

Manufactured by: N-[4-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 7

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 13% (9 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.33 - 6.83 (m, 3H), 4.53 (s, 1H), 3.84 - 3.41 (m, 5H), 3.23 - 2.94 (m, 4H) ), 1.97 - 1.70 (m, 9H), 0.82 - 0.67 (m, 4H); LC-MS: m/z 370.2 (MH+).

Manufactured by: N-[4-(6-oxa-3-azabicyclo[3.1.1]heptane-3-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 8

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 75% (49 mg).

1H NMR (400 MHz, DMF-d7) δ 10.07 (s, 1H), 7.07 (d, 1H), 7.01 - 6.85 (m, 2H), 4.53 (d, 2H), 3.84 (d, 1H), 3.61 - 3.44 (m, 2H), 3.26 (s, 2H), 3.24 - 2.93 (m, 5H), 1.94 - 1.56 (m, 5H), 0.77 (dd, 4H); LC-MS: m/z 356.2 (MH+)

Manufactured by: N-[4-(3-azabicyclo[3.1.1]heptane-3-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 9

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was used instead of 2-phenylpyrrolidine. The title compound was obtained in a yield of 78% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 7.05 (s, 1H), 6.93 (s, 2H), 3.73 - 3.34 (m, 4H), 3.29 - 3.01 (m, 6H), 2.39 - 2.32 (m, 1H), 2.17 - 2.04 (m, 2H), 1.97 - 1.68 (m, 4H), 1.33 - 1.13 (m, 2H), 0.78 (dd, 4H); LC-MS: m/z 354.2 (MH+)

Manufactured by: tert-Butyl N-[1-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperidin-4-yl]-N-methylcarbamate

Example 10

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where 4-N-BOC-4-N-methyl-aminopiperidine was used instead of 2-phenylpyrrolidine. The title compound was obtained in quantitative yield (140 mg).

LC-MS: m/z 471.49 (MH+)

Manufactured by: tert-Butyl N-[1-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperidin-4-yl]carbamate

Example 11

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where N-(4-piperidinyl)carbamic acid tert-butyl ester was used instead of 2-phenylpyrrolidine. The title compound was obtained in quantitative yield (140 mg).

LC-MS: m/z 457.48 (MH+)

Manufactured by: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine-1-carboxyl rate

Example 12

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-[2-(trifluoromethyl)phenyl]piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 19% (24 mg).

LC-MS: m/z 587.30 (MH+).

Manufactured by: tert-Butyl 3-(3-cyanophenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

Example 13

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-(3-cyanophenyl)piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 47% (55 mg).

LC-MS: m/z 544.27 (MH+).

Manufactured by: tert-Butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl) Piperazine-1-carboxylate

Example 14

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 60% (73 mg).

LC-MS: m/z 554.25 (MH+)

Manufactured by: tert-Butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-methylphenyl)piperazine-1-carboxylate

Example 15

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-(4-methylphenyl)piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 70% (96 mg).

Manufactured by: tert-Butyl 3-(3-chloro-5-methylphenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

Example 16

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-(3-chloro-5-methylphenyl)piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in a yield of 90% (130 mg).

LC-MS: m/z 567.29 (MH+).

Manufactured by: tert-Butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(3-methylphenyl)piperazine-1-carboxylate

Example 17

The synthesis of the title compound was similar to the synthesis of compound N-[4-(2-phenylpyrrolidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide in Example 1. was performed, where tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate was used instead of 2-phenylpyrrolidine. The title compound was obtained as a racemic mixture in quantitative yield (150 mg).

LC-MS: m/z 533.33 (MH+).

Scheme 2

Step 1

Compounds of formula II are typically treated at 90° C. with a suitable chlorinating agent, such as SOCl ₂ to form the acyl chloride of a compound of formula I (commercially available from Enamine), followed by 1 in the presence of a suitable organic base, such as DIPEA. It can be obtained through coupling with -methyl-3-phenylpiperazine (commercially available from Enamine). The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 12 hours to complete.

Step 2

Compounds of formula II can be obtained from compounds of formula II by SNAr substitution with pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes approximately 36 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by Buchwald reaction with a suitable heteroaryl aniline in the presence of a suitable palladium precatalyst, such as tBuBrettPhos Pd G3, and a suitable base such as K ₃ PO ₄ . The reaction is typically carried out at 120° C. in a suitable solvent, such as 1-butanol. The reaction takes about 12 hours to about 24 hours to complete.

Step 4

Compounds of formula (V) have a suitable commercial affinity with compounds of formula (III), typically at 95° C., in the presence of a suitable catalyst, for example palladium tetrakis triphenylphosphine, in a suitable solvent, 1,2-dimethoxyethane, a suitable inorganic base, Na ₂ CO ₃ It can be obtained through Suzuki coupling between boronic acids, which are available as The reaction takes approximately 2 days to complete.

Scheme 2, Preparation of Cpd II : (2-fluoro-4-iodophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 2-fluoro-4-iodobenzoic acid (2.0 g, 7.52 mmol) and thionyl dichloride (10.97 mL, 150.37 mmol) was heated to reflux for 2.5 hours. After this time, the reaction was cooled to RT and concentrated under vacuum. The mixture was stripped three times with cyclohexane to remove excess thionyl dichloride. The remainder was suspended in dry DCM (40 mL), triethylamine (3.14 mL, 22.56 mmol) was added, and then 1-methyl-3-phenylpiperazine (1.33 g, 7.52 mmol) was added. The reaction mixture was stirred at RT overnight. The next day, the mixture was diluted with DCM and washed with saturated NaHCO ₃ solution. The combined organic phases were dried in a phase separator and concentrated under vacuum to give the product of the formula (2-fluoro-4-iodophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. Provided as a semi-mixture. The product was used in the next step without further purification.

Yield: 3.2 g

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.75 (dd, 2H), 7.47 (d, 2H), 7.42 - 7.20 (m, 4H), 4.74 - 3.64 (m, 1H), 3.55 - 3.34 (m , 1H), 3.25 - 2.57 (m, 2H), 2.36 - 2.24 (m, 1H), 2.18 (d, 3H), 2.07 - 1.83 (m, 1H), 0.97 (t, 1H); LC-MS: m/z 425.05 (MH+).

Scheme 2, Preparation of Cpd III : (4-iodo-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

To a solution of (2-fluoro-4-iodophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (2.79 g, 6.56 mmol) in DMSO (50 mL) was added pyrrolidine ( 1.64 mL, 19.69 mmol) was added and the reaction mixture was stirred at 120 °C overnight. After 16 h additional pyrrolidine (0.55 mL, 6.56 mmol) was added and the reaction was stirred for 1 day. The next day the reaction was cooled to RT, diluted with water and the aqueous phase was extracted three times with AcOEt. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 95:5 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product of the formula (4-iodo-2-pyrrolidin-1-ylphenyl)-(4-methyl -2-phenylpiperazin-1-yl)methanone was provided.

Yield: 1.0 g

1H NMR (400 MHz, DMSO) δ 7.73 (d, 1H), 7.53 - 7.14 (m, 4H), 7.10 - 6.76 (m, 2H), 6.68 (d, 1H), 5.84 - 5.57 (m, 1H), 4.77 - 4.29 (m, 1H), 3.14 - 2.58 (m, 7H), 2.43 - 1.99 (m, 7H), 1.75 - 1.49 (m, 2H); LC-MS: m/z 476.1 (MH+).

Preparation: [4-[(3-methyl-1,2-oxazol-5-yl)amino]-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazine-1- 1) Methanone

Example 18

(4-iodo-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (150.0 mg, 0.320 mmol) in 1-butanol (1.2 mL) , 3-methyl-5-isoxazolamine (37.15 mg, 0.380 mmol), tripotassium phosphate (66.98 mg, 0.320 mmol) and tBuBrettPhos Pd G3 (26.96 mg, 0.030 mmol) were degassed with a N ₂ -vacuum cycle. The reaction was stirred at 120°C for 24 hours. After this time, the reaction was cooled to RT, diluted with MeOH and purified by SCX, first washing with MeOH and then eluting with 1N NH ₃ in MeOH. Basic fractions were collected and concentrated under vacuum. The residue was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 95:5 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product of formula [4-[(3-methyl-1,2-oxazol-5-yl)amino] -2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone was provided as a racemic mixture.

Yield: 16 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.75 (d, 1H), 7.83 - 7.14 (m, 6H), 6.97 (ddd, 1H), 6.78 - 6.66 (m, 1H), 6.61 - 6.35 (m , 1H), 3.55 - 3.30 (m, 2H), 3.10 - 2.55 (m, 7H), 2.37 - 2.10 (m, 7H), 1.94 (s, 4H), 1.67 (d, 1H); LC-MS: m/z 446.48 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidin-1-yl-4-([1,2,4]triazolo[1,5-a]pyridine- 2-ylamino)phenyl]methanone

Example 19

The synthesis of the title compound was carried out using the compound of Example 18 [4-[(3-methyl-1,2-oxazol-5-yl)amino]-2-pyrrolidin-1-ylphenyl]-(4-methyl- It was carried out similarly to the synthesis of 2-phenylpiperazin-1-yl)methanone, where [1,2,4]triazolo[1,5-a]pyridin-2-amine was reacted with 3-methyl-5-isox. It was used instead of sazolamine. The title compound was obtained in a yield of 16% (25 mg).

1H NMR (500 MHz, DMSO-d6) δ ppm 9.52 (br d, 1H), 8.74 (d, 1H), 7.84 - 6.50 (m, 11H), 5.93 - 4.61 (m, 1H), 4.54 - 3.36 (m , 2H), 3.30 - 3.17 (m, 2H), 3.06 (br s, 4H), 2.44 - 2.09 (m, 4H), 2.09 - 1.51 (m, 5H); LC-MS: m/z 482.24 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[4-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]-2-pyrrolidine- 1-ylphenyl]methanone

Example 20

The synthesis of the title compound was carried out using the compound of Example 18 [4-[(3-methyl-1,2-oxazol-5-yl)amino]-2-pyrrolidin-1-ylphenyl]-(4-methyl- It was performed similarly to the synthesis of 2-phenylpiperazin-1-yl)methanone, where 5-methyl-1,3,4-thiadiazol-2-amine was used instead of 3-methyl-5-isoxazolamine. did. The title compound was obtained in a yield of 39% (56 mg).

1H NMR (400 MHz, DMSO- d ₆ ) δ 10.18 (d, 1H), 7.76 - 7.68 (m, 1H), 7.54 - 7.17 (m, 5H), 7.15 - 6.99 (m, 1H), 6.94 - 6.81 ( m, 1H), 5.90 - 4.27 (m, 1H), 3.43 (d, 1H), 3.12 - 2.53 (m, 8H), 2.37 (dt, 1H), 2.22 (d, 4H), 2.07 - 1.84 (m, 4H), 1.81 - 1.55 (m, 2H); LC-MS: m/z 463.2 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[4-(1H-pyrazol-4-yl)-2-pyrrolidin-1-ylphenyl]methanone

Example 21

(4-Bromo-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (50.0 mg) in 1,2-dimethoxyethane (1.052 mL) , 0.120 mmol), 1H-pyrazole-4-boronic acid (14.37 mg, 0.130 mmol) and 2M aqueous Na ₂ CO ₃ solution (0.18 mL, 0.350 mmol) was degassed with 5 cycles of nitrogen/vacuum. Palladium tetrakis triphenylphosphine (6.74 mg, 0.010 mmol) was then added and the vessel was sealed. The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and then heated to 95° C. for 2 days. After this time the mixture was immediately purified by RP FC using acid conditions (5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1% HCOOH). (eluted with ), and then purified with SCX by eluting first with MeOH and then with 1N NH ₃ in MeOH. The basic fractions were collected and concentrated under vacuum to give the product of the formula (4-methyl-2-phenylpiperazin-1-yl)-[4-(1H-pyrazol-4-yl)-2-pyrrolidin- 1-Ylphenyl]methanone was provided.

Yield: 14 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.91 (bs, 1H), 8.29 - 8.15 (m, 1H), 7.98 - 7.85 (m, 1H), 7.74 (d, 1H), 7.60 - 7.15 (m , 4H), 7.08 - 6.80 (m, 3H), 5.98 - 4.37 (m, 1H), 3.52 - 3.39 (m, 2H), 3.16 - 2.61 (m, 5H), 2.44 - 2.13 (m, 5H), 2.05 -1.90 (m, 3H), 1.83 - 1.63 (m, 2H); LC-MS: m/z 416.18 (MH+).

Scheme 3

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Enamine) by coupling with an appropriate amine in the presence of a coupling agent such as HATU, and an organic base such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete. Alternatively, compounds of formula II can be treated with a suitable chlorinating agent such as SOCl ₂ , typically at 90° C., to form the acyl chloride of a compound of formula I (commercially available from Enamine), followed by oxidation in the presence of a suitable organic base, for example TEA. It can be obtained through coupling with an appropriate amine. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes about 1 hour to about 12 hours to complete.

Step 2

Compounds of formula III can be obtained by nitro reduction of compounds of formula II using Zn dust in a suitable solvent, such as AcOH, typically at room temperature. The reaction takes about 3 hours to about 12 hours to complete. Alternatively, compounds of formula III can be obtained by reduction of compounds of formula II using tin(III) chloride dehydrate in a suitable solvent, such as EtOH, typically at 80°C. The reaction takes approximately 12 hours to complete.

Step 3

Compounds of formula IV can be obtained by a coupling reaction between a compound of formula III and a suitable commercially available acyl chloride, for example cyclopropanecarbonyl chloride, in the presence of an organic base, for example TEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 3 hours to complete.

Step 4

The compounds of formula V are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 100° C. It can be obtained via Suzuki coupling between a compound of formula IV and the desired heteroaryl boronic acid ester or heteroaryl boronic acid. The reaction takes about 3 to 12 hours to complete.

Step 5

Compounds of formula (VI) are reacted with compounds of formula (IV) in the presence of a suitable catalyst, such as PdCl ₂ (dppf)·CH ₂ Cl ₂ , a suitable base, such as AcOK, in a suitable solvent, such as 1,4 dioxane, typically at 100° C. , the desired aryl bromide, and bis(pinacolato)diborone can be obtained through Miyaura coupling. The reaction takes approximately 12 hours to complete.

Step 6

Compounds of formula (V) are commercially available with compounds of formula (VI) in the presence of a suitable catalyst, for example palladium tetrakis triphenylphosphine, a suitable inorganic base, Na ₂ CO ₃ and in a suitable solvent, 1,2-dimethoxyethane, typically at 95° C. It can be obtained through Suzuki coupling between available heteroaryl halides. The reaction takes approximately 12 hours to complete.

Scheme 3, Cpd (II)*a preparation: (2-bromo-4-nitrophenyl)-(4,4-difluoropiperidin-1-yl)methanone

[Dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate, HATU (2.32 g, 6.1 mmol), 2-bromo- in DMF (25 mL) 4,4-difluoropiperidine hydrochloride (768.7 mg, 4.88 mmol) in a solution of 4-notrobenzoic acid (1.0 g, 4.06 mmol) and N,N-diisopropylethylamine (3.15 g, 24.39 mmol) ) was added. The reaction was stirred at RT for 3 h. After this time saturated aqueous NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water, and the solvent was filtered and evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with 100% cHex to AcOEt/cHex 25:75) to give the product of the formula (2-bromo-4-nitrophenyl)-(4,4-difluoropiperidine). -1-day) Methanone was provided.

Yield: 1.2 g

1H NMR (400 MHz, DMSO) δ 8.51 (d, 1H), 8.32 (dd, 1H), 7.77 (d, 1H), 3.89 (dt, 1H), 3.68 (ddd, 1H), 3.25 (t, 2H) , 2.32 - 1.88 (m, 4H); LC-MS: m/z 349.0, 351.0 (MH+)

Scheme 3, Cpd (II)*b Preparation: (2-bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone

A mixture of 2-bromo-4-nitrobenzoic acid (1.5 g, 6.1 mmol) and thionyl dichloride (8.9 mL, 121.95 mmol) was heated to 90 °C and stirred for 2 hours. The reaction was cooled to RT and concentrated under vacuum. The mixture was stripped three times with cyclohexane to remove excess thionyl dichloride. The residue was taken up with DCM (10 mL) and added to a solution of triethylamine (5.96 mL, 42.68 mmol) and 1-propylpiperazine dihydrobromide (1.77 g, 6.1 mmol) in DCM (75 mL). The reaction mixture was stirred at RT for 1 h, then it was diluted with DCM, washed with saturated NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product of the formula (2- Bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone was provided. The product was used in the next step without further purification.

Yield: 2.2 g

1H NMR (400 MHz, DMSO) δ 8.49 (d, 1H), 8.29 (dd, 1H), 7.65 (d, 1H), 3.65 (qdd, 2H), 3.18 - 3.05 (m, 2H), 2.49 - 2.38 ( m, 2H), 2.37 - 2.31 (m, 2H), 2.30 - 2.24 (m, 2H), 1.44 (h, 2H), 0.86 (t, 3H); LC-MS: m/z 256.05, 358.07 (MH+).

Scheme 3, Cpd (II)*c Preparation: (2-bromo-4-nitrophenyl)-(1,1-dioxo-1,4-thiazinin-4-yl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (2-bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone, where 1,4-thiazinane 1,1- Dioxide hydrochloride was used instead of 1-propylpiperazine dihydrobromide. The title compound was obtained in a yield of 74% (3.3 g).

1H NMR (400 MHz, DMSO) δ 8.52 (d, 1H), 8.36 (dd, 1H), 7.89 (d, 1H), 4.50 - 4.36 (m, 1H), 3.74 (ddd, 1H), 3.60 - 3.51 ( m, 2H), 3.42 (d, 1H), 3.28 - 3.23 (m, 1H), 3.12 - 3.05 (m, 2H); LC-MS: m/z 362.87, 364.94 (MH+).

Scheme 3, Cpd (II)*d Preparation: (2-bromo-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (2-bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone, where 1-methyl-3-phenylpiperazine It was used instead of 1-propylpiperazine dihydrobromide. The title compound was obtained in a yield of 100% (1.8 g).

1H NMR (400 MHz, DMSO) δ 8.50 (td, 1H), 8.37 - 8.09 (m, 1H), 7.89 - 7.17 (m, 6H), 5.95 - 5.71 (m, 1H), 4.47 (d, 1H), 3.50 (dd, 1H), 3.17 - 2.57 (m, 2H), 2.40 (td, 1H), 2.30 - 1.90 (m, 4H); LC-MS: 404.01, 405.96 (MH+).

Scheme 3, Cpd (III)*a preparation: (4-amino-2-bromophenyl)-(4,4-difluoropiperidin-1-yl)methanone

Zinc (2.19 g) to a solution of (2-bromo-4-nitrophenyl)-(4,4-difluoropiperidin-1-yl)methanone (1.17 g, 3.35 mmol) in AcOH (28 mL). , 33.51 mmol) was added and the reaction mixture was stirred at RT for 24 h. The reaction was filtered and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted with AcOEt (3 times). The combined organic fractions were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The crude material was purified by FC on silica gel (eluted with cHex/EtOAc 80:20 to cHex/EtOAc 4:6) to give the product of the formula (4-amino-2-bromophenyl)-(4,4-difluoro). Piperidin-1-yl)methanone was provided.

Yield: 650 mg

^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 (d, 1H), 6.80 (d, 1H), 6.57 (dd, 1H), 5.62 (s, 2H), 3.86 - 3.73 (m, 2H), 3.67 - 3.55 (m, 2H), 2.13 - 1.91 (m, 4H); LC-MS: m/z 319.25, 321.25 (MH+).

Scheme 3, Cpd (III)*b Preparation: (4-amino-2-bromophenyl)-(1,1-dioxo-1,4-thiazinin-4-yl)methanone

(2-bromo-4-nitrophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone (1.2 g, 3.3 mmol) and stannous chloride (24 mL) III) A mixture of dihydrate (2.26 g, 9.91 mmol) was heated to reflux for 8 h. After this time, the mixture was cooled to RT, filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% DCM to DCM/MeOH 95:5 as eluent) to obtain the product of the above formula (4-amino-2-bromophenyl)-(1,1-dioxo- 1,4-thiazinan-4-yl)methanone was provided.

Yield: 1.0 g

1H NMR (400 MHz, DMSO-d6) δ 7.10 (d, 1H), 6.80 (d, 1H), 6.57 (dd, 1H), 5.75 (s, 2H), 7H), 4.27 (s, 1H), 3.40 (d, 7H); LC-MS: m/z 332.93, 334.9 (MH+).

Scheme 3, Cpd (III)*c Preparation: (4-amino-2-bromophenyl)-(4-propylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (4-amino-2-bromophenyl)-(4,4-difluoropiperidin-1-yl)methanone, where (2-bromo -4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone to (2-bromo-4-nitrophenyl)-(4,4-difluoropiperidin-1-yl)methane Used instead of on. The title compound was obtained in a yield of 88% (1.7 g).

1H NMR (400 MHz, DMSO) δ 6.91 (d, 1H), 6.79 (d, 1H), 6.56 (dd, 1H), 5.57 (s, 2H), 3.57 (s, 2H), 3.15 (s, 2H) , 2.35 (d, 3H), 2.29 - 2.14 (m, 3H), 1.43 (h, 2H), 0.85 (t, 3H); LC-MS: m/z 326.04, 327.99 (MH+).

Scheme 3, Cpd (III)*d Preparation: (4-amino-2-bromophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (4-amino-2-bromophenyl)-(4,4-difluoropiperidin-1-yl)methanone, where (2-bromo -4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone is converted to (2-bromo-4-nitrophenyl)-(4,4-difluoropiperidine-1 -1) It was used instead of methanone. The title compound was obtained in a yield of 91% (850 mg).

1H NMR (400 MHz, DMSO) δ 7.57 (d, 1H), 7.30 (d, 5H), 6.80 (td, 2H), 5.75 (s, 1H), 5.60 (s, 2H), 4.95 - 4.27 (m, 1H), 3.45 (d, 1H), 3.23 - 2.87 (m, 2H), 2.77 - 2.57 (m, 1H), 2.38 - 2.13 (m, 3H), 1.89 (s, 1H); LC-MS: m/z 374.09, 376.08 (MH+).

Scheme 3, Cpd (IV)*a Preparation: N-[3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide

N,N-diisopropylethylamine (0.69 mL, 4.09 mmol) and (4-amino-2-bromophenyl)-(4,4-difluoropiperidin-1-yl) in DCM (20 mL) ) Cyclopropanecarbonyl chloride (0.22 mL, 2.45 mmol) was added dropwise to the cooled mixture of methanone (652.0 mg, 2.04 mmol) at 0°C. The mixture was stirred at RT for 1 h. After this time, the mixture was diluted with DCM, washed with saturated NaHCO ₃ solution and dried with a phase separator. The solvent was evaporated and the crude material was purified by FC on silica gel (eluted with 100% DCM to DCM/MeOH 95:5) to give the product N-[3-bromo-4-(4,4-difluoro) of the formula: Lopiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide was provided.

Yield: 830 mg

1H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 8.03 (d, 1H), 7.56 (dd, 1H), 7.33 (d, 1H), 3.82 (s, 1H), 3.66 (d, 1H) , 3.24 (t, 2H), 2.17 - 1.85 (m, 4H), 1.82 - 1.71 (m, 1H), 0.87 - 0.80 (m, 4H); LC-MS: m/z 387.16, 389.16 (MH+).

Scheme 3, Cpd (IV)*b Preparation: N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out similarly to the synthesis of the compound N-[3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide, where ( 4-Amino-2-bromophenyl)-(4-propylpiperazin-1-yl)methanone is converted to (4-amino-2-bromophenyl)-(4,4-difluoropiperidine-1 -1) It was used instead of methanone. The title compound was obtained in a yield of 96% (2.0 g).

1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.02 (d, 1H), 7.55 (dd1H), 7.24 (d, 1H), 3.61 (d, 2H), 3.12 (td, 2H), 2.46 - 2.09 (m, 6H), 1.77 (p, 1H), 1.42 (dt, 2H), 0.92 - 0.78 (m, 7H); LC-MS: m/z 394.10, 396.04 (MH+).

Scheme 3, Cpd (IV)*c Preparation: N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out similarly to the synthesis of the compound N-[3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide, where ( 4-amino-2-bromophenyl)-(1,1-dioxo-1,4-thiazinin-4-yl)methanone is replaced with (4-amino-2-bromophenyl)-(4,4- Difluoropiperidin-1-yl) was used instead of methanone. The title compound was obtained in a yield of 43% (1.6 g).

1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 8.04 (d, 1H), 7.59 (dd, 1H), 7.46 (d, 1H), 4.35 (s, 1H), 3.75 (s, 1H) , 3.56 (s, 3H), 3.23 (s, 2H), 3.06 (s, 1H), 1.78 (p, 1H), 0.84 (d, 4H); LC-MS: m/z 401.27, 403.27 (MH+).

Scheme 3, Cpd (IV)*d Preparation: N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out similarly to the synthesis of the compound N-[3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide, where ( 4-Amino-2-bromophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone is reacted with (4-amino-2-bromophenyl)-(4,4-difluorophenyl) Peridin-1-yl) was used instead of methanone. The title compound was obtained in a yield of 69% (3.9 g).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 10.44 (d, 1H), 8.14 - 7.94 (m, 1H), 7.58 (d, 2H), 7.31 (dt, 5H), 5.84 - 5.52 (m, 1H) ), 3.47 (d, 1H), 3.17 - 2.57 (m, 2H), 2.46 - 2.12 (m, 4H), 2.11 - 1.60 (m, 2H), 1.08 (dt, 1H), 0.82 (d, 4H); LC-MS: m/z 442.12, 444.14 (MH+).

Manufactured by: N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-methylpyrazol-3-yl)phenyl]cyclopropanecarboxamide

Example 22

1-Methyl-1H-pyrazole-3-boronic acid pinacol ester (83.83 mg, 0.400 mmol) in water (0.3 mL)/1,2-dimethoxyethane (3 mL), N-[3-bromo- 4-(4,4-difluoropiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide (120.0 mg, 0.310 mmol), X-Phos aminobiphenyl palladium chloride precatalyst (24.35 mg, 0.030 mmol) ) and tripotassium phosphate (197.35 mg, 0.930 mmol) were degassed under nitrogen flux for 5 min and then heated to 100 °C overnight. The next day the reaction was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The residue was purified by FC on silica gel (eluted with DCM/EtOAc 90:10 to DCM:AcOEt 20:80) and again by reverse-phase FC using acid conditions (5:95 CH ₃ CN/H ₂ O + 0.1 % HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product N-[4-(4,4-difluoropiperidine-1-carbonyl) -3-(1-methylpyrazol-3-yl)phenyl]cyclopropanecarboxamide was provided.

Yield: 22 mg

1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 7.95 (d, 1H), 7.73 (d, 1H), 7.63 (dd, 1H), 7.20 (d, 1H), 6.35 (d, 1H) , 3.85 (s, 4H), 3.51 (ddd, 1H), 3.13 (tt, 2H), 2.13 - 1.89 (m, 2H), 1.79 (tt, 2H), 1.60 - 1.47 (m, 1H), 0.85 - 0.75 (m, 4H); LC-MS: m/z 389.2 (MH+)

Manufactured by: N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl]cyclopropanecarboxamide

Example 23

The synthesis of the title compound was carried out using the compound N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-methylpyrazol-3-yl)phenyl]cyclopropane of Example 22. The synthesis was performed similarly to the carboxamide, but here 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H - Pyrazole was used instead of 1-methyl-1H-pyrazole-3-boronic acid pinacol ester. The title compound was obtained in a yield of 42% (54 mg).

1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.65 (dd, 1H), 7.21 (d, 1H), 6.34 (d, 1H) , 4.51 (hept, 1H), 3.93 - 3.82 (m, 1H), 3.51 (ddd, 1H), 3.20 - 3.02 (m, 2H), 2.14 - 1.66 (m, 4H), 1.42 (dd, 6H), 1.36 - 1.21 (m, 1H), 0.85 - 0.75 (m, 4H); LC-MS: m/z 417.3 (MH+).

Manufactured by: N-[3-(1-propan-2-ylpyrazol-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

Example 24

The synthesis of the title compound was carried out using the compound N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-methylpyrazol-3-yl)phenyl]cyclopropane of Example 22. It was carried out similarly to the synthesis of carboxamides, but here N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide and 1-isopropyl-3-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was reacted with N-[3-bromo-4-(4,4-difluoromethylene), respectively. It was used instead of lopiperidine-1-carbonyl)phenyl]cyclopropanecarboxamide and 1-methyl-1H-pyrazole-3-boronic acid pinacol ester. The title compound was obtained in a yield of 38% (61 mg).

1H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.64 (dd, 1H), 7.13 (d, 1H), 6.30 (d, 1H) , 4.52 (hept, 1H), 3.62 - 3.43 (m, 2H), 3.06 - 2.96 (m, 1H), 2.90 - 2.78 (m, 1H), 2.30 (dt, 2H), 2.20 - 2.03 (m, 3H) , 1.88 - 1.66 (m, 2H), 1.44 (dd, 6H), 1.36 (h, 2H), 0.84 - 0.74 (m, 7H); LC-MS: m/z 424.3 (MH+).

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl]cyclopropanecarboxamide

Example 25

4,4,5,5-Tetramethyl-2-(5-methyl-2-thiophenyl)-1,3,2-dioxaborolane (72.61 mg, 0.320 mmol), N-[3-bromo- 4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.250 mmol), X-Phos aminobiphenyl palladium chloride precatalyst (19.58 mg , 0.020 mmol) and tripotassium phosphate (158.69 mg, 0.750 mmol) were suspended in a mixture of water (0.3 mL) and 1,2-dimethoxyethane (3.3 mL). The resulting suspension was degassed under nitrogen flux for 5 min and then heated to 90 °C overnight. The next day the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 60:40 CH ₃ CN/H ₂ O + 0.1% HCOOH). The product of the formula N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl]cyclopropanecarboxamide provided.

Yield: 23 mg

1H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.35 (d, 1H), 6.94 (d, 1H), 6.84 (dt, 1H) , 4.06 - 3.98 (m, 1H), 3.97 - 3.90 (m, 1H), 3.53 - 3.44 (m, 1H), 3.33 (d, 1H), 3.10 - 2.97 (m, 2H), 2.50 (d, 1H) , 2.47 (d, 3H), 2.28 (d, 1H), 1.84 - 1.73 (m, 1H), 0.85 - 0.78 (m, 4H); LC-MS: m/z 419.1 (MH+).

Manufactured by: N-[3-(5-cyanothiophen-2-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 26

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl of Example 25. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, where (5-cyanothiophen-2-yl)boronic acid was reacted with 4,4,5,5-tetramethyl-2-(5-methyl-2-thio It was used instead of phenyl)-1,3,2-dioxaborolane. The title compound was obtained in a yield of 11% (11 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.95 (dd, 2H), 7.72 (dd, 1H), 7.53 (d, 1H), 7.26 (d, 1H), 4.27 (s, 1H), 3.55 (dd, 3H), 3.12 (s, 3H), 2.67 (p, 1H), 1.79 (p, 1H), 0.84 (d, 4H); LC-MS: m/z 430.2 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[2-(trifluoromethyl)-1,3-thiazol-5-yl ]phenyl]cyclopropanecarboxamide

Example 27

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl of Example 25. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, here 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1,3- Thiazole was used instead of 4,4,5,5-tetramethyl-2-(5-methyl-2-thiophenyl)-1,3,2-dioxaborolane. The title compound was obtained in a yield of 55% (62 mg).

1H NMR (400 MHz, DMSO-d6) δ10.56 (s, 1H), 8.13 (q, 1H), 7.97 (d, 1H), 7.74 (dd, 1H), 7.61 (d, , 1H), 4.37 ( s, 1H), 3.57 (s, 3H), 3.30 (s, 4H), 1.80 (p, 1H), 0.88 - 0.81 (m, 4H); LC-MS: m/z 474.1 (MH+).

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl]cyclopropancar copymid

Example 28

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl of Example 25. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, herein 1-propan-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- 1) Pyrazole was used instead of 4,4,5,5-tetramethyl-2-(5-methyl-2-thiophenyl)-1,3,2-dioxaborolane. The title compound was obtained in a yield of 37% (38 mg).

^1H NMR (400 MHz, DMSO _- d6 ) δ 10.38 (s, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.66 (dd, 1H), 7.28 (d, 1H), 6.38 ( d, 1H), 4.52 (p, 1H), 4.09 (s, 1H), 3.97 - 3.86 (m, 1H), 3.56 - 3.36 (m, 2H), 3.10 - 3.00 (m, 2H), 2.58 - 2.53 ( m, 2H), 1.80 (p, 1H), 1.44 (dd, 6H), 0.85 - 0.68 (m, 4H); LC-MS: m/z 431.2 (MH+).

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[5-(trifluoromethyl)thiophen-2-yl]phenyl]cyclopropane Carboxamide

Example 29

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(5-methylthiophen-2-yl)phenyl of Example 25. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, where [5-(trifluoromethyl)thiophen-2-yl]boronic acid was reacted with 4,4,5,5-tetramethyl-2-(5- It was used instead of methyl-2-thiophenyl)-1,3,2-dioxaborolane. The title compound was obtained in a yield of 11% (12 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.96 (d, 1H), 7.76 - 7.68 (m, 2H), 7.51 (d, 1H), 7.22 (dq, 1H), 4.21 ( s, 1H), 3.74 (s, 1H), 3.56 (s, 1H), 3.32 (s, 3H), 3.17 (d, 1H), 3.04 (s, 1H), 1.79 (p, 1H), 0.87 - 0.80 (m, 4H); LC-MS: m/z 473.1 (MH+).

Manufactured by: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl]cyclopropanecarboxamide

Example 30

X-phos amino bipenyl palladium chloride catalyst (10.94 mg, 0.010 mmol), phosphate sampatium (88.68 mg, 0.420 mmol), 1-propane -2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (32.88 mg, 0.140 mmol) and N-[3-bro A mixture of parent-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (80.0 mg, 0.140 mmol) was degassed for 5 min and then stirred at 100° C. overnight. . The next day the mixture was diluted with water and extracted with EtOAc x3. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by reverse-phase FC using basic conditions (from 5:95 CH ₃ CN/H ₂ O + 0.1% NH ₄ OH to 40:60 CH ₃ CN/H ₂ O + 0.1% NH ₄ OH). elution), and purified again by FC on a NH column (eluted with 100% DCM to DCM/EtOAc 60:40) to produce the product of the formula N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl) )-3-(1-Propan-2-ylpyrazol-3-yl)phenyl]cyclopropanecarboxamide was provided as a racemic mixture.

Yield: 24 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 10.42 - 10.28 (m, 1H), 8.00 - 6.93 (m, 10H), 6.47 - 5.66 (m, 3H), 4.70 - 4.30 (m, 3H), 3.41 - 3.33 (m, 1H), 3.10 - 2.55 (m, 4H), 2.41 - 1.72 (m, 2H), 1.56 - 1.00 (m, 5H), 0.86 - 0.75 (m, 4H); LC-MS: m/z 472.28 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl]cyclo Propanecarboxamide

Example 31

The synthesis of the title compound was carried out using the compound N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl of Example 30. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, here 5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1,3- Thiazole was used instead of 1-propan-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. The title compound was obtained as a racemic mixture in a yield of 14% (10 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 - 10.49 (m, 1H), 8.38 - 7.12 (m, 8H), 5.80 - 5.64 (m, 1H), 4.43 - 4.32 (m, 1H), 3.35 - 3.28 (m, 2H), 2.44 - 1.70 (m, 8H), 0.88 - 0.72 (m, 4H); LC-MS: m/z 515.17 (MH+).

Manufactured by: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(2-methyl-1,3-thiazol-5-yl)phenyl]cyclopropanecarboxamide

Example 32

The synthesis of the title compound was carried out using the compound N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl of Example 30. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, here 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 ,3-thiazole was used instead of 1-propan-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. The title compound was obtained as a racemic mixture in a yield of 47% (19 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.54 - 10.34 (m, 1H), 7.94 - 7.60 (m, 2H), 7.55 - 7.16 (m, 6H), 5.73 - 5.64 (m, 1H), 4.60 - 4.28 (m, 2H), 3.12 - 2.53 (m, 5H), 2.02 (s, 6H), 1.17 - 0.90 (m, 1H), 0.89 - 0.74 (m, 4H); LC-MS: m/z 461.25 (MH+).

Manufactured by: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[5-(trifluoromethyl)thiophen-2-yl]phenyl]cyclopropanecarboxamide

Example 33

The synthesis of the title compound was carried out using the compound N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl of Example 30. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, where [5-(trifluoromethyl)thiophen-2-yl]boronic acid was reacted with 1-propan-2-yl-3-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) was used instead of pyrazole. The title compound was obtained as a racemic mixture in a yield of 20% (11 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 - 10.41 (m, 1H), 8.04 - 7.15 (m, 10H), 5.78 - 5.66 (m, 1H), 4.55 - 4.28 (m, 1H), 3.39 - 3.25 (m, 1H), 3.13 - 2.54 (m, 3H), 2.41 - 2.27 (m, 1H), 2.23 - 2.12 (m, 2H), 2.05 - 1.73 (m, 1H), 1.57 - 1.45 (m, 1H) ), 0.83 (br d, 4H); LC-MS: m/z 514.29 (MH+).

Manufactured by: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(5-methylthiophen-2-yl)phenyl]cyclopropanecarboxamide

Example 34

The synthesis of the title compound was carried out using the compound N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)phenyl of Example 3.1. ] was carried out similarly to the synthesis of cyclopropanecarboxamide, where 4,4,5,5-tetramethyl-2-(5-methyl-2-thiophenyl)-1,3,2-dioxaborolane It was used instead of 1-propan-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. The title compound was obtained as a racemic mixture in a yield of 61% (38 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.48 - 10.26 (m, 1H), 7.90 - 7.56 (m, 2H), 7.50 - 7.33 (m, 2H), 7.25 (dtd, 4H), 7.09 - 6.55 (m, 2H), 5.86 - 4.17 (m, 1H), 3.38 - 3.29 (m, 2H), 3.08 - 2.56 (m, 3H), 2.45 - 2.11 (m, 3H), 2.05 - 1.52 (m, 4H) , 1.38 - 0.74 (m, 5H); LC-MS: m/z 460.18 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)phenyl]cyclopropanecarboxamide

Example 35

N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide (100.0) in 1,4-dioxane (2.442 mL) mg, 0.240 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3 , 2-dioxaborolane (74.42 mg, 0.290 mmol), potassium acetate (72.64 mg, 0.730 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] complex of dichloropalladium(II) and dichloromethane. The mixture of (4.0 mg, 0 mmol) was degassed using the Shlenk line technique and stirred at 100 °C overnight. The next day the reaction was cooled to RT, filtered through a pad of Celite, and washed with EtOAc. The solution was concentrated under vacuum to give the product of the formula: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(4,4,5,5-tetramethyl- This gave 1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide, which was used in the next step without further purification.

Yield: 100 mg

1H NMR (400 MHz, DMSO) δ 10.37 (d, 1H), 7.81 (dd, 1H), 7.70 - 7.60 (m, 1H), 7.44 (d, 1H), 3.57 (s, 8H), 1.84 - 1.77 ( m, 1H), 1.27 (s, 6H), 1.07 (s, 6H), 0.90 - 0.76 (m, 4H); LC-MS: m/z 449.21 (MH+).

