JPWO2021222858A5 - - Google Patents

Description

Related applications

This application claims priority to U.S. Provisional Patent Application No. 63/018,371, filed April 30, 2020, entitled "ANTAGONISTS OF GPR39 PROTEIN," which is incorporated herein by reference in its entirety. shall be provided.

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

Background of the invention

The use of GPR39 antagonists has been described for methods of treating pain sensitivity, including hyperalgesia, and for suppressing appetite (US Patent Application Publication No. 2009/0298756 - Jin et al.).

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

In the paper Altered