Manufactured by: N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo Rolan-2-yl)phenyl]cyclopropanecarboxamide

Example 36

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(4,4,5,5-tetra of Example 3.N. The synthesis of methyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide was carried out similarly, but here N-[3-bromo-4-(2-oxa-7- Azaspiro[3.5]nonane-7-carbonyl)phenyl]cyclopropanecarboxamide was converted to N-[3-bromo-4-(1,1-dioxo-1,4-thiagin-4-carbonyl) It was used instead of [phenyl]cyclopropanecarboxamide. The title compound was obtained in quantitative yield (80 mg).

LC-MS: m/z 441.25 (MH+)

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[6-(trifluoromethyl)pyridin-2-yl]phenyl]cyclopropancar copymid

Example 37

Palladium tetrakis triphenylphosphine (14.43 mg, 0.010 mmol) and N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide (112.0 mg, 0.250 mmol) was suspended in 1,2-dimethoxyethane (2.5 mL). 2M aqueous sodium carbonate solution (0.37 mL, 0.750 mmol) was added. The mixture was degassed with 5 cycles of nitrogen/vacuum and 2-bromo-6-(trifluoromethyl)pyridine (62.1 mg, 0.270 mmol) was added. The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and heated to 90° C. overnight. The next day the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The mixture was purified by RP FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 35:65 CH ₃ CN/H ₂ O + 0.1% HCOOH) to The product of the formula N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[6-(trifluoromethyl)pyridin-2-yl]phenyl]cyclopropane Carboxamide was provided.

Yield: 22 mg

1H NMR (400 MHz, DMSO) δ 10.52 (s, 1H), 8.21 (t, 1H), 8.04 (d, 1H), 7.95 (d, 1H), 7.89 (dd, 1H), 7.75 (dd, 1H) , 7.55 (d, 1H), 4.37 (s, 1H), 3.30 (s, 7H), 1.81 (p, 1H), 0.84 (d, 4H); LC-MS: m/z 468.17 (MH+).

Manufactured by: N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-[6-(trifluoromethyl)pyridin-2-yl]phenyl]cyclopropanecarboxylic mid

Example 38

The synthesis of the title compound was carried out using the compound N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[6-(trifluoromethyl)pyridine-2 of Example 37. -yl]phenyl]cyclopropanecarboxamide was carried out similarly to the synthesis, but here N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-(4,4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] cyclopropanecarboxamide was added to N-[4-(1,1-dioxo-1,4-thiazanyl) -4-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained in a yield of 23% (20 mg).

1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 8.17 (t, 1H), 7.98 (d, 1H), 7.86 (dd, 2H), 7.74 (dd, 1H), 7.30 (d, 1H) , 4.44 - 4.07 (m, 4H), 3.30 (s, 4H), 1.81 (p, 1H), 1.76 - 1.37 (m, 4H), 0.88 - 0.79 (m, 4H); LC-MS: m/z 460.20 (MH+).

Scheme 4

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Asstatech) by coupling with an appropriate amine in the presence of a coupling agent such as HATU and an organic base such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete.

Step 2

The compounds of formula III are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 100° C. It can be obtained via Suzuki coupling between a compound of formula II and the desired heteroaryl boronic acid ester. The reaction takes about 3 hours to about 12 hours to complete.

Step 3

Compounds of formula IV can be reacted with nitrile catalysis of compounds of formula III using ethanimidamide hydrochloride in the presence of a suitable catalyst, for example CuBr, a suitable base, for example Cs ₂ CO ₃ and in a suitable solvent such as DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Step 4

Compounds of formula (V) can be reacted with nitrile catalysis of compounds of formula (III) using ethanimidamide hydrochloride in the presence of a suitable catalyst, eg CuBr, a suitable base, eg Cs ₂ CO ₃ and a suitable solvent, eg DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Step 5

The compounds of formula IV are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 100° C. It can be obtained through Suzuki coupling between a compound of formula V and the desired heteroaryl boronic acid ester. The reaction takes about 3 hours to about 12 hours to complete.

Scheme 4, Cpd (II)*a Preparation: 3-Bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile

HATU (0.63 g, 1.66 mmol), 2-bromo-4-cyanobenzoic acid (250.0 mg, 1.11 mmol) and N,N-diisopropylethylamine (1.13 mL, 6.64 mmol) in DMF (7.374 mL) 4-Methoxy-4-methyl-piperidine hydrochloride (219.87 mg, 1.33 mmol) was added to the solution. The reaction was stirred at RT for 2.5 h. After this time saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with cHex/AcOEt 95:5 to cHex/AcOEt 50:50) to obtain the product 3-bromo-4-(4-methoxy-4-methyl-piperidine- 1-carbonyl)benzonitrile was provided.

Yield: 170 mg

1H NMR (400 MHz, DMSO) δ 8.27 (t, 1H), 7.94 (ddd, 1H), 7.62 - 7.50 (m, 1H), 4.13 (ddd, 1H), 3.22 - 3.02 (m, 5H), 3.00 - 2.89 (m, 1H), 1.86 - 1.72 (m, 1H), 1.68 - 1.57 (m, 1H), 1.57 - 1.33 (m, 2H), 1.12 (d, 3H); LC-MS: m/z 337.25, 339.25 (MH+).

Scheme 4, Cpd (II)*b Preparation: 3-bromo-4-(4-tert-butylpiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of the compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, herein 4-tert-butylpipery Dean was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 90% (346 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 - 8.25 (m, 1H), 7.98 - 7.87 (m, 1H), 7.66 - 7.47 (m, 1H), 4.59 (t, 1H), 3.23 - 3.11 (m, 1H), 3.02 - 2.91 (m, 1H), 2.76 - 2.63 (m, 1H), 1.90 - 1.50 (m, 2H), 1.34 - 1.03 (m, 3H), 0.89 - 0.81 (m, 9H) ; LC-MS: m/z 349.17, 351.13 (MH+).

Scheme 4, Cpd (II)*c Preparation: 3-Bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, here 4,4-difluoro Piperidine hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 77% (500 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.31 (d, 1H), 7.98 (dd, 1H), 7.66 (d, 1H), 3.95 - 3.83 (m, 1H), 3.78 - 3.61 (m, 1H) ), 3.23 (t2H), 2.23 - 1.87 (m, 4H); LC-MS: m/z 329.25, 331.25 (MH+).

Scheme 4, Cpd (II)*d preparation: 3-bromo-4-(1-oxa-7-azaspiro[3.5]nonane-7-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 1-oxa-7-aza Spiro[3.5]nonane was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 74% (487 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (d, 1H), 7.93 (dt, 1H), 7.56 (dd, 1H), 4.46 - 4.33 (m, 2H), 3.73 - 3.51 (m, 2H) , 3.27 (s, 1H), 2.99 (s, 2H), 2.37 (br d, 2H), 1.96 - 1.70 (m, 3H); LC-MS: m/z 335.09, 337.06 (MH+).

Scheme 4, Cpd (II)*e Preparation: 3-Bromo-4-(4-ethoxypiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out analogously to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 4-ethoxypiperidine hydro Chloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 56% (210 mg).

1H NMR (400 MHz, DMSO) δ 8.28 (t, 1H), 7.94 (dd, 1H), 7.56 (dd, 1H), 3.97 (td, 1H), 3.54 (tt, 1H), 3.46 (qd, 2H) , 3.35 - 3.31 (m, 1H), 3.19 (ddt, 1H), 2.99 (tdd, 1H), 1.89 (s, 1H), 1.81 - 1.72 (m, 1H), 1.58 - 1.31 (m, 2H), 1.10 (t, 3H); LC-MS: m/z 337.35, 339.35 (MH+).

Scheme 4, Cpd (II)*f Preparation: 3-bromo-4-(6,6-difluoro-2-azaspiro[3.3]heptane-2-carbonyl)benzonitrile

The synthesis of the title compound was carried out analogously to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 6,6-difluoro -2-azaspiro[3.3]heptane hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 50% (70 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.30 (d, 1H), 7.96 (dd, 1H), 7.61 (d, 1H), 4.19 (s, 2H), 3.97 (s, 2H), 2.96 - 2.78 (m, 4H); LC-MS: m/z 341.25, 343.25 (MH+)

Scheme 4, Cpd (II)*g Preparation: 3-bromo-4-[4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of the compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 4-(trifluoromethoxy ) Piperidine hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 62% (260 mg).

1H NMR (400 MHz, DMSO) δ 8.29 (dd, 1H), 7.96 (ddd, 1H), 7.72 - 7.49 (m, 1H), 4.74 (dt, 1H), 4.02 (td, 1H), 3.42 (dddd, 1H), 3.30 - 3.06 (m, 2H), 2.09 - 1.97 (m, 1H), 1.90 (s, 1H), 1.84 - 1.56 (m, 2H); LC-MS: m/z 377.26, 379.26 (MH+).

Scheme 4, Cpd (II)*h Preparation: 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of the compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 4-(trifluoromethoxy ) Piperidine hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 78% (560 mg).

1H NMR (400 MHz, DMSO) δ 8.29 (dd, 1H), 7.95 (ddd, 1H), 7.71 - 7.50 (m, 1H), 4.60 (t, 1H), 3.26 (d, 1H), 3.09 (dtd, 1H), 2.83 (tdd1H), 2.66 (d, 1H), 1.94 (t, 1H), 1.82 - 1.65 (m, 1H), 1.55 - 1.29 (m, 2H); LC-MS: m/z 361.10, 363.09 (MH+).

Scheme 4, Cpd (II)*i Preparation: 3-bromo-4-(4-fluoro-4-methylpiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of the compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, herein 4-fluoro-4- Methylpiperidine hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 52% (186 mg).

1H NMR (400 MHz, DMSO) δ 8.29 (d, 1H), 7.95 (ddd, 1H), 7.65 - 7.53 (m, 1H), 4.26 (d, 1H), 3.25 - 2.97 (m, 3H), 1.94 - 1.79 (m, 1H), 1.78 - 1.54 (m, 3H), 1.42 - 1.28 (m, 3H); LC-MS: m/z 325.25, 327.25 (MH+).

Scheme 4, Cpd (II)*j Preparation: 3-bromo-4-(4-methoxypiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 4-methoxypiperidine was It was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 56% (200 mg).

1H NMR (400 MHz, DMSO) δ 8.28 (d, 1H), 7.94 (dt, 1H), 7.56 (dd, 1H), 3.97 - 3.87 (m, 1H), 3.49 - 3.33 (m, 2H), 3.25 ( s, 3H), 3.18 (qd, 1H), 3.06 - 2.92 (m, 1H), 1.95 - 1.84 (m, 1H), 1.76 (s, 1H), 1.59 - 1.34 (m, 2H); LC-MS: 323.25, 325.25 (MH+).

Scheme 4, Cpd (II)*k Preparation 3-bromo-4-(4-methylpiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 4-methylpiperidine was It was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 78% (265 mg).

1H NMR (400 MHz, DMSO) δ 8.27 (dd, 1H), 7.93 (ddd, 1H), 7.60 - 7.46 (m, 1H), 4.45 (t, 1H), 3.14 (d, 1H), 3.07 - 2.91 ( m, 1H), 2.78 (tt, 1H), 1.76 - 1.45 (m, 3H), 1.26 - 0.97 (m, 2H), 0.91 (d, 3H); LC-MS: m/z 307.10, 309.09 (MH+).

Scheme 4, Cpd (II)*l preparation: 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile, where 6-azaspiro[2.5] Octane hydrochloride was used instead of 4-methoxy-4-methyl-piperidine hydrochloride. The title compound was obtained in a yield of 78% (550 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.94 (dd, 1H), 7.57 (d, 1H), 3.67 (t, 2H), 3.16 - 3.05 (m, 2H), 1.56 - 1.20 (m, 4H), 0.51 - 0.24 (m, 4H); LC-MS: m/z 319.14, 321.10 (MH+).

Scheme 4, Cpd (III)*a Preparation: 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile

1-(Propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)- in water (0.755 mL)/1,2-dimethoxyethane (7.554 mL) 1H-pyrazole (138.64 mg, 0.590 mmol), 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile (180.0 mg, 0.530 mmol), A mixture of phos aminobiphenyl palladium chloride precatalyst (41.95 mg, 0.050 mmol) and tripotassium phosphate (339.92 mg, 1.6 mmol) was degassed for 5 minutes under nitrogen flux and then heated to 90 °C for 1 h. After this time, the reaction mixture was cooled to room temperature, diluted with water and extracted with AcOEt (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The residue was purified by FC on silica gel (eluted with 100% cHex to AcOEt/cHex 30:70) to obtain the product 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy- 4-Methyl-piperidine-1-carbonyl)benzonitrile was provided.

Yield: 120 mg

1H NMR (400 MHz, DMSO) δ 8.23 - 8.05 (m, 1H), 7.89 - 7.76 (m, 2H), 7.44 (dd, 1H), 6.69 - 6.50 (m, 1H), 4.52 (dp, 1H), 4.19 - 4.08 (m, 1H), 3.09 - 2.79 (m, 6H), 1.75 (t, 1H), 1.52 - 1.26 (m, 9H), 1.10 - 0.95 (m, 3H); LC-MS: m/z 367.5 (MH+).

Scheme 4, Cpd (III)*b Preparation: 4-(4-tert-butylpiperidine-1-carbonyl)-3-(1-isopropylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4-tert-butylpiperidine-1-carbonyl)benzonitrile is 3-bromo-4-(4-methoxy-4-methyl-piperidine-1 -Carbonyl) used instead of benzonitrile. The title compound was obtained in a yield of 91% (100 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.24 - 8.06 (m, 1H), 7.87 - 7.76 (m, 2H), 7.49 - 7.37 (m, 1H), 6.64 - 6.47 (m, 1H), 4.71 - 4.40 (m, 2H), 3.28 - 3.01 (m, 2H), 2.91 - 2.53 (m, 2H), 1.83 - 1.63 (m, 1H), 1.57 - 1.38 (m, 7H), 1.32 - 1.13 (m, 2H), 0.91 - 0.60 (m, 9H); LC-MS: m/z 379.36 (MH+).

Scheme 4, Cpd (III)*c Preparation: 3-(1-isopropylpyrazol-3-yl)-4-(1-oxa-7-azaspiro[3.5]nonane-7-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(1-oxa-7-azaspiro[3.5]nonane-7-carbonyl)benzonitrile was reacted with 3-bromo-4-(4-methoxy-4-methyl-p). Peridine-1-carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 60% (65 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (dd, 1H), 7.86 - 7.80 (m, 2H), 7.45 (dd, 1H), 6.59 (dd, 1H), 4.57 - 4.28 (m, 2H) ), 3.71 - 3.50 (m, 2H), 3.15 - 2.79 (m, 2H), 2.43 - 2.18 (m, 2H), 1.90 - 1.73 (m, 2H), 1.63 - 1.55 (m, 1H), 1.49 - 1.36 (m, 7H), 1.32 - 1.21 (m, 1H); LC-MS: m/z 365.24 (MH+).

Scheme 4, Cpd (III)*d Preparation: 4-(4-ethoxypiperidine-1-carbonyl)-3-(1-isopropylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4-ethoxypiperidine-1-carbonyl)benzonitrile is 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-car Bornyl) was used instead of benzonitrile. The title compound was obtained in a yield of 79% (180 mg).

1H NMR (400 MHz, DMSO) δ 8.16 (dd, 1H), 7.88 - 7.77 (m, 2H), 7.44 (t, 1H), 6.58 (t, 1H), 4.53 (dp, 1H), 4.00 - 3.84 ( m, 1H), 3.44 (qd, 2H), 3.40 - 2.99 (m, 3H), 2.94 - 2.73 (m, 1H), 1.88 - 1.75 (m, 1H), 1.59 - 1.49 (m, 2H), 1.43 ( td, 6H), 1.34 - 1.18 (m, 1H), 1.07 (dt, 3H); LC-MS: m/z 367.3 (MH+).

Scheme 4, Cpd (III)*e Preparation: 4-(6,6-difluoro-2-azaspiro[3.3]heptan-2-carbonyl)-3-(1-isopropylpyrazol-3-yl )Benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(6,6-difluoro-2-azaspiro[3.3]heptane-2-carbonyl)benzonitrile was used as 3-bromo-4-(4-methoxy-4) -Methyl-piperidine-1-carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 60% (52 mg).

LC-MS: m/z 371.46 (MH+)

Scheme 4, Cpd (III)*f Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile is 3-bromo-4-(4-methoxy-4-methyl-piperidine) -1-Carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 100% (90 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.22 - 8.17 (m, 1H), 7.89 - 7.82 (m, 2H), 7.57 - 7.47 (m, 1H), 6.65 (d, 1H), 4.51 (p , 1H), 3.80 - 3.66 (m, 2H), 3.25 - 2.99 (m, 2H), 2.16 - 1.77 (m, 2H), 1.54 (dq, 1H), 1.43 (dd, 7H); LC-MS: m/z 359.2 (MH+).

Scheme 4, Cpd (III)*g Compensation: 4-(4-fluoro-4-methylpiperidine-1-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)benzo nitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4-fluoro-4-methylpiperidine-1-carbonyl)benzonitrile was used as 3-bromo-4-(4-methoxy-4-methyl-piperi). Dean-1-carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 100% (204 mg).

1H NMR (400 MHz, DMSO) δ 8.22 - 8.08 (m, 1H), 7.89 - 7.78 (m, 2H), 7.47 (dd, 1H), 6.67 - 6.51 (m, 1H), 4.52 (h, 1H), 4.33 - 4.17 (m, 1H), 3.13 - 2.88 (m, 3H), 1.84 - 1.12 (m, 13H); LC-MS: m/z 355.2 (MH+).

Scheme 4, Cpd (III)*h Preparation: 3-(1-propan-2-ylpyrazol-3-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo nitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was reacted with 3-bromo-4-(4-methoxy-4-methyl-piperi). Dean-1-carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 100% (220 mg).

1H NMR (400 MHz, DMSO) δ 8.25 - 8.06 (m, 1H), 7.88 - 7.77 (m, 2H), 7.56 - 7.40 (m, 1H), 6.67 - 6.47 (m, 1H), 4.62 (s, 1H) ), 4.57 - 4.46 (m, 1H), 3.26 - 2.62 (m, 4H), 1.43 (ddd, 6H), 1.96 - 1.12 (m, 4H); LC-MS: m/z 391.3 (MH+).

Scheme 4, Cpd (III)*i preparation: 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(1-propan-2-ylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile was reacted with 3-bromo-4-(4-methoxy-4-methyl-piperidine-1 -Carbonyl) used instead of benzonitrile. The title compound was obtained in a yield of 80% (130 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.16 (d, 1H), 7.85 (d, 1H), 7.81 (dd, 1H), 7.45 (d, 1H), 6.60 (d, 1H), 4.60 - 4.45 (m, 1H), 3.76 - 3.49 (m, 2H), 3.15 - 2.85 (m, 2H), 1.50 - 1.40 (m, 7H), 1.37 - 1.30 (m, 1H), 1.22 - 1.12 (m, 1H) ), 0.93 - 0.85 (m, 1H), 0.40 - 0.13 (m, 4H); LC-MS: 349.2 (MH+).

Scheme 4, Cpd (III)*j Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-(2-ethylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile and 1-ethyl-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyrazole was reacted with 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile and 1-(propane), respectively. -2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead. The title compound was obtained in a yield of 30% (76 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 - 7.99 (m, 2H), 7.77 - 7.70 (m, 1H), 7.52 (d, 1H), 6.26 (d, 1H), 4.10 - 3.93 (m, 2H), 3.71 - 3.42 (m, 2H), 3.26 - 2.95 (m, 2H), 2.12 - 1.64 (m, 4H), 1.30 (t, 3H); LC-MS: m/z 345.24 (MH+).

Scheme 4, Cpd (III)*k Preparation: 3-[1-(2-methylpropyl)pyrazol-3-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl] Benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile and 1-(2-methylpropyl)-3-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (see Scheme 12, Cpd (III)*e ) was reacted with 3-bromo-4-(4-methoxy-4- Methyl-piperidine-1-carbonyl)benzonitrile and 1-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole It was used instead. The title compound was obtained in a yield of 35% (12 mg).

1H NMR (400 MHz, DMSO) δ 8.26 - 8.11 (m, 1H), 7.87 - 7.76 (m, 2H), 7.59 - 7.40 (m, 1H), 6.62 (dd, 1H), 4.73 - 4.54 (m, 1H) ), 3.93 (dd, 2H), 3.27 - 2.53 (m, 4H), 2.11 (dq, 1H), 1.97 - 1.80 (m, 1H), 1.70 - 0.89 (m, 3H), 0.90 - 0.76 (m, 6H) ); LC-MS: m/z 405.2 (MH+).

Scheme 4, Cpd (III)*1 Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-(1-methylpyrazol-3-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile and 1-methyl-1H-pyrazole-3-boronic acid pinacol ester were each used as 3- Bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile and 1-(propan-2-yl)-3-(tetramethyl-1,3,2-di Oxaborolan-2-yl)-1H-pyrazole was used instead. The title compound was obtained in a yield of 56% (56 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.20 (d, 1H), 7.85 (dd, 1H), 7.80 (d, 1H), 7.51 (d, 1H), 6.67 (d, 1H), 3.97 - 3.84 (m, 4H), 3.59 (ddd, 1H), 3.24 - 3.05 (m, 2H), 2.21 - 1.97 (m, 2H), 1.94 - 1.79 (m, 1H), 1.78 - 1.59 (m, 1H); LC-MS: m/z 331.12 (MH+).

Scheme 4, Cpd (III)*m Preparation: 3-(1-cyclobutylpyrazol-3-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile and 1-cyclobutyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazole (see Scheme 12, Cpd (III)*a ) was reacted with 3-bromo-4-(4-methoxy-4-methyl-piperi), respectively. Dean-1-carbonyl)benzonitrile and 1-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were used instead. The title compound was obtained in a yield of 79% (165 mg).

1H NMR (400 MHz, DMSO) δ 8.17 (dd, 1H), 7.92 (q, 1H), 7.84 (ddd, 1H), 7.49 (dd, 1H), 6.60 (dd, 1H), 4.84 (p, 1H) , 4.62 (d, 1H), 3.21 - 3.11 (m, 1H), 3.03 - 2.69 (m, 2H), 2.57 (d, 1H), 2.44 - 2.30 (m, 3H), 1.97 - 1.65 (m, 4H) , 1.56 - 1.12 (m, 3H); LC-MS: m/z 403.2 (MH+).

Scheme 4, Cpd (III)*n Preparation: 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(1-propan-2-ylpyrazol-4-yl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. Here, 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole was reacted with 3-bromo-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile and 1- (Propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead. The title compound was obtained in a yield of 78% (85 mg).

1H NMR (400 MHz, DMSO) δ 8.08 (d, 1H), 8.03 (d1H), 7.74 (dd, 1H), 7.72 (d, 1H), 7.45 (d, 1H), 4.57 (p, 1H), 3.95 - 3.82 (m, 1H), 3.43 (ddd, 1H), 3.13 - 2.93 (m, 1H), 2.93 - 2.83 (m, 1H), 1.44 (dd, 6H), 1.41 - 1.33 (m, 1H), 1.27 (s, 1H), 0.99 - 0.90 (m, 1H), 0.71 (td, 1H), 0.37 - 0.14 (m, 4H); LC-MS: m/z 349.18 (MH+).

Scheme 4, Cpd (IV)*a preparation: [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-(4-methoxy-4-methyl-1-piperidyl)methanone

Example 39

3-(1-Isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile (120.0 mg, 0.330 mmol) in DMSO (3.713 mL) ), disesium carbonate (320.08 mg, 0.980 mmol), etanimidamide hydrochloride (46.44 mg, 0.490 mmol), and CuBr (2.35 mg, 0.020 mmol) were stirred at 120 °C for 8 h. After this time, the reaction was cooled to RT, H ₂ O was added and the mixture was extracted three times with AcOEt. The aqueous phase was acidified with 1M HCl until pH = 5 and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated under vacuum and purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 95:5) to give Product [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methoxy-4- Methyl-1-piperidyl)methanone was provided.

Yield 63 mg

1H NMR (400 MHz, DMSO) δ 13.78 (s, 1H), 8.33 (dd, 1H), 7.93 (ddd, 1H), 7.82 (dd, 1H), 7.30 (dd, 1H), 6.43 (dd, 1H) , 4.55 (dp, 1H), 4.28 - 3.96 (m, 1H), 3.15 - 2.86 (m, 6H), 2.41 (s, 3H), 1.72 (t, 1H), 1.53 - 1.20 (m, 9H), 1.14 - 0.87 (m, 3H); LC-MS: m/z 423.5 (MH+).

Preparation: (4-tert-butyl-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazole- 3-yl)phenyl]methanone

Example 40

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, where 4-(4-tert-butylpiperidine-1-carbonyl)-3-(1 -Isopropylpyrazol-3-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzo It was used instead of nitrile. The title compound was obtained in a yield of 20% (22 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (s, 1H), 7.98 - 7.90 (m, 1H), 7.79 (s, 1H), 7.36 - 7.23 (m, 1H), 6.44 - 6.36 (m, 1H), 4.74 - 4.45 (m, 2H), 3.28 - 3.18 (m, 2H), 2.85 - 2.55 (m, 2H), 2.41 (s, 3H), 1.83 - 1.41 (m, 7H), 1.29 - 0.93 ( m, 3H), 0.88 - 0.66 (m, 9H), 0.29 - 0.15 (m, 1H); 435.38 (MH+).

Manufactured by: [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(1-oxa-7- Azaspiro[3.5]nonan-7-yl)methanone

Example 41

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 3-(1-isopropylpyrazol-3-yl)-4-(1-oxa- 7-Azaspiro[3.5]nonane-7-carbonyl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1- Carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 50% (37 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.35 - 8.28 (m, 1H), 7.98 - 7.91 (m, 1H), 7.84 - 7.76 (m, 1H), 7.32 - 7.26 (m, 1H), 6.46 - 6.39 (m, 1H), 4.60 - 4.48 (m, 1H), 4.43 - 4.28 (m, 2H), 3.75 - 3.42 (m, 3H), 3.13 - 2.84 (m, 2H), 2.45 - 2.16 (m, 4H) ), 1.88 - 1.67 (m, 2H), 1.61 - 1.52 (m, 1H), 1.49 - 1.39 (m, 6H), 1.30 - 1.06 (m, 2H); LC-MS: m/z 421.48 (MH+).

Manufactured by: (4-ethoxy-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazole-3 -1) phenyl] methanone

Example 42

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, where 4-(4-ethoxypiperidine-1-carbonyl)-3-(1-iso Propylpyrazol-3-yl)benzonitrile is replaced with 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile. used. The title compound was obtained in a yield of 38% (80 mg).

1H NMR (400 MHz, DMSO) δ 13.79 (s, 1H), 8.33 (dd, 1H), 7.93 (dt, 1H), 7.81 (dd, 1H), 7.30 (dd, 1H), 6.42 (t, 1H) , 4.53 (dp, 1H), 4.05 - 3.91 (m, 1H), 3.48 - 3.36 (m, 2H), 3.28 - 3.05 (m, 3H), 2.95 - 2.74 (m, 1H), 2.41 (s, 3H) , 1.79 (d, 1H), 1.55 - 1.32 (m, 8H), 1.29 - 1.18 (m, 1H), 1.06 (dt, 3H); LC-MS: m/z 423.3 (MH+).

Preparation: (4-fluoro-4-methylpiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propane -2-ylpyrazol-3-yl)phenyl]methanone

Example 43

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 4-(4-fluoro-4-methylpiperidine-1-carbonyl)-3 -(1-Propan-2-ylpyrazol-3-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine- 1-Carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 75% (32 mg).

1H NMR (400 MHz, DMSO) δ 13.80 (s, 1H), 8.33 (dd, 1H), 7.94 (td, 1H), 7.82 (dd, 1H), 7.33 (t, 1H), 6.43 (dd, 1H) , 4.55 (dp, 1H), 4.40 - 4.13 (m, 1H), 3.19 - 2.86 (m, 3H), 2.41 (s, 3H), 1.86 - 1.40 (m, 10H), 1.37 - 1.13 (m, 3H) ; LC-MS: m/z 411.6 (MH+).

Manufactured by: (4,4-difluoropiperidin-1-yl)-[2-(2-ethylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-tria sol-3-yl)phenyl]methanone

Example 44

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 4-(4,4-difluoropiperidine-1-carbonyl)-3- (2-ethylpyrazol-3-yl)benzonitrile as 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl) It was used instead of benzonitrile. The title compound was obtained in a yield of 60% (53 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 - 8.08 (m, 1H), 7.96 (d, 1H), 7.52 (d, 2H), 6.26 (d, 1H), 4.01 (d, 2H), 3.68 - 3.49 (m, 2H), 3.25 - 3.01 (m, 3H), 2.41 (s, 3H), 2.10 - 1.64 (m, 4H), 1.32 (t, 3H); LC-MS: m/z 401.23 (MH+).

Preparation: [2-[1-(2-methylpropyl)pyrazol-3-yl]-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4- (trifluoromethyl)piperidin-1-yl]methanone

Example 45

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 3-[1-(2-methylpropyl)pyrazol-3-yl]-4-[ 4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile is replaced with 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine -1-Carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 10% (4 mg).

1H NMR (400 MHz, DMSO) δ 13.80 (s, 1H), 8.36 (dd, 1H), 7.95 (ddd, 1H), 7.77 (dd, 1H), 7.39 - 7.25 (m, 1H), 6.52 - 6.37 ( m, 1H), 4.75 - 4.58 (m, 1H), 3.99 - 3.91 (m, 2H), 3.02 - 2.55 (m, 3H), 2.41 (s, 3H), 2.21 - 2.06 (m, 1H), 1.97 - 1.79 (m, 1H), 1.73 - 0.89 (m, 4H), 0.88 (s, 6H); LC-MS: m/z 461.2 (MH+).

Manufactured by: (4,4-difluoropiperidin-1-yl)-[2-(1-methylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-tria sol-3-yl)phenyl]methanone

Example 46

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 4-(4,4-difluoropiperidine-1-carbonyl)-3- (1-Methylpyrazol-3-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl) It was used instead of benzonitrile. The title compound was obtained in a yield of 36% (23 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.93 - 13.69 (m, 1H), 8.34 (d, 1H), 7.95 (dd, 1H), 7.77 (d, 1H), 7.37 (d, 1H), 6.49 (d, 1H), 3.88 (s, 4H), 3.64 - 3.49 (m, 1H), 3.25 - 3.09 (m, 2H), 2.41 (s, 3H), 2.17 - 1.77 (m, 3H), 1.69 - 1.49 (m, 1H); LC-MS: m/z 387.19 (MH+).

Preparation: [2-(1-cyclobutylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoro methyl)piperidin-1-yl]methanone

Example 47

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, where 3-(1-cyclobutylpyrazol-3-yl)-4-[4-(tri fluoromethyl)piperidine-1-carbonyl]benzonitrile to 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-car Bornyl) was used instead of benzonitrile. The title compound was obtained in a yield of 36% (67 mg).

1H NMR (400 MHz, DMSO) δ 13.80 (s, 1H), 8.33 (dd, 1H), 7.96 (ddd, 1H), 7.86 (dd, 1H), 7.35 (dd, 1H), 6.46 (t, 1H) , 4.87 (p, 1H), 4.66 (d, 1H), 3.40 (d, 1H), 3.21 (d, 1H), 3.03 - 2.70 (m, 2H), 2.56 (d, 1H), 2.47 - 2.31 (m , 6H), 2.03 - 1.63 (m, 3H), 1.56 - 1.18 (m, 2H), 0.40 (qd, 1H); LC-MS: m/z 459.48 (MH+).

Preparation: [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propan-2-ylpyrazol-3-yl)phenyl]-[4-( trifluoromethyl)piperidin-1-yl]methanone

Example 48

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 3-(1-propan-2-ylpyrazol-3-yl)-4-[4 -(trifluoromethyl)piperidine-1-carbonyl]benzonitrile is replaced with 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine- 1-Carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 27% (67 mg).

1H NMR (400 MHz, DMSO) δ 13.80 (s, 1H), 8.43 - 8.23 (m, 1H), 7.95 (ddd, 1H), 7.81 (dd, 1H), 7.39 - 7.27 (m, 1H), 6.42 ( d, 1H), 4.66 (d, 1H), 4.54 (pd, 1H), 3.47 - 2.45 (m, 4H), 2.41 (s, 3H), 1.46 (s, 2H), 1.44 (dd, 6H), 1.38 - 0.29 (m, 2H); LC-MS: m/z 447.2 (MH+).

Manufactured by: 6-azaspiro[2.5]octan-6-yl-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propan-2-ylpyra sol-4-yl)phenyl]methanone

Example 49

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, where 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(1 -Propan-2-ylpyrazol-4-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-car Bornyl) was used instead of benzonitrile. The title compound was obtained in a yield of 19% (18 mg).

1H NMR (400 MHz, DMSO) δ 13.77 (s, 1H), 8.09 (d, 1H), 7.97 (s, 1H), 7.88 (dd, 1H), 7.64 (s, 1H), 7.32 (d, 1H) , 4.58 (hept, 1H), 3.96 - 3.80 (m, 1H), 3.41 (ddd, 1H), 3.09 - 2.88 (m, 2H), 2.41 (s, 3H), 1.45 (dd, 6H), 1.38 (ddd) , 1H), 1.23 (dt, 1H), 0.92 (dt, 1H), 0.71 (ddd, 1H), 0.38 - 0.13 (m, 4H); LC-MS: m/z 405.57 (MH+).

Manufactured by: 6-azaspiro[2.5]octan-6-yl-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propan-2-ylpyra sol-3-yl)phenyl]methanone

Example 50

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, where 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-(1 -Propan-2-ylpyrazol-3-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-car Bornyl) was used instead of benzonitrile. The title compound was obtained in a yield of 39% (31 mg).

1H NMR (400 MHz, DMSO-d6) δ 13.80 (s, 1H), 8.35 (d, 1H), 7.94 (dd, 1H), 7.84 (d, 1H), 7.32 (d, 1H), 6.46 (d, 1H), 4.57 (p, 1H), 3.77 - 3.54 (m, 2H), 3.04 (dddd, 2H), 2.42 (s, 3H), 1.47 (dd, 6H), 1.35 (q, 2H), 1.16 - 1.06 (m, 1H), 0.85 (ddd, 1H), 0.44 - 0.05 (m, 4H); LC-MS: m/z 405.24 (MH+).

Preparation: (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propane- 2-ylpyrazol-3-yl)phenyl]methanone

Example 51

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -(4-methoxy-4-methyl-1-piperidyl)methanone was carried out similarly to the synthesis, here 4-(4,4-difluoropiperidine-1-carbonyl)-3- (1-Propan-2-ylpyrazol-3-yl)benzonitrile is replaced with 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1 -Carbonyl) used instead of benzonitrile. The title compound was obtained in a yield of 48% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 14.61 - 12.76 (m, 1H), 8.31 (d, 1H), 7.96 (dd, 1H), 7.84 (d, 1H), 7.38 (d, 1H), 6.48 (d, 1H), 4.54 (spt, 1H), 3.97 - 3.78 (m, 1H), 3.64 - 3.52 (m, 1H), 3.23 - 3.02 (m, 2H), 2.41 (s, 3H), 2.16 - 1.70 (m, 3H), 1.44 (dd, 6H), 1.54 - 1.19 (m, 1H); LC-MS: m/z 415.3 (MH+).

Manufactured by: (6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H- 1,2,4-triazol-3-yl)phenyl]methanone

Example 52

The synthesis of the title compound was carried out using the compound of Example 39 [2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] -Carried out similarly to the synthesis of (4-methoxy-4-methyl-1-piperidyl)methanone, here 4-(6,6-difluoro-2-azaspiro[3.3]heptane-2- Carbonyl)-3-(1-isopropylpyrazol-3-yl)benzonitrile is 3-(1-isopropylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperi) Dean-1-carbonyl) was used instead of benzonitrile. The title compound was obtained in a yield of 35% (21 mg).

1H NMR (400 MHz, DMSO-d6) δ 13.73 (s, 1H), 8.30 (d, 1H), 7.93 (d, 1H), 7.84 (d, 1H), 7.33 (d, 1H), 6.48 (d, 1H), 4.56 (p, 1H), 4.06 (s, 2H), 3.69 (s, 2H), 2.89 - 2.56 (m, 4H), 2.42 (s, 3H), 1.47 (d, 6H); LC-MS: m/z 427.30

Scheme 4, Preparation of Cpd (V)*a : [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy )piperidin-1-yl]methanone

3-Bromo-4-[4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile (268.0 mg, 0.710 mmol), disesium carbonate (694.56 mg, 2.13 mmol) in DMSO (3.5 mL) ), ethanimimidamide hydrochloride (100.77 mg, 1.07 mmol) and CuBr (5.1 mg, 0.040 mmol) were stirred at 120 °C for 7 h. After this time the reaction was cooled and immediately purified by reverse phase FC using acid conditions (from 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1%). % HCOOH) product of the formula [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy) Piperidin-1-yl]methanone was provided.

Yield: 34 mg

1H NMR (400 MHz, DMSO) δ 13.88 (s, 1H), 8.18 (d, 1H), 8.05 - 7.98 (m, 1H), 7.54 - 7.39 (m, 1H), 4.74 (dt, 1H), 4.08 - 3.98 (m, 1H), 3.50 - 3.37 (m, 2H), 3.30 - 3.11 (m, 1H), 2.41 (s, 3H), 2.14 - 1.59 (m, 4H); LC-MS: m/z 433.07, 435.05 (MH+).

Scheme 4, Cpd (V)*b preparation: [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methylpiperidine- 1-day) Methanone

The synthesis of the title compound was carried out by the compound [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy)piperidine- The synthesis of 1-yl]methanone was performed similarly, where 3-bromo-4-(4-methylpiperidine-1-carbonyl)benzonitrile was reacted with 3-bromo-4-[4-(tri Fluoromethoxy)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 61% (65 mg).

1H NMR (400 MHz, DMSO) δ 13.82 (s, 1H), 8.17 (d, 1H), 8.00 (ddd, 1H), 7.35 (d, 1H), 4.46 (s, 1H), 3.23 (s, 1H) , 3.08 - 2.92 (m, 1H), 2.77 (dt, 1H), 2.41 (s, 3H), 1.77 - 1.43 (m, 3H), 1.23 - 0.98 (m, 2H), 0.92 (d, 3H); LC-MS: m/z 363.10, 365.12 (MH+).

Scheme 4, Cpd (V)*c Preparation: [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methoxypiperidine- 1-day) Methanone

The synthesis of the title compound was carried out by the compound [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy)piperidine- The synthesis of 1-yl]methanone was performed similarly, where 3-bromo-4-(4-methoxypiperidine-1-carbonyl)benzonitrile was reacted with 3-bromo-4-[4-(tri Fluoromethoxy)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 52% (120 mg).

1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 8.17 (d, 1H), 8.00 (dd, 1H), 7.41 (t, 1H), 3.93 (d, 1H), 3.44 (d, 1H) , 3.39 - 3.32 (m, 2H), 3.25 (s, 3H), 3.10 - 2.96 (m, 1H), 2.41 (s, 3H), 1.96 - 1.86 (m, 1H), 1.79 (s, 1H), 1.56 - 1.32 (m, 2H); LC-MS: m/z 379.36, 381.36 (MH+).

Scheme 4, Cpd (V)*d preparation: [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl )piperidin-1-yl]methanone

The synthesis of the title compound was carried out by the compound [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy)piperidine- The synthesis of 1-yl]methanone was carried out similarly, where 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was reacted with 3-bromo-4- It was used instead of [4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile. The title compound was obtained in a yield of 54% (252 mg).

1H NMR (400 MHz, DMSO) δ 13.87 (s, 1H), 8.18 (dd, 1H), 8.01 (dt, 1H), 7.51 (dd, 1H), 4.62 (s, 1H), 3.36 (d, 1H) , 3.19 - 3.03 (m, 1H), 2.83 (t, 1H), 2.71 - 2.61 (m, 1H), 2.41 (s, 3H), 1.94 (s, 1H), 1.84 - 1.71 (m, 1H), 1.57 - 1.27 (m, 2H); LC-MS: m/z 417.05, 419.07 (MH+).

Scheme 4, Cpd (V)*e Preparation: [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoro piperidin-1-yl)methanone

The synthesis of the title compound was carried out by the compound [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethoxy)piperidine- The synthesis of 1-yl]methanone was carried out similarly, where 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was reacted with 3-bromo-4- It was used instead of [4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile. The title compound was obtained in a yield of 53% (268 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 8.20 (d, 1H), 8.03 (dd, 1H), 7.52 (d, 1H), 3.92 - 3.81 (m, 1H), 3.74 - 3.63 (m, 1H), 3.30 - 3.14 (m, 2H), 2.42 (s, 3H), 2.17 - 1.92 (m, 4H); LC-MS: m/z 385.05, 387.06 (MH+).

Preparation: [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluorozoline) Romethyl)-1-piperidyl]methanone

Example 53

Tripotassium phosphate (154.67 mg, 0.730 mmol) in 1,2-dimethoxyethane (2.128 mL)/water (0.142 mL), -Butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (95 mg, 0.380 mmol) and [2-bromo-4- (5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone (80.0 mg, 0.190 mmol) The mixture was degassed with N 2 for 5 min and then with 3 N ₂ /vacuum cycles. The reaction was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The mixture was purified by FC with a NH column (eluted with 100% DCM to DCM/MeOH 95:5) and again by reverse-phase FC using acid conditions (CH ₃ CN/H ₂ O + 0.1 at 5:95). % HCOOH to 60:40 CH ₃ CN/H ₂ O + eluting with 0.1% HCOOH) the product of the formula [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl -4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone was provided.

Yield: 35 mg

1H NMR (400 MHz, DMSO) δ 13.80 (s, 1H), 8.30 (dd, 1H), 7.95 (ddd, 1H), 7.86 (t, 1H), 7.33 (dd, 1H), 6.60 - 6.26 (m, 1H), 4.65 (d, 1H), 3.45 - 3.16 (m, 1H), 2.93 - 2.67 (m, 2H), 2.49 (d, 1H), 2.41 (s, 3H), 1.97 - 1.63 (m, 1H) , 1.55 (d, 9H), 1.47 - 0.09 (m, 3H); LC-MS: m/z 461.3 (MH+).

Preparation: [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-di Fluoropiperidin-1-yl)methanone

Example 54

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where [2-bromo-4-(5-methyl-4H-1,2,4- Triazol-3-yl)phenyl]-(4,4-difluoropiperidin-1-yl)methanone was converted to [2-bromo-4-(5-methyl-4H-1,2,4- Triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone was used instead. The title compound was obtained in a yield of 61% (68 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.29 (d, 1H) 7.92 - 7.98 (m, 1H) 7.89 (d, 1H) 7.34 - 7.43 (m, 1H) 6.44 - 6.50 (m, 1H) 3.67 - 3.77 (m, 2H) 3.00 - 3.25 (m, 2H) 2.41 (s, 3H) 1.75 - 2.15 (m, 3H) 1.55 (s, 9H) 1.25 - 1.37 (m, 2H); LC-MS: m/z 429.29 (MH+).

Preparation: [2-(1-cyclobutylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoro Lopiperidin-1-yl)methanone

Example 55

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where [2-bromo-4-(5-methyl-4H-1,2,4- triazol-3-yl)phenyl]-(4,4-difluoropiperidin-1-yl)methanone and 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyrazole ( Scheme 12, Cpd(III)*a Reference) respectively [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidine-1- [yl]methanone and 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole were used instead. The title compound was obtained in a yield of 37% (29 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.91 - 13.70 (m, 1H), 8.31 (d, 1H), 7.99 - 7.94 (m, 1H), 7.88 (d, 1H), 7.39 (d, 1H) , 6.51 (d, 1H), 4.87 (p, 1H), 3.82 - 3.68 (m, 2H), 3.26 - 3.09 (m, 2H), 2.48 - 2.35 (m, 6H), 2.15 - 1.75 (m, 6H) , 1.56 - 1.38 (m, 1H); LC-MS: m/z 427.27 (MH+).

Preparation: 1-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[1-(propan-2-yl)-1H-pyrazol-3-yl] benzoyl]-4-(trifluoromethoxy)piperidine

Example 56

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where [2-bromo-4-(5-methyl-4H-1,2,4- triazol-3-yl)phenyl]-[4-(trifluoromethoxy)piperidin-1-yl]methanone and 1-(propan-2-yl)-3-(tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrazole, respectively [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[ 4-(trifluoromethyl)piperidin-1-yl]methanone and 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-day) was used instead of pyrazole. The title compound was obtained in a yield of 29% (10 mg).

1H NMR (400 MHz, DMSO) δ 13.78 (s, 1H), 8.33 (dd, 1H), 7.95 (ddd, 1H), 7.88 - 7.78 (m, 1H), 7.35 (dd, 1H), 6.45 (dd, 1H), 4.69 - 4.49 (m, 2H), 4.15 - 4.00 (m, 1H), 3.26 - 2.90 (m, 3H), 2.42 (s, 3H), 1.96 (d, 1H), 1.80 - 0.82 (m, 9H); LC-MS: m/z 463.5 (MH+).

Preparation: [2-[1-(1-cyclopropylethyl)pyrazol-3-yl]-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4 ,4-difluoro-1-piperidyl)methanone

Example 57

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where [2-bromo-4-(5-methyl-4H-1,2,4- triazol-3-yl)phenyl]-(4,4-difluoropiperidin-1-yl)methanone and 1-(1-cyclopropylethyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole, respectively [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl) phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone and 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl) was used instead of pyrazole. The title compound was obtained as a racemic mixture in a yield of 30% (34 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.32 (t, 1H), 8.00 - 7.93 (m, 1H), 7.87 (t, 1H), 7.39 (d, 1H), 6.48 (dd, 1H), 3.93 - 3.79 (m, 1H), 3.75 - 3.64 (m, 1H), 3.64 - 3.48 (m, 1H), 3.22 - 3.04 (m, 2H), 2.42 (s, 3H), 2.14 - 1.97 (m, 1H) ), 1.97 - 1.72 (m, 1H), 1.58 - 1.47 (m, 3H), 1.44 - 1.15 (m, 1H), 0.71 - 0.56 (m, 1H), 0.46 - 0.37 (m, 1H), 0.34 (t , 2H); LC-MS: m/z 441.25 (MH+).

The racemic mixture ( Example 57 ) was then separated into single enantiomers ( Examples 57a and 57b ) by chiral semipreparative HPLC.

Preparation: (4-methoxypiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propan-2-ylpyra sol-3-yl)phenyl]methanone

Example 58

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where [2-bromo-4-(5-methyl-4H-1,2,4- triazol-3-yl)phenyl]-(4-methoxypiperidin-1-yl)methanone and 1-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxabo Rolan-2-yl)-1H-pyrazole was respectively [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoropolymer) Romethyl)piperidin-1-yl]methanone and 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra It was used instead of sol. The title compound was obtained in a yield of 41% (55 mg).

1H NMR (400 MHz, DMSO) δ 13.72 (s, 1H), 8.34 (dd, 1H), 7.93 (dt, 1H), 7.81 (dd, 1H), 7.30 (s, 1H), 6.42 (t, 1H) , 4.54 (pd, 1H), 4.05 - 3.84 (m, 1H), 3.30 (s, 2H), 3.24 - 3.05 (m, 4H), 2.96 - 2.76 (m, 1H), 2.41 (s, 3H), 1.81 (s, 1H), 1.58 - 0.68 (m, 9H); LC-MS: m/z 409.2 (MH+).

Manufactured by: (4,4-difluoro-1-piperidyl)-[2-(1-ethylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazole -3-yl)phenyl]methanone

Example 59

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where 1-ethyl-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyrazole and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4 -Difluoropiperidin-1-yl)methanone, respectively, 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Pyrazole (383.71 mg, 0.380 mmol) and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl ) Piperidin-1-yl] was used instead of methanone. The title compound was obtained in a yield of 24% (12 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (d, 1H), 7.96 (dd, 1H), 7.82 (d, 1H), 7.37 (d, 1H), 6.48 (d, 1H), 4.17 (q , 2H), 3.90 (br d, 1H), 3.56 (m, 1H), 3.24 - 3.08 (m, 2H), 2.41 (s, 3H), 2.17- 1.75 (m, 4H), 1.39 (t, 4H) ; LC-MS: m/z 401.31 (MH+).

Preparation: (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[1-(oxetane -3-yl)pyrazol-3-yl]phenyl]methanone

Example 60

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where 1-(oxetan-3-yl)-3-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl) phenyl]-(4,4-difluoropiperidin-1-yl)methanone, respectively, 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyrazole and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl ) Piperidin-1-yl] was used instead of methanone. The title compound was obtained in a yield of 55% (42 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (d, 1H), 8.02 - 7.91 (m, 2H), 7.42 (d, 1H), 6.60 (d, 1H), 5.68 - 5.58 (m, 1H) , 5.00 - 4.84 (m, 4H), 3.86 - 3.65 (m, 2H), 3.23 - 3.11 (m, 2H), 2.45 - 2.35 (m, 3H), 2.17 - 1.83 (m, 4H), 1.67 - 1.50 ( m, 1H); LC-MS: m/z 429.38 (MH+).

Preparation: (4-methylpiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(1-propan-2-ylpyra sol-3-yl)phenyl]methanone

Example 61

The synthesis of the title compound was carried out using the compound of Example 53 [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)-1-piperidyl]methanone was carried out similarly to the synthesis, where 1-(propan-2-yl)-3-(tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazole and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4- Methylpiperidin-1-yl)methanone is reacted with 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole. and [2-bromo-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methane Used instead of on. The title compound was obtained in a yield of 60% (22 mg).

1H NMR (400 MHz, DMSO) δ 13.79 (s, 1H), 8.42 - 8.28 (m, 1H), 7.93 (ddd, 1H), 7.81 (dd, 1H), 7.28 (dd, 1H), 6.42 (td, 1H), 4.63 - 4.45 (m, 2H), 3.26 - 3.08 (m, 1H), 2.89 - 2.57 (m, 2H), 2.41 (s, 3H), 1.76 - 1.32 (m, 9H), 1.24 - 0.94 ( m, 2H), 0.92 - 0.70 (m, 3H); LC-MS: m/z 393.57 (MH+).

Scheme 5

Step 1

Compounds of formula (II) can be reacted with a suitable transition metal catalyst, such as Pd(dppf)Cl ₂ , in the presence of a suitable base, such as potassium acetate, in a suitable solvent, such as 1,4-dioxane, typically at 100° C. It can be obtained via Miyaura borylation between a compound of (commercially available from Asstatech) and B ₂ Pin ₂ . The reaction takes about 3 hours to about 12 hours to complete.

Step 2

The compounds of formula III are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 100° C. It can be obtained through Suzuki coupling between the compound of formula II and the desired heteroaryl halide. The reaction takes about an hour to about 12 hours to complete.

Step 3

Compounds of formula IV can be obtained by hydrolysis of compounds of formula III with LiOH in the presence of a suitable solvent mixture such as MeOH/THF/water, typically at room temperature. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained from compounds of formula (IV) by coupling with an appropriate amine in the presence of a coupling agent, such as HATU, and an organic base, such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete.

Step 5

Compounds of formula (VI) can be prepared using ethanimidamide hydrochloride in the presence of a suitable catalyst, such as CuBr, a suitable base, such as Cs ₂ CO ₃ , in a suitable solvent, such as DMSO, typically at 120° C. It can be obtained by nitrile cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Scheme 5, Preparation of Cpd (II) : Methyl 4-cyano-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (0.07 g, 0.080 mmol) in 1,4-dioxane (30.41 mL), potassium acetate (1.24 g, 12.5 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2 A suspension of -dioxaborolane (1.27 g, 5 mmol) and methyl 2-bromo-4-cyanobenzoate (1.0 g, 4.17 mmol) was degassed for 10 min under nitrogen flux and heated to 100 °C overnight. The next day the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum to give the product methyl 4-cyano-2-(4,4,5,5- This gave tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, which was used in the next step without further purification.

Yield: 1.19 g.

LC-MS: m/z 288.14 (MH+).

Scheme 5, Cpd (III)*a Preparation: Methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate

2-Bromo-4-(trifluoromethyl)thiazole (169.7 mg, 0.730 mmol), methyl 4-cyano-2-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210.0 mg, 0.730 mmol), X-Phos Pd G2 (0.06 g, 0.070 mmol) and phosphoric acid A mixture of tripotassium (0.47 g, 2.19 mmol) was degassed for 10 min under nitrogen flux and heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The crude material was purified by FC on silica gel (eluting with 100% cHex to cHex/EtOAc 90:10) to give the product methyl 4-cyano-2-[4-(trifluoromethyl)thiazole-2- Mono]benzoate was provided.

Yield: 52 mg

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.70 (d, 1H), 8.43 (d, 1H), 8.15 (dd, 1H), 7.91 (d, 1H), 3.72 (s, 3H); LC-MS: m/z 313.09 (MH+).

Scheme 5, Cpd (III)*b Preparation: Methyl 4-cyano-2-(6-cyclopropyl-2-pyridyl)benzoate

The synthesis of the title compound was carried out similarly to the synthesis of the compound methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate, here 2-bromo-6-cyclopropyl Pyridine was used instead of 2-bromo-4-(trifluoromethyl)thiazole. The title compound was obtained in a yield of 45% (303.7 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.20 (d, 1H), 7.98 (dd, 1H), 7.81 - 7.76 (m, 2H), 7.59 (dd, 1H), 7.34 (dd, 1H) , 3.66 (s, 3H), 2.17 - 2.09 (m, 1H), 0.98 - 0.83 (m, 4H); LC-MS: m/z 279.22 (MH+).

Scheme 5, Cpd (III)*c Preparation: Methyl 2-(1-tert-butylpyrazol-3-yl)-4-cyano-benzoate

The synthesis of the title compound was carried out similarly to the synthesis of the compound methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate, herein 1-tert-butyl-3-io Dopyrazole was used instead of 2-bromo-4-(trifluoromethyl)thiazole. The title compound was obtained in a yield of 12% (60 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.20 (d, 1H), 7.90 (d, 1H), 7.84 (dd, 1H), 7.65 (d, 1H), 6.73 (d, 1H), 3.77 (s, 3H) 1.53 (s, 9H); LC-MS: m/z 284.20 (MH+).

Scheme 5, Cpd (IV)*a Preparation: 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid

To a solution of methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate (53.0 mg, 0.170 mmol) in THF (1.178 mL) in methanol (0.294 mL) was added water ( A solution of lithium hydroxide (8.13 mg, 0.255 mmol) in 0.294 mL) was added. The reaction was allowed to stir overnight at room temperature. After this time, the solution was evaporated under reduced pressure, and the residue was taken together with water. The aqueous phase was washed with DCM, acidified with 1N HCl solution until pH = 4 and extracted with EtOAc (x6). The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid of the formula: .

Yield: 44.7 mg.

1H NMR (400 MHz, DMSO-d6) δ ppm 13.71 (br s, 1H), 8.68 (s, 1H), 8.30 (d, 1H), 8.12 (dd, 1H), 7.93 (d, 1H); LC-MS: m/z 299.07 (MH+).

Scheme 5, Cpd (IV)*b Preparation: 4-Cyano-2-(6-cyclopropyl-2-pyridyl)benzoic acid

The synthesis of the title compound was carried out similarly to the synthesis of compound 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid, where methyl 4-cyano-2-(6- Cyclopropyl-2-pyridyl)benzoate was used instead of methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate. The title compound was obtained in a yield of 93% (269.5 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (br s, 1H), 8.13 (d, 1H), 7.94 (dd, 1H), 7.78 - 7.71 (m, 2H), 7.55 (d, 1H), 7.34 (d, 1H), 2.16 - 2.06 (m, 1H), 1.05 - 0.87 (m, 4 H); LC-MS: m/z 265.22 (MH+).

Scheme 5, Cpd (IV)*c Preparation: 2-(1-tert-butylpyrazol-3-yl)-4-cyano-benzoic acid

The synthesis of the title compound was carried out similarly to the synthesis of the compound 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid, where methyl 2-(1-tert-butylpyrazole -3-yl)-4-cyano-benzoate was used instead of methyl 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoate. The title compound was obtained in a yield of 100% (58 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br s, 1H), 8.15 (d, 1H), 7.88 (d, 1H), 7.81 (dd, 1H), 7.62 (d, 1H), 6.65 ( d, 1H), 1.55 (s, 9 H); LC-MS: m/z 270.22 (MH+).

Scheme 5, Cpd (V)*a Preparation: 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile

N,N-diisopropylethylamine to a stirred solution of 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid (44.7 mg, 0.150 mmol) in DMF (1.041 mL). (0.08 mL, 0.450 mmol) and HATU (85.48 mg, 0.220 mmol) were added. The reaction was stirred at room temperature for 15 minutes. Then 4-methylpiperidine (14.86 mg, 0.150 mmol) was added and the reaction mixture was stirred at room temperature overnight. The next day saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with 100% cHex to cHex/EtOAc 70:30) to give the product of the formula 4-(4-methylpiperidine-1-carbonyl)-3-[4-(tri Fluoromethyl)thiazol-2-yl]benzonitrile was provided.

Yield: 46.8 mg.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 - 8.66 (m, 1H), 8.45 - 8.34 (m, 1H), 8.07 (dd, 1H), 7.62 (dd, 1H), 4.46 - 4.35 (m, 1H), 3.27 (s, 2H), 3.06 - 2.97 (m, 1H), 2.81 - 2.58 (m, 8H); LC-MS: m/z 380.20 (MH+).

Scheme 5, Cpd (V)*b Preparation: 3-(6-cyclopropyl-2-pyridyl)-4-(4-methylpiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile, Here, 4-cyano-2-(6-cyclopropyl-2-pyridyl)benzoic acid was used instead of 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid. The title compound was obtained in a yield of 85% (55.3 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 - 8.25 (m, 1H), 8.14 - 8.06 (m, 1H), 7.92 (q, 1H), 7.75 - 7.60 (m, 2H), 7.49 (dd, 1H), 4.61 - 4.50 (m, 1H), 2.96 - 2.71 (m, 2H), 2.37 - 2.23 (m, 1H), 1.88 - 1.49 (m, 3H), 1.43 - 1.04 (m, 6H), 0.97 - 0.79 (m, 3H), 0.18 -0.09 (m, 1H); LC-MS: m/z 346.25 (MH+).

Scheme 5, Cpd (V)*c Preparation: 3-(1-tert-butylpyrazol-3-yl)-4-(4-methylpiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile, Here, 2-(1-tert-butylpyrazol-3-yl)-4-cyano-benzoic acid is used instead of 4-cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid. did. The title compound was obtained in a yield of 84% (60 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (dd, 1H), 7.90 (dd, 1H), 7.81 (ddd, 1H), 7.43 (dd, 1H), 6.56 (dd, 1H), 4.55 - 4.41 (m, 1H), 3.99 - 2.23 (m, 1H), 2.89 - 2.64 (m, 2H), 1.54 (d, 10H), 1.29 - 0.93 (m, 3H), 0.92 - 0.71 (m, 3H), 0.13 (qd, 1H); LC-MS: m/z 351.35 (MH+).

Scheme 5, Cpd (V)*d Preparation: 3-(6-cyclopropyl-2-pyridyl)-4-(4-fluoro-4-methyl-piperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile, Here, 4-fluoro-4-methyl-piperidine hydrochloride was used instead of 4-methylpiperidine, and 4-cyano-2-(6-cyclopropyl-2-pyridyl)benzoic acid was used as 4-cyano -2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid was used instead. The title compound was obtained in a yield of 29% (13 mg).

LC-MS: m/z 364.35 (MH+).

Scheme 5, Cpd (V)*e Preparation: 3-(1-tert-butylpyrazol-3-yl)-4-(4-methoxy-4-methyl-piperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile, Here, 4-methoxy-4-methyl-piperidine hydrochloride was used instead of 4-methylpiperidine, and 2-(1-tert-butylpyrazol-3-yl)-4-cyano-benzoic acid was used as 4-methylpiperidine. -Cyano-2-[4-(trifluoromethyl)thiazol-2-yl]benzoic acid was used instead. The title compound was obtained in a yield of 81% (41 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (dd, 1H), 7.90 (dd, 1H), 7.84 - 7.78 (m, 1), 7.45 (dd, 1H), 6.58 (dd, 1H), 4.19 - 4.05 (m, 1H), 3.14 - 2.77 (m, 6H), 1.84 - 1.66 (m, 1H), 1.54 (d, 11H), 1.11 - 0.89 (m, 3H), 0.57 - 0.43 (m, 1H) ; LC-MS: m/z 381.36 (MH+).

Scheme 5, Cpd (V)*f Preparation: 4-(4-methoxy-4-methyl-piperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl ]Benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile, Here, 4-methoxy-4-methyl-piperidine hydrochloride was used instead of 4-methylpiperidine. The title compound was obtained in a yield of 65% (88.8 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 - 8.65 (m, 1H), 8.45 - 8.35 (m, 1H), 8.12 - 8.03 (m, 1H), 7.69 - 7.57 (m, 1H), 4.19 - 4.01 (m, 1H), 3.29 (s, 3H), 3.26 - 2.95 (m, 3H), 1.81 - 1.70 (m, 1H), 1.60 - 1.20 (m, 3H), 1.04 (s, 3H); LC-MS: m/z 410.27 (MH+).

Scheme 5, Preparation of Cpd (VI)*a : (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[ 4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone

Example 62

Discesium carbonate (120.57 mg, 0.370 mmol), etanimidamide hydrochloride (17.49 mg, 0.190 mmol), CuBr (0.88 mg, 0.010 mmol) and 4-(4-methylpiperidine-) in DMSO (1.199 mL) A mixture of 1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile (46.8 mg, 0.120 mmol) was stirred at 120° C. for 4 h. After this time, the reaction was cooled to room temperature and H ₂ O was added. The mixture was then extracted three times with AcOEt. The aqueous phase was diluted with saturated potassium sodium tartrate solution and extracted with EtOAc and THF x5. The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 95:5) to obtain the product of the formula (4-methyl-1-piperidyl)-[4-(5-methyl-4H- 1,2,4-triazol-3-yl)-2-[4-(trifluoromethyl)thiazol-2-yl]phenyl] was provided.

Yield: 26.6 mg.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.69 - 8.61 (m, 1H), 8.54 - 8.38 (m, 1H), 8.20 - 8.13 (m, 1H), 7.56 - 7.40 (m, 1H), 4.56 - 4.41 (m, 1H), 3.09 - 2.94 (m, 1H), 3.12 - 2.62 (m, 3H), 2.46 (s, 2H), 1.84 - 0.71 (m, 9H); LC-MS: m/z 436.28 (MH+).

Preparation: [2-(6-cyclopropyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methyl-1-p Peridyl) methanone

Example 63

The synthesis of the title compound was carried out using the compound of Example 62 (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4 -(trifluoromethyl)thiazol-2-yl]phenyl]methanone was carried out similarly to the synthesis, but here 3-(6-cyclopropyl-2-pyridyl)-4-(4-methylpiperidine -1-Carbonyl)benzonitrile was used instead of 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. The title compound was obtained in a yield of 65% (42 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (br d, 1H), 8.03 (d, 1H), 7.74 (td, 1H), 7.47 - 7.25 (m, 3H), 4.47 - 4.35 (m, 1H) ), 2.84 - 2.53 (m, 3H), 2.44 - 2.36 (m, 3H), 2.20 - 2.06 (m, 1H), 1.74 - 0.62 (m, 12H), 0.32 - 0.25 (m, 1H); LC-MS: m/z 402.36 (MH+).

Preparation: [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methyl-1 -piperidyl)methanone

Example 64

The synthesis of the title compound was carried out using the compound of Example 62 (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4 -(trifluoromethyl)thiazol-2-yl]phenyl]methanone was carried out similarly to the synthesis, herein 3-(1-tert-butylpyrazol-3-yl)-4-(4-methylpyrazol-3-yl)-4-(4-methylpyrazol-3-yl) Peridine-1-carbonyl)benzonitrile was used instead of 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. . The title compound was obtained in a yield of 68% (47.3 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.30 (dd, 1H), 7.98 - 7.79 (m, 2H), 7.28 (t, 1H), 6.42 (dd, 1H), 4.49 (br d, 1H) ), 2.85 - 2.57 (m, 2H), 2.40 (s, 3H), 1.55 (d, 11H), 1.30 - 0.67 (m, 7H), 0.11 -0.09 (m, 1H); LC-MS: m/z 407.47 (MH+).

Preparation: [2-(6-cyclopropyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-fluoro-4- Methyl-1-piperidyl)methanone

Example 65

The synthesis of the title compound was carried out using the compound of Example 62 (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4 -(trifluoromethyl)thiazol-2-yl]phenyl]methanone was carried out similarly to the synthesis, here 3-(6-cyclopropyl-2-pyridyl)-4-(4-fluoro-4 -Methyl-piperidine-1-carbonyl)benzonitrile is replaced with 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzo It was used instead of nitrile. The title compound was obtained in a yield of 53% (8 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.27 - 8.21 (m, 1H), 8.07 - 8.00 (m, 1H), 7.79 - 7.71 (m, 1H), 7.49 - 7.40 (m, 2H), 7.33 - 7.26 (m, 1H), 4.29 - 4.13 (m, 1H), 3.08 - 2.87 (m, 3H), 2.41 (s, 3H), 2.18 - 2.06 (m, 1H), 1.88 - 0.71 (m, 11H) ), 0.39 - 0.16 (m, 1H); LC-MS: m/z 420.37 (MH+).

Preparation: [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-methoxy- 4-methyl-1-piperidyl)methanone

Example 66

The synthesis of the title compound was carried out using the compound of Example 62 (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4 -(trifluoromethyl)thiazol-2-yl]phenyl]methanone was carried out similarly to the synthesis, but here 3-(1-tert-butylpyrazol-3-yl)-4-(4-methoxy -4-Methyl-piperidine-1-carbonyl)benzonitrile is replaced with 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl ]Used instead of benzonitrile. The title compound was obtained in a yield of 40% (19 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (dd, 1H), 7.98 - 7.85 (m, 2H), 7.30 (dd, 1H), 6.44 (dd, 1H), 4.22 - 4.07 (m, 1H) , 3.05 (d, 6H), 2.41 (s, 3H), 1.80 - 1.65 (m, 1H), 1.57 (d, 9H), 1.51 - 1.22 (m, 3H), 1.12 - 0.89 (m, 3H), 0.45 - 0.28 (m, 1H); LC-MS: m/z 437.48 (MH+).

Preparation: (4-methoxy-4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-(tri Fluoromethyl)thiazol-2-yl]phenyl]methanone

Example 67

The synthesis of the title compound was carried out using the compound of Example 62 (4-methyl-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4 -(trifluoromethyl)thiazol-2-yl]phenyl]methanone was carried out similarly to the synthesis, here 4-(4-methoxy-4-methyl-piperidine-1-carbonyl)-3 -[4-(trifluoromethyl)thiazol-2-yl]benzonitrile is replaced with 4-(4-methylpiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazole- 2-yl] was used instead of benzonitrile. The title compound was obtained in a yield of 25% (27.3 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (s, 1H), 8.52 - 8.35 (m, 1H), 8.15 (dd, 1H), 7.53 - 7.42 (m, 1H), 4.22 - 3.98 (m, 1H), 3.23 - 2.95 (m, 6H), 2.42 (s, 3H), 1.83 - 1.69 (m, 1H), 1.58 - 1.36 (m, 3H), 1.25 - 0.99 (m, 4H);LC-MS: m/z 466.29 (MH+).

Scheme 6

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Asstatech) by coupling with a suitable amine in the presence of a coupling agent such as HATU, and a suitable organic base such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete.

Step 2

Compounds of formula III can be reacted with a suitable transition metal catalyst, such as Pd(dppf)Cl ₂ , in the presence of a suitable base, such as potassium acetate, in a suitable solvent, such as 1,4-dioxane, typically at 95° C. It can be obtained through Miyaura borylation between the compound and B ₂ Pin ₂ . The reaction takes approximately 12 hours to complete.

Step 3

The compounds of formula IV are reacted in the presence of a suitable catalyst, such as palladium tetrakis triphenylphosphine, a suitable inorganic base, such as Na ₂ CO _{3 ,} in a suitable solvent mixture such as 1,2-dimethoxyethane/water, typically at 95° C. It can be obtained through Suzuki coupling between a compound of formula III and a commercially available heteroaryl halide. The reaction takes about 3 hours to about 12 hours to complete.

Step 4

Compounds of formula (V ₎ can be reacted with nitrile catalysis of compounds of formula (IV) using ethanimidamide hydrochloride, typically at ₁₂₀ ° C., in the presence of a suitable catalyst, eg CuBr, a suitable base, eg DMSO, in the presence of a suitable base, eg DMSO. It can be obtained by cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Scheme 6, Cpd (II)*a Preparation: 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

HATU (1.14 g, 2.99 mmol), 2-bromo-4-cyanobenzoic acid (450.0 mg, 1.99 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (415.24 mg, N,N-diisopropylethylamine (2.03 mL, 11.95 mmol) was added to the solution (2.19 mmol). The reaction was stirred at RT for 5 h. After this time, the reaction was diluted with H ₂ O and then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% cHex to AcOEt/cHex 60:40) to obtain the product 3-bromo-4-[4-(trifluoromethyl)piperidine-1-car of the formula above. Bornyl]benzonitrile was provided.

Yield: 560 mg

1H NMR (400 MHz, DMSO) δ 8.29 (dd, 1H), 7.95 (ddd, 1H), 7.71 - 7.50 (m, 1H), 4.60 (t, 1H), 3.26 (d, 1H), 3.09 (dtd, 1H), 2.83 (tdd, 1H), 2.66 (d, 1H), 1.94 (t, 1H), 1.82 - 1.65 (m, 1H), 1.55 - 1.29 (m, 2H); LC-MS: m/z 361.07, 363.10 (MH+).

Scheme 6, Preparation of Cpd (III)*a : 4-(4,4-difluoropiperidine-1-carbonyl)-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)benzonitrile

3-Bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile (950.0 mg, 2.8 mmol), 4,4,5,5-tetramethyl-2-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.13 g, 8.4 mmol), potassium acetate (832.78 mg, 8.4 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] complex of dichloropalladium (II) and dichloromethane (68.76 mg, 0.080 mmol) were placed in a vial, and 1,4-dioxane (25 mL) was suspended in The mixture was degassed via N ₂ -vacuum cycles (3 times). The mixture was stirred at 90° C. overnight under N ₂ atmosphere. After this time the reaction was cooled, filtered through a pad of Celite and washed with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product of the formula 4-(4,4-difluoropiperidine-1-carbonyl)-3-( This gave 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, which was used in the next step without further purification.

Yield: 1.0 g

LC-MS: m/z 377.26 (MH+).

Scheme 6, Preparation of Cpd (III)*b : 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[4-(trifluoro methyl)piperidine-1-carbonyl]benzonitrile

3-Bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (750.0 mg, 2.08 mmol), 4,4,5,5-tetramethyl-2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.58 g, 6.23 mmol), potassium acetate (617.7 mg, 6.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane complex (34.0 mg, 0.040 mmol) were suspended in 1,4-dioxane (20 mL). , the mixture was degassed through N ₂ -vacuum cycles (3 times). The mixture was stirred overnight at 95° C. under N ₂ atmosphere. After this time, complete consumption of the starting material was observed, so the mixture was cooled to RT, filtered through a pad of Celite and washed with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product 3-(4,4,5,5-tetramethyl-1,3,2-dioxabor). Rolan-2-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was provided. The product was used in the next step without further purification.

Yield: 800 mg

LC-MS: m/z 409.16 (MH+).

Scheme 6, Cpd (IV)*a Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-(6-isopropyl-2-pyridyl)benzonitrile

Palladium tetrakis triphenylphosphine (80.17 mg, 0.070 mmol) and 2-bromo-6-isopropyl-pyridine (277.62 mg, 1.39 mmol) were suspended in 1,2-dimethoxyethane (13.88 mL), 2M Na ₂ CO ₃ aqueous solution (2.08 mL, 4.16 mmol) was added. The mixture was degassed with 5 cycles of nitrogen/vacuum and 4-(4,4-difluoropiperidine-1-carbonyl)-3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzonitrile (0.5 g, 1.39 mmol) was added. The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and then heated to 95° C. for 8 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The mixture was purified by RP FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 60:460 CH ₃ CN/H ₂ O + 0.1% HCOOH) to This gave the product of the formula 4-(4,4-difluoropiperidine-1-carbonyl)-3-(6-isopropyl-2-pyridyl)benzonitrile.

Yield: 160 mg

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.25 (d, 1H), 7.98 (dd, 1H), 7.89 - 7.85 (m, 1H), 7.72 - 7.62 (m, 2H), 7.33 (dd, 1H) ), 4.06 - 3.97 (m, 1H), 3.40 - 3.24 (m, 2H), 3.14 - 3.05 (m, 1H), 2.99 (p, 1H), 2.23 - 1.84 (m, 3H), 1.71 - 1.51 (m , 1H), 1.29 - 1.20 (m, 6H); LC-MS: m/z 370.31 (MH+).

Scheme 6, Cpd (IV)*b Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-[6-(trifluoromethyl)pyridin-2-yl]benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 4-(4,4-difluoropiperidine-1-carbonyl)-3-(6-isopropyl-2-pyridyl)benzonitrile, where 2-Bromo-6-(trifluoromethyl)pyridine was used instead of 2-bromo-6-isopropyl-pyridine. The title compound was obtained in a yield of 40% (130 mg).

1H NMR (400 MHz, DMSO) δ 8.37 (d, 1H), 8.26 (t, 1H), 8.20 (d, 1H), 8.06 (dd, 1H), 7.95 (dd, 1H), 7.75 (d, 1H) , 4.04 -3.93 (m, 1H), 3.50 -3.39 (m, 1H), 2.54 -2.50 (m, 2H), 2.23 -1.97 (m, 3H), 1.93 -1.83 (m, 1H); LC-MS: m/z 396.26 (MH+).

Scheme 6, Cpd (IV)*c Preparation: 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1 -carbonyl]benzonitrile

Palladium tetrakis triphenylphosphine (42.46 mg, 0.040 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[4- (Trifluoromethyl)piperidine-1-carbonyl]benzonitrile (0.33 g, 0.730 mmol) was suspended in 1,2-dimethoxyethane (7.349 mL), then 2M Na ₂ CO ₃ aqueous solution (1.1 mL). , 2.2 mmol) was added. The reaction was degassed with 5 cycles of nitrogen/vacuum and 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine (158.9 mg, 0.810 mmol) was added. The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and then heated to 95° C. for 8 h. After this time, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The residue was purified by FC on silica gel (eluted with AcOEt/cHex 5:95 to AcOEt/cHex 60:40) and again by reverse-phase FC using acid conditions (CH ₃ CN/H ₂ O + 0.1 at 5:95). % HCOOH to 40:60 CH ₃ CN/H ₂ O + eluting with 0.1% HCOOH) the product of the formula 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]- 4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was provided.

Yield: 34 mg

1H NMR (400 MHz, DMSO) δ 8.60 - 8.42 (m, 1H), 8.10 (dd, 1H), 7.99 (s, 1H), 7.73 - 7.59 (m, 1H), 4.54 (d, 1H), 3.30 ( s, 3H), 2.68 (s, 4H), 1.97 (d, 1H), 1.73 (d, 1H), 1.47 (d, 2H); LC-MS: m/z 443.4 (MH+).

Scheme 6, Cpd (IV)*d Preparation: 3-(4-cyclopropylthiazol-2-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out using the compound 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo The synthesis was performed similarly to the nitrile, except that 2-bromo-4-cyclopropylthiazole was used instead of 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine. The title compound was obtained in a yield of 11% (33 mg).

1H NMR (400 MHz, DMSO) δ 8.33 - 8.22 (m, 1H), 7.98 (td, 1H), 7.65 - 7.53 (m, 1H), 7.47 (d, 1H), 4.58 (s, 1H), 3.28 ( s, 1H), 3.06 - 2.65 (m, 3H), 2.14 - 2.06 (m, 1H), 1.99 - 1.10 (m, 4H), 0.98 - 0.70 (m, 4H); LC-MS: m/z 406.47 (MH+).

Scheme 6, Cpd (IV)*e Preparation: 3-(6-propan-2-ylpyridin-2-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out using the compound 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo The synthesis was performed similarly to the nitrile, except that 2-bromo-6-propan-2-ylpyridine was used instead of 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine. The title compound was obtained in a yield of 37% (47 mg).

1H NMR (400 MHz, DMSO) δ 8.27 - 8.11 (m, 1H), 7.96 (ddd, 1H), 7.84 (td, 1H), 7.64 (dd, 1H), 7.59 - 7.49 (m, 1H), 7.37 - 7.26 (m, 1H), 4.52 (d, 1H), 3.30 (s, 4H), 2.50 (p, 1H), 1.94 - 0.02 (m, 10H); LC-MS: m/z 402.28 (MH+).

Scheme 6, Cpd (IV)*f Preparation: 3-(6-cyclopropylpyridin-2-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out using the compound 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo The synthesis was performed similarly to the nitrile, except that 2-bromo-6-cyclopropylpyridine was used instead of 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine. The title compound was obtained in a yield of 34% (90 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.25 - 8.09 (m, 1H), 8.01 - 7.86 (m, 1H), 7.82 - 7.72 (m, 1H), 7.64 - 7.46 (m, 2H), 7.35 - 7.25 (m, 1H), 4.54 (d, 1H), 3.12 - 2.59 (m, 3H), 2.11 (tq, 1H), 1.97 - 1.63 (m, 2H), 1.54 - 1.20 (m, 3H), 0.99 - 0.62 (m, 4H); LC-MS: m/z 400.47 (MH+).

Scheme 6, Cpd (IV)*g Preparation: 4-[4-(trifluoromethyl)piperidine-1-carbonyl]-3-[4-(trifluoromethyl)-1,3-thiazole -2-day]benzonitrile

The synthesis of the title compound was carried out using the compound 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo The synthesis was performed similarly to the nitrile, except that 2-bromo-4-(trifluoromethyl)thiazole was used instead of 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine. The title compound was obtained in a yield of 23% (67 mg).

LC-MS: m/z 434.38 (MH+).

Scheme 6, Cpd (IV)*h Preparation: 4-[4-(trifluoromethyl)piperidine-1-carbonyl]-3-[6-(trifluoromethyl)pyridin-2-yl]benzo nitrile

The synthesis of the title compound was carried out using the compound 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo The synthesis was performed similarly to the nitrile, except that 2-bromo-6-(trifluoromethyl)pyridine was used instead of 2-chloro-4-methyl-6-(trifluoromethyl)pyrimidine. The title compound was obtained in a yield of 17% (77 mg).

LC-MS: m/z 428.10 (MH+).

Scheme 6, preparing Cpd (V)*a : [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl) pyrimidin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone

Example 68

3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzo in DMSO (0.791 mL) A mixture of nitrile (35.0 mg, 0.080 mmol), disesium carbonate (77.34 mg, 0.240 mmol), etanimidamide hydrochloride (11.22 mg, 0.120 mmol), and CuBr (0.57 mg, 0 mmol) was incubated at 120 °C for 2 h. It was stirred for a while. After this time, the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 95:5) to obtain the product of the formula [4-(5-methyl-4H-1,2,4-triazol-3-yl )-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone was provided.

Yield: 3 mg

1H NMR (400 MHz, MeOD) δ 9.18 - 8.88 (m, 1H), 8.24 (d, 1H), 7.72 (s, 1H), 7.53 (d, 1H), 4.75 (d, 1H), 3.68 (d, 1H), 3.29 - 2.77 (m, 3H), 2.72 (s, 3H), 2.52 (s, 3H), 2.06 (t, 1H), 1.83 (d, 1H), 1.64 (p, 2H); LC-MS: m/z 499.39 (MH+).

Preparation: [2-(4-cyclopropylthiazol-2-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoro methyl)-1-piperidyl]methanone

Example 69

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, here 3-(4-cyclopropylthiazol-2-yl) -4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile is replaced with 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[ It was used instead of 4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile. The title compound was obtained in a yield of 48% (18 mg).

1H NMR (400 MHz, DMSO) δ 13.87 (s, 1H), 8.34 (dd, 1), 8.12 - 8.03 (m, 1H), 7.56 - 7.29 (m, 2H), 4.62 (s, 1H), 3.41 ( d, 1H), 3.07 - 2.57 (m, 3H), 2.42 (s, 3H), 2.11 (tt, 1H), 2.02 - 1.84 (m, 1H), 1.74 - 1.53 (m, 1H), 1.52 - 1.01 ( m, 2H), 0.99 - 0.66 (m, 4H); LC-MS: m/z 462.22 (MH+).

Preparation: [2-(6-isopropyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl )-1-piperidyl]methanone

Example 70

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, herein 3-(6-propan-2-ylpyridin-2- 1)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile to 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4 -[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 47% (25 mg).

1H NMR (400 MHz, DMSO) δ 13.83 (s, 1H), 8.31 - 8.25 (m, 1H), 8.10 - 8.02 (m, 1H), 7.82 (t, 1H), 7.58 - 7.39 (m, 2H), 7.34 - 7.23 (m, 1H), 4.55 (d, 1H), 3.61 - 2.55 (m, 4H), 2.41 (s, 4H), 1.97 - 1.33 (m, 3H), 1.30 - 1.20 (m, 6H), 0.98 - 0.13 (m, 1H); LC-MS: m/z 458.48 (MH+).

Preparation: [2-(6-cyclopropylpyridin-2-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl )piperidin-1-yl]methanone

Example 71

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, here 3-(6-cyclopropylpyridin-2-yl)- 4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile to 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4 -(Trifluoromethyl)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 17% (17 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 13.83 (s, 1H), 8.30 - 8.15 (m, 1H), 8.06 (dt, 1H), 7.76 (td, 1H), 7.51 - 7.35 (m, 2H) ), 7.28 (dd, 1H), 4.57 (d, 1H), 4.24 - 3.43 (m, 1H), 3.22 - 2.58 (m, 3H), 2.42 (s, 5H), 2.00 - 1.63 (m, 1H), 1.55 - 0.19 (m, 6H); LC-MS: m/z 456.22 (MH+).

Preparation: [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl ]-[4-(trifluoromethyl)piperidin-1-yl]methanone

Example 72

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, herein 4-[4-(trifluoromethyl)piperidine -1-carbonyl]-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]benzonitrile to 3-[4-methyl-6-(trifluoromethyl)pyrimidine -2-yl]-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 48% (37 mg).

1H NMR (400 MHz, DMSO) δ 13.91 (s, 1H), 8.65 (d, 1H), 8.44 (d, 1H), 8.18 (dd, 1H), 7.53 (dd, 1H), 4.62 (d, 1H) , 3.49 (d, 1H), 3.12 (t, 1H), 2.80 (t, 1H), 2.60 (s, 1H), 2.44 (s, 3H), 2.05 - 1.29 (m, 3H), 1.03 (d, 1H) ); LC-MS: m/z 490.13 (MH+).

Preparation: [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[6-(trifluoromethyl)pyridin-2-yl]phenyl]-[4-( trifluoromethyl)piperidin-1-yl]methanone

Example 73

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, herein 4-[4-(trifluoromethyl)piperidine -1-carbonyl]-3-[6-(trifluoromethyl)pyridin-2-yl]benzonitrile to 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]- It was used instead of 4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile. The title compound was obtained in a yield of 36% (31 mg).

1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 8.32 (d, 1H), 8.23 (t, 1H), 8.13 (dd, 1H), 8.06 (d, 1H), 7.92 (s, 1H) , 7.52 (d, 1H), 4.51 (d, 1H), 3.50 (d, 1H), 3.10 - 2.70 (m, 2H), 2.59 (s, 1H), 2.43 (s, 3H), 2.00 - 1.37 (m , 3H), 0.77 (d, 1H); LC-MS: m/z 484.13 (MH+).

Manufactured by: 4,4-difluoro-1-piperidyl)-[2-(6-isopropyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazole- 3-yl)phenyl]methanone

Example 74

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, where 4-(4,4-difluoropiperidine- 1-carbonyl)-3-(6-isopropyl-2-pyridyl)benzonitrile is 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4-[4- (Trifluoromethyl)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 50% (80 mg).

^1H NMR (400 MHz, DMSO _- d6 ) δ 13.75 (bs, 1H), 8.30 (d, 1H), 8.07 (dd, 1H), 7.85 (t, 1H), 7.54 (dd, 2H), 7.30 ( d, 1H), 3.93 -3.83 (m, 1H), 3.45 -3.37 (m, 2H), 3.15 -3.07 (m, 1H), 3.01 (p, 1H), 2.42 (s, 3H), 2.16 -1.74 ( m, 3H), 1.56 -1.44 (m, 1H), 1.25 (dd, 6H); LC-MS: m/z 426.35 (MH+).

Preparation: (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[6-(tri Fluoromethyl)pyridin-2-yl]phenyl]methanone

Example 75

The synthesis of the title compound was carried out using the compound [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-methyl-6-(trifluoromethyl)pyri of Example 68. was carried out similarly to the synthesis of midin-2-yl]phenyl]-[4-(trifluoromethyl)-1-piperidyl]methanone, where 4-(4,4-difluoropiperidine- 1-carbonyl)-3-[6-(trifluoromethyl)pyridin-2-yl]benzonitrile is converted to 3-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-4 -[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile was used instead. The title compound was obtained in a yield of 26% (25 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (d, 1H), 8.28 - 8.20 (m, 1H), 8.17 - 8.08 (m, 2H), 7.92 (d, 1H), 7.59 (d, 1H) , 3.96 - 3.83 (m, 2H), 3.58 - 3.34 (m, 3H), 2.42 (s, 3H), 2.18 - 1.71 (m, 4H); LC-MS: m/z 452.20 (MH+).

Scheme 7

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Asstatech) by coupling with an appropriate amine in the presence of a coupling agent such as HATU, and an organic base such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes about 3 hours to about 12 hours to complete.

Step 2

Compounds of formula III can be reacted with a suitable transition metal catalyst, such as Pd(dppf)Cl ₂ , in the presence of a suitable base, such as potassium acetate, in a suitable solvent, such as 1,4-dioxane, typically at 95° C. (commercially available from Asstatech) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2-dioxa It can be obtained through Miyaura borylation between borinans; the reaction takes about 12 hours to complete.

Step 3

Compounds of formula IV can be reacted with the formula III in the presence of a suitable palladium catalyst, for example palladium tetrakis triphenylphosphine, a suitable inorganic base Na ₂ CO ₃ in a suitable solvent mixture, 1,2-dimethoxyethane/water, typically at 95° C. It can be obtained through Suzuki coupling between a compound of and a commercially available heteroaryl halide. The reaction takes about 3 hours to about 12 hours to complete.

Step 4

Compounds of formula (V) can be reacted with nitrile catalysis of compounds of formula (IV) using ethanimidamide hydrochloride in the presence of a suitable catalyst, eg CuBr, a suitable base, eg Cs ₂ CO ₃ and in a suitable solvent, eg DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Scheme 7, Cpd (II)*a Preparation: 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

[dimethylammonium(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate HATU (1.14 g, 2.99 mmol), 2-bromo-4 in DMF (13.27 mL) -4,4-difluoropiperidine hydrochloride (376.49 mg, 2.39 mmol) in a solution of cyanobenzoic acid (450.0 mg, 1.99 mmol) and N,N-diisopropylethylamine (2.03 mL, 11.95 mmol) was added. The reaction was stirred at RT for 3 h. After this time saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with 100% cHex to cHexAcOEt/65:35) to give the product 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl) of the formula above. Benzonitrile was provided.

Yield: 500 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (d, 1H) 7.98 (dd, 1H) 7.66 (d, 1H) 3.82 - 3.93 (m, 1H) 3.60 - 3.73 (m, 1H) 3.22 (t, 2H) 1.88 - 2.22 (m, 4H); LC-MS: m/z 329.00, 331.00 (MH+).

Scheme 7, Cpd (II)*b Preparation: 3-bromo-4-[4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile

[Dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate HATU (630.83 mg, 1.66 mmol), 2-bromo-4 in DMF (5.821 mL) -N,N-diisopropylethylamine (1.13 mL, 6.64 mmol) in a solution of cyanobenzoic acid (250.0 mg, 1.11 mmol) and 4-(trifluoromethoxy)piperidine hydrochloride (272.9 mg, 1.33 mmol) ) was added. The reaction was stirred at RT for 6 h. After this time the reaction was diluted with H ₂ O. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with AcOEt:cHex 5:95 to 60:40) to obtain the product 3-bromo-4-[4-(trifluoromethoxy)piperidine-1-carbonyl of the above formula. ]Benzonitrile was provided.

Yield: 260 mg

1H NMR (400 MHz, DMSO) δ 8.29 (dd, 1H), 7.96 (ddd, 1H), 7.72 - 7.49 (m, 1H), 4.74 (dt, 1H), 4.02 (td, 1H), 3.42 (dddd, 1H), 3.30 - 3.06 (m, 2H), 2.09 - 1.97 (m, 1H), 1.90 (s, 1H), 1.84 - 1.56 (m, 2H); LC-MS: m/z 377.36, 379.26 (MH+).

Scheme 7, Cpd (III)*a preparation: [5-cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]boronic acid

Potassium acetate (40.67 mg, 0.410 mmol), [1,1'-bis(diphenylphosphino)ferrocene] complex of dichloropalladium(II) and dichloromethane (5.6 mg, 0.010 mmol), 3-bromo-4- (4,4-difluoropiperidine-1-carbonyl)benzonitrile (45.0 mg, 0.140 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl )-5,5-dimethyl-1,3,2-dioxaborinane (46.33 mg, 0.210 mmol) was suspended in 1,4-dioxane (1 mL). The mixture was then degassed three times via N ₂ -vacuum cycle. The vial was sealed and the mixture was stirred at 90° C. for 3 h. After this time the reaction was cooled, filtered through a pad of Celite and washed with EtOAc. The organic phase was washed with saturated NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product of the formula [5-cyano-2-(4,4-difluoropiperi) Dean-1-carbonyl)phenyl]boronic acid was provided. The product was used in the next step without further purification.

Yield: 40 mg

LC-MS: m/z 295.24 (MH+).

Scheme 7, Cpd (III)*b preparation: [5-cyano-2-[4-(trifluoromethoxy)piperidine-1-carbonyl]phenyl]boronic acid

The synthesis of the title compound was carried out similarly to the synthesis of the compound [5-cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]boronic acid, here 3-bromo-4 -[4-(Trifluoromethoxy)piperidine-1-carbonyl]benzonitrile is used instead of 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile. did. The title compound was obtained in a yield of 61% (145 mg).

LC-MS: m/z 343.20 (MH+).

Scheme 7, Cpd (IV)*a Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzo nitrile

Palladium tetrakis triphenylphosphine (15.72 mg, 0.010 mmol) and [5-cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]boronic acid (80.0 mg, 0.270 mmol) ) was suspended in 1,2-dimethoxyethane (2 mL), and then 2M Na ₂ CO ₃ aqueous solution (86.5 mg, 0.820 mmol) was added. The mixture was degassed with 5 cycles of nitrogen/vacuum and then with 2-bromo-4-(trifluoromethyl)thiazole (69.43 mg, 0.300 mmol). The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and heated to 100° C. overnight. After this time, the reaction was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The mixture was purified by FC on silica gel (eluting with 100% cHex to cHex:EtOAc 50:50) to give the product of the formula 4-(4,4-difluoropiperidine-1-carbonyl)-3-[ 4-(trifluoromethyl)thiazol-2-yl]benzonitrile was provided.

Yield: 35 mg

1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, 1H), 8.44 (d, 1H), 8.11 (dd, 1H), 7.70 (d, 1H), 3.87 - 3.78 (m, 1H), 3.63 - 3.53 (m, 1H), 2.20 - 1.85 (m, 6H); LC-MS: m/z 402.15 (MH+).

Scheme 7, Cpd (IV)*b Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)pyrimidin-2-yl]benzo nitrile

The synthesis of the title compound is similar to the synthesis of compound 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. It was performed as follows, where 2-chloro-4-(trifluoromethyl)pyrimidine was used instead of 2-bromo-4-(trifluoromethyl)thiazole. The title compound was obtained in a yield of 40% (44 mg).

1H NMR (400 MHz, DMSO-d6) δ 9.33 (d, 1H), 8.58 (d, 1H), 8.15 (dd, 1H), 8.09 - 8.04 (m, 1H), 7.76 (dd, 1H), 4.17 - 3.86 (m, 1H), 2.21 - 1.92 (m, 6H); LC-MS: m/z 397.21 (MH+).

Scheme 7, Cpd (IV)*c Preparation: 3-(6-cyclopropyl-2-pyridyl)-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound is similar to the synthesis of compound 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. It was performed as follows, where 2-bromo-6-cyclopropylpyridine was used instead of 2-bromo-4-(trifluoromethyl)thiazole. The title compound was obtained in a yield of 47% (28 mg).

1H NMR (400 MHz, DMSO) δ 8.22 (d, 1H), 7.96 (td, 2H), 7.79 (t, 1H), 7.67 (dd, 2H), 3.93 (d, 1H), 3.74 (s, 1H) , 3.41 (t, 1H), 2.98 (d, 1H), 2.20 - 1.81 (m, 6H), 1.41 (s, 1H), 1.00 - 0.91 (m, 2H); LC-MS: m/z 368.22 (MH+).

Scheme 7, Cpd (IV)*d Preparation: 3-(6-tert-butyl-2-pyridyl)-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound is similar to the synthesis of compound 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. It was performed as follows, where 2-bromo-6-tert-butyl-pyridine was used instead of 2-bromo-4-(trifluoromethyl)thiazole. The title compound was obtained in a yield of 82% (94 mg).

H NMR (400 MHz, DMSO) δ 8.22 (d, 1H), 7.99 (dd, 1H), 7.87 (t, 1H), 7.73 (d, 1H), 7.61 (dd, 1H), 7.47 (dd, 1H) , 4.11 - 3.96 (m, 1H), 3.25 - 3.14 (m, 2H), 3.06 - 2.90 (m, 1H), 2.19 - 1.77 (m, 3H), 1.56 - 1.38 (m, 1H), 1.30 (s, 9H); LC-MS: m/z 384.47 (MH+).

Scheme 7, Cpd (IV)*e Preparation: 3-(1-tert-butylpyrazol-3-yl)-4-[4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound is similar to the synthesis of compound 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile. was performed, wherein [5-cyano-2-[4-(trifluoromethoxy)piperidine-1-carbonyl]phenyl]boronic acid and 1-tert-butyl-3-iodopyrazole, respectively. [5-Cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]boronic acid and 2-bromo-4-(trifluoromethyl)thiazole were used instead. The title compound was obtained in a yield of 33% (96 mg).

1H NMR (400 MHz, DMSO) δ 8.22 - 8.12 (m, 1H), 7.96 - 7.88 (m, 1H), 7.82 (td, 1H), 7.50 (dd, 1H), 6.61 (dd, 1H), 4.65 ( dt, 1H), 3.51 (ddd, 1H), 3.28 - 2.88 (m, 3H), 1.99 (s, 2H), 1.81 - 1.63 (m, 2H), 1.54 (d, 9H); LC-MS: m/z 421.23 (MH+).

Scheme 7, Preparation of Cpd (V)*a : (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl) -2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone

Example 76

4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiazol-2-yl]benzonitrile (35.0 mg, A mixture of 0.070 mmol), CuBr (0.52 mg, 0 mmol), disesium carbonate (94.33 mg, 0.290 mmol) and ethanimidamide hydrochloride (13.69 mg, 0.140 mmol) was stirred at 120 °C for 2 h. After this time the reaction was cooled to RT. After addition of H ₂ O, the mixture was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM:MeOH 95:5) and then purified by reverse-phase FC using acid conditions (CH ₃ CN/H ₂ O + 0.1 at 5:95). % HCOOH to 55:45 CH ₃ CN/H ₂ O + eluting with 0.1% HCOOH) The product of the formula (4,4-difluoro-1-piperidyl)-[4-(5-methyl -4H-1,2,4-triazol-3-yl)-2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone was provided.

Yield: 14 mg

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.65 (d, 1H), 8.43 (d, 1H), 8.19 (dd, 1H), 7.56 (d, 1H), 3.94 - 3.82 (m, 1H), 3.67 - 3.52 (m, 1H), 3.38 - 3.30 (m, 2H), 2.44 (s, 3H), 2.20 - 1.79 (m, 4H); LC-MS: m/z 458.38 (MH+).

Preparation: (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[4-(trifluoro Romethyl)pyrimidin-2-yl]phenyl]methanone

Example 77

The synthesis of the title compound was carried out using the compound of Example 76 (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)- The synthesis was carried out similarly to the synthesis of 2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone, here 4-(4,4-difluoropiperidine-1-carbonyl) -3-[4-(trifluoromethyl)pyrimidin-2-yl]benzonitrile is replaced with 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)benzonitrile Romethyl)thiazol-2-yl]benzonitrile was used instead. The title compound was obtained in a yield of 11% (5 mg).

1H NMR (400 MHz, DMSO-d6) δ 9.30 (d, 1H), 8.86 (d, 1H), 8.19 (dd, 1H), 8.01 (d, 1H), 7.56 (d, 1H), 3.95 - 3.82 ( m, 1H), 3.58 - 3.40 (m, 2H) 2.55 - 2.52 (m, 2H), 2.43 (s, 3H), 2.20 - 1.90 (m, 4H); LC-MS: m/z 453.26 (MH+).

Preparation: [2-(6-cyclopropyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoro -1-piperidyl)methanone

Example 78

The synthesis of the title compound was carried out using the compound of Example 76 (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)- 2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone), herein 3-(6-cyclopropyl-2-pyridyl)-4-(4 , 4-difluoropiperidine-1-carbonyl) benzonitrile is mixed with 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiamine. Zol-2-yl] was used instead of benzonitrile. The title compound was obtained in a yield of 33% (8 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.80 (bs, 1H), 8.26 (d, 1H), 8.06 (dd, 1H), 7.78 (t, 1H), 7.56 - 7.46 (m, 2H), 7.30 (dd, 1H), 3.92 - 3.80 (m, 1H), 3.54 - 3.45 (m, 2H), 3.08 - 2.93 (m, 1H), 2.42 (s, 3H), 2.19 - 1.80 (m, 3H), 1.36 (s, 1H), 1.12 - 0.69 (m, 4H); LC-MS: m/z 424.31 (MH+).

Preparation: [2-(6-tert-butyl-2-pyridyl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoro rho-1-piperidyl)methanone

Example 79

The synthesis of the title compound was carried out using the compound of Example 76 (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)- The synthesis was carried out similarly to the synthesis of 2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone, here 3-(6-tert-butyl-2-pyridyl)-4-(4 , 4-difluoropiperidine-1-carbonyl) benzonitrile is mixed with 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl)thiamine. Zol-2-yl] was used instead of benzonitrile. The title compound was obtained in a yield of 35% (38 mg).

1H NMR (400 MHz, DMSO) δ 13.85 (s, 1H), 8.29 (d, 1H), 8.07 (dd, 1H), 7.86 (t, 1H), 7.62 - 7.49 (m, 2H), 7.45 (dd, 1H), 3.93 (d, 1H), 3.41 (s, 2H), 3.01 (t, 1H), 2.42 (s, 3H), 1.93 (d, 3H), 1.32 (s, 10H); LC-MS: m/z 440.31 (MH+)

Preparation: [2-(1-tert-butylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluorozoline) lomethoxy)-1-piperidyl]methanone

Example 80

The synthesis of the title compound was carried out using the compound of Example 76 (4,4-difluoro-1-piperidyl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)- It was carried out similarly to the synthesis of 2-[4-(trifluoromethyl)thiazol-2-yl]phenyl]methanone, here 3-(1-tert-butylpyrazol-3-yl)-4-[ 4-(trifluoromethoxy)piperidine-1-carbonyl]benzonitrile is reacted with 4-(4,4-difluoropiperidine-1-carbonyl)-3-[4-(trifluoromethyl ) Thiazol-2-yl] was used instead of benzonitrile. The title compound was obtained in a yield of 3.5% (4 mg).

1H NMR (400 MHz, DMSO) δ 13.73 (s, 1H), 8.30 (dd, 1H), 8.01 - 7.81 (m, 2H), 7.33 (d, 1H), 6.53 - 6.43 (m, 1H), 4.67 - 4.55 (m, 1H), 4.14 - 3.95 (m, 1H), 3.29 - 2.85 (m, 3H), 2.42 (s, 3H), 1.99 - 1.88 (m, 1H), 1.74 - 1.61 (m, 1H), 1.56 (d, 11H); LC-MS: m/z 477.49 (MH+).

Scheme 8

Step 1

Compounds of formula II can be prepared from compounds of formula I (synthesized according to Scheme 7) in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ , in the presence of a suitable solvent mixture, for example 1, It can be obtained from 2-dimethoxyethane/water, typically through Suzuki coupling with 2-bromo-4-thiazolecarboxylic acid ethyl ester at 90°C. The reaction takes approximately 5 hours to complete.

Step 2

Compounds of formula III can be reacted with nitrile catalysis of compounds of formula II using ethanimidamide hydrochloride in the presence of a suitable catalyst, for example CuBr, a suitable base, for example Cs ₂ CO ₃ and in a suitable solvent such as DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes about 3 hours to about 12 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by hydrolysis in a suitable solvent mixture such as MeOH/THF/H ₂ O, typically at 50° C. The reaction takes approximately 12 hours to complete.

Scheme 8, Preparation of Cpd (II) : Ethyl 2-[5-cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]thiazole-4-carboxylate

Example 81

2-Bromo-4-thiazolecarboxylic acid ethyl ester (134.88 mg, 0.570 mmol), [5-cyano-2-(4,4-difluoropiperidine-1-carbonyl) in an appropriate vial. Phenyl]boronic acid (560.0 mg, 0.380 mmol), -suspended in a mixture of dimethoxyethane (5.7 mL). The resulting suspension was degassed with nitrogen and heated to 90° C. for 5 h. After this time, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The crude material was purified by FC on silica gel (eluted with cHex/EtOAc 95:5 to cHex/EtOAc 50:50) to give the product ethyl 2-[5-cyano-2-(4,4-difluoropy) of the formula: Peridine-1-carbonyl)phenyl]thiazole-4-carboxylate was provided.

Yield: 115 mg

1H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.42 (d, 1H), 8.09 (dd, 1H), 7.68 (d, 1H), 4.40 - 4.26 (m, 2H), 3.97 - 3.83 ( m, 1H), 3.68 - 3.52 (m, 1H), 3.43 - 3.33 (m, 2H), 2.29 - 1.86 (m, 4H), 1.32 (t, 3H); LC-MS: m/z 406.37 (MH+).

Scheme 8, Preparation of Cpd (III) : Ethyl 2-[2-(4,4-difluoropiperidine-1-carbonyl)-5-(5-methyl-4H-1,2,4-triazole -3-yl)phenyl]thiazole-4-carboxylate

Example 82

Ethyl 2-[5-cyano-2-(4,4-difluoropiperidine-1-carbonyl)phenyl]thiazole-4-carboxylate (115.0 mg, 0.280 mmol) in DMSO (3.618 mL) ), CuBr (2.03 mg, 0.010 mmol), disesium carbonate (277.26 mg, 0.850 mmol), and etanimidamide hydrochloride (40.23 mg, 0.430 mmol) were stirred at 120 °C for 90 min. After this time the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% DCM to DCM:EtOH 90:10) to give the product ethyl 2-[2-(4,4-difluoropiperidine-1-carbonyl) of the formula above. -5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]thiazole-4-carboxylate was provided.

Yield: 30 mg

^1H NMR (400 MHz, DMSO _- d6 ) δ 13.90 (bs, 1H), 8.66 (s, 1H), 8.42 (d, 1H), 8.16 (dd, 1H), 7.54 (d, 1H), 4.34 ( q, 2H), 4.01 - 3.92 (m, 1H), 3.65 - 3.55 (m, 1H), 3.41 - 3.36 (m, 2H), 2.44 (s, 3H), 2.29 - 1.83 (m, 4H), 1.33 ( t, 3H); LC-MS: m/z 462.38 (MH+).

Scheme 8, Preparation of Cpd (IV) : 2-[2-(4,4-difluoropiperidine-1-carbonyl)-5-(5-methyl-4H-1,2,4-triazole- 3-yl)phenyl]thiazole-4-carboxylic acid

Example 83

Ethyl 2-[2-(4,4-difluoropiperidine-1-carbonyl)-5-(5-methyl-4H-1,2,4 in methanol (0.142 mL)/THF (0.712 mL) To a solution of -triazol-3-yl)phenyl]thiazole-4-carboxylate (23.0 mg, 0.040 mmol) was added a solution of lithium hydroxide (1.61 mg, 0.070 mmol) in water (0.142 mL). The reaction was stirred at 50° C. overnight. The next day the reaction was cooled to RT, acidified with 1N HCl until pH = 1, and immediately purified by reverse phase FC using acid conditions (CH ₃ CN/H ₂ O + 0.1% of FA 5:95 + (eluted with 0.1% FA to CH ₃ CN/H ₂ O + 0.1% FA 35:65) the product of the formula 2-[2-(4,4-difluoropiperidine-1-carbonyl)- 5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]thiazole-4-carboxylic acid was provided.

Yield: 6 mg

1H NMR (400 MHz, DMSO) δ 13.86 (s, 1H), 8.71 - 8.30 (m, 2H), 8.14 (dd, 1H), 7.50 (d, 1H), 4.17 - 4.03 (m, 1H), 3.52 - 3.29 (m, 3H), 2.45 (s, 3H), 2.31 - 1.78 (m, 4H).

Scheme 9

Step 1

Compounds of formula II can be prepared from compounds of formula I (commercially available from Enamine) with 4,4-difluoropiperidine hydrochloride in the presence of a suitable coupling agent such as HATU, and an organic base such as DIPEA. It can be obtained by coupling. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes approximately 12 hours to complete.

Step 2

The compounds of formula III are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 95° C. A compound of formula II and 1-(1-methylethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Enamine (commercially available from) can be obtained through a Suzuki coupling. The reaction takes approximately 3 hours to complete.

Step 3

Compounds of formula IV may be prepared by formula III in the presence of a suitable palladium precatalyst, e.g. palladium tritert-butylphosphine, a suitable base, e.g. CsF, in a suitable solvent, e.g. 1,4-dioxane, typically at 100° C. It can be obtained through Stille coupling reaction between a compound and an appropriate THP-protected stannane. The reaction takes about 3 hours to about 5 hours to complete.

Step 4

Compound V can be obtained from a compound of formula IV by removing the THP protecting group under acid conditions, for example in a 6N HCl solution, typically at 50°C. The reaction takes approximately 3 hours to complete.

Scheme 9, Preparation of Cpd (II) : (2-bromo-4-chlorophenyl)-(4,4-difluoropiperidin-1-yl)methanone

A solution of HATU (1.45 g, 3.82 mmol), 2-bromo-4-chlorobenzoic acid (600.0 mg, 2.55 mmol) and N,N-diisopropylethylamine (2.66 mL, 15.29 mmol) in DMF (16.99 mL) 4,4-difluoropiperidine;hydrochloride (481.89 mg, 3.06 mmol) was added. The reaction was stirred at RT overnight. The next day saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted with 100% cHex to AcOEt/cHex 30:70) to obtain the product of the formula (2-bromo-4-chlorophenyl)-(4,4-difluoropiperidine). -1-day) Methanone was provided.

Yield: 715 mg

1H NMR (400 MHz, DMSO) δ 7.87 (d, 1H), 7.58 (dd, 1H), 7.48 (d, 1H), 3.86 (dt, 1H), 3.66 (ddd, 1H), 3.24 (t, 2H) , 2.31 - 1.85 (m, 4H); LC-MS: m/z 338.00, 340.03 (MH+).

Scheme 9, Preparation of Cpd (III) : [4-chloro-2-(1-propan-2-ylpyrazol-3-yl)phenyl]-(4,4-difluoropiperidin-1-yl) Methanone

X-phos aminobiphenyl palladium chloride precatalyst (162.46 mg, 0.210 mmol), tripotassium phosphate (1316.58 mg, 6.2 mmol) in water (0.952 mL)/1,2-dimethoxyethane (14.95 mL) in an appropriate vial. (2-Bromo-4-chlorophenyl)-(4,4-difluoropiperidin-1-yl)methanone (700.0 mg, 2.07 mmol) and 1-(1-methylethyl)-3-( A mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (390.53 mg, 1.65 mmol) was bubbled with N ₂ for 10 min. Degassed. The mixture was then subjected to a N ₂ -vacuum cycle and then stirred at 95° C. for 3 h. After this time the reaction was cooled to RT. Water was added to the mixture and the aqueous phase was extracted three times with AcOEt. The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% cHex to cHex/EtOAc 40:60) to obtain the product of the above formula [4-chloro-2-(1-propan-2-ylpyrazol-3-yl)phenyl. ]-(4,4-difluoropiperidin-1-yl)methanone was provided.

Yield: 450 mg,

^1H NMR (400 MHz, DMSO _- d6 ) δ 7.84 (d, 1H), 7.76 (d, 1H), 7.45 (dd, 1H), 7.34 (d, 1H), 6.55 (d, 1H), 4.51 ( hept, 1H), 3.82 - 3.61 (m, 2H), 3.24 - 3.02 (m, 2H), 2.16 - 1.72 (m, 4H), 1.43 (dd, 6H); LC-MS: m/z 368.36 (MH+).

Scheme 9, Preparation of Cpd (IV)*a : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydro pyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methanone

Palladium tritert-butylphosphine (4.42 mg, 0.010 mmol) and cesium fluoride (72.21 mg, 0.480 mmol) were placed in an appropriate vial and N ₂ -vacuum cycled three times. Next, trimethyl-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]stannane (283.73 mg, 0.260 mmol) in 1,4-dioxane (3 mL). ) and [4-chloro-2-(1-propan-2-ylpyrazol-3-yl)phenyl]-(4,4-difluoropiperidin-1-yl)methanone (85.0 mg, 0.220 mmol) solution was added. The resulting suspension was degassed by bubbling N ₂ for 5 min, followed by 5 cycles of N ₂ -vacuum. The mixture was stirred at 100 °C for 4 h. After this time the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, washed with EtOAc and concentrated under high vacuum. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 65:35 CH ₃ CN/H ₂ O + 0.1% HCOOH). A product of the formula (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl-5 -(trifluoromethyl)pyrazol-3-yl]phenyl]methanone was provided.

Yield: 51 mg

1H NMR (400 MHz, DMSO) δ 7.98 (dd, 1H), 7.90 - 7.81 (m, 1H), 7.63 - 7.53 (m, 1H), 7.49 (dd, 1H), 7.12 (d, 1H), 6.54 ( t, 1H), 5.46 - 5.37 (m, 1H), 4.52 (p, 1H), 4.11 - 3.95 (m, 1H), 3.89 - 3.76 (m, 1H), 3.75 - 3.49 (m, 2H), 3.26 - 3.21 (m, 1H), 3.21 - 3.11 (m, 1H), 2.43 - 2.35 (m, 1H), 2.18 - 1.80 (m, 5H), 1.74 - 1.47 (m, 5H), 1.47 - 1.33 (m, 6H) ); LC-MS: m/z 552.29 (MH+)

Scheme 9, Preparation of Cpd (IV)*b : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-isopropyl -1-tetrahydropyran-2-yl-pyrazol-3-yl)phenyl]methanone

The synthesis of the title compound was carried out by the compound (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl -5-(trifluoromethyl)pyrazol-3-yl]phenyl]methanone was carried out similarly to the synthesis, where (5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-3- 1)-trimethyl-stannane was used instead of trimethyl-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]stannane. The title compound was obtained in a yield of 59% (55 mg).

1H NMR (400 MHz, DMSO) δ 8.07 (d, 1H), 7.85 (d, 1H), 7.80 (d, 1H), 7.32 (d, 1H), 6.70 (s, 1H), 6.54 (d, 1H) , 5.45 (d, 1H), 4.54 (p, 1H), 3.97 - 3.80 (m, 2H), 3.76 - 3.62 (m, 1H), 3.62 - 3.51 (m, 1H), 3.15 - 3.04 (m, 2H) , 2.45 - 2.36 (m, 1H), 2.15 - 2.01 (m, 3H), 1.98 - 1.67 (m, 6H), 1.64 - 1.51 (m, 5H), 1.48 - 1.39 (m, 8H); LC-MS: m/z 526.33 (MH+).

Scheme 9, preparing Cpd (IV)*c : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl- 1-tetrahydropyran-2-yl-pyrazol-3-yl)phenyl]methanone

The synthesis of the title compound was carried out by the compound (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl -5-(trifluoromethyl)pyrazol-3-yl]phenyl]methanone was carried out similarly to the synthesis, herein trimethyl-(5-methyl-1-tetrahydropyran-2-yl-pyrazole-3 -yl)stannane was used instead of trimethyl-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]stannane. The title compound was obtained in a yield of 40% (24 mg).

1H NMR (400 MHz, DMSO) δ 8.05 (d, 1H), 7.84 (d, 1H), 7.77 (d, 1H), 7.32 (d, 1H), 6.65 (s, 1H), 6.51 (d, 1H) , 5.43 (d, 1H), 4.53 (p, 1H), 3.92 (d, 2H), 3.69 (d, 1H), 3.57 (s, 1H), 3.23 - 3.04 (m, 2H), 2.40 - 2.31 (m , 3H), 2.12 - 2.01 (m, 2H), 1.97 - 1.51 (m, 7H), 1.46 - 1.42 (m, 7H); LC-MS: m/z 498.49 (MH+).

Scheme 9, Preparation of Cpd (V)*a : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-(tri fluoromethyl)-1H-pyrazol-3-yl]phenyl]methanone

Example 84

(4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl in ethanol (2 mL) To a solution of -5-(trifluoromethyl)pyrazol-3-yl]phenyl]methanone (50.0 mg, 0.090 mmol) was added 6N HCl aqueous solution (45.33 uL, 0.270 mmol). The mixture was stirred at 60° C. for 2 h. After this time, the reaction mixture was cooled to RT, saturated NaHCO ₃ solution was added and the mixture was extracted with EtOAc (3 times). The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 55:45 CH ₃ CN/H ₂ O + 0.1% HCOOH). A product of the formula (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-(trifluoromethyl)-1H- Pyrazol-3-yl]phenyl]methanone was provided.

Yield: 20 mg

1H NMR (400 MHz, DMSO) δ 14.19 (s, 1H), 8.15 (d, 1H), 7.87 (d, 1H), 7.82 (dd, 1H), 7.42 (d, 1H), 7.33 (s, 1H) , 6.62 (d, 1H), 4.52 (hept, 1H), 3.86 - 3.58 (m, 2H), 3.23 - 3.07 (m, 2H), 2.17 - 1.75 (m, 3H), 1.44 (dd, 7H); LC-MS: m/z 468.22 (MH+).

Preparation: (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-isopropyl-1H-pyrazol-3-yl )phenyl]methanone

Example 85

The synthesis of the title compound was carried out using the compound of Example 84 (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-(trifluoro The synthesis of romethyl)-1H-pyrazol-3-yl]phenyl]methanone was carried out similarly, herein (4,4-difluoro-1-piperidyl)-[2-(1-isopropyl) pyrazol-3-yl)-4-(5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)phenyl]methanone (4,4-difluoro-1-p) Peridyl)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]phenyl] It was used instead of methanone. The title compound was obtained in a yield of 40% (15 mg).

1H NMR (400 MHz, DMSO) δ 12.67 (s, 1H), 8.07 (s, 1H), 7.84 (d, 1H), 7.76 (d, 1H), 7.30 (d, 1H), 6.56 (d, 2H) , 4.52 (hept, 1H), 3.95 - 3.79 (m, 1H), 3.65 - 3.57 (m, 1H), 3.23 - 2.92 (m, 3H), 2.18 - 1.72 (m, 3H), 1.44 (dd, 7H) , 1.28 (d, 6H); LC-MS: m/z 442.48 (MH+).

Preparation: (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-1H-pyrazol-3-yl) phenyl]methanone

Example 86

The synthesis of the title compound was carried out using the compound of Example 84 (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-(trifluoro The synthesis of romethyl)-1H-pyrazol-3-yl]phenyl]methanone was carried out similarly, herein (4,4-difluoro-1-piperidyl)-[2-(1-isopropyl) pyrazol-3-yl)-4-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)phenyl]methanone (4,4-difluoro-1-piperic acid) dil)-[2-(1-isopropylpyrazol-3-yl)-4-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]phenyl]methane Used instead of on. The title compound was obtained in a yield of 66% (14 mg).

1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 8.07 (s, 1H), 7.84 (d, 1H), 7.74 (d, 1H), 7.30 (d, 1H), 6.53 (d, 2H) , 4.52 (hept, 1H), 3.92 - 3.75 (m, 1H), 3.73 - 3.52 (m, 1H), 3.24 - 3.06 (m, 2H), 2.29 (s, 3H), 2.15 - 1.71 (m, 3H) , 1.44 (dd, 7H); LC-MS: m/z 414.47 (MH+).

Scheme 10

Step 1

Compounds of formula (II) are reacted with compounds of formula (I) in the presence of a suitable catalyst, for example palladium tritert-butylphosphine, a suitable base, for example CsF, in a suitable solvent, for example 1,4-dioxane, typically at 100° C. (synthesized according to Scheme 9) and trimethyl-[2-[(5-methyl-2-trimethylstannyl-imidazol-1-yl)methoxy]ethyl]silane. . The reaction takes approximately 5 hours to complete.

Step 2

Compounds of formula III can be obtained from compounds of formula II by removing the SEM protecting group under acid conditions, for example in a 6N HCl solution, typically at 75°C. The reaction takes approximately 16 hours to complete.

Scheme 10, Preparation of Cpd (II)*a : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-methyl- 1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]methanone and (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazole- 3-yl)-4-[4-methyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]methanone

Palladium tritert-butylphosphine (3.21 mg, 0.010 mmol) and cesium fluoride (69.96 mg, 0.460 mmol) were placed in an appropriate vial and 3 cycles of N ₂ -vacuum were performed. Next, trimethyl-[2-[(5-methyl-2-trimethylstannyl-imidazol-1-yl)methoxy]ethyl]silane/trimethyl-[2- in 1,4-dioxane (2.093 mL) [(4-methyl-2-trimethylstannyl-imidazol-1-yl)methoxy]ethyl]silane (78.54 mg, 0.210 mmol) and [4-chloro-2-(1-propan-2-ylpyrazole) A solution of -3-yl)phenyl]-(4,4-difluoropiperidin-1-yl)methanone (77.0 mg, 0.210 mmol) was added. The resulting suspension was degassed by bubbling N ₂ for 5 min, followed by 5 cycles of N ₂ -vacuum. The mixture was stirred at 100 °C for 5 h. After this time the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite, washed with EtOAc and concentrated under high vacuum. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 45:55 CH ₃ CN/H ₂ O + 0.1% HCOOH). A product of the formula (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-methyl-1-(2-trimethylsilyl) Ethoxymethyl)imidazol-2-yl]phenyl]methanone and (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4- [4-Methyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]methanone was provided as a mixture of regioisomers. The mixture of regioisomers was used in the next step without further purification.

Yield: 18 mg

LC-MS: m/z 544.57 (MH+).

Scheme 10, Preparation of Cpd (III)*a : (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl- 1H-imidazol-2-yl)phenyl]methanone

Example 87

(4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-[5-methyl-1-(2-) in ethanol (1 mL) trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]methanone/(4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)- A solution of 4-[4-methyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]phenyl]methanone (mixture of positional isomers) (17.0 mg, 0.030 mmol) was added to a 6N HCl aqueous solution (15.63). uL, 0.090 mmol) was added. The mixture was stirred at 75 °C for 16 h. After this time, the mixture was cooled, saturated NaHCO ₃ solution was added to the solution and the mixture was extracted with EtOAc (3X). The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 30:70 CH ₃ CN/H ₂ O + 0.1% HCOOH). A product of the formula (4,4-difluoro-1-piperidyl)-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-1H-imidazole-2- 1) phenyl] methanone was provided.

Yield: 8 mg

1H NMR (400 MHz, DMSO) δ 12.18 (d, 1H), 8.01 (d, 1H), 7.82 (d, 1H), 7.69 - 7.57 (m, 2H), 7.28 (d, 1H), 6.45 (d, 1H), 4.52 (hept, 1H), 3.98 - 3.80 (m, 1H), 3.68 - 3.48 (m, 1H), 3.23 - 3.07 (m, 2H), 2.45 (s, 3H), 2.16 - 1.71 (m, 3H), 1.44 (dd, 7H); LC-MS: m/z 414.28 (MH+).

Scheme 11

Step 1

Compounds of formula II are reacted in the presence of a suitable catalyst, for example palladium tetrakis triphenylphosphine, in the presence of a suitable base, for example Na ₂ CO _{3 ,} in a suitable solvent mixture, for example toluene/ethanol/water, typically at 100° C. A compound of formula I (synthesized according to Scheme 3) and the desired boronic acid ester such as 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxa It can be obtained through Suzuki coupling between borolans. The reaction takes about 2 to 12 hours to complete.

Step 2

Compounds of formula III can be obtained by reduction of the double bond of compounds of formula II under catalytic hydrogenation conditions using, for example, Pd/C in a suitable solvent such as ethanol, typically at room temperature. The reaction takes approximately 2 hours to complete.

Manufactured by: N-[3-(cyclopenten-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 88

Palladium tetrakis triphenylphosphine (11.55 mg, 0.010 mmol), sodium carbonate (369.78 mg, 3.49 mmol) and 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1 in a vial; 3,2-dioxaborolane (96.73 mg, 0.500 mmol) was added sequentially. The solid was suspended in a mixture of ethanol (1.7 mL), toluene (1.7 mL), and water (0.500 mL), and the resulting suspension was degassed using the Shlenk line technique. N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide (200.0 mg, 0.500 mmol) was added under nitrogen flux. . The mixture was degassed again and heated to 100° C. for 2 h. After this time, the reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was removed under vacuum. The crude material was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 40:60 CH ₃ CN/H ₂ O + 0.1% HCOOH). The product of the above formula gave N-[3-(cyclopenten-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide. .

Yield: 23 mg

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 7.28 (d, 1H), 5.88 (p, 1H), 4.28 (s, 1H), 3.73 (s, 1H), 3.47 (d, 3H), 3.14 (d, 3H), 2.88 (s, 1H), 2.68 - 2.52 (m, 1H), 2.46 (s, 2H), 1.97 - 1.84 (m, 2H), 1.77 (tt, 1H), 0.85 - 0.75 (m, 4H); LC-MS: m/z 389.2 (MH+).

Manufactured by: N-[3-(cyclopenten-1-yl)-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

Example 89

The synthesis of the title compound was carried out using the compound N-[3-(cyclopenten-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropane of Example 88. The synthesis was performed similarly to the carboxamide, where N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was synthesized with N-[3 -Bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained in a yield of 51% (30 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 - 10.17 (m, 1H), 7.70 - 7.53 (m, 3H), 7.50 - 6.93 (m, 5H), 6.16 - 4.25 (m, 2H), 3.53 - 3.33 (m, 1H), 3.09 - 2.50 (m, 5H), 2.38 - 1.51 (m, 10H), 0.92 - 0.70 (m, 4H); LC-MS: m/z 430.27 (MH+).

Manufactured by: N-[3-cyclopentyl-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 90

N-[3-(cyclopenten-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide ( A mixture of 23.0 mg, 0.060 mmol) and Pd-C 10% (6.3 mg, 0.010 mmol) was stirred for 2 h at RT under H ₂ atmosphere (1 atm). After this time the reaction was filtered and concentrated under vacuum. The residue was purified by reverse phase FC using acid conditions (eluted with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 60:40 CH ₃ CN/H ₂ O + 0.1% HCOOH) to obtain the above The product of the formula N-[3-cyclopentyl-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide was provided.

Yield: 7.6 mg

1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.63 (d, 1H), 7.48 (dd, 1H), 7.26 (d, 1H), 4.46 (d, 1H), 3.71 - 3.44 ( m, 3H), 3.20 (d, 3H), 2.93 (p, 2H), 1.94 (dt, 2H), 1.75 (td, 3H), 1.61 (q, 2H), 1.47 (dq, 2H), 0.84 - 0.74 (m, 4H); LC-MS: m/z 391.5 (MH+).

Manufactured by: N-[3-cyclopentyl-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

Example 91

The synthesis of the title compound is the synthesis of compound N-[3-cyclopentyl-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide of Example 90 and This was performed similarly, where N-[3-(cyclopenten-1-yl)-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was replaced with N-[3 -(Cyclopenten-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained in a yield of 54% (16 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.22 (s, 1H), 7.76 - 7.53 (m, 3H), 7.50 - 7.07 (m, 5H), 5.95 - 4.29 (m, 1H), 3.53 - 3.40 (m, 1H), 3.22 - 2.62 (m, 4H), 2.42 - 2.13 (m, 4H), 2.07 - 1.10 (m, 10H), 0.86 - 0.70 (m, 4H); LC-MS: m/z 432.29 (MH+)

Scheme 12

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Combi-Blocks) via a Mitsunobu-Tsunoda reaction in the presence of the desired alcohol. The reaction is typically carried out at 150° C. under microwave irradiation in a suitable solvent, such as 1,4-dioxane. The reaction takes approximately 30 minutes to complete. Alternatively, compounds of formula II can be subjected to N-alkylation of compounds of formula I using a suitable electrophilic reagent, for example a suitable tosylate, in the presence of a suitable base, for example NaH, in a suitable solvent such as DMF, typically at 50° C. can be obtained by The reaction takes approximately 12 hours to complete.

Step 2

Compounds of formula III can be reacted with a suitable transition metal catalyst, for example Pd(dppf)Cl ₂ , in the presence of a suitable base, for example potassium acetate, in a suitable solvent, for example 1,4-dioxane, typically at 100° C. It can be obtained through Miyaura borylation between the compound and B ₂ Pin ₂ . The reaction takes approximately 12 hours to complete.

Step 3

Compounds of formula III can be obtained from compounds of formula IV (commercially available from Activate Scientific) via the Mitsunobu-Tsunoda reaction at 150°C under microwave irradiation in ^1,4 -dioxane as the solvent in the presence of the desired alcohol. The reaction takes approximately 30 minutes to complete.

Scheme 12, Cpd (II)*a Preparation: 1-cyclobutyl-3-iodopyrazole

3-Iodo-1H-pyrazole (1.0 g, 5.16 mmol), cyclobutanol (371.76 mg, 5.16 mmol), 2-tributylphosphoranylideneacetonitrile (2.7 mmol) in 1,4-dioxane (17.78 mL) mL, 10.31 mmol) was stirred at 150 °C for 30 min under microwave irradiation. The mixture was diluted with water (20 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under high vacuum. The crude material was purified by FC on silica gel (eluting with 100% cHex to cHex/EtOAc 90:10) to give the product 1-cyclobutyl-3-iodopyrazole of the formula above.

Yield: 295 mg.

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.27 (d, 1H), 6.40 (d, 1H), 4.82 - 4.70 (m, 1H), 2.61 - 2.39 (m, 4H), 1.95 - 1.79 (m , 2H); LC-MS: m/z 249.06 (MH+).

Scheme 12, Cpd (II)*b Preparation: 1-(1-cyclopropylethyl)-3-iodopyrazole

The synthesis of the title compound was performed similarly to the synthesis of the compound 1-cyclobutyl-3-iodopyrazole, where 1-cyclopropylethanol was used instead of cyclobutanol. The title compound was obtained in a yield of 44% (877 mg).

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.56 (dd, 1H), 6.43 (t, 1H), 3.81 (dq, 1H), 1.46 (dd, 3H), 1.40 - 1.29 (m, 1H), 0.62 - 0.22 (m, 4H); LC-MS: m/z 263.1 (MH+).

Scheme 12, Cpd (II)*c Preparation: 1-tert-butyl-3-iodopyrazole

To a solution of 3-iodo-1H-pyrazole (1.0 g, 5.16 mmol) in 2-methyl-2-propanol (5.08 mL, 53.1 mmol) was added H ₂ SO ₄ 95-97% (0.35 mL, 6.19 mmol). Added. The mixture was stirred at 100° C. overnight. After this time the mixture was diluted with saturated NaHCO ₃ solution until pH = 7 and extracted with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the crude material, which was purified by FC on silica gel (eluting with 100% cHex to cHex/EtOAc 80:20) to give the formula This gave the product 1-tert-butyl-3-iodopyrazole.

Yield: 713 mg.

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.73 (d, 1H), 6.43 (d, 1H), 1.49 (s, 9H); LC-MS: m/z 251.00 (MH+).

Scheme 12, Cpd (II)*d Preparation: 3-iodo-1-(oxetan-3-yl)pyrazole

To a solution of 3-iodo-1H-pyrazole (0.51 g, 2.63 mmol) in DMF (10 mL) was added sodium hydride (0.42 g, 10.52 mmol) at 0 °C and the reaction was stirred at the same temperature for 10 min. did. After this time oxetan-3-yl 4-methylbenzenesulfonate (0.9 g, 3.94 mmol) was added. The reaction was allowed to reach RT and then stirred at 50 °C overnight. After this time the mixture was diluted with water and extracted with EtOAt. The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude material was purified by FC on a NH column (eluted with 100% cHex to cHex/EtOAc 90:10) to give the product 3-iodo-1-(oxetan-3-yl)pyrazole of the formula above.

Yield: 445 mg.

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.80 (d, 1H), 6.52 (d, 1H), 5.57 (tt, 1H), 4.91 - 4.81 (m, 4H); LC-MS: m/z 251.12 (MH+).

Manufactured by: Oxetan-3-yl 4-methylbenzenesulfonate

To a solution of 3-oxetanol (1.0 g, 13.5 mmol) in DCM (20 mL) was added pyridine (2.17 mL, 27 mmol), followed by DMAP (0.33 g, 2.7 mmol) and 4-methylbenzenesulfonyl chloride ( 2.83 g, 14.85 mmol) was added. The reaction was allowed to stir overnight at room temperature. After this time the mixture was diluted with 1N aqueous HCl solution and extracted with DCM. The organic phase was washed with saturated NaHCO ₃ solution. The organic phase was dried using a phase separator and concentrated to give the crude material, which was purified by FC on silica gel (eluting with cHex 100% to cHex/EtOAc 80:20) to give the product oxetane- 3-day 4-methylbenzenesulfonate was provided.

Yield: 1.96 g.

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.80 (d, 2H), 7.49 (d, 2H), 5.39 - 5.31 (m, 1H), 4.71 - 4.63 (m, 2H), 4.49 - 4.37 (m , 2H), 2.42 (s, 3H); LC-MS: m/z 229.07 (MH+).

Scheme 12, Cpd (III)*a Preparation: 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

1-Cyclobutyl-3-iodopyrazole (290.0 mg, 1.17 mmol) in 1,4-dioxane (5 mL), 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (356.25 mg, 1.4 mmol), potassium acetate (401.56 mg, 4.09 mmol) and [ A mixture of the complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (382.82 mg, 0.470 mmol) was degassed with N ₂ for 5 min, followed by 3 cycles of vacuum/N. Degassed with ₂ . The reaction was stirred at 100° C. overnight. The next day the mixture was cooled to room temperature and diluted with water. The mixture was extracted three times with EtOAc. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1,3). ,2-dioxaborolan-2-yl)pyrazole ( see Scheme 12, Cpd(III)*a ) was provided. The product was used as is in the next step.

Yield: 314.6 mg

LC-MS: m/z 167.06 (MH+) mass of boronic acid.

Scheme 12, Cpd (III)*b Preparation: 1-(1-cyclopropylethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole

The synthesis of the title compound is described in Scheme 12, Cpd(III)*a Compound 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) It was performed similarly to the synthesis of pyrazole, except that 1-(1-cyclopropylethyl)-3-iodopyrazole was used instead of 1-cyclobutyl-3-iodopyrazole. The title compound was obtained in a yield of 76% (459 mg).

1H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.79 (d, 1H), 6.58 (d, 1H), 4.20 - 4.09 (m, 1H), 1.55 - 1.43 (m, 3H), 1.25 - 1.20 (m , 1H), 1.07 (s, 12H), 0.63 - 0.17 (m, 4H); LC-MS: m/z 181.1 (MH+) mass of boronic acid.

Scheme 12, Cpd (III)*c Preparation: 1-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

The synthesis of the title compound is described in Scheme 12, Cpd(III)*a Compound 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) It was performed similarly to the synthesis of pyrazole, except that 1-tert-butyl-3-iodopyrazole was used instead of 1-cyclobutyl-3-iodopyrazole. The title compound was obtained in quantitative yield (472 mg).

LC-MS: m/z 167.06 (MH+) mass of boronic acid.

Scheme 12, Cpd (III)*d Preparation: 1-(oxetan-3-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Pyrazole

The synthesis of the title compound is described in Scheme 12, Cpd(III)*a Compound 1-cyclobutyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) It was performed similarly to the synthesis of pyrazole, except that 3-iodo-1-(oxetan-3-yl)pyrazole was used instead of 1-cyclobutyl-3-iodopyrazole. The title compound was obtained in quantitative yield (228 mg).

LC-MS: m/z 247.18 (MH+)

Scheme 12, Cpd (III)*e Preparation: 1-(2-methylpropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra sol

2-Methyl-1-propanol (0.57 mL, 6.18 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in 1,4-dioxane (12 mL) A mixture of -2-yl)-1H-pyrazole (1.2 g, 6.18 mmol) and 2-tributylphosphoranylideneacetonitrile (3.24 mL, 12.37 mmol) was stirred at 150 °C for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3x). The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent removed under vacuum to give the product 1-(2-methylpropyl)-3-(4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (see Scheme 12, Cpd(III)*e ) was provided, which was used in the next step without further purification.

Yield: 1g.

1H NMR (400 MHz, MeOD) δ ppm 7.48 (d, 1H), 6.68 (d, 1H), 4.21 (d, 2H), 2.13 (dp, 1H), 1.35 (s, 12H), 0.86 (d, 6H) ); LC-MS: m/z 169.0 (MH+) mass of boronic acid.

Scheme 12, Cpd (III)*f Preparation: 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole

The synthesis of the title compound is carried out in Scheme 12, Cpd (III)*e , compound 1-(2-methylpropyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) was performed similarly to the synthesis of pyrazole, but here ethanol was used instead of 2-methyl-1-propanol. The title compound was obtained in quantitative yield (2.99 g).

LC-MS: mass of boronic acid, m/z 141.01 (MH+).

Scheme 13

Step 1

Compounds of formula II can be obtained by N-protection of compounds of formula I using 3,4-dihydro-2H-pyran, typically at RT, in the presence of a catalytic amount of 4-toluenesulfonic acid in a suitable solvent, such as DCM. You can. The reaction takes approximately 12 hours to complete.

Step 2

Compounds of formula III can be prepared from compounds of formula II in the reaction with trimethyl(trimethylstannyl)stannane in the presence of a suitable catalyst, such as palladium tetrakis triphenylphosphine, and a suitable solvent, such as toluene, typically at 100° C. can be obtained by The reaction takes about 1 to 20 hours to complete.

Scheme 13, Cpd (II)*a Preparation: 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole

To a stirred solution of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (200.0 mg, 0.930 mmol) in DCM (9.304 mL) was added 3,4-dihydro-2H-pyran (126.5 uL, 1.4 μL). mmol) and 4-toluenesulfonic acid (16.02 mg, 0.090 mmol) were added. The mixture was stirred at RT overnight. After this time, the mixture was washed with saturated NaHCO ₃ solution and the aqueous phase was back-extracted with DCM. The organic phases were combined, washed with brine, dried on a phase separator and concentrated under vacuum. The crude material was purified by FC on silica gel (eluting with 100% cHex to cHex/EtOAc 85:15) to give the product 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl ) pyrazole ( Scheme 13, Cpd (II)*a) was provided.

Yield: 218 mg

^1H NMR (400 MHz, DMSO- d ₆ ) δ 7.14 (d, 1H), 5.59 (dd, 1H), 3.98 - 3.87 (m, 1H), 3.72 - 3.58 (m, 1H), 2.30 - 2.15 (m) , 1H), 2.04 - 1.86 (m, 2H), 1.81 - 1.64 (m, 1H), 1.60 - 1.50 (m, 2H).

Scheme 13, Cpd (II)*b Preparation: 3-iodo-1-(oxan-2-yl)-5-propan-2-ylpyrazole

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole in Scheme 13, Cpd(II)*a , where 3-Iodo-5-propan-2-yl-1H-pyrazole was used instead of 3-bromo-5-(trifluoromethyl)-1H-pyrazole. The title compound was obtained in a yield of 94% (320 mg).

LC-MS: m/z 321.07

Scheme 13, Cpd (II)*c Preparation: 3-iodo-5-methyl-1-(oxan-2-yl)pyrazole

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole in Scheme 13, Cpd(II)*a , where 3-Iodo-5-propan-2-yl-1H-pyrazole was used instead of 3-bromo-5-(trifluoromethyl)-1H-pyrazole. The title compound was obtained in a yield of 79% (560 mg).

LC-MS: m/z 293.14 (MH+).

Scheme 13, Cpd (III)*a Preparation: Trimethyl-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazol-3-yl]stannane

Trimethyl(trimethylstannyl)stannane (178.87 uL, 0.860 mmol), 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole (215.0 mg, 0.720 mmol) in an appropriate vial. , see Scheme 13, Cpd (II)*a ), palladium tetrakis triphenylphosphine (16.61 mg, 0.010 mmol) was added, and suspended in toluene (5 mL). The mixture was degassed by bubbling N ₂ for 5 min and then subjected to 5 cycles of N ₂ -vacuum. The mixture was stirred at 100 °C for 20 h. After this time, the reaction was cooled to RT, filtered and concentrated in vacuo. The residue was dissolved in EtOAc and washed with water. The aqueous phase was back extracted with EtOAc (X2). The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product trimethyl-[1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyra. This gave zol-3-yl]stannane, which was used in the next step without further purification.

Yield: 270 mg

LC-MS: m/z 385.11 (MH+).

Scheme 13, Cpd (III)*b Preparation: (5-isopropyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)-trimethyl-stannane

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole in Scheme 13, Cpd(II)*a , where 3-Iodo-1-(oxan-2-yl)-5-propan-2-ylpyrazole is converted to 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole. It was used instead. The title compound was obtained in a yield of 83% (250 mg).

LC-MS: m/z 359.18 (MH+).

Scheme 13, Cpd (III)*c Preparation: Trimethyl-(5-methyl-1-tetrahydropyran-2-yl-pyrazol-3-yl)stannane

The synthesis of the title compound was carried out similarly to the synthesis of compound 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole in Scheme 13, Cpd(II)*a , where 3-Iodo-5-methyl-1-(oxan-2-yl)pyrazole was used instead of 3-bromo-1-tetrahydropyran-2-yl-5-(trifluoromethyl)pyrazole. The title compound was obtained in a yield of 88% (150 mg).

LC-MS: m/z 331.20 (MH+).

Scheme 14

Step 1

Compounds of formula II can be obtained via N-protection of compounds of formula I using SEM-Cl in the presence of a suitable base, for example K ₂ CO ₃ , in a suitable solvent, for example acetone, typically at RT. The reaction takes approximately 2 hours to complete.

Step 2

Compounds of formula III can be prepared from compounds of formula II in the reaction with trimethyl(trimethylstannyl)stannane in the presence of a suitable catalyst, such as palladium tetrakis triphenylphosphine, and a suitable solvent, such as toluene, typically at 100° C. can be obtained by The reaction takes approximately 3 hours to complete.

Scheme 14, Preparation of Cpd (II) : 2-[(2-iodo-5-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane and 2-[(2-iodo-4-methyl -imidazol-1-yl)methoxy]ethyl-trimethyl-silane

A mixture of 2-iodo-5-methyl-1H-imidazole (200.0 mg, 0.960 mmol) and potassium carbonate (398.68 mg, 2.88 mmol) in acetone (8.013 mL) was dissolved in 2-(chloromethoxy)ethyl-trimethylsilane. (204.21 uL, 1.15 mmol) was added dropwise, and the resulting mixture was stirred for 2 h. After this time, the mixture was filtered and concentrated under vacuum. The crude material was purified by FC on silica gel (eluting with cHex/EtOAc 90:10 to cHex/EtOAc 30:70) to give the product 2-[(2-iodo-5-methyl-imidazol-1-yl) Methoxy]ethyl-trimethyl-silane and 2-[(2-iodo-4-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane were provided as a mixture of regioisomers. The mixture was used in the next step without further purification.

Yield: 100 mg

LC-MS: m/z 339.25 (MH+).

Scheme 14, Preparation of Cpd (III) : trimethyl-[2-[(5-methyl-2-trimethylstannyl-imidazol-1-yl)methoxy]ethyl]silane and trimethyl-[2-[(4-methyl -2-trimethylstannyl)-imidazol-1-yl)methoxy]ethyl]silane

Trimethyl(trimethylstannyl)stannane (40.46 uL, 0.200 mmol), 2-[(2-iodo-5-methyl-imidazol-1-yl)methoxy]ethyl-trimethyl-silane in toluene (1.7 mL) A mixture of (55.0 mg, 0.160 mmol) and palladium tetrakis triphenylphosphine (3.76 mg, 0 mmol) was degassed by bubbling N ₂ for 15 min. Then, 5 cycles of N ₂ -vacuum were performed and the mixture was stirred at 100° C. for 3 h. The mixture was concentrated under vacuum and the residue was dissolved in EtOAc and washed with water. The aqueous phase was extracted with EtOAc (X2). The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product of the formula trimethyl-[2-[(5-methyl-2-trimethylstannyl-imidazole-1- 1)methoxy]ethyl]silane and trimethyl-[2-[(4-methyl-2-trimethylstannyl-imidazol-1-yl)methoxy]ethyl]silane were provided as a mixture of regioisomers. This mixture was used in the next step without further purification.

Yield: 65 mg

LC-MS: m/z 377.2 (MH+)

Scheme 15

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Combi-Blocks) by hydroxycarbonylation using oxalic acid and acetic anhydride as in situ carbon monoxide generators. The reaction is typically carried out at 100° C. in a suitable solvent such as DMF using a suitable phosphine ligand such as Xantphos in the presence of a suitable organic base such as DIPEA, a suitable catalyst such as palladium diacetate. The reaction takes approximately 12 hours to complete.

Step 2

Compounds of formula III can typically be obtained by treatment with a suitable chlorinating agent, such as SOCl ₂ at 90° C. to form an acyl chloride of a compound of formula II, followed by coupling with a suitable amine in the presence of a suitable organic base, such as TEA. . The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes about 1 hour to about 12 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by SNAr substitution with pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes about 12 hours to about 24 hours to complete.

Step 4

Compounds of formula (V) can be obtained by nitro reduction of compounds of formula (IV) under catalytic hydrogenation conditions using a suitable catalyst such as Pd/C in a suitable solvent such as methanol, typically at room temperature. The reaction takes about 4 hours to about 12 hours to complete.

Step 5

Compounds of formula VI can be obtained by coupling reaction between compounds of formula V and a suitable commercially available acyl chloride, for example cyclopropanecarbonyl chloride, in the presence of a suitable organic base, for example DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes about 1 hour to about 12 hours to complete.

Scheme 15, Cpd (II)*a Preparation: 2-Fluoro-5-methyl-4-nitrobenzoic acid

1-Bromo-2-fluoro-5-methyl-4-nitrobenzene (500.0 mg, 2.14 mmol), oxalic acid (288.53 mg, 3.2 mmol), and [Pd(AcO) ₂ in a 40 mL vial equipped with a magnetic bar. ] ₃ (4.8 mg, 0.020 mmol) and (5-diphenylphosphino-9,9-dimethyl-4-xanthenyl)-diphenylphosphine (12.36 mg, 0.020 mmol) were introduced. A solution of acetic acid acetyl ester (0.3 mL, 3.2 mmol) and N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) in DMF (11 mL) was added and the mixture was bubbled with N ₂ for 10 min. Next, 3 cycles of N ₂ -vacuum were performed. The mixture was stirred at 100° C. overnight. After this time saturated NaHCO ₃ solution was added and the aqueous phase was washed with DCM. The aqueous phase was then acidified with concentrated HCl until pH = 1 and extracted with EtOAc. The organic fractions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum to give the product 2-fluoro-5-methyl-4-nitrobenzoic acid of the formula ( Scheme 15, Cpd (II )*a ), which was used in the next step without further purification.

Yield: 410 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 - 7.83 (m, 2H), 2.51 (s, 3H); LC-MS: m/z 198.18 (MH+).

Scheme 15, Cpd (II)*b Preparation: 2-Fluoro-3-methyl-4-nitrobenzoic acid

The synthesis of the title compound was carried out similarly to the synthesis of compound 2-fluoro-5-methyl-4-nitrobenzoic acid in Scheme 15, Cpd (II)*a , where 1-bromo-2-fluoro-3- Methyl-4-nitrobenzene was used instead of 1-bromo-2-fluoro-5-methyl-4-nitrobenzene. The title compound was obtained in a yield of 68% (289 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (s, 1H), 7.91 - 7.83 (m, 2H), 2.39 (s, 3H); LC-MS: m/z 198.17 (MH+).

Scheme 15, Cpd (III)*a Preparation: (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 2-fluoro-5-methyl-4-nitrobenzoic acid (205.0 mg, 1.03 mmol, Scheme 15, Cpd (II)*a ) and thionyl dichloride (1.5 mL, 20.59 mmol) was heated to reflux for 2 h. did. After this time, the reaction was cooled to RT and then concentrated under vacuum. The mixture was stripped three times with cyclohexane to remove excess thionyl dichloride. The remainder was suspended in dry DCM (4.1 mL), triethylamine (0.43 mL, 3.09 mmol) was added, and then 1-methyl-3-phenylpiperazine (181.45 mg, 1.03 mmol) was added. The reaction mixture was stirred at RT overnight. The next day the reaction was diluted with DCM and washed three times with saturated NaHCO ₃ solution. The aqueous phases were combined and back-extracted with DCM. The combined organic phases were washed with brine, dried in a phase separator and concentrated under vacuum to give the product of the formula (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazine- 1-day) Methanone was provided. The product was used in the next step without further purification.

Yield: 297 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, 1H), 7.68 (s, 1H), 7.55 - 7.03 (m, 5H), 5.90 - 5.33 (m, 1H), 4.92 - 4.30 (m, 1H), 4.00 - 3.43 (m, 2H), 3.26 - 2.71 (m, 3H), 2.53 (s, 3H), 2.29 - 2.17 (m, 3H); LC-MS: m/z 358.36 (MH+).

Scheme 15, Cpd (III)*b Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-5-methyl-4-nitrophenyl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone, where 1, 4-Thiazanine 1,1-dioxide hydrochloride was used instead of 1-methyl-3-phenylpiperazine. The title compound was obtained in a yield of 81% (297 mg).

^1H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (d, 1H), 7.78 (d, 1H), 4.58 - 4.16 (m, 1H), 3.85 - 3.58 (m, 3H), 3.19 - 2.92 (m , 4H), 2.51 (s, 3H). ; LC-MS: m/z 317.10 (MH+).

Scheme 15, Cpd (III)*c Preparation: (2-fluoro-3-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone, where 2- Fluoro-3-methyl-4-nitrobenzoic acid was used instead of 2-fluoro-5-methyl-4-nitrobenzoic acid (see Scheme 15, Cpd (II)*a ). The title compound was obtained in quantitative yield (272 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 - 7.78 (m, 1H), 7.66 - 7.15 (m, 6H), 5.79 (s, 1H), 4.73 - 4.34 (m, 1H), 3.62 (dd, 1H), 3.26 - 2.69 (m, 4H), 2.42 (s, 2H), 2.25 - 2.13 (m, 3H), 2.01 - 1.88 (m, 1H); LC-MS: m/z 358.36 (MH+).

Scheme 15, Cpd (III)*d Preparation: (1,1-dioxo-1,4-thiazinin-4-yl)-(2-fluoro-3-methyl-4-nitrophenyl)methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone, where 1, 4-thiazinane 1,1-dioxide hydrochloride was used instead of 1-methyl-3-phenylpiperazine, and 2-fluoro-3-methyl-4-nitrobenzoic acid was used instead of 2-fluoro-5-methyl-4- Nitrobenzoic acid (see Scheme 15, Cpd(II)*a ) was used instead. The title compound was obtained in a yield of 84% (193 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, 1H), 7.80 - 7.54 (m, 1H), 4.34 (d, 2H), 3.65 (s, 4H), 2.98 (d, 2H), 2.41 (d, 3H); LC-MS: m/z 317.09 (MH+).

Scheme 15, Cpd (IV)*a Preparation: (5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

in a solution of (2-fluoro-5-methyl-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (290.0 mg, 0.810 mmol) in DMSO (4.0 mL). Rollidine (0.2 mL, 2.43 mmol) was added and the reaction mixture was stirred at 120° C. overnight. After this time, the reaction mixture was cooled to RT, diluted with H ₂ O and extracted three times with EtOAc. The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product of the formula (5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)- (4-methyl-2-phenylpiperazin-1-yl)methanone was provided. The crude material was used in the next step without further purification.

Yield: 351 mg

LC-MS: m/z 409.27 (MH+).

Scheme 15, Cpd (IV)*b Preparation: (1,1-dioxo-1,4-thiazinin-4-yl)-(5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl ) Methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. Here, (1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-5-methyl-4-nitrophenyl)methanone is (2-fluoro-5-methyl) -4-Nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone was used instead. The title compound was obtained in a yield of 92% (247 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.38 (d, 1H), 7.18 (s, 1H), 4.52 (d, 1H), 3.77 (d, 1H), 3.69 - 3.49 (m, 2H), 3.40 - 3.35 (m, 2H), 3.27 - 3.01 (m, 6H), 2.37 (s, 3H), 1.90 (d, 4H); LC-MS: m/z 368.13 (MH+).

Scheme 15, Cpd (IV)*c Preparation: (1,1-dioxo-1,4-thiazinin-4-yl)-(3-methyl-4-nitro-2-pyrrolidin-1-ylphenyl ) Methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. Here, (1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-3-methyl-4-nitrophenyl)methanone is (2-fluoro-5-methyl) -4-Nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone was used instead. The title compound was obtained in a yield of 37% (82 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.63 (d, 1H), 7.47 (d, 1H), 4.58 (d, 1H), 3.73 (d, 1H), 3.63 - 3.33 (m, 4H), 3.26 - 2.95 (m, 6H), 2.28 (s, 3H), 1.93 - 1.77 (m, 4H); LC-MS: m/z 368.2 (MH+).

Scheme 15, Cpd (V)*a Preparation: (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

(5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (350.0 mg, 0.860 mmol) and palladium (182.36 mg) , 0.090 mmol) was stirred at RT under H ₂ atmosphere (1 atm) for 4 h. After this time the reaction was filtered and concentrated under vacuum to give the product of the formula (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazine-1- 1) Methanone was provided. The product was used in the next step without further purification.

Yield: 292 mg

LC-MS: m/z 379.3 (MH+).

Scheme 15, Cpd (V)*b Preparation: (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(1,1-dioxo-1,4-thiazinan-4-yl ) Methanone

The synthesis of the title compound was carried out similarly to the synthesis of the compound (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. Here, (1,1-dioxo-1,4-thiazinin-4-yl)-(5-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)methanone is (5-methyl -4-Nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone was used instead. The title compound was obtained in a yield of 96% (215 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 6.76 (d, 1H), 6.04 (s, 1H), 4.95 (s, 2H), 4.22 (s, 1H), 3.96 - 3.45 (m, 3H), 3.27 - 2.92 (m, 8H), 1.96 (s, 3H), 1.89 - 1.77 (m, 4H); LC-MS: m/z 338.17 (MH+).

Scheme 15, Cpd (V)*c Manufactured by: (4-amino-3-methyl-2-pyrrolidin-1-ylphenyl)-(1,1-dioxo-1,4-thiazinin-4-yl)methanone

The synthesis of the title compound was performed similarly to the synthesis of the compound (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. Here, (1,1-dioxo-1,4-thiazinan-4-yl)-(3-methyl-4-nitro-2-pyrrolidin-1-ylphenyl)methanone is (5-methyl -4-Nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone was used instead. The title compound was obtained in quantitative yield (95 mg).

LC-MS: m/z 338.2 (MH+).

Scheme 15, Cpd (VI)*a Preparation: N-[2-methyl-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropane Carboxamide

Example 92

N,N-diisopropylethylamine (0.27 mL, 1.54 mmol) and (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2) in DCM (20 mL) To a mixture of -phenylpiperazin-1-yl)methanone (292.0 mg, 0.770 mmol), cyclopropanecarbonyl chloride (84.0 uL, 0.930 mmol) was added dropwise at 0°C. The mixture was stirred at RT overnight. Then MeOH was added and concentrated under vacuum. The residue was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product N-[2-methyl-4-(4-methyl-2-phenylpiperazine-1- Carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was provided.

Yield: 138 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 9.50 - 9.23 (m, 1H), 7.82 - 7.16 (m, 5H), 7.09 - 6.68 (m, 2H), 5.86 - 4.34 (m, 1H), 3.63 - 3.35 (m, 1H), 3.28 - 2.57 (m, 6H), 2.42 - 2.05 (m, 7H), 1.93 (d, 5H), 1.63 (dt, 2H), 0.85 - 0.67 (m, 4H); LC-MS: m/z 447.3 (MH+).

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-2-methyl-5-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 93

The synthesis of the title compound was carried out using the compound N-[2-methyl-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropancar of Example 92. It was carried out similarly to the synthesis of boxamid, but herein (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(1,1-dioxo-1,4-thiazin-4-yl ) Methanone was used instead of (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. The title compound was obtained in a yield of 86% (224 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 7.01 (d, 2H), 4.38 (d, 1H), 3.89 - 3.45 (m, 3H), 3.25 - 2.98 (m, 8H) , 2.12 (s, 3H), 1.97 - 1.77 (m, 5H), 0.84 - 0.71 (m, 4H); LC-MS: m/z 406.2 (MH+).

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-2-methyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 94

The synthesis of the title compound was carried out using the compound N-[2-methyl-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropancar of Example 92. The synthesis was carried out similarly to the synthesis of boxamid, but herein (4-amino-3-methyl-2-pyrrolidin-1-ylphenyl)-(1,1-dioxo-1,4-thiazin-4-yl ) Methanone was used instead of (4-amino-5-methyl-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. The title compound was obtained in a yield of 19% (22 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (s, 1H), 7.21 (d, 1H), 7.13 (d, 1H), 4.53 (d, 1H), 3.76 (d, 1H), 3.60 - 3.46 (m, 1H), 3.42 - 3.33 (m, 2H), 3.28 - 3.13 (m, 2H), 3.11 - 2.91 (m, 5H), 2.10 (s, 3H), 1.94 - 1.71 (m, 5H), 0.79 (d, 4H); LC-MS: m/z 406.2 (MH+).

Scheme 16

Step 1

Compounds of formula II can be obtained from compounds of formula I (commercially available from Fluorochem) by SNAr substitution with pyrrolidine, typically at 80° C., in a suitable aprotic solvent, such as CH ₃ CN. The reaction takes approximately 1 hour to complete.

Step 2

Compounds of formula III can be obtained by nitro reduction of compounds of formula II using Zn dust in a suitable solvent, such as AcOH, typically at room temperature. The reaction takes approximately 4 hours to complete.

Step 3

Compounds of formula IV can be obtained by coupling reaction between a compound of formula III and a suitable commercially available acyl chloride, for example cyclopropanecarbonyl chloride, in the presence of a suitable organic base, for example DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained by chlorination of compounds of formula (IV) using N-chlorosuccinimide in a suitable solvent such as 2-propanol, typically at 60°C. The reaction takes approximately 2 hours to complete.

Step 5

Compounds of formula VI can be obtained from compounds of formula V by hydrolysis in a suitable solvent mixture such as MeOH/THF/H ₂ O, typically at 50° C., using, for example, LiOH. The reaction takes about 3 hours to about 24 hours to complete.

Step 6

Compounds of formula VII can be obtained from compounds of formula VI by coupling with a suitable amine in the presence of a coupling agent such as HATU and an organic base such as DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes from about 1 hour to about 30 hours to complete.

Scheme 16, Preparation of Cpd (II) : Methyl 4-nitro-2-pyrrolidin-1-ylbenzoate

To a solution of 2-fluoro-4-nitrobenzoate (5.0 g, 25.11 mmol) in CH ₃ CN (50 mL) was added pyrrolidine (5.36 g, 75.32 mmol) and the reaction mixture was incubated at 80° C. for 1 h. It was stirred for a while. After this time, the mixture was cooled to RT and then concentrated under vacuum. The residue was suspended in water and filtered. The solid was dried under vacuum to give the product methyl 4-nitro-2-pyrrolidin-1-ylbenzoate, which was used in the next step without further purification.

Yield: 6.0 g

1H NMR (400 MHz, DMSO-d6) δ ppm 7.64 (d, 1H), 7.50 (d, 1H), 7.44 (dd, 1H), 3.86 (s, 3), 3.19 - 3.27 (m, 4H), 1.88 - 1.99 (m, 4H); LC-MS: m/z 251.10 (MH+).

Scheme 16, Preparation of Cpd (III) : Methyl 4-amino-2-pyrrolidin-1-ylbenzoate

To a solution of methyl 4-nitro-2-pyrrolidin-1-ylbenzoate (6.0 g, 22.06 mmol) in acetic acid (150 mL) was added zinc (14.4 g, 220.58 mmol). The reaction was stirred at RT for 4 h. After this time the reaction was filtered, washed with EtOAc and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with EtOAc. The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product methyl 4-amino-2-pyrrolidin-1-ylbenzoate, which It was used in the next step without further purification.

Yield: 5.75 g

1H NMR (400 MHz, DMSO-d6) δ ppm 7.28 (d, 1H), 5.98 (d, 1H), 5.94 (dd, 1H), 5.46 (s, 2H), 3.67 (s, 3H), 3.18 - 2.94 (m, 4H), 1.91 - 1.71 (m, 4H); LC-MS: m/z 221.99 (MH+).

Scheme 16, Cpd (IV) Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate

To a stirred solution of methyl 4-amino-2-pyrrolidin-1-ylbenzoate (5.75 g, 26.1 mmol) and N,N-diisopropylethylamine (9.09 mL, 52.21 mmol) in DCM (145.57 mL) Cyclopropanecarbonyl chloride (3.08 mL, 33.94 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at RT overnight. The reaction was diluted with DCM and washed twice with saturated NaHCO ₃ solution. The organic portion was washed with water, then with brine, dried in a phase separator and the solvent was evaporated under vacuum. The crude material was purified by FC on silica gel (eluted with cHex/EtOAc 9:1 to cHex/EtOAc 50:50) to give the product methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-yl. Benzoate was provided.

Yield: 5.57 g

1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 6.92 (dd, 1H), 3.75 (s, 3H), 3.16 - 3.02 (m, 4H), 1.93 - 1.73 (m, 5H), 0.84 - 0.76 (m, 4H); LC-MS: m/z 288.74 (MH+).

Scheme 16, Preparation of Cpd (V) : Methyl 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate and methyl 3-chloro-4-(cyclopropanecarbonylamino) -2-pyrrolidin-1-ylbenzoate

1-Chloropyrrolidine-2,5-dione (272.3 mg, 2.04 mmol) was dissolved in methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate in 2-propanol (15 mL). (490.0 mg, 1.7 mmol) was added in one-pot to the stirred solution. The reaction was stirred at 60° C. for 2 hours. After this time, the mixture was cooled to RT, water was added and the mixture was concentrated under high vacuum. The residue was dissolved in EtOAc and washed with saturated NaHCO ₃ solution. The aqueous phase was extracted twice with EtoAc. The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by FC on silica gel (eluted with Chex 100% to Chex/EtOAc 80:20) to give the product methyl 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidine-1- Ylbenzoate and methyl 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate were provided.

Yield of methyl 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate: 175 mg

1H NMR (400MHz, DMSO-d6) δppm 9.60(s, 1H), 7.51(s, 1H), 7.46(s, 1H), 3.79(s, 3H), 3.18 - 2.95(m, 4H), 2.08 (dd , 1H), 1.87(q, 4H), 0.94 - 0.66(m, 4H); LC-MS: m/z 323.14 (MH+).

Yield of methyl 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate: 80 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 7.64 (d, 1H), 7.44 (d, 1H), 3.82 (s, 3H), 3.18 (q, 4H), 2.07 (p , 1H), 1.96 - 1.85 (m, 4H), 0.83 (d, 4H); LC-MS: m/z 323.12 (MH+).

Scheme 16, Cpd (VI)*a Preparation: 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid

A solution of methyl 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate (175.0 mg, 0.540 mmol) in methanol (6 mL) and THF (6 mL) in water 0.5 A solution of lithium hydroxide hydrate (52.32 mg, 1.25 mmol) in mL was added and the reaction mixture was stirred at 50° C. for 24 h. After this time, the reaction was cooled, diluted with water and washed three times with DCM. The aqueous phase was acidified with 6N HCl until pH = 2 and then extracted three times with EtOAc. The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under high vacuum to give the product methyl 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-yl. The benzoate was provided, which was used in the next step without further purification.

Yield: 76 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (s, 1H), 7.50 (s, 1H), 7.43 (s, 1H), 3.20 - 3.00 (m, 4H), 1.96 - 1.70 (m, 4H) , 1.50 (tt, 1H), 0.95 - 0.43 (m, 4H); LC-MS: m/z 309.24 (MH+).

Scheme 16, Cpd (VI)*b Preparation: 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid

The synthesis of the title compound was carried out analogously to the synthesis of the compound 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid, where methyl 3-chloro-4-(cyclopropanecarboxyl Bornylamino)-2-pyrrolidin-1-ylbenzoate was used instead of methyl 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate. The title compound was obtained in a yield of 80% (58 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.94 (s, 1H), 7.96 - 7.85 (m, 2H), 3.57 - 3.33 (m, 4H), 2.20 - 1.97 (m, 5H), 1.00 - 0.64 ( m, 4H); LC-MS: m/z 309.24 (MH+).

Scheme 16, Cpd (VII)*a Preparation: N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropane Carboxamide

Example 95

HATU (70.19 mg, 0.180 mmol), 5-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (38.0 mg, 0.120 mmol) and N,N in DMF (1.5 mL) -1-Methyl-3-phenylpiperazine (26.03 mg, 0.150 mmol) was added to a solution of diisopropylethylamine (0.74 mL, 0.740 mmol). The reaction was stirred at RT for 30 hours. After this time saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted three times with EtOAc. The organic portion was collected, washed with brine, Na ₂ SO ₄ was added to remove residual water and the solvent was evaporated under reduced pressure. The residue was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 35:65 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1- Carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was provided as a yellow powder.

Yield: 13 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 9.57 (d, 1H), 7.73 (d, 1H), 7.47 (d, 1H), 7.42 - 7.06 (m, 5H), 6.91 (s, 1H), 5.89 - 4.32 (m, 1H), 3.52 - 3.38 (m, 1H), 3.14 - 2.58 (m, 5H), 2.45 - 1.82 (m, 9H), 1.77 - 1.51 (m, 1H), 1.40 - 1.05 (m, 1H), 0.80 (d, 4H); LC-MS: m/z 467.48 (MH+).

Manufactured by: N-[2-chloro-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 96

The synthesis of the title compound was carried out using the compound N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropancar of Example 95. It was performed similarly to the synthesis of boxamid, except that 1,4-thiazinane 1,1-dioxide hydrochloride was used instead of 1-methyl-3-phenylpiperazine. The title compound was obtained in a yield of 62% (32 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.54 (s, 1H), 7.38 (s, 1H), 7.24 (s, 1H), 4.46 (d, 1H), 3.80 (d, 1H), 3.64 - 3.51 (m, 2H), 3.39 (t, 1H), 3.17 (p, 3H), 3.05 (d, 3H), 2.70 (s, 1H), 2.10 - 1.96 (m, 1H), 1.87 (s, 4H), 0.80 (d, 4H); LC-MS: m/z 426.13 (MH+).

Manufactured by: N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 97

The synthesis of the title compound was carried out using the compound N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropancar of Example 95. The synthesis was carried out similarly to the synthesis of boxamid, where 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid was reacted with 5-chloro-4-(cyclopropanecarbonylamino)- It was used instead of 2-pyrrolidin-1-ylbenzoic acid. The title compound was obtained in a yield of 68% (29 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (d, 1H), 7.60 (dd, 2H), 7.54 - 7.10 (m, 5H), 7.02 - 5.75 (m, 1H), 5.75 - 4.65 (m, 1H), 3.07 - 2.95 (m, 3H), 2.82 (d, 1H), 2.63 (d, 1H), 2.36 - 2.10 (m, 4H), 2.05 - 1.74 (m, 8H), 0.82 (d, 4H) ; LC-MS: m/z 467.48 (MH+).

Manufactured by: N-[2-chloro-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 98

The synthesis of the title compound was carried out using the compound N-[2-chloro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)-5-pyrrolidin-1-ylphenyl]cyclopropancar of Example 95. The synthesis was carried out similarly to the synthesis of boxamid, where 3-chloro-4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid was reacted with 5-chloro-4-(cyclopropanecarbonylamino)- It was used instead of 2-pyrrolidin-1-ylbenzoic acid, and 1,4-thiazinane 1,1-dioxide hydrochloride was used instead of 1-methyl-3-phenylpiperazine. The title compound was obtained in a yield of 31% (12 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 7.54 (d, 1H), 7.30 (d, 1H), 4.52 (d, 1H), 3.74 (d, 1H), 3.55 (t) , 2H), 3.36 (t, 1H), 3.24 - 3.08 (m, 6H), 3.01 (t, 1H), 2.08 - 1.99 (m, 1H), 1.85 (s, 4H), 0.82 (d, 4H); LC-MS: m/z 426.13 (MH+).

Scheme 17

Step 1

Compounds of formula II can be obtained from compounds of formula I (synthesized according to Scheme 17) by reaction with hydrazine hydrate in a suitable solvent such as EtOH, typically at 80°C. The reaction takes approximately 3 days to complete.

Step 2

Compounds of formula III can be obtained by cyclization of compounds of formula II with triphosgene in the presence of a suitable organic base, for example DIPEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 1 hour to complete.

Step 3

Compounds of formula IV can be obtained by activation of compounds of formula III with a suitable phosphonium reagent, for example pyBOP, in the presence of an organic base, for example DIPEA, followed by SnAr substitution with a suitable amine. The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes approximately 12 hours to complete.

Scheme 17, Preparation of Cpd (II) : N-[4-(hydrazinecarbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

To a suspension of methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate (2.0 g, 6.45 mmol) in ethanol (10 mL) was added hydrazine hydrate (2.48 g, 32.25 mmol) , the reaction was stirred at 80 °C for 3 days. After this time, the reaction mixture was cooled to RT and concentrated under vacuum. The residue was taken up with H ₂ O and filtered. The solid was dried under vacuum to give the product N-[4-(hydrazinecarbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide of the formula above. The product was used in the next step without further purification.

Yield: 1.2g

1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1H), 9.20 (s, 1H), 7.07 - 6.99 (m, 2H), 6.88 (dd, 1H), 4.32 (d, 2H), 3.19 - 3.09 (m, 4H), 1.88 - 1.82 (m, 4H), 1.78 - 1.69 (m, 1H), 0.77 (dq, 4H); LC-MS: m/z 289.25 (MH+).

Scheme 17, Preparation of Cpd (III) : N-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3-pyrrolidin-1-ylphenyl]cyclopropancar Copymid

N-[4-(hydrazinecarbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (0.5 g, 1.73 mmol) and N,N-diisopropylethylamine in DCM (35 mL) To a suspension of (0.6 mL, 3.47 mmol) was added a solution of bis(trichloromethyl) carbonate (205.83 mg, 0.690 mmol) in DCM (1 mL). The reaction mixture was stirred at RT for 1 hour. After this time, MeOH was added and the mixture was concentrated under vacuum. The residue was taken up with DCM and filtered. The solid was washed with DCM and dried under vacuum to give the product of the formula N-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3-pyrrolidin-1- Ylphenyl]cyclopropanecarboxamide was provided.

Yield: 300 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (s, 1H), 10.25 (s, 1H), 7.36 - 7.12 (m, 2H), 7.01 (dd, 1H), 3.16 - 3.03 (m, 4H) , 1.92 - 1.82 (m, 4H), 1.78 (dt, 1H), 0.87 - 0.71 (m, 4H); LC-MS: m/z 315.2 (MH+).

Scheme 17, Preparation of Cpd (V)*a : N-[3-pyrrolidin-1-yl-4-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl )phenyl]cyclopropanecarboxamide

Example 99

N-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide ( To a solution of 50.0 mg, 0.160 mmol), N,N-diisopropylethylamine (0.06 mL, 0.320 mmol) was added, and then 1-benzotriazolyloxy-tris(1-pyrrolidinyl)phosphonium hexafluoro Phosphate (91.05 mg, 0.170 mmol) and pyrrolidine (0.03 mL, 0.320 mmol) were added. The reaction mixture was stirred at RT overnight. The next day, the reaction mixture was immediately purified by reverse-phase FC using basic conditions (5:95 CH ₃ CN/H ₂ O + 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia to 95:5 CH ₃ CN /H ₂ O + 10 mM ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia). Fractions containing the desired product were collected and concentrated under vacuum. The residue was purified again by FC on silica gel (eluted with DCM/EtOAc 8:2 to DCM/EtOAc 2:8) to obtain the product N-[3-pyrrolidin-1-yl-4-(5-pyrroli) of the above formula. din-1-yl-1,3,4-oxadiazol-2-yl)phenyl]cyclopropanecarboxamide was provided.

Yield: 8.1 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1H), 7.34 - 7.17 (m, 2H), 7.00 (dd, 1H), 3.43 (d, 4H), 3.07 - 2.96 (m, 4H) , 2.02 - 1.89 (m, 4H), 1.86 - 1.72 (m, 5H), 0.79 (dt, 4H); LC-MS: m/z 368.26 (MH+).

Preparation: N-[4-[5-(4,4-difluoropiperidin-1-yl)-1,3,4-oxadiazol-2-yl]-3-pyrrolidin-1- Ilphenyl]cyclopropanecarboxamide

Example 100

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-(5-pyrrolidin-1-yl-1,3,4-oxadiazol-2-yl) of Example 99. It was performed similarly to the synthesis of [phenyl]cyclopropanecarboxamide, but here 4,4-difluoropiperidine was used instead of pyrrolidine. The title compound was obtained in a yield of 19% (13 mg).

1H NMR (400 MHz, DMSO-d6) δppm 10.24 (s, 1H), 7.32 - 7.23 (m, 2H), 7.01 (dd, 1H), 3.58 (t, 4H), 3.10 - 2.96 (m, 4H), 2.11 (dt, 4H), 1.81(d, 5H), 0.80(d, 4H); LC-MS: m/z 418.24 (MH+).

Scheme 18

Step 1

Compounds of formula II can be reacted with compounds of formula I in the presence of a suitable catalyst such as PdCl ₂ (dppf)·CH ₂ Cl ₂ , a suitable base such as AcOK in a suitable solvent such as 1,4 dioxane, typically at 100° C. It can be obtained via Miyaura coupling between (commercially available from Fluorochem) and bis(pinacolato)diborone. The reaction takes approximately 20 hours to complete.

Step 2

The compounds of formula III are typically 95° C. in the presence of a suitable palladium precatalyst, such as XPhos Pd G2, a suitable base, such as K ₃ PO ₄ , in a suitable solvent mixture, such as 1,2-dimethoxyethane/water. can be obtained via Suzuki coupling between a compound of formula II and the desired commercially available heteroaryl halide. The reaction takes approximately 12 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by SNAr substitution with pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained by nitro reduction of compounds of formula (IV) under catalytic hydrogenation conditions using, for example, Pd/C in a suitable solvent such as MeOH, typically at room temperature. The reaction takes approximately 2 hours to complete.

Step 5

Compounds of formula VI can be obtained by a coupling reaction between a compound of formula V and a suitable commercially available acyl chloride, for example acetyl chloride, in the presence of an organic base, for example TEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 2 hours to complete.

Scheme 18, Preparation of Cpd (II) : 2-(2-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4-Bromo-3-fluoronitrobenzene (1.6 g, 7.27 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.94 g, 7.64 mmol), potassium acetate (2.16 g, 21.82 mmol) and [1,1'-bis(diphenylphosphino) ) Ferrocene] A complex of dichloropalladium(II) and dichloromethane (119.08 mg, 0.150 mmol) was suspended in 1,4-dioxane (70 mL). The mixture was degassed through a N ₂ -vacuum cycle and then stirred at 100° C. for 20 h under N ₂ atmosphere. After this time, the mixture was filtered through a pad of Celite, washed with EtOAc and concentrated under vacuum to give the product of the formula 2-(2-fluoro-4-nitrophenyl)-4,4,5,5-tetra. Methyl-1,3,2-dioxaborolane was provided, which was used in the next step without further purification.

Yield: 2.76 g

1H NMR (400 MHz, CDCl ₃ ) δppm 8.02 (dd, 1H), 7.97 - 7.84 (m, 2H), 1.40 (s, 12H).

Scheme 18, Preparation of Cpd (III) : 2-(2-fluoro-4-nitrophenyl)-4-pyrrolidin-1-ylpyrimidine

2-Chloro-4-pyrrolidin-1-ylpyrimidine (250.0 mg, 1.36 mmol), 2-(2-fluoro-4-nitrophenyl)-4,4,5,5-tetramethyl in an appropriate vial. -1,3,2-dioxaborolane (0.62 g, 1.63 mmol), 2 mL) and 1,2-dimethoxyethane (15 mL). The vial was sealed and the resulting suspension was degassed under nitrogen flux for 5 min and then heated to 95 °C for 12 h. After this time, the reaction mixture was cooled to room temperature, diluted with water and extracted three times with EtOAc. The organic portions were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and solvent removed under vacuum to give the product 2-(2-fluoro-4-nitrophenyl)-4-pyrrolidine. This provided -1-ylpyrimidine, which was used in the next step without further purification.

Yield: 570 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (d, 1H), 8.27 - 8.05 (m, 3H), 6.54 (d, 1H), 3.71 - 3.38 (m, 4H), 1.99 (d, 4H) ; LC-MS: m/z 289.18 (MH+).

Scheme 18, Preparation of Cpd (IV) : 2-(4-nitro-2-pyrrolidin-1-ylphenyl)-4-pyrrolidin-1-ylpyrimidine

To a stirred solution of 2-(2-fluoro-4-nitrophenyl)-4-pyrrolidin-1-ylpyrimidine (275.0 mg, 0.670 mmol) in DMSO (4 mL) was added pyrrolidine (0.17 mL, 2 mmol) was added and the mixture was stirred at 120° C. overnight. The next day, the reaction was cooled to RT, diluted with water and the aqueous phase was extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% cHex to AcOEt/cHex 70:30) to give the product 2-(4-nitro-2-pyrrolidin-1-ylphenyl)-4-p. Rollidin-1-ylpyrimidine was provided.

Yield: 140 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (d, 1H), 7.47 (d, 3H), 6.42 (d, 1H), 3.31 (s, 4H), 3.03 (d, 4H), 1.94 (d) , 4H), 1.78 (d, 4H); LC-MS: m/z 340.2 (MH+).

Scheme 18, Cpd (V) preparation: 3-pyrrolidin-1-yl-4-(4-pyrrolidin-1-ylpyrimidin-2-yl)aniline

Pd/C 10% (43.9 mg) in a solution of 2-(4-nitro-2-pyrrolidin-1-ylphenyl)-4-pyrrolidin-1-ylpyrimidine (140.0 mg, 0.410 mmol) in MeOH , 0.040 mmol) was added. The reaction mixture was stirred at room temperature under H ₂ atmosphere for 2 hours. After this time, the mixture was filtered through a pad of Celite, washed with MeOH and concentrated under vacuum to give the product 3-pyrrolidin-1-yl-4-(4-pyrrolidin-1-ylpyri). midin-2-yl)aniline was provided, which was used in the next step without further purification.

Yield: 142 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (d, 1H), 7.12 (d, 1H), 6.20 (d, 1H), 6.06 - 5.85 (m, 2H), 4.99 (s, 2H), 3.49 - 3.10 (m, 4H), 3.17 - 2.75 (m, 4H), 1.93 (t, 4H), 1.80 - 1.67 (m, 4H); LC-MS: m/z 310.26 (MH+).

Scheme 18, Preparation of Cpd (VI) : N-[3-pyrrolidin-1-yl-4-(4-pyrrolidin-1-ylpyrimidin-2-yl)phenyl]acetamide

Example 101

N,N-diisopropylethylamine (119.91 uL, 0.690 mmol) and 3-pyrrolidin-1-yl-4-(4-pyrrolidin-1-ylpyrimidin-2- in DCM (4.494 mL) 1) Acetyl chloride (30 uL, 0.410 mmol) was added dropwise to a mixture of aniline (142.0 mg, 0.460 mmol) at 0 °C, and the mixture was stirred at RT for 2 hours. After this time, MeOH was added and the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 40:60 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with EtOAc. The combined organic portions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product of the formula N-[3-pyrrolidin-1-yl-4-(4-pyrrolidin- 1-ylpyrimidin-2-yl)phenyl]acetamide was provided.

Yield: 22 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.16 (d, 1H), 7.23 (d, 1H), 7.05 (d, 1H), 6.95 (dd, 1H), 6.30 (d) , 1H), 3.42 (s, 4H), 3.00 - 2.89 (m, 4H), 2.04 (s, 3H), 1.94 (s, 4H), 1.80 - 1.68 (m, 4H); LC-MS: m/z 352.46 (MH+).

Scheme 19

Step 1

Compounds of formula II can be obtained by SNAr substitution between compounds of formula I and benzyl mercaptan in the presence of a suitable base, for example K ₂ CO ₃ , in a suitable aprotic solvent, for example DMF, typically at RT. The reaction takes approximately 20 hours to complete.

Step 2

Compounds of formula III can be prepared by oxidative chlorination of compounds of formula II with the corresponding sulfonyl chlorides in the presence of a suitable oxidizing agent, for example dichloro-5,5-dimethylimidazolidine-2,4-dione, followed by treatment with a suitable amine. You can get it by doing this. The reaction is carried out in a suitable solvent, such as DCM, at a temperature between 0° C. and room temperature. The reaction takes approximately 16 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by SNAr substitution with pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained by nitro reduction of compounds of formula (IV) in the presence of tin(III) chloride dehydrate in a suitable solvent, such as EtOH, typically at 80°C. The reaction takes approximately 1 hour to complete.

Step 5

Compounds of formula VI can be obtained by a coupling reaction between a compound of formula V and a suitable commercially available acyl chloride, for example cyclopropanecarbonyl chloride, in the presence of an organic base, for example TEA. The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 12 hours to complete.

Scheme 19, Cpd (II) preparation: 1-benzylsulfanyl-2-fluoro-4-nitrobenzene

To a solution of 1,2-difluoro-4-nitrobenzene (2.0 g, 12.57 mmol) in DMF (13.5 mL) was added phenylmethanethiol (1.48 mL, 12.57 mmol) followed by potassium carbonate (1.91 g, 13.83 mmol). ) was added. The reaction was stirred at room temperature overnight. After this time, the reaction was diluted with H ₂ O and filtered. The solid was washed with H ₂ O and dried under vacuum to give the product 1-benzylsulfanyl-2-fluoro-4-nitrobenzene (N0806-30-1: 3.3 g, 12.53 mmol, 99.7% yield). This was used in the next step without further purification.

1H NMR (400MHz, DMSO-d6) δppm 8.13 - 8.03 (m, 2H), 7.72 (t, 1H), 7.46 (d, 2H), 7.39 - 7.24 (m, 3H)

4.47(s, 2H); LC-MS: m/z 264.01 (MH+).

Scheme 19, Cpd (III)*a Preparation: 1-(2-fluoro-4-nitrophenyl)sulfonyl-4-methylpiperazine

1 in a suspension of 1-benzylsulfanyl-2-fluoro-4-nitrobenzene (100.0 mg, 0.380 mmol) in a mixture of MeCN (3.8 mL), water (0.100 mL) and acetic acid (49.0 uL, 0.860 mmol). 3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (149.66 mg, 0.760 mmol) was added at 0°C. After stirring at 0 °C for 2 h, the reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (1.5 mL) and cooled back to 0 °C. Then, saturated NaHCO ₃ solution was added and the mixture was stirred at 0° C. for 15 minutes. The mixture was then extracted with DCM (X2) and the combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The residue was dissolved in DCM (1.5 mL), 1-methyl-3-phenylpiperazine (66.95 mg, 0.380 mmol) was added at 0 °C, and then 1,4-diazabicyclo[2.2.2]octane ( 51.12 mg, 0.460 mmol) was added and the mixture was allowed to warm to room temperature. After stirring for 16 h, the reaction mixture was quenched with water and extracted with DCM (x3). The organic layer was washed with brine, dried using a phase separator, and concentrated to give the crude material, which was purified by FC on silica gel (eluting with 100% cHex to cHex/EtOAc 80:20) to give the product of the formula: 1-(2-Fluoro-4-nitrophenyl)sulfonyl-4-methyl-2-phenylpiperazine was provided.

Yield: 130 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.37 (dd, 1H), 8.24 - 8.17 (m, 1H), 8.15 - 8.05 (m, 1H), 7.47 - 7.43 (m, 2H), 7.36 - 7.18 (m, 3H), 5.09 - 5.02 (m, 1H), 3.75 - 3.66 (m, 1H), 3.31 - 3.18 (m, 2H), 2.77 - 2.62 (m, 1H), 2.20 - 2.07 (m, 4H) , 1.79 (td, 1H); LC-MS: m/z 380.12 (MH+).

Scheme 19, Cpd (III)*b Preparation: 1-(2-fluoro-4-nitrophenyl)sulfonyl-4-methylpiperazine

The synthesis of the title compound was performed similarly to the synthesis of compound 1-(2-fluoro-4-nitrophenyl)sulfonyl-4-methylpiperazine, where 1-methylpiperazine was reacted with 1-methyl-3-phenylpipe It was used instead of Rajin. The title compound was obtained in quantitative yield (700 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (dd, 1H), 8.28 - 8.22 (m, 1H), 8.08 - 8.02 (m, 1H), 3.15 (t, 4H), 2.37 (t, 4H) ), 2.17 (s, 3H); LC-MS: m/z 304.05 (MH+).

Scheme 19, Cpd (IV)*a Preparation: 4-methyl-1-(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonyl-2-phenylpiperazine

Pyrrolidine (0.56 g, 7.91 mmol) and 1-(2-fluoro-4-nitrophenyl)sulfonyl-4-methyl-2-phenylpiperazine (1.0 g, 2.64 mmol) in DMSO (15 mL) The mixture was heated to 120° C. for 12 h. After this time the reaction was diluted with water and then extracted with AcOEt x3. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FC on silica gel (eluting with cHex 100% to cHex/EtOAc 80:20) to give the product 4-methyl-1-(4-nitro-2-pyrrolidin-1-yl). Phenyl)sulfonyl-2-phenylpiperazine was provided.

Yield: 397 mg

LC-MS: m/z 431.19 (MH+).

Scheme 19, Cpd (IV)*b Preparation: 1-methyl-4-(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonylpiperazine

The synthesis of the title compound was carried out similarly to the synthesis of the compound 4-methyl-1-(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonyl-2-phenylpiperazine, where 1-(2- Fluoro-4-nitrophenyl)sulfonyl-4-methylpiperazine was used instead of 1-(2-fluoro-4-nitrophenyl)sulfonyl-4-methyl-2-phenylpiperazine. The title compound was obtained in a yield of 70% (490 mg).

LC-MS: m/z 355.15 (MH+).

Scheme 19, Cpd (V)*a Preparation: 4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline

Tin(III) chloride was added to a solution of 4-methyl-1-(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonyl-2-phenylpiperazine (397.0 mg, 0.920 mmol) in ethanol (10 mL). ) dihydrate (1.3 g, 5.53 mmol) was added and the reaction was stirred at 80° C. for 1 h. After this time EtOH was evaporated under reduced pressure and the residue was dissolved in EtOAc. A precipitate formed and it was filtered under reduced pressure in a Hirsch funnel. The filtrate was evaporated under reduced pressure, first washed with MeOH, then eluted with 1N NH ₃ in MeOH and purified by SCX. The basic fractions were collected and concentrated under vacuum to give the product 4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline. The product was used in the next step without further purification.

Yield: 200 mg

LC-MS: m/z 401.27 (MH+).

Scheme 19, Cpd (V)*b Preparation: 4-(4-methylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline

The synthesis of the title compound was carried out similarly to the synthesis of compound 4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline, herein 1-methyl-4 -(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonylpiperazine is converted to 4-methyl-1-(4-nitro-2-pyrrolidin-1-ylphenyl)sulfonyl-2-phenyl It was used instead of piperazine. The title compound was obtained in a yield of 9% (40 mg).

LC-MS: m/z 323.18 (MH+).

Scheme 19, Cpd (VI)*a Preparation: N-[4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 102

In a solution of 4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline (199.0 mg, 0.500 mmol) in DCM (6.387 mL) N,N- Diisopropylethylamine (0.13 mL, 0.750 mmol) was added followed by cyclopropanecarbonyl chloride (0.06 mL, 0.650 mmol). The reaction was stirred RT/ON. The next day the reaction was diluted with DCM, washed with saturated NaHCO ₃ solution, brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by RP FC using basic conditions (eluted with 100% water + 0.1% NH ₄ OH to 20:80 CH ₃ CN/water + 0.1% NH ₄ OH) to give the product N- [4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was provided.

Yield: 72 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.46 (s, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.43 - 7.35 (m, 2H), 7.32 - 7.12 (m, 4H) ), 5.01 - 4.93 (m, 1H), 3.57 - 3.47 (m, 1H), 3.26 - 2.91 (m, 8H), 2.63 - 2.57 (m, 1H), 2.19 (dd, 1H), 1.90 - 1.65 (m , 6H), 0.91 - 0.67 (m, 5H); LC-MS: m/z 467.21 (MH+).

Manufactured by: N-[4-(4-methylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 103

The synthesis of the title compound was carried out using the compound N-[4-(4-methyl-2-phenylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide of Example 102. The synthesis was performed similarly, where 4-(4-methylpiperazin-1-yl)sulfonyl-3-pyrrolidin-1-ylaniline was reacted with 4-(4-methyl-2-phenylpiperazine-1- 1) It was used instead of sulfonyl-3-pyrrolidin-1-ylaniline. The title compound was obtained in a yield of 73% (33 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 - 10.43 (m, 1H), 7.72 - 7.61 (m, 2H), 7.26 (d, 1H), 3.24 - 3.13 (m, 4H), 3.06 - 2.95 (m, 3H), 2.37 - 2.21 (m, 5H), 2.18 - 2.10 (m, 3H), 1.93 - 1.73 (m, 5H), 0.83 (d, 4H); LC-MS: m/z 393.18 (MH+).

Scheme 20

Step 1

Compounds of formula II can be obtained from compounds of formula I (synthesized according to Scheme 1) by removing the Boc protecting group under acid conditions, e.g. TFA, typically at RT. The reaction takes about 3 to 12 hours to complete.

Step 2

Compounds of formula III can be obtained via sulfonamide formation between compounds of formula II and methanesulfonyl chloride in the presence of a suitable organic base, such as TEA, in a suitable solvent, such as DCM, typically at RT. The reaction takes approximately 5 minutes to complete.

Scheme 20, Cpd (II)*a Manufactured by: N-[4-[4-(methylamino)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

tert-Butyl N-[1-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperidin-4-yl]-N-methylcarba in DCM (5.128 mL) To a solution of mate (160.0 mg, 0.340 mmol) was added trifluoroacetic acid (0.26 mL, 3.4 mmol) at RT, and the resulting reaction mixture was stirred at RT overnight. The mixture was concentrated under vacuum, dissolved in 1 mL of MeOH, and purified by SCX, first washing with MeOH and then eluting with 1N NH ₃ in MeOH. The basic fractions were collected and concentrated under vacuum to give the product of the formula: N-[4-[4-(methylamino)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropancar Copamide was provided and used in the next step without further purification.

Yield: 86 mg

LC-MS: m/z 371.28 (MH+).

Scheme 20, Cpd (II)*b Preparation: N-[4-(4-aminopiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out similarly to the synthesis of the compound N-[4-[4-(methylamino)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. Here, tert-butyl N-[1-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperidin-4-yl]carbamate is tert-butyl N- [1-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperidin-4-yl]-N-methylcarbamate was used instead. The title compound was obtained in a yield of 70% (86 mg).

LC-MS: m/z 457.48 (MH+)

Scheme 20, Cpd (III)*a Preparation: N-[4-[4-[methyl(methylsulfonyl)amino]piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclo Propanecarboxamide

Example 104

N-[4-[4-(methylamino)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (86.0 mg, 0.230 mmol) in DCM (3.479 mL) ) and triethylamine (0.05 mL, 0.350 mmol) were added to a 0 °C cooled solution of methanesulfonyl chloride (0.02 mL, 0.280 mmol). The mixture was warmed to room temperature and stirred for 5 minutes. The mixture was diluted with DCM and washed with brine. The organic layer was filtered through a phase separator and concentrated under reduced pressure. The residue was purified by RP FC using acid conditions (eluted with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 35:65 CH ₃ CN/H ₂ O + 0.1% HCOOH) to obtain the above It gave the product of the formula N-[4-[4-[methyl(methylsulfonyl)amino]piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide.

Yield: 33 mg

1H NMR (400 MHz, DMSO-d6) δ 10.09 (d, 1H), 7.17 - 6.79 (m, 3H), 4.70 - 4.50 (m, 1H), 3.85 - 3.77 (m, 1H), 3.62 - 3.49 (m , 1H), 3.23 - 2.82 (m, 8H), 2.68 (d, 4H), 1.94 - 1.48 (m, 9H),0.78 (dd, 4H); LC-MS: m/z 449.26 (MH+).

Manufactured by: N-[4-[4-(methanesulfonamido)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 105

The synthesis of the title compound was carried out similarly to the synthesis of the compound N-[4-[4-(methylamino)piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. Here, N-[4-(4-aminopiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was replaced with N-[4-[4-(methylamino ) Piperidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was used instead. The title compound was obtained in a yield of 33% (35 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.16 (dd, 1H), 7.09 - 7.02 (m, 1H), 6.96 - 6.83 (m, 2H), 4.31 (dd, 1H), 3.53 - 3.35 (m, 2H), 3.21 - 2.78 (m, 9H), 1.87 (dd, 5H), 1.76 (h, 2H), 1.33 (dd, 2H), 0.77 (dt, 4H); LC-MS: m/z 435.23 (MH+).

Scheme 21

Step 1

Compounds of formula II can be obtained from compounds of formula I by removing the Boc protecting group under acidic conditions, for example TFA, typically at RT. The reaction takes approximately 2 hours to complete.

Step 2

Compounds of formula III can be obtained via reductive amination between compounds of formula II and a suitable aldehyde, such as formaldehyde, in the presence of a suitable reducing agent, such as sodium triacetoxyborohydride. The reaction is typically carried out at RT in a suitable solvent, such as MeOH. The reaction takes approximately 12 hours to complete.

Scheme 21, Cpd (II)*a preparation: N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl] Cyclopropanecarboxamide

tert-Butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine- in DCM (2 mL) To a solution of 1-carboxylate (24.3 mg, 0.041 mmol) was added trifluoroacetic acid (0.095 mL, 1.243 mmol). The reaction mixture was stirred at RT for 2 hours. After this time, the mixture was concentrated to dryness under vacuum. The residue was first washed with MeOH, then eluted with 1N NH ₃ in MeOH and purified by SCX. The basic fractions were collected and concentrated under vacuum to give the product N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl. ]phenyl]cyclopropanecarboxamide was provided as a racemic mixture. The product was used in the next step without further purification.

Yield: 19 mg

LC-MS: m/z 487.18 (MH+).

Scheme 21, Cpd (II)*b Preparation: N-[4-[2-(3-cyanophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxylic mid

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was carried out similarly to the synthesis, where tert-butyl 3-(3-cyanophenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1 -Carboxylate is tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine-1 -Used instead of carboxylate. The title compound was obtained as a racemic mixture in a yield of 97% (44 mg).

Scheme 21, Cpd (II)*c Preparation: N-[4-[2-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carbonyl]-3-pyrroly din-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was carried out similarly to the synthesis, where tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4,5-dimethyl-1,3- Thiazol-2-yl)piperazine-1-carboxylate was reacted with tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-( Trifluoromethyl)phenyl]piperazine-1-carboxylate was used instead. The title compound was obtained as a racemic mixture in quantitative yield (59 mg).

LC-MS: m/z 454.24 (MH+).

Scheme 21, Cpd (II)*d Preparation: N-[4-[2-(4-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was carried out similarly to the synthesis, where tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-methylphenyl)piperazine-1-car The boxylate was tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine-1-carboxylate. It was used instead of voxylate. The title compound was obtained as a racemic mixture in a yield of 46% (36 mg).

LC-MS: m/z 433.38 (MH+).

Scheme 21, Cpd (II)*e Preparation: N-[4-[2-(3-chloro-5-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropane Carboxamide

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was carried out similarly to the synthesis of tert-butyl 3-(3-chloro-5-methylphenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine. -1-carboxylate is tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine -1-Carboxylate was used instead. The title compound was obtained as a racemic mixture in a yield of 63% (68 mg).

LC-MS: m/z 467.25 (MH+).

Scheme 21, Cpd (II)*f Preparation: N-[4-[2-(3-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was carried out similarly to the synthesis of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(3-methylphenyl)piperazine-1-car The boxylate was tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-[2-(trifluoromethyl)phenyl]piperazine-1-carboxylate. It was used instead of voxylate. The title compound was obtained as a racemic mixture in a yield of 90% (118 mg).

LC-MS: m/z 433.31 (MH+).

Scheme 21, Cpd (III)*a Preparation: N-[4-[4-methyl-2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]-3-pyrrolidine-1 -Ylphenyl]cyclopropanecarboxamide

Example 106

N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide in methanol (1.000 mL) To a solution of (19.0 mg, 0.040 mmol), formaldehyde (0.03 mL, 0.390 mmol) was added, followed by sodium triacetoxyborohydride (99.66 mg, 0.234 mmol). The reaction was stirred at room temperature overnight. The next day the reaction was diluted with EtOAc and washed with saturated NaHCO ₃ solution. The organic phase was dried using a phase separator and concentrated. The crude material was purified by FC on silica gel (eluting with cHex/EtOAc 50:50 to cHex/EtOAc 20:80) to give the product N-[4-[4-methyl-2-[2-(trifluoromethyl )phenyl]piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained as a racemic mixture.

Yield: 6.5 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 -10.02 (m, 1H), 7.99 - 7.77 (m, 1H), 7.77 - 7.58 (m, 2H), 7.56 - 7.44 (m, 1H), 7.13 - 7.06 (m, 1H), 7.00 - 6.97 (m, 1H), 6.91 - 6.61 (m, 1H), 5.84 - 5.32 (m, 1H), 3.88 - 3.60 (m, 2H), 3.26 - 3.05 (m, 3H), 2.86 - 2.72 (m, 3H), 2.47 - 2.38 (m, 1H), 2.24 - 2.05 (m, 4H), 2.05 - 1.84 (m, 3H), 1.82 - 1.57 (m, 2H), 0.81 - 0.67 (m, 4H); LC-MS: m/z 501.31 (MH+).

Manufactured by: N-[4-[2-(3-cyanophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 107

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was performed similarly to the synthesis, where N-[4-[2-(3-cyanophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained as a racemic mixture in a yield of 35% (16 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.11 (s, 1H), 8.16 - 7.86 (m, 1H), 7.82 - 7.37 (m, 3H), 7.21 - 6.67 (m, 3H), 5.92 - 5.54 (m, 1H), 3.44 (dd, 2H), 3.24 - 2.83 (m, 4H), 2.78 - 2.59 (m, 2H), 2.40 - 2.10 (m, 4H), 2.09 - 1.86 (m, 3H), 1.83 - 1.57 (m, 3H), 0.82 - 0.62 (m, 4H); LC-MS: m/z 458.29 (MH+).

Preparation: N-[4-[2-(4,5-dimethyl-1,3-thiazol-2-yl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-yl Phenyl]cyclopropanecarboxamide

Example 108

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was performed similarly to the synthesis of N-[4-[2-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carbonyl]-3-pyrrolidine- 1-Ylphenyl]cyclopropanecarboxamide is replaced with N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl] It was used instead of cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 89% (54 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 - 10.06 (m, 1H), 7.21 - 6.77 (m, 3H), 5.90 - 4.26 (m, 1H), 3.61 - 3.35 (m, 2H), 3.30 - 2.56 (m, 6H), 2.39 - 2.12 (m, 10H), 2.08 - 1.61 (m, 6H), 0.89 - 0.70 (d, 4H); LC-MS m/z 468.49 (MH+).

Manufactured by: N-[4-[4-methyl-2-(4-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 109

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was performed similarly to the synthesis, where N-[4-[2-(4-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was reacted with N- [3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained as a racemic mixture in a yield of 32% (11 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.21 - 9.95 (m, 1H), 7.66 - 7.23 (m, 2H), 7.22 - 6.69 (m, 5H), 5.84 - 4.25 (m, 1H), 3.46 - 3.38 (m, 1H), 3.27 - 2.55 (m, 6H), 2.46 - 2.08 (m, 7H), 2.06 - 1.85 (m, 4H), 1.81 - 1.53 (m, 3H), 0.93 -0.65 (m, 4H); LC-MS: m/z 447.30 (MH+).

Manufactured by: N-[4-[2-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 110

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. It was performed similarly to the synthesis of N-[4-[2-(3-chloro-5-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxylic Mead was used instead of N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 60% (41 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 7.59 - 6.76 (m, 6H), 5.79 - 5.64 (m, 1 H), 4.72 - 4.35 (m, 1 H), 3.48 - 2.60 (m, 7 H), 2.40 - 2.13 (m, 7 H), 2.08 - 1.63 (m, 6 H), 0.85 - 0.69 (m, 4 H); LC-MS: m/z 481.28 (MH+)

The racemic mixture ( Example 110) was then separated into single enantiomers by chiral semipreparative HPLC.

N-[4-[2S or 2R-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide hydrochloride manufacture of

Example 110a

N-[4-[2S or 2R-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (mirror image Isomer 1) (15.7 mg, 0.033 mmol) was dissolved in dry methanol (1 mL) and treated with 1 eq of HCl in dioxane (0.033 mL, 0.033 mmol) to give, after evaporation, the product N-[4-[ 2R or 2S-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide hydrochloride was provided.

Yield: 16.1 mg

LC-MS: m/z 481.25 (MH+).

N-[4-[2S or 2R-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide hydrochloride manufacture of

Example 110b

N-[4-[2S or 2R-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (mirror image Isomer 2) (14.9 mg, 0.031 mmol) was dissolved in dry methanol (1 mL) and treated with 1 eq of HCl in dioxane (0.031 mL, 0.031 mmol) to give, after evaporation, the product N-[4-[ 2R or 2S-(3-chloro-5-methylphenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide hydrochloride was provided.

Yield: 13.7

LC-MS: m/z 481.25 (MH+).

Manufactured by: N-[4-[4-methyl-2-(3-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Example 111

The synthesis of the title compound was carried out using the compound N-[3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide. was performed similarly to the synthesis, where N-[4-[2-(3-methylphenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was reacted with N- [3-pyrrolidin-1-yl-4-[2-[2-(trifluoromethyl)phenyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was used instead. The title compound was obtained as a racemic mixture in a yield of 65% (79 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.17 - 10.03 (m, 1H), 7.54 - 7.42 (m, 1H), 7.30 - 7.12 (m, 2H), 7.11 - 6.92 (m, 3H), 6.87 - 6.81 (m, 1H), 5.84 - 4.30 (m, 1H), 3.50 - 3.34 (m, 1H), 3.26 - 2.59 (m, 6H), 2.40 - 2.11 (m, 7H), 2.05 - 1.84 (m, 4H), 1.80 - 1.58 (m, 3H), 0.95 - 0.66 (m, 4H); LC-MS: m/z 447.29 (MH+)

Scheme 22

Step 1

Compounds of formula II can be prepared from compounds of formula I (commercially available from Enamine) by 4-(trifluoromethyl)piperidine hydrochloride in the presence of a suitable coupling agent such as HATU and a suitable organic base such as DIPEA. It can be obtained by coupling with . The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes approximately 5 hours to complete.

Step 2

Compounds of formula III can be obtained from compounds of formula II by SNAr substitution with pyrrolidine in a suitable aprotic solvent, such as CH ₃ CN, typically at 80° C. The reaction takes approximately 12 hours to complete.

Step 3

Compounds of formula IV can be obtained by nitrile hydrolysis of compounds of formula III under standard literature conditions, for example by reaction with NaOH in the presence of H ₂ O ₂ . The reaction is carried out in a suitable solvent, such as MeOH, typically at RT. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained from compounds of formula (IV) by reaction with a suitable formylating agent such as 1,1-dimethoxy-N,N-dimethylmethanamine to form N-formyl imide, followed by a ring reaction using NH ₂ NH ₂ You can get it through anger. The reaction is typically carried out at temperatures from RT to 120° C. in a suitable solvent, such as DMF.

Scheme 22, Preparation of Cpd (II) : 3-fluoro-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

HATU (3454.12 mg, 9.08 mmol), 4-cyano-2-fluorobenzoic acid (1.5 g, 9.08 mmol) and 4-(trifluoromethyl)piperidine hydrochloride (1722.47 mg, DIPEA (4.85 mL, 27.25 mmol) was added to the solution (9.08 mmol). The reaction was stirred at RT for 5 h. After this time, the reaction was diluted with H ₂ O and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% cHex to AcOEt/cHex 1:1) to obtain the product 3-fluoro-4-[4-(trifluoromethyl)piperidine-1-car of the above formula. Bornyl]benzonitrile was provided.

Yield: 2.5 g

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.00 (dd, 1H), 7.81 (dd, 1H), 7.75 - 7.62 (m, 1H), 4.60 (d, 1H), 3.41 (d, 1H), 3.14 (t, 1H), 2.85 (td, 1H), 2.75 - 2.60 (m, 2H), 2.00 - 1.90 (m, 1H), 1.85 - 1.76 (m, 1H), 1.53 - 1.28 (m, 1H); LC-MS: m/z 301.19 (MH+).

Scheme 22, Preparation of Cpd (III) : 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

To a solution of 3-fluoro-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (1.5 g, 5 mmol) in MeCN (20 mL) was added pyrrolidine (1.67 mL, 19.98 mmol) was added and the reaction was stirred at 80° C. overnight. After this time, the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% cHex to cHex/AcOEt 3:7) to give the product 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)pipery. Dean-1-carbonyl]benzonitrile was provided.

Yield: 1.6 g

1H NMR (400 MHz, DMSO-d6) δ 7.19 (dd, 1H), 7.10 - 7.00 (m, 2H), 4.60 (t, 1H), 3.51 (dd, 1H), 3.21 - 2.56 (m, 7H), 1.97 - 1.68 (m, 6H), 1.55 - 1.24 (m, 2H); LC-MS: m/z 352.20 (MH+).

Scheme 22, Cpd (IV) preparation: 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzamide

To a solution of 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (285.37 mg, 0.810 mmol) in methanol (3 mL) was added sodium hydroxide. (0.27 mL, 0.810 mmol) was added and the reaction was stirred at RT overnight. The next day hydrogen peroxide (0.2 mL, 1.97 mmol) was added followed by additional sodium hydroxide (0.27 mL, 0.810 mmol) and the reaction was stirred at RT for 4 h. After this time, the reaction was diluted with H ₂ O and extracted three times with AcOEt. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)pipery. Dean-1-carbonyl]benzamide was provided. The product was used in the next step without further purification.

Yield: 120 mg

1H NMR (400 MHz, DMSO-d6) δ 7.24 - 6.97 (m, 3H), 4.62 (t, 1H), 3.53 (t, 1H), 3.26 - 2.52 (m, 7H), 1.96 - 1.67 (m, 6H) ), 1.49 - 1.27 (m, 2H); LC-MS: m/z 370.18 (MH+).

Scheme 22, Preparation of Cpd (V) : [2-pyrrolidin-1-yl-4-(4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl) piperidin-1-yl] methanone

Example 112

1 to a solution of 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzamide (120.0 mg, 0.320 mmol) in DMF (1.793 mL), 1-Dimethoxy-N,N-dimethylmethanamine (0.09 mL, 0.650 mmol) was added and the reaction was stirred at 120 °C for 1.5 h. After this time, the reaction was cooled to RT and H ₂ O was added. The reaction was treated with EtOAc (x3), washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was dissolved in ethanol (5 mL), and hydrazine (0.5 mL, 5.52 mmol) was added. The reaction was stirred at RT for 2 h. After this time, the reaction was diluted with H ₂ O and extracted three times with AcOEt. The combined organic fractions were washed with brine, filtered and concentrated under vacuum. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 9:1) to give the product of the formula [2-pyrrolidin-1-yl-4-(4H-1,2,4- Triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone was provided.

Yield: 40 mg

1H NMR (400 MHz, DMSO-d6) δ 14.17 (s, 1H), 8.36 (s, 1H), 7.46 -7.29 (m, 2H), 7.12 (dd, 1H), 4.64 (t, 1H), 3.61 ( t, 1H), 3.28 (s, 2H), 3.17 -2.94 (m, 2H), 2.90 -2.59 (m, 3H), 2.05 -1.72 (m, 6H), 1.53 -1.27 (m, 2H); LC-MS: m/z 394.22 (MH+).

Scheme 23

Step 1

Compounds of formula II are typically treated with a suitable chlorinating agent such as SOCl ₂ at 90° C. to form the acyl chloride of a compound of formula I (commercially available from Enamine) followed by 1-methyl in the presence of a suitable organic base such as TEA. It can be obtained through coupling with -3-phenylpiperazine (commercially available from Enamine). The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 16 hours to complete.

Step 2

Compounds of formula III can be obtained from compounds of formula II by SNAr substitution with pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes approximately 3 hours to complete.

Step 3

Compounds of formula IV can be obtained by nitro reduction of compounds of formula III using Zn dust in a suitable solvent, such as AcOH, typically at room temperature. The reaction takes approximately 2 hours to complete.

Step 4

Compounds of formula (V) can be obtained by cyclization of compounds of formula (IV) with a suitable aldehyde, for example cyclopropanecarboxaldehyde, in the presence of a suitable oxidizing agent, for example oxone. The reaction is typically carried out at RT in a suitable solvent mixture, for example DMF/H ₂ O. The reaction takes approximately 4 hours to complete.

Scheme 23, Preparation of Cpd (II) : (4-amino-2-fluoro-5-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 4-amino-2-fluoro-5-nitrobenzoic acid (200.0 mg, 1 mmol) and thionyl dichloride (1.46 mL, 19.99 mmol) was heated to reflux for 4 hours. After this time, the reaction was cooled to RT and then concentrated under vacuum. The mixture was stripped three times with cyclohexane to remove excess thionyl dichloride. The residue was suspended in DCM (4 mL), 1-methyl-3-phenylpiperazine (176.15 mg, 1 mmol) was added, followed by TEA (0.42 mL, 3 mmol), and the reaction was stirred at RT overnight. . After this time the mixture was diluted with DCM and washed three times with saturated NaHCO ₃ solution. The aqueous phases were collected together and back-extracted with DCM. The combined organic phases were dried in a phase separator and concentrated under vacuum to give the product of the formula (4-amino-2-fluoro-5-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methane. On was provided. The product was used in the next step without further purification.

Yield: 380 mg

LC-MS: m/z 359.36 (MH+).

Scheme 23, Preparation of Cpd (III) : (4-amino-5-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

in a solution of (4-amino-2-fluoro-5-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (386.0 mg, 1.08 mmol) in DMSO (8 mL). Rollidine (0.27 mL, 3.23 mmol) was added. The mixture was stirred at 120°C for 2 h. After this time, the mixture was cooled to RT and diluted with H ₂ O. The mixture was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with cHex/AcOEt 8:2 to cHex/AcOEt 3:7) to obtain the product of the formula (4-amino-5-nitro-2-pyrrolidin-1-ylphenyl)- (4-methyl-2-phenylpiperazin-1-yl)methanone was provided.

Yield: 230 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.77 -7.70 (m, 1H), 7.59 -7.44 (m, 1H), 7.44 -7.15 (m, 5H), 6.11 -4.31 (m, 1H), 3.63 -3.31 (m, 3H), 3.20 -2.98 (m, 2H), 2.88 -2.76 (m, 1H), 2.74 -2.66 (m, 1H), 2.45 -2.11 (m, 5H), 2.10 -1.85 (m, 3H), 1.82 -1.59 (m, 2H); LC-MS: m/z 410.22 (MH+).

Scheme 23, Preparation of Cpd (IV) : (4,5-diamino-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

(4-Amino-5-nitro-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (232.3 mg, 0.570 mmol) in AcOH (8 mL) ) was added to the solution of zinc (370.9 mg, 5.67 mmol), and the reaction was stirred at RT for 2 h. After this time the mixture was filtered and concentrated by rotary evaporation to obtain the residue. The crude material was then purified by SCX, first washed with MeOH and then eluted with 1N NH ₃ in MeOH. The basic fractions were collected and concentrated under vacuum to give the product of the formula (4,5-diamino-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methane. On was provided. The product was used in the next step without further purification.

Yield: 190 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.63 (d, 1H), 7.53 - 7.10 (m, 5H), 6.49 - 5.58 (m, 2H), 4.92 - 3.97 (m, 2H), 3.23 - 2.60 (m, 7H), 2.29 - 2.13 (m, 5H), 1.88 (d, 5H), 1.62 (d, 2H); LC-MS: m/zm/z 381.06 (M+2H).

Scheme 23, prepare Cpd (V)*a : (2-cyclopropyl-6-pyrrolidin-1-yl-3H-benzimidazol-5-yl)-(4-methyl-2-phenylpiperazine-1 -1) Methanone

Example 113

(4,5-diamino-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone in DMF (1.5 mL)/water (0.250 mL) Oxone (87.48 mg, 0.140 mmol) was added to a mixture of 90.0 mg, 0.240 mmol) and cyclopropanecarboxaldehyde (24.93 mg, 0.360 mmol). The reaction was stirred at RT for 4 h. After this time, saturated NaHCO ₃ solution was added and the reaction was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated by rotary evaporation. The residue was purified by RP FC using basic conditions (from 5:95 CH ₃ CN/H ₂ O + 0.1 % NH ₄ OH to 40:60 CH ₃ CN/H ₂ O + 0.1 % NH ₄ OH). ) The product of the above formula (2-cyclopropyl-6-pyrrolidin-1-yl-3H-benzimidazol-5-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone provided.

Yield: 45 mg

^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.95 (s, 1H), 7.76 -7.45 (m, 2H), 7.37 (dt, 2H), 7.28 (t, 1H), 7.21 - 7.14 (m, 1H) ), 7.12 -6.69 (m, 1H), 5.92 -3.44 (m, 2H), 3.17 -2.53 (m, 6H), 2.46 -2.12 (m, 5H), 2.05 -1.78 (m, 5H), 1.73 -1.60 (m, 1H), 1.10 - 0.83 (m, 4H); LC-MS: m/z 430.52 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-(2-methyl-6-pyrrolidin-1-yl-3H-benzimidazol-5-yl)methanone

Example 114

The synthesis of the title compound was carried out using the compound of Example 113 (2-cyclopropyl-6-pyrrolidin-1-yl-3H-benzimidazol-5-yl)-(4-methyl-2-phenylpiperazine-1- 1) It was performed similarly to the synthesis of methanone, where acetaldehyde was used instead of cyclopropanecarboxaldehyde. The title compound was obtained in a yield of 49% (47 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.05 - 11.81 (m, 1H), 7.78 - 7.44 (m, 1H), 7.44 - 7.21 (m, 3H), 7.20 - 6.93 (m, 2H), 6.85 - 6.67 (m, 1H), 5.88 - 3.44 (m, 2H), 3.24 - 2.74 (m, 6H), 2.64 - 2.56 (m, 1H), 2.45 - 2.11 (m, 5H), 2.07 - 1.87 (m, 5H), 1.80 - 1.59 (m, 2H); LC-MS: m/z 403.68 (MH+).

Scheme 24

Step 1

Compounds of formula II are typically formed from compounds of formula I (commercially available from Enamine) by treatment with a suitable chlorinating agent, such as SOCl ₂ at 90° C. to form an acyl chloride, followed by 1- in the presence of a suitable organic base, such as TEA. It can be obtained through coupling with methyl-3-phenylpiperazine (commercially available from Enamine). The reaction is typically carried out at room temperature in a suitable solvent such as DCM. The reaction takes approximately 16 hours to complete.

Step 2

Compounds of formula III can be prepared from compounds of formula II by a Buchwald reaction with a suitable amide, for example cyclopropanecarboxamide, in the presence of a suitable palladium precatalyst, for example XPhos Pd G3 and a suitable base, such as Cs ₂ CO ₃ You can get it. The reaction is typically carried out at 80° C. in a suitable solvent, such as 1,4-dioxane. The reaction takes approximately 12 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by Buchwald reaction with a suitable amine, for example pyrrolidine, in the presence of a suitable palladium precatalyst, for example XPhos Pd G3 and a suitable base such as K ₂ CO ₃ there is. The reaction is typically carried out at 100° C. in a suitable solvent, such as 1,4-dioxane. The reaction takes approximately 12 hours to complete.

Scheme 24, Preparation of Cpd (II) : (2,6-dichloro-5-fluoropyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 2,6-dichloro-5-fluoropyridine-3-carboxylic acid (1.0 g, 4.76 mmol) and thionyl dichloride (3.47 mL, 47.62 mmol) was heated to reflux for 3 h. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was dissolved in DCM (1.667 mL) and cooled to 0 °C. After 10 min a solution of DIPEA (1.66 mL, 9.52 mmol) and 1-methyl-3-phenylpiperazine (0.84 g, 4.76 mmol) in DCM (10 mL) was added and the reaction was stirred at RT overnight. After this time the reaction was diluted with DCM and washed three times with saturated NaHCO ₃ solution. The organic phase was washed with brine, dried in a phase separator and concentrated under vacuum to give the product of the formula (2,6-dichloro-5-fluoropyridin-3-yl)-(4-methyl-2-phenylpipe Razin-1-yl)methanone was provided. The product was used in the next step without further purification.

Yield: 1.6 g

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 - 8.10 (m, 1H), 7.53 (dd, 1H), 7.44 - 7.19 (m, 4H), 5.83 - 3.45 (m, 1H), 3.16 - 2.56 (m, 2H), 2.47 - 2.29 (m, 1H), 2.25 - 2.12 (m, 3H), 2.12 - 1.89 (m, 1H), 0.95 (d, 2H); LC-MS: m/z 368.04 (MH+)

Scheme 24, Preparation of Cpd (III) : N-[6-chloro-3-fluoro-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

(2,6-dichloro-5-fluoropyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (200.0 mg) in dry 1,4-dioxane (4.964 mL) , 0.540 mmol), cyclopropanecarboxamide (50.84 mg, 0.600 mmol), disesium carbonate (356.13 mg, 1.09 mmol) and XPHOS PD G3 (23.01 mg, 0.030 mmol) were degassed using the Schlenk technique. The resulting mixture was heated to 80° C. and stirred overnight. The next day the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by RP FC using basic conditions (5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 60:40 CH ₃ CN/H ₂ O + 0.1% eluted with HCOOH). Pure fractions were collected and evaporated under vacuum to give the product of the formula (N-[6-chloro-3-fluoro-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl ]Cyclopropanecarboxamide was provided.

Yield: 65 mg

1H NMR (500 MHz, DMSO-d6) δ ppm 11.28 - 10.70 (m, 1 H), 8.33 - 7.83 (m, 1 H), 7.60 - 7.31 (m, 4 H), 7.31 - 7.24 (m, 1 H) ), 5.85 - 4.58 (m, 1 H), 3.57 - 3.24 (m, 1 H), 4.46 - 3.19 (m, 1 H), 3.17 - 2.84 (m, 1 H), 2.83 - 2.54 (m, 1 H) ), 2.50 (dt, 1 H), 2.26 - 2.14 (m, 3 H), 2.13 - 1.97 (m, 1 H), 1.97 - 1.83 (m, 1 H), 0.96 - 0.70 (m, 4 H); LC-MS: m/z 417.17 (MH+).

Scheme 24, Preparation of Cpd (IV) : N-[3-fluoro-5-(4-methyl-2-phenylpiperazine-1-carbonyl)-6-pyrrolidin-1-ylpyridin-2-yl ]Cyclopropanecarboxamide

Example 115

N-[6-chloro-3-fluoro-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropane in dry 1,4-dioxane (1.5 mL) Solutions of carboxamide (65.0 mg, 0.160 mmol), potassium carbonate (0.04 mL, 0.310 mmol), , and stirred at 100°C overnight. The next day the reaction was cooled to RT, diluted with water and extracted three times with EtOAc. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% cHex to cHex/AcOEt 50:50) and again by RP FC using acid conditions (5:95 CH ₃ CN/H ₂ O + 0.1% Eluting with HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and concentrated under vacuum. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the product N-[3-fluoro-5-(4-methyl-2-phenylpiperazine-1). -carbonyl)-6-pyrrolidin-1-ylpyridin-2-yl]cyclopropanecarboxamide was provided.

Yield: 6 mg

1H NMR (500 MHz, DMSO-d6) δ ppm 10.39 - 10.07 (m, 1 H), 7.83 - 7.00 (m, 6 H), 5.84 - 4.74 (m, 1 H), 4.56 - 2.60 (m, 8 H) ), 2.47 - 1.80 (m, 5 H), 2.03 - 1.47 (m, 5 H), 0.91 - 0.63 (m, 4 H); LC-MS: m/z 452.23 (MH+).

Scheme 25

Step 1

Compounds of formula II can be prepared by reacting a compound of formula I (see Scheme 3 It can be obtained by the Ullmann reaction between a suitable commercially available pyrazole (synthesized as follows) and a suitable commercially available pyrazole. The reaction takes approximately 12 hours to complete.

Manufactured by: N-[3-[3-(difluoromethyl)pyrazol-1-yl]-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropane Carboxamide

Example 116

N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.240 mmol), tripotassium phosphate (107.03 mg, 0.500 mmol) and 3-(difluoromethyl)-1H-pyrazole (33.55 mg, 0.280 mmol) in a mixture of copper(I) iodide (2.27 mg, 0.010 mmol) and N,N'-dimethyl. Cyclohexane-1,2-diamine (3.37 mg, 0.020 mmol) was added. The reaction was degassed with 5 cycles of N ₂ /vacuum and stirred at 120° C. overnight. The next day the reaction mixture was cooled to RT, diluted with EtOAc, and filtered through a pad of Celite. The organic layer was evaporated under reduced pressure and purified by RP FC using acid conditions (5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 40:60 CH ₃ CN/H ₂ O + 0.1% eluted with HCOOH) product of the formula N-[3-[3-(difluoromethyl)pyrazol-1-yl]-4-(1,1-dioxo-1,4-thiazinan-4- Carbonyl)phenyl]cyclopropanecarboxamide was provided.

Yield: 3.4 mg

1H NMR (400 MHz, MeOD) δ 8.11 (d, 1H), 8.05 (d, 1H), 7.61 (dd, 1H), 7.45 (d, 1H), 7.01 - 6.67 (m, 2H), 4.49 (d, 1H), 3.97 (d, 1H), 3.78 (dd, 2H), 3.45 (d, 2H), 3.25 - 3.14 (m, 2H), 3.00 (d, 1H), 1.79 (tt, 1H), 1.10 - 0.86 (m, 4H); LC-MS: 439.11 (MH+).

Manufactured by: N-[3-(3-cyanopyrazol-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 117

The synthesis of the title compound was carried out using the compound N-[3-[3-(difluoromethyl)pyrazol-1-yl]-4-(1,1-dioxo-1,4-thiazinin)- of Example 116. It was performed similarly to the synthesis of 4-carbonyl)phenyl]cyclopropanecarboxamide, where 1H-pyrazole-3-carbonitrile was used instead of 3-(difluoromethyl)-1H-pyrazole. The title compound was obtained in a yield of 4% (6 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1 H), 8.41 (d, 1 H), 8.05 (d, 1 H), 7.67 (dd, 1 H), 7.55 (d, 1 H) ), 7.24 (d, 1 H), 4.05 - 3.51 (m, 4 H), 3.43 - 2.90 (m, 4 H), 1.88 - 1.70 (m, 1 H), 0.92 - 0.72 (m, 4 H); LC-MS: m/z 414.18 (MH+).

Manufactured by: N-[3-(3-tert-butylpyrazol-1-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 118

The synthesis of the title compound was carried out using the compound N-[3-[3-(difluoromethyl)pyrazol-1-yl]-4-(1,1-dioxo-1,4-thiazinin)- of Example 116. It was performed similarly to the synthesis of 4-carbonyl)phenyl]cyclopropanecarboxamide, except that 3-tert-butyl-1H-pyrazole was used instead of 3-(difluoromethyl)-1H-pyrazole. The title compound was obtained in a yield of 15% (9 mg).

1H NMR (400 MHz, DMSO) δ 10.53 (s, 1H), 7.88 (dd, 2H), 7.59 (dd, 1H), 7.44 (d, 1H), 6.42 (d, 1H), 4.13 (s, 1H) , 3.75 (t, 1H), 3.61 (dd, 1H), 3.36 (s, 1H), 3.19 -3.09 (m, 1H), 2.99 (dd, 1H), 2.52 (d, 2H), 1.80 (p, 1H) ), 1.26 (s, 9H), 0.83 (d, 4H); LC-MS: m/z 445.16 (MH+).

Manufactured by: N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

Example 119

The synthesis of the title compound was carried out using the compound N-[3-[3-(difluoromethyl)pyrazol-1-yl]-4-(1,1-dioxo-1,4-thiazinin)- of Example 116. The synthesis of 4-carbonyl)phenyl]cyclopropanecarboxamide was carried out similarly, here N-[3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)phenyl] Cyclopropanecarboxamide and 3-(trifluoromethyl)pyrazole were each reacted with N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl] Cyclopropanecarboxamide and 3-(difluoromethyl)-1H-pyrazole were used instead. The title compound was obtained in a yield of 44% (60 mg).

1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.33 (dd, 1H), 8.01 (d, 1H), 7.66 (dd, 1H), 7.44 (d, 1H), 7.00 (d, 1H) , 3.98 - 3.82 (m, 1H), 3.38 - 3.31 (m, 3H), 2.17 - 1.63 (m, 5H), 0.89 - 0.80 (d, 4H); LC-MS: m/z 443.14 (MH+).

Scheme 26

Step 1

The compounds of formula II are reacted in the presence of a suitable precatalyst, for example XPhos Pd G2, a suitable base, for example K ₃ PO ₄ in a suitable solvent mixture, for example 1,2-dimethoxyethane/water, typically at 90° C. Compounds of formula I and suitable heterocyclic boronic acid esters, such as 1-(propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyra It can be obtained through Suzuki coupling between sols (commercially available from Enamine). The reaction takes approximately 3 hours to complete.

Step 2

Compounds of formula III can be reacted with the nitrile reaction of compounds of formula II using ethanimidamide hydrochloride in the presence of a suitable catalyst, for example CuBr, a suitable base, for example Cs ₂ CO ₃ , in a suitable solvent such as DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes approximately 6 hours to complete.

Step 3

Compounds of formula IV can be obtained from compounds of formula III by hydrolysis with LiOH in a suitable solvent mixture such as MeOH/THF/H ₂ O, typically at 50°C. The reaction takes approximately 12 hours to complete.

Step 4

Compounds of formula (V) can be obtained from compounds of formula (IV) by coupling with a suitable amine, for example 4-piperidinecarbonitrile, in the presence of a suitable coupling reagent, for example HATU and an organic base, for example DIPEA. . The reaction is typically carried out at room temperature in a suitable solvent such as DMF. The reaction takes approximately 12 hours to complete.

Scheme 26, Preparation of Cpd (II) : Methyl 4-cyano-2-(1-isopropylpyrazol-3-yl)benzoate

X-phos aminobiphenyl palladium chloride precatalyst (98.2 mg, 0.120 mmol), tripotassium phosphate (795.85 mg, 3.75 mmol), 1-( Propan-2-yl)-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (236.07 mg, 1 mmol) and methyl 2-bromo-4-cya The mixture of norbenzoate (300.0 mg, 1.25 mmol) was degassed using the Shlenk line technique and then stirred at 90° C. for 3 h. After this time the reaction was cooled. Water was added to the mixture and the aqueous phase was extracted three times with AcOEt. The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by FC on silica gel (eluted with 100% cHex to 40:60 cHex/AcOEt) to give the product methyl 4-cyano-2-(1-isopropylpyrazol-3-yl)benzoate. provided.

Yield: 250 mg

1H NMR (400 MHz, DMSO-d6) δ 8.00 - 7.96 (m, 2H), 7.93 - 7.89 (m, 1H), 7.86 (d, 1H), 6.67 (d, 1H), 4.52 (p, 1H), 3.76 (s, 3H), 1.42 (d, 6H); LC-MS: m/z 270.24 (MH+).

Scheme 26, Preparation of Cpd (III) : Methyl 2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate

Methyl 4-cyano-2-(1-isopropylpyrazol-3-yl)benzoate (250.0 mg, 0.930 mmol), disesium carbonate (907.41 mg, 2.78 mmol), ethanimide in DMSO (10 mL) A mixture of amide hydrochloride (131.65 mg, 1.39 mmol) and CuBr (6.66 mg, 0.050 mmol) was stirred at 120 °C for 6 h. After this time, the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% DCM to 95:5 DCM/MeOH) to give the product methyl 2-(1-isopropylpyrazol-3-yl)-4-(5- Methyl-4H-1,2,4-triazol-3-yl)benzoate was provided.

Yield: 118 mg

1H NMR (400 MHz, DMSO-d6) δ 13.81 (s, 1H), 8.16 - 7.99 (m, 2H), 7.88 - 7.63 (m, 2H), 6.52 (d, 1H), 4.51 (p, 1H), 3.74 (s, 3H), 2.40 (s, 3H), 1.43 (d, 6H); LC-MS: m/z 326.4 (MH+).

Scheme 26, Cpd (IV) preparation: 2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid

Methyl 2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl) in methanol (0.400 mL)/THF (2 mL) To a solution of benzoate (118.0 mg, 0.360 mmol) was added a solution of lithium hydroxide (13.03 mg, 0.540 mmol) in water (0.400 mL). The reaction was stirred at 50° C. overnight. The next day the reaction was cooled to RT, acidified with 3N HCl and concentrated in vacuo. The residue was purified by reverse-phase FC using acid conditions (eluting with 5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 50:50 CH ₃ CN/H ₂ O + 0.1% HCOOH) and purified as above. This gave the product of the formula 2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid.

Yield: 80 mg

1H NMR (400 MHz, DMSO-d6) δ 13.74 (bs, 1H), 12.89 (bs, 1H), 8.15 -7.99 (m, 2H), 7.85 -7.63 (m, 2H), 6.48 (s, 1H), 4.52 (p, 1H), 2.43 (s, 3H), 1.46 (d, 6H); LC-MS: m/z 312.35 (MH+).

Scheme 26, Preparation of Cpd (V) : 1-[2-(1-isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl ]Piperidine-4-carbonitrile

Example 120

2-(1-Isopropylpyrazol-3-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (33.3 mg, 0.110 mmol) in DMF (0.491 mL) ) N,N-diisopropylethylamine (0.06 mL, 0.320 mmol) and HATU (52.87 mg, 0.140 mmol) were added to the solution. The reaction was stirred at RT for 15 min. After this time 4-piperidinecarbonitrile (11.78 mg, 0.110 mmol) was added and the reaction was stirred at RT overnight. After this time, the reaction was diluted with saturated aqueous NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% DCM to 100% EtOAc) and again by RP FC using acid conditions (5:95 CH ₃ CN/H ₂ O + 0.1% HCOOH to 20% :80 CH ₃ CN/H ₂ O + 0.1% HCOOH). Pure fractions were collected and evaporated. The residue was taken up with saturated NaHCO ₃ solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the product of the formula 1-[2-(1-isopropylpyrazol-3-yl)-4-(5 -methyl-4H-1,2,4-triazol-3-yl)benzoyl]piperidine-4-carbonitrile was provided.

Yield: 19 mg.

1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (dt, 1 H), 7.77 - 7.87 (m, 3 H), 6.49 (dd, 1 H), 4.53 (e, 1 H), 3.88 - 4.10 ( m, 1 H), 3.35 - 3.44 (m, 1 H), 3.00 - 3.11 (m, 2 H), 2.89 (dt, 1 H), 2.37 - 2.43 (m, 3 H), 1.87 - 1.98 (m, 1 H), 1.51 - 1.82 (m, 3 H), 1.41 - 1.50 (m, 6 H), 0.98 - 1.10 (m, 1 H); LC-MS: m/z 404.37 (MH+).

Scheme 27

Step 1

Compounds of formula II can be prepared by reacting a compound of formula I (see Scheme 4 It can be obtained by the Ullman reaction between a suitable commercially available pyrazole (synthesized as follows) and a suitable commercially available pyrazole. The reaction takes approximately 2 days to complete.

Step 2

Compounds of formula III can be reacted with the nitrile reaction of compounds of formula II using ethanimidamide hydrochloride in the presence of a suitable catalyst, for example CuBr, a suitable base, for example Cs ₂ CO ₃ , in a suitable solvent such as DMSO, typically at 120° C. It can be obtained by cyclization. The reaction takes approximately 2 hours to complete.

Scheme 27, Cpd (II)*a Preparation: 3-(3-cyclopropylpyrazol-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

In a vial, 3-bromo-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (200.0 mg, 0.550 mmol), tripotassium phosphate (250.36 mg, 1.16 mmol), 3- Cyclopropyl-1H-pyrazole (71.86 mg, 0.660 mmol) was suspended in dry 1,4-dioxane (3.038 mL). The resulting suspension was degassed by bubbling N ₂ for 15 min and then added to copper(I) iodide (5.3 mg, 0.030 mmol) and N,N'-dimethylcyclohexane-1,2-diamine (7.88 mg). , 0.060 mmol) was added under nitrogen flux and degassed again using the Schlenk line technique. The vial was sealed and stirred at 120 °C for 2 days. The next day the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the product of the formula 3-(3-cyclopropylpyrazol-1-yl)-4-[4-(trifluor Romethyl)piperidine-1-carbonyl]benzonitrile was provided, which was used in the next step without further purification.

Yield: 180 mg

LC-MS: m/z 389.20 (MH+).

Scheme 27, Cpd (II)*b Preparation: 3-(3-tert-butylpyrazol-1-yl)-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

The synthesis of the title compound was performed similarly to the synthesis of compound 3-(3-cyclopropylpyrazol-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile. , where 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile and 3-tert-butyl-1H-pyrazole are combined with 3-bromo-4-[4- (trifluoromethyl)piperidine-1-carbonyl]benzonitrile and 3-cyclopropyl-1H-pyrazole were used instead. The title compound was obtained in quantitative yield (150 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 2H), 7.90 - 7.83 (m, 1H), 7.70 - 7.63 (m, 1H), 6.51 - 6.45 (m, 1H), 4.02 - 3.94 ( m, 1H), 3.42 - 3.32 (m, 1H), 3.08 - 2.95 (m, 1H), 2.20 - 1.85 (m, 3H), 1.72 - 1.55 (m, H), 1.25 (s, 9H); LC-MS: m/z 373.36 (MH+).

Scheme 27, Preparation of Cpd (III)*a : [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl ]-[4-(trifluoromethyl)piperidin-1-yl]methanone

Example 121

3-(3-cyclopropylpyrazol-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (180.0 mg, 0.460 mmol) in DMSO (5.143 mL) , disesium carbonate (453.01 mg, 1.39 mmol), etanimidamide hydrochloride (65.72 mg, 0.700 mmol), and CuBr (3.32 mg, 0.020 mmol) were stirred at 120 °C for 2 h. After this time, the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 9:1) to obtain the product of the formula [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl -4H-1,2,4-triazol-3-yl)phenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone was provided.

Yield: 16 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.86 (bs, 1H), 8.12 - 8.09 (m, 1H), 8.06 - 7.87 (m, 2H), 7.51 - 7.39 (m, 1H), 6.30 - 6.15 (m, 1H), 4.66 - 4.44 (m, 1H), 3.47 - 3.36 (m, 1H), 3.04 - 2.91 (m, 1H), 2.78 - 2.57 (m, 2H), 2.41 (s, 3H), 2.00 - 1.62 (m, 3H), 1.54 - 1.06 (m, 2H), 0.97 - 0.84 (m, 2H), 0.79 - 0.56 (m, 2H); LC-MS: m/z 445.2 (MH+).

Preparation: [2-(3-tert-butylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-di Fluoropiperidin-1-yl)methanone

Example 122

The synthesis of the title compound was carried out using the compound of Example 121 [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl] The synthesis of -[4-(trifluoromethyl)piperidin-1-yl]methanone was carried out similarly, herein 3-(3-tert-butylpyrazol-1-yl)-4-(4, 4-difluoropiperidine-1-carbonyl)benzonitrile is replaced with 3-(3-cyclopropylpyrazol-1-yl)-4-[4-(trifluoromethyl)piperidine-1-car Bornyl] was used instead of benzonitrile. The title compound was obtained in a yield of 35% (50 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.08 (d, 1H), 7.99 - 7.89 (m, 2H), 7.41 (d, 1H), 6.43 (d, 1H), 3.66 (q, 2H), 3.14 - 3.02 (m, 1H), 2.30 (s, 3H), 2.12 - 1.99 (m, 1H), 1.94 - 1.77 (m, 2H), 1.43 - 1.21 (m, 11H); LC-MS: m/z 429.26 (MH+).

Scheme 28

Step 1

Compounds of formula (II) can be prepared according to formula (I) in the presence of a suitable catalyst, for example CuI, a suitable ligand, for example trans- N,N' -dimethylcyclohexane-1,2-diamine and a suitable base, for example K ₂ CO ₃ It can be obtained by the reaction between a compound (synthesized according to Scheme 3) and 2-pyrrolidinone. The reaction is typically carried out at 120° C. in a suitable solvent such as 1,4-dioxane. The reaction takes approximately 12 hours to complete. Alternatively, compounds of formula II can be synthesized according to Scheme 3 in the presence of a suitable catalyst, such as Pd ₂ (dba) ₃ , a suitable ligand, such as XPhos, and a suitable base, such as Cs ₂ CO ₃ . It can be obtained by the Buchwald reaction between and 2-pyrrolidinone. The reaction is typically carried out at 110° C. in a suitable solvent such as 1,4-dioxane. The reaction takes approximately 12 hours to complete.

Manufactured by: N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxamide

Example 123

N-[3-bromo-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl]cyclopropanecarboxamide (200.0) in 1,4-dioxane (3 mL) mg, 0.500 mmol), potassium carbonate (137.77 mg, 1 mmol) and 2-pyrrolidinone (0.05 mL, 0.600 mmol) in N,N'-dimethylcyclohexane-1,2-diamine (0.02 mL, 0.100 mmol). mmol) and copper(I) iodide (9.49 mg, 0.050 mmol) were added. The mixture was degassed with N ₂ for 10 min and then heated to 120° C. overnight. The next day the reaction was diluted with AcOEt and washed with brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluted with 100% DCM to DCM/MeOH 9:1) to obtain the product N-[4-(1,1-dioxo-1,4-thiazinan-4-car) of the formula above. Bornyl)-3-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxamide was provided.

Yield: 54 mg

1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.67 (d, 1H), 7.47 (dd, 1H), 7.38 (d, 1H), 4.21 - 3.56 (m, 6H), 3.39 ( s, 1H), 3.21 (t, 3H), 2.45 - 2.31 (m, 1H), 2.19 - 1.63 (m, 4H), 0.83 (d, 4H); LC-MS: m/z 406.2 (MH+)

Manufactured by: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxamide

Example 124

N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (200.0 mg, 0.450 mmol) in 1,4-dioxane (1.5 mL) ), 2-pyrrolidinone (57.71 mg, 0.680 mmol) and (5-diphenylphosphino-9,9-dimethyl-4-xanthenyl)-diphenylphosphine (130.81 mg, 0.230 mmol) Disesium carbonate (294.63 mg, 0.900 mmol) and (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone palladium (62.1 mg, 0.070 mmol) were added. The mixture was degassed with N ₂ for 10 min and then heated to 110° C. overnight. The next day the reaction was diluted with AcOEt and washed with brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with cHex/AcOEt 80:20 to cHex/AcOEt 40:60) and again by RP FC using basic conditions (CH ₃ CN/H ₂ O at 5:95). + 0.1% NH ₄ OH to 30:70 eluting with CH ₃ CN/H ₂ O + 0.1% NH ₄ OH) product of the formula (N-[4-(4-methyl-2-phenylpiperazine- 1-Carbonyl)-3-(2-oxopyrrolidin-1-yl)phenyl]cyclopropanecarboxamide was provided.

Yield: 66 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 7.73 - 7.62 (m, 1H), 7.59 - 7.40 (m, 2H), 7.41 - 7.21 (m, 5H), 5.86 - 4.34 (m, 1H), 3.82 - 3.35 (m, 4H), 2.89 (d, 2H), 2.39 - 1.67 (m, 10H), 0.86 - 0.79 (m, 4H); LC-MS: m/z 447.25 (MH+).

Scheme 29

Step 1

Compounds of formula II can be obtained from commercially available SnAP reagents (compound I) by reaction with a suitable aromatic aldehyde followed by Cu-mediated cyclization. The reaction is typically carried out at RT in a suitable solvent, such as DCM. The reaction takes approximately 12 hours to complete.

Scheme 29, Cpd (II)*a Manufactured by: tert-Butyl 3-(3-methylphenyl)piperazine-1-carboxylate

To a solution of SnAP Pip reagent (771.19 mg, 1.66 mmol) in dry DCM (8.3 mL) was added 3-methylbenzaldehyde (200.0 mg, 1.66 mmol) and previously activated MS 3A at room temperature. The reaction was stirred at rt overnight, then filtered through a short bed of Celite and washed with DCM. The filtrate was concentrated under reduced pressure to provide the imine. Separately, 2,6-lutidine (178.36 mg, 1.66 mmol) was added in one portion to a suspension of dry copper(II) trifluoromethanesulfonate (602.05 mg, 1.66 mmol) in anhydrous HFIP (6.6 mL, 1.66 mmol). , stirred at RT for 1 h, during which time a homogeneous suspension was formed. A solution of the imine in dry DCM (26 mL) was added in one portion and the resulting mixture was stirred at rt overnight. After 18 h, the reaction was quenched at rt with 15 mL of 10% aqueous NH4OH solution and stirred vigorously for 15 min. The layers were separated and the aqueous layer was extracted with DCM x3. The combined organic layers were washed with H ₂ O, brine, dried using a phase separator and concentrated. The crude material was purified by RP FC using basic conditions (5:95 CH ₃ CN/H ₂ O + 0.1% NH ₄ OH to 30:70 CH ₃ CN/H ₂ O + 0.1% NH ₄ Elution with OH) gave the product of the above formula: tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate.

Yield: 336 mg

1H NMR (400 MHz, DMSO-d6) δ ppm 7.25 - 7.15 (m, 3H), 7.08 (d, 1H), 3.92 - 3.74 (m, 2H), 3.51 (dd, 1 H), 2.99 - 2.57 (m) , 5H), 2.29 (s, 3H), 1.40 (s, 9H); LC-MS: m/z 277.46 (MH+).

Scheme 29, Cpd (II)*b Preparation: tert-Butyl 3-(3-chloro-5-methylphenyl)piperazine-1-carboxylate

The synthesis of the title compound was performed similarly to the synthesis of the compound tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate, except that 3-chloro-5-methylbenzaldehyde was used instead of 3-methylbenzaldehyde. The title compound was obtained in a yield of 69% (276 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.25 (s, 1H), 7.22 - 7.14 (m, 2H), 3.88 - 3.74 (m, 2H), 3.54 (dt, 1H), 2.97 - 2.88 (m, 1H), 2.87 - 2.76 (m, 2H), 2.69 - 2.55 (m, 2H), 2.30 (s, 3H), 1.40 (s, 9H); LC-MS: m/z 311.14 (MH+).

Scheme 29, Cpd (II)*c Preparation: tert-butyl 3-(4-methylphenyl)piperazine-1-carboxylate

The synthesis of the title compound was performed similarly to the synthesis of the compound tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate, except that 4-methylbenzaldehyde was used instead of 3-methylbenzaldehyde. The title compound was obtained in a yield of 66% (306 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.32 - 7.10 (m, 4H), 3.92 - 3.74 (m, 2H), 3.56 - 3.47 (m, 1H), 2.99 - 2.58 (m, 5 H), 2.28 (s, 3H), 1.40 (s, 9H); LC-MS: m/z 277.71 (MH+).

Scheme 29, Cpd (II)*d Preparation: tert-butyl 3-[2-(trifluoromethyl)phenyl]piperazine-1-carboxylate

The synthesis of the title compound was performed similarly to the synthesis of the compound tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate, where 2-(trifluoromethyl)benzaldehyde was used instead of 3-methylbenzaldehyde. . The title compound was obtained in a yield of 70% (200 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, 1H), 7.76 - 7.64 (m, 2H), 7.49 (t, 1H), 3.96 - 3.81 (m, 3H), 2.96 (d, 2H) , 2.89 - 2.74 (m, 1H), 2.74 - 2.59 (m, 2H), 1.38 (s, 9H); LC-MS: m/z 275.12 (MH+).

Scheme 29, Cpd (II)*e Preparation: tert-butyl 3-(3-cyanophenyl)piperazine-1-carboxylate

The synthesis of the title compound was performed similarly to the synthesis of the compound tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate, where 3-formylbenzonitrile was used instead of 3-methylbenzaldehyde. The title compound was obtained in a yield of 51% (168 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (s, 1 H), 7.81 - 7.71 (m, 2 H), 7.59 - 7.53 (m, 1 H), 3.92 - 3.75 (m, 2 H), 3.70 - 3.61 (m, 1 H), 2.98 - 2.78 (m, 3 H), 2.70 - 2.57 (m, 2 H), 1.40 (s, 9 H); LC-MS: m/z 288.23 (MH+).

Scheme 29, Cpd (II)*f Preparation: tert-Butyl 3-(4,5-dimethyl-1,3-thiazol-2-yl)piperazine-1-carboxylate

The synthesis of the title compound was carried out similarly to the synthesis of the compound tert-butyl 3-(3-methylphenyl)piperazine-1-carboxylate, where 4,5-dimethylthiazole-2-carboxaldehyde was reacted with 3-methyl It was used instead of benzaldehyde. The title compound was obtained in a yield of 64% (203 mg).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.99 (s, 1H), 3.86 - 3.75 (m, 1H), 3.71 (d, 1H), 3.10 - 3.05 (m, 1H), 2.98 - 2.80 (m) , 2H), 2.71 - 2.62 (m, 2H), 2.30 (s, 3H), 2.23 (s, 3H), 1.41 (s, 9H); LC-MS: m/z 297.61 (MH+).

Scheme 30

Step 1

Compounds of formula II can be prepared by coupling a compound of formula I (commercially available from Zantec) with a suitable amine, such as 1-methyl-3-phenyl, in the presence of a suitable coupling agent, such as HATU, a suitable organic base, such as DIPEA. It can be obtained by a coupling reaction between piperazines. The reaction is typically carried out at RT in a suitable solvent, such as DMF. The reaction takes approximately 2 hours to complete.

Step 2

Compounds of formula III can be obtained from compounds of formula II by SNAr substitution with 3-(propan-2-yl)pyrrolidine, typically at 120° C., in a suitable aprotic solvent, such as DMSO. The reaction takes approximately 2 days to complete.

Scheme 30, Preparation of Cpd (II) : 3-fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)benzonitrile

of 4-cyano-2-fluorobenzoic acid (500.0 mg, 3.03 mmol), N,N-diisopropylethylamine (2.64 mL, 15.14 mmol) and HATU (1727.06 mg, 4.54 mmol) in DMF (15.14 mL) The solution was stirred at RT for 15 minutes. 1-Methyl-3-phenylpiperazine (640.48 mg, 3.63 mmol) was then added and the reaction was stirred at RT for 2 hours. Saturated NaHCO ₃ solution was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected, washed with brine, the remaining water was removed with Na ₂ SO ₄ and the solvent was filtered and evaporated under reduced pressure. The crude material was purified by FC on silica gel (eluting with 100% cHex to cHex/AcOEt 1:1) to give the product 3-fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl). ) Benzonitrile was provided.

Yield: 880 mg

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.03 (d, 1H), 7.89 - 7.63 (m, 2H), 7.54 - 7.22 (m, 5H), 5.91 - 4.26 (m, 1H), 3.59 - 3.43 (m, 1H), 3.24 - 2.60 (m, 3H), 2.41 - 2.28 (m, 1H), 2.20 (s, 3H), 2.07 - 1.82 (m, 1H); LC-MS: m/z 324.20 (MH+).

Scheme 30, Preparation of Cpd (III) : 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-propan-2-ylpyrrolidin-1-yl)benzonitrile

3-Fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)benzonitrile (300.0 mg, 0.930 mmol) and 3-(propan-2-yl)pyrroli in DMSO (8.737 mL) To a solution of Dean hydrochloride (166.62 mg, 1.11 mmol) was added N,N-diisopropylethylamine (0.4 mL, 2.32 mmol). The mixture was stirred at 120 °C for 2 days. After this time, the reaction was cooled to RT, diluted with H ₂ O and extracted with Acoet. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by FC on a NH column (eluting with 100% cHex to cHex/AcOEt 75:25) to give the product 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3- (3-Propan-2-ylpyrrolidin-1-yl)benzonitrile is provided as a mixture of diastereomers.

Yield: 95 mg

LC-MS: m/z: m/z 471.34 (MH+).

Scheme 30, Preparation of Cpd (IV) : (4-methyl-2-phenylpiperazin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2 -(3-propan-2-ylpyrrolidin-1-yl)phenyl]methanone

Example 125a, Example 125b, Example 125c, and Example 125d

4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-propan-2-ylpyrrolidin-1-yl)benzonitrile (95.0 mg, 0.230 mmol) in DMSO (3.5 mL) ), disesium carbonate (222.92 mg, 0.680 mmol), etanimidamide hydrochloride (32.34 mg, 0.340 mmol) and bromocopper (1.64 mg, 0.010 mmol) were stirred at 120°C for 6 h. After this time, the reaction was cooled to RT and H ₂ O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FC on a NH column (eluted with 100% DCM to DCM/MeOH 95:5) to obtain the product of the formula (4-methyl-2-phenylpiperazin-1-yl)-[4-(5- Methyl-4H-1,2,4-triazol-3-yl)-2-(3-propan-2-ylpyrrolidin-1-yl)phenyl]methanone was provided as a mixture of diastereomers.

Yield: 58 mg

LC-MS: m/z 473.59 (MH+)

The mixture of diastereomers was then separated into single enantiomers by chiral semipreparative HPLC.

Claims (123)

A compound of formula (IA): or a pharmaceutically acceptable salt thereof:

here:
X ₁ is



is selected from the group consisting of;
n _a is an integer selected from the group of 0, 1, and 2;
n _b is an integer selected from the group of 0, 1, 2, 3, and 4;
However, the sum n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
X ₂ is


is selected from the group of;
wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;
Y ₁ is selected from the group of C and N;
Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;
However, one or less of Y ₁ and Y ₂ is C;
n _c is an integer selected from the group of 1, 2, and 3;
n _d is an integer selected from the group of 1, 2, and 3;
However, the sum n _c + n _d is 2 or more and 6 or less;
Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;
R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;
n1 is an integer selected from the group of 0, 1, 2, and 3;
R ₂ is bonded through a carbocycle, and a carbon atom and 3, 4, 5, 6, 7, or 8 ring carbon atoms and 1, 2, 3 selected from the group of N, S, and O, or selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 4 ring heteroatoms, any of the preceding being C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C (=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl), -(CH ₂ ) _n1 -heterocyclyl (3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S , and a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system containing 1, 2, 3, or 4 ring heteroatoms selected from the group of ^is substituted with 0, 1 ^, 2, or ₃ substituents selected from the group of _{, wherein} R selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents, provided that R ₂ is at least -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl or phenyl. Not pyridinyl unless substituted once;
R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;
R ₃ occurs one or more times and is independently selected from the group:
ee) hydrogen, halogen, cyano, or OH;
ff) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
gg) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;
hh) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;
ii) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and
jj) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;
R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;
where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or heterocyclic rings having 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from the group N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ - is substituted with 0, 1, 2, or 3 substituents selected from the group of C ₃ alkyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;
R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
n ₂ is in each case an integer selected from the group 0, 1, 2, and 3. A compound of formula (IB):

here:
X ₁ is



is selected from the group of:
n _a is an integer selected from the group of 0, 1, and 2;
n _b is an integer selected from the group of 0, 1, 2, 3, and 4;
However, the sum n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
X ₂ is


is selected from the group of;
wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;
Y ₁ is selected from the group of C and N;
Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or once or exists twice;
However, one or less of Y ₁ and Y ₂ is C;
n _c is an integer selected from the group of 1, 2, and 3;
n _d is an integer selected from the group of 1, 2, and 3;
However, the sum n _c + n _d is 2 or more and 6 or less;
Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;
R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;
n1 is an integer selected from the group of 0, 1, 2, and 3;
R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl; provided that R ₂ is not pyridinyl unless substituted at least once by -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl or phenyl;
R ₂ 'is selected from the group of OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;
R ₃ occurs one or more times and is independently selected from the group:
kk) hydrogen, halogen, cyano, or OH;
ll) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
mm) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;
nn) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;
oo) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and
pp) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;
R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;
where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or heterocyclic rings having 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are selected from the group N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ - is substituted with 0, 1, 2, or 3 substituents selected from the group of C ₃ alkyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;
R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
n ₂ is in each case an integer selected from the group 0, 1, 2, and 3. A compound of formula (IC): or a pharmaceutically acceptable salt thereof:

here:
X ₁ is



is selected from the group of;
n _a is an integer selected from the group of 0, 1, and 2;
n _b is an integer selected from the group of 0, 1, 2, 3, and 4;
However, the sum n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
X ₂ is selected from the group:
;
wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;
Y ₁ is selected from the group of C and N;
Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;
However, one or less of Y ₁ and Y ₂ is C;
n _c is an integer selected from the group of 1, 2, and 3;
n _d is an integer selected from the group of 1, 2, and 3;
provided that the sum n _c + n _d is 2, 3, 5, or 6;
Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;
R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;
n1 is an integer selected from the group of 0, 1, 2, and 3;
R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -C ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl, provided that R ₂ is -(CH ₂ ) is not pyridinyl unless substituted at least once by _n1 -C ₃ -C ₆ cycloalkyl or phenyl;
R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;
R ₃ occurs one or more times and is independently selected from the group:
qq) hydrogen, halogen, cyano, or OH;
rr) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
ss) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;
tt) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;
uu) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and
vv) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;
R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl;
When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;
where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or heterocyclic rings having 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from the group N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ -C ₃ is substituted with 0, 1, 2, or 3 substituents selected from the group of alkyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;
R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from -OC ₁ -C ₃ alkyl;
n ₂ is in each case an integer selected from the group 0, 1, 2, and 3. A compound of formula (ID), or a pharmaceutically acceptable salt thereof:

here:
X ₁ is

is selected from the group of:
n _a is an integer selected from the group of 0, 1, and 2;
n _b is an integer selected from the group of 0, 1, 2, 3, and 4;
However, the sum n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
X ₂ is


is selected from the group of;
wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;
Y ₁ is selected from the group of C and N;
Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;
However, one or less of Y ₁ and Y ₂ is C;
n _c is an integer selected from the group of 1, 2, and 3;
n _d is an integer selected from the group of 1, 2, and 3;
However, the sum n _c + n _d is 2 or more and 6 or less;
Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;
R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;
n1 is an integer selected from the group of 0, 1, 2, and 3;
R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and C ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from the group of -OC ₁ -C ₃ alkyl, provided that R ₂ is -(CH ₂ ) _n1 is not pyridinyl unless substituted at least once by -C ₃ -C ₆ cycloalkyl or phenyl;
R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;
R ₃ occurs one or more times and is independently selected from the group:
ww) hydrogen, halogen, cyano, or OH;
xx) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
yy) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;
zz) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;
aaa) a 5- or 6-membered heterocyclic ring containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, - the 5- or 6-membered heterocyclic ring is OH, halogen , benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3 selected from the group of halogen and OH. , further substituted with 4 or 5 substituents -; and
bbb) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;
R ₄ is present once or twice, H, halogen, oxo, C ₁ -C ₆ alkyl, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , -N( ^R _{​ ​ ​} , 3, or 4 ring atoms are independently selected from the group of N, O, and S, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
When Y ₂ is carbon, R ₄ may also be -OC ₁ -C ₆ alkyl or two R ₄ may form a spirocyclic carbocycle or spirocyclic heterocycle;
where R ₄ represents C ₁ -C ₆ alkyl, -C(=O)-OC ₁ -C ₆ alkyl, and -OC ₁ -C ₆ alkyl groups, and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. and -O-(CH ₂ ) _n2 -C ₃ -C ₆ The rings of the cycloalkyl, phenyl, and benzyl groups are each independently halogen, CF ₃ , OH, 3, 4, 5, 6, 7, 8, 9, or a heterocyclic ring having 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from the group of N, O, and S, substituted or unsubstituted phenyl, and -OC ₁ - is substituted with 0, 1, 2, or 3 substituents selected from the group of C ₃ alkyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , -C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;
R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl substituted with 0, 1, 2, or 3 substituents selected from -OC ₁ -C ₃ alkyl;
n ₂ is in each case an integer selected from the group 0, 1, 2, and 3. A compound of formula (IE), or a pharmaceutically acceptable salt thereof:

here:
X ₁ is



is selected from the group of;
n _a is an integer selected from the group of 0, 1, and 2;
n _b is an integer selected from the group of 0, 1, 2, 3, and 4;
However, the sum n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ taken together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
X ₂ is
is selected from the group of;
wavy line represents a bond at each occurrence, through which each X ₁ and X ₂ moiety is joined;
Y ₁ is selected from the group of C and N;
Y ₂ is selected from the group of C, N, S, and O, provided that when Y ₂ is O, R ₄ is not present, and provided that when Y ₂ is S, R ₄ is not present or is present once or exists twice;
However, one or less of Y ₁ and Y ₂ is C;
n _c is an integer selected from the group of 1, 2, and 3;
n _d is an integer selected from the group of 1, 2, and 3;
However, the sum n _c + n _d is 2 or more and 6 or less;
Z ₁ , Z ₂ , and Z ₃ are each independently selected from the group of C and N, provided that Z ₁ , Z ₂ , and Z ₃ are C when bonded to R ₂ or non-hydrogen R ₂ ′;
R ₁ is selected from the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl, and benzyl, wherein a C ₁ -C ₆ alkyl group and -(CH ₂ ) _n1 -C ₃ -C ₆ rings of cycloalkyl, phenyl, and benzyl groups are 0, 1, 2, or selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. is substituted with 3 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with;
n1 is an integer selected from the group of 0, 1, 2, and 3;
R ₂ is phenyl, pyridinyl bonded through a carbon atom, and bonded through a nitrogen heteroatom and is selected from the group of 3, 4, 5, 6, 7, or 8 ring carbon atoms and N, S, and O. selected from the group of monocyclic heterocyclic rings or bicyclic or spirocyclic heterocyclic ring systems containing 0, 1, 2, 3, or 4 additional ring heteroatoms of choice, and any of the foregoing. One of them is C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen, oxo, cyano, -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, -C(=O)OH, -C(=O)-OC ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C( ^{= O )} _{-NR ​ ​ ​ ​} monocyclic heterocyclic ring or bicyclic or spirocyclic ring containing 7 or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O containing a heterocyclic ring system), and phenyl; provided that R ₂ is not pyridinyl unless substituted at least once by -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl or phenyl;
R ₂ 'is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ ;
R ₃ occurs one or more times and is independently selected from the group:
ccc) hydrogen, halogen, cyano, or OH;
ddd) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
eee) C ₁ -C ₆ alkyl or -OC ₁ -C ₆ alkyl substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, CF ₃ , and OH;
fff) phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, -phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ Each ring of the cycloalkyl group is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, cyano, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is halogen, -CF ₃ , and further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of OH -;
ggg) a 5- or 6-membered heterocyclic ring containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, - the 5- or 6-membered heterocyclic ring is OH, halogen, benzyl, and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group is 0, 1, 2, 3, halogen, or OH, further substituted with 4 or 5 substituents -; and
hhh) When R ₃ is present two or more times, a bridge is formed between carbon atoms, wherein the atoms of the bridge comprise 1, 2, or 3 atoms independently selected from the group of carbon, N, O, and S. box;
R ₄ occurs once or twice and is halogen;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl group of R ₅ is 0, 1 selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. , further substituted with 2, 3, 4 or 5 substituents, wherein R ^x and R ^y are each independently selected from the group of H, and halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. , C ₁ -C ₆ alkyl substituted with 1, 2, or 3 substituents;
R ₆ is H, C ₁ -C ₆ alkyl, has 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, of which 1, 2, 3, or 4 ring atoms are N, O, and a heterocyclic ring selected from the group of S, phenyl, and benzyl, wherein the C ₁ -C ₆ alkyl group of R ₆ is selected from the group of halogen, -CF ₃ , -NR ^x R ^y , and OH. is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group, and the rings and heterocyclic rings of the phenyl and benzyl groups of R ₆ are C ₁ -C ₆ alkyl, -OC ₁ -C ₆ is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of alkyl, halogen, -CF ₃ , and OH, wherein R ^x and R ^y are each independently H, and halogen, OH, is selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2, or 3 substituents selected from CF ₃ , and -OC ₁ -C ₃ alkyl;
n ₂ is in each case an integer selected from the group 0, 1, 2, and 3,
However, the compound is N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide; (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[3-(trifluoro methyl)pyrazol-1-yl]phenyl]methanone; [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoropy peridin-1-yl)methanone; (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-(3-propane-2- Ilpyrazol-1-yl)phenyl]methanone; or not N-[4-(4-fluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The compound according to any one of claims 1 to 5, wherein R ₄ is not unsubstituted benzyl. Paragraph 1: Error! Reference source not found. The compound according to any one of the preceding claims, wherein R ₄ is not unsubstituted pyridinyl. The compound according to any one of claims 1 to 5, wherein R ₄ is not substituted or unsubstituted phenyl. Paragraph 1: Error! Reference source not found. The compound according to any one of the preceding claims, wherein R ₃ is not H. The compound according to any one of claims 1 to 9, having the formula:
(I')
where X ₁ , X ₂ , and R ₂ are as defined in any one of claims 1 to 9;
where Z ₁ , Z ₂ , and Z ₃ are C;
where R ₂ ^' is R ₂ ^' _a and is selected from the group of OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ . The compound according to any one of claims 1 to 9, having the formula:
(I")
where X ₁ , X ₂ , and R ₂ are as defined in any one of claims 1 to 9;
where Z ₁ , Z ₂ , and Z ₃ are C;
where R ₂ ^' is R ₂ ^' _b and is selected from the group of OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ . The compound according to any one of claims 1 to 9, having the formula:
(I"')
where X ₁ , X ₂ , and R ₂ are as defined in any one of claims 1 to 9;
where Z ₁ , Z ₂ , and Z ₃ are C;
where R ₂ ^' is R ₂ ^' _c and is selected from the group of hydrogen, OH, halogen, C ₁ -C ₆ alkyl, and -CF ₃ . The compound according to any one of claims 1, 2 and 4, having the formula:

_{wherein ​ ​ ​ ​ ​ ​ ​ ​ ​} . The compound according to any one of claims 1, 2 and 4, having the formula:

_{wherein ​ ​ ​ ​ ​ ​} The compound according to any one of claims 1, 2 and 4, having the formula:

_{wherein ​ ​ ​ ​ ​ ​} The compound according to any one of claims 1, 2 and 4, having the formula:

_{wherein ​ ​ ​ ​ ​ ​} The compound according to any one of claims 1, 2 and 4, having the formula:

_{where ​ ​ ​ ​ ​ ​ ​} and R ₆ is as defined in paragraph 1, paragraph 2, or paragraph 4. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, having the formula:
(I-6)
where X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', and R ₄ is as defined in any one of claims 1 to 4. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, having the formula:
(I-7);
where X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', and R ₄ is as defined in any one of claims 1 to 5. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R _a , R ₁ , R ₂ , R ₂ ', R ₃ , and R ₄ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ are as defined in clause 1 or clause 2. The compound according to claim 11 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', _R5 , and R ₆ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R _a , R ₁ , R ₂ , R ₂ ', R ₃ , and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', R ₅ , and R ₆ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ are as defined in clause 1 or clause 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', R ₅ , and R ₆ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R _a , R ₁ , R ₂ , R ₂ ', R ₃ , and R ₄ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ are as defined in clause 1 or clause 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₄ are as defined in clause 1 or clause 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', and R ₃ are as defined in clause 1 or clause 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₂ , R ₂ ', R ₅ , and R ₆ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R ₁ , R ₂ , R ₂ ', R ₃ , and R ₄ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

Here, Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₃ are as defined in clause 1 or clause 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R ₁ , R ₂ , R ₂ ', R ₃ , and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₄ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', and R ₃ is as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₁ , R ₂ , R ₂ ', R ₅ , and R ₆ are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R ₂ , R ₂ ', R ₃ , R ₄ , n _a , and n _b are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', R ₃ , n _a , and n _b are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', R ₄ , n _a , and n _b are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:

where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', R ₃ , n _a , and n _b are as defined in paragraph 1 or 2. The compound according to claim 1 or 2, having the formula:
and
where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', R ₅ , and R ₆ are as defined in paragraph 1 or 2. The compound according to any one of claims 1, 2, 3, and 5, having the formula:
(I-ii)
where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', and X ₂ is as defined in paragraph 1, paragraph 2, paragraph 3, or paragraph 5. The compound according to any one of claims 1, 2, 3, and 5, having the formula:
(I-jj);
where Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₂ ', and X ₂ is as defined in paragraph 1, paragraph 2, paragraph 3, or paragraph 5. The compound according to any one of claims 1, 2, 3, and 5, having the formula:
(I-kk)
where Z ₁ , Z ₂ , Z ₃ , R ₂ ', and X ₂ are as defined in claim 1, 2, 3, or 5;
R ₇ is -OH; halogen; -C ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -heterocycle (3, 4, 5, 6, 7, or 8 ring carbon atoms and 1, 2, 3, or 4 ring heteroatoms selected from the group of N, S, and O) containing a monocyclic heterocyclic ring or a bicyclic or spirocyclic heterocyclic ring system); cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, where n1 is 0, 1, 2, and It is an integer selected from the group of 3. The compound according to any one of claims 1, 2, 3, and 5, having the formula:
(I-ll)
where Z ₁ , Z ₂ , Z ₃ , R ₂ ', and X ₂ are as defined in claim 1, 2, 3, or 5;
where R ₇ is -OH; halogen; -C ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, where n1 is 0, 1, 2, and It is an integer selected from the group of 3. The compound according to any one of claims 1 to 57, wherein Z ₁ , Z ₂ , and Z ₃ are each C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein one of Z ₁ , Z ₂ , and Z ₃ is N and the other is C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein two of Z ₁ , Z ₂ , and Z ₃ are N and the remainder is C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein Z ₁ , Z ₂ , and Z ₃ are each N, or a pharmaceutically acceptable salt thereof. 58. The method of any one of claims 1 to 57, wherein Z ₁ and Z ₂ are each C, Z ₃ is N, or Z ₁ is N, A compound where Z ₂ and Z ₃ are C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein Z ₁ and Z ₃ are each C and Z ₂ is N, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein Z ₁ and Z ₃ are each N and Z ₂ is C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein Z ₁ and Z ₂ are each N and Z ₃ is C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 57, wherein Z ₂ and Z ₃ are each N and Z ₁ is C, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 and 6 to 66, wherein R ₂




is selected from the group of,
Here, R ₇ occurs once or twice and is independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, wherein n1 is 0, 1, 2, and A compound that is an integer selected from the group of 3, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 1 and 6 to 66, wherein R ₂
and A compound selected from the group, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 2 to 66, wherein R ₂



and is selected from the group of;
Here, R ₅ and R ₆ are each independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, wherein n1 is a substituent of 0, 1, 2, and 3. A compound that is an integer selected from the group, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 2 to 66, wherein R ₂


is selected from the group of;
where R ₇ and R ₈ are each independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, wherein n1 is a substituent of 0, 1, 2, and 3. A compound that is an integer selected from the group, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 2 to 66, wherein R ₂
is selected from the group of;
Here, R ₅ and R ₆ are each independently hydrogen, -OH; halogen; -C ₁ -C ₆ alkyl; -OC ₁ -C ₆ alkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl; -(CH ₂ ) _n1 -C ₃ -C ₆ heterocycle containing at least one heteroatom selected from O, N, and S; cyano; -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl; -C(=O)OH; -C(=O)-OC ₁ -C ₆ alkyl; -S(=O) ₂ -C ₁ -C ₆ alkyl; -C(=O)-NR ^x R ^y ; -N(R ^x )(S(=O) ₂ -C ₁ -C ₆ alkyl); and -CF ₃ , wherein any alkyl group is further substituted with 0, 1, 2, 3, or 4 substituents selected from halogen and -OH, wherein n1 is a substituent of 0, 1, 2, and 3. A compound that is an integer selected from the group, or a pharmaceutically acceptable salt thereof. The method according to any one of claims 2 to 66, wherein R ₂
is selected from the group of;
Here, R ₅ and R ₆ are each independently hydrogen, halogen, C ₁ -C ₆ alkyl; A compound selected from -OC ₁ -C ₆ alkyl, and -CF ₃ , or a pharmaceutically acceptable salt thereof. The method according to any one of claims 2 to 66, wherein R ₂
is selected from the group of;
wherein R ₅ and R ₆ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, and -CF ₃ , or a pharmaceutically acceptable salt thereof. 74. The compound according to any one of claims 1 to 73, wherein R ₅ and R ₆ are each independently selected from the group of hydrogen, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy, or a compound thereof. Pharmaceutically acceptable salt. 75. The compound according to any one of claims 1 to 74, wherein R ₅ and R ₆ are each independently selected from the group of hydrogen, C ₁ -C ₃ alkyl, and C ₁ -C ₃ alkoxy, or a compound thereof. Pharmaceutically acceptable salt. 76. A compound according to any one of claims 1 to 75, wherein R ₃ is present 1-3 times, 2 times, or only 1 time; Optionally, R ₃ is selected from the group of hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -C ₁ -C ₄ alkyl-OH, phenyl, benzyl, pyrazolyl, and thiophenyl. being selected; wherein the phenyl, pyrazolyl and thiophenyl rings are substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF3, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy; or phenyl, benzyl, pyrazolyl and thio wherein R ₃ is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF3, C ₁ -C ₄ alkyl, and C ₁ -C ₄ alkoxy. A compound selected from the group of phenyl, or a pharmaceutically acceptable salt thereof. 77. The compound according to any one of claims 1 to 76, wherein Y ₁ and Y ₂ are each N, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 76, wherein Y ₁ is N and Y ₂ is C, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 76, wherein Y ₁ is C and Y ₂ is N, or a pharmaceutically acceptable salt thereof. 79. The method of any one of claims 1 to 79, wherein R ₁ is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. C ₁ -C ₆ alkyl compound, or a pharmaceutically acceptable salt thereof. 79. The method of any one of claims 1 to 79, wherein R ₁ is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. A C ₁ -C ₄ alkyl compound, or a pharmaceutically acceptable salt thereof. 79. The method of any one of claims 1 to 79, wherein R ₁ is selected from the group of -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, phenyl, and benzyl, wherein -(CH ₂ ) _n1 - wherein the rings of C ₃ -C ₆ cycloalkyl, phenyl, and benzyl groups are substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, OH, CF ₃ , and -OC ₁ -C ₃ alkyl. A phosphorus compound, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 82, wherein R _a is H, or a pharmaceutically acceptable salt thereof. 84. The compound according to any one of claims 1 to 83, wherein R _a is C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 84, wherein R ₃ is H, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 85, wherein R ₃ is C ₁ -C ₃ alkyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 86, wherein R ₃ is selected from the group of CO ₂ H and -CO ₂ -(C ₁ -C ₆ alkyl), or a pharmaceutically acceptable salt thereof. . 88. The method of any one of claims 1 to 87, wherein R ₃ is selected from the group of phenyl, benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl, wherein phenyl, Benzyl, C ₃ -C ₆ cycloalkyl, and -CH ₂ -C ₃ -C ₆ cycloalkyl groups each have 0, 1, 2, or 3 rings selected from OH, halogen, and C ₁ -C ₆ alkyl. a compound substituted with a substituent, wherein the C ₁ -C ₆ alkyl group is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF ₃ , and OH, or a compound thereof Pharmaceutically acceptable salt. 89. A 5- or 6-membered heterocyclic ring according to any one of claims 1 to 88, wherein R ₃ contains 1, 2, or 3 ring heteroatoms independently selected from O, S, and N. and wherein the 5- or 6-membered heterocyclic ring is substituted with 0, 1, 2, or 3 substituents selected from OH, halogen, and C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ A compound wherein the alkyl group is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen and OH, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 89, wherein the sum n _a + n _b is 3, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 90, wherein the sum n _a + n _b is 4, or a pharmaceutically acceptable salt thereof. 92. The method of any one of claims 1 to 91, wherein R ₄ is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, CF ₃ , OH, and -OC ₁ -C ₃ alkyl. C ₁ -C ₆ alkyl compound, or a pharmaceutically acceptable salt thereof. 93. The method of any one of claims 1 to 92, wherein R ₄ is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, CF ₃ , OH, and -OC ₁ -C ₃ alkyl. A C ₁ -C ₄ alkyl compound, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 93, wherein R ₄ is C ₁ -C ₄ alkyl substituted by 0, 1, 2, or 3 halogens and OH, or a pharmaceutically acceptable salt thereof. . 95. The method of any one of claims 1 to 94, wherein R ₄ is -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, wherein -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl group the cycloalkyl ring is substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, CF ₃ , OH, and -OC ₁ -C ₃ alkyl, and n2 is 0, 1, 2, and 3. A compound that is an integer selected from, or a pharmaceutically acceptable salt thereof. 96. The method according to any one of claims 1 to 95, wherein R ₄ is selected from the group of phenyl and benzyl, and the rings of the phenyl and benzyl groups are of halogen, CF ₃ , OH, and -OC ₁ -C ₃ alkyl. A compound substituted with 0, 1, 2, or 3 substituents selected from the group, or a pharmaceutically acceptable salt thereof. 97. The method of any one of claims 1 to 96, wherein R ₄ is a heterocyclic or heteroaromatic ring having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1 , 2, 3, or 4 ring atoms are selected from the group of N, O, and S; wherein the rings of the phenyl and benzyl groups are each independently substituted with 0, 1, 2, or 3 substituents selected from the group of halogen, CF ₃ , OH, and -OC ₁ -C ₃ alkyl, or Pharmaceutically acceptable salts thereof. 98. The method of any one of claims 1 to 97, wherein Y ₂ is C, R ₄ is H, -OC ₁ -C ₆ alkyl, and -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl. is selected from the group of; Here, the OC ₁ -C ₆ alkyl group and the cycloalkyl ring of -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl are each independently the group of halogen, CF ₃ , OH, and -OC ₁ -C ₆ alkyl. C substituted with 0, 1, 2, or 3 substituents selected from, or wherein two R ₄ contains 2-5 ring carbon atoms and 1 or 2 ring heteroatoms selected from the group of N and O A compound forming _{a 3} -C ₆ cycloalkyl carbocycle or heterocycle, or a pharmaceutically acceptable salt thereof. 99. The method according to any one of claims 1 to 98, wherein the -C ₁ -C ₆ alkyl group and the cycloalkyl ring of -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl are each independently selected from halogen and A compound substituted with 0, 1, 2, or 3 substituents selected from the group of OH, or a pharmaceutically acceptable salt thereof. A pharmaceutically effective amount of a compound selected from any one of claims 1 to 99, a compound selected from Examples 1-125, or a pharmaceutically acceptable salt of any of the foregoing compounds, and a pharmaceutically acceptable A pharmaceutical composition containing a carrier or excipient. Use of a compound selected from any one of claims 1 to 100, a compound selected from Examples 1-125, or a pharmaceutically acceptable salt of any of the foregoing compounds in the manufacture of a pharmaceutical. Pharmaceutically acceptable use of a compound selected from any one of claims 1 to 101, a compound selected from Examples 1-125, a compound of formula (I'), or any of the foregoing compounds for use as a medicament. Salt that becomes. A method of inhibiting the activity of GPR39 protein in a subject, comprising administering to a subject in need of inhibition the activity of GPR39 protein a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, from Examples 1-125. A method comprising administering a compound of choice, a compound of formula (I'), or a pharmaceutically acceptable salt of any of the foregoing compounds. A method of treating hypertension in a human in need of treatment for hypertension, comprising: providing the human in need of treatment with a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, selected from Examples 1-125. A method comprising administering a compound, a compound of formula (I'), or a pharmaceutically acceptable salt of any of the foregoing compounds. 105. The method of claim 104, wherein said hypertension is primary hypertension. 105. The method of claim 104, wherein said hypertension is secondary hypertension. 105. The method of claim 104, wherein said hypertension is treatment-resistant or refractory hypertension. 105. The method of claim 104, wherein said hypertension is pulmonary hypertension. A method of treating heart failure in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I) '), or a pharmaceutically acceptable salt of any of the foregoing compounds. 1. A method for breast cancer treatment in a human in need thereof, comprising: a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I') A method comprising administering a compound of, or a pharmaceutically acceptable salt of any of the foregoing compounds. 1. A method for gastric adenocarcinoma in a human in need of treatment for gastric adenocarcinoma, comprising administering to said human a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I) '), or a pharmaceutically acceptable salt of any of the foregoing compounds. 1. A method of promoting or improving colonic epithelial function and tight junction barrier integrity in a human, comprising administering to said human a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, selected from Examples 1-125. A method comprising administering a compound, a compound of formula (I'), or a pharmaceutically acceptable salt of any of the foregoing compounds. 1. A method of treating ulcerative colon disease in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I) '), or a pharmaceutically acceptable salt of any of the foregoing compounds. 114. The method of claim 113, wherein the ulcerative colon disease is ulcerative colitis. 114. The method of claim 113, wherein the ulcerative colon disease is Crohn's disease. A method of treating inflammatory bowel disease in a human, comprising administering to a human in need thereof a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I) '), or a pharmaceutically acceptable salt of any of the foregoing compounds. A method of treating diarrhea in humans, comprising: providing to a human in need thereof a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula (I') A method comprising administering a compound of, or a pharmaceutically acceptable salt of any of the foregoing compounds. A method of improving the delivery of an anesthetic to a human experiencing microvascular complications, comprising comprising: a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102 to a human experiencing microvascular complications in need thereof; A method comprising administering a compound selected from Examples 1-125, a compound of Formula (I'), or a pharmaceutically acceptable salt of any of the foregoing compounds, and a pharmaceutically effective amount of an anesthetic agent. 119. The method of claim 118, wherein the human experiences microvascular complications associated with or caused by pre-diabetes. 119. The method of claim 118, wherein the human is experiencing microvascular complications related to or caused by diabetes. 1. A method of treating stroke in a human in need thereof, comprising administering to said human a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, Formula ( A method comprising administering a compound of I'), or a pharmaceutically acceptable salt of any of the foregoing compounds. a) a pharmaceutically effective amount of a compound selected from any one of claims 1 to 102, a compound selected from Examples 1-125, or a pharmaceutically acceptable salt of any of the foregoing compounds, and pharmaceutically One or more compositions each comprising an acceptable carrier or excipient; and
b) Instructions for administering said one or more compositions to humans in need thereof.
Kit containing . The compound of any one of Examples 1-125, or a pharmaceutically acceptable salt thereof.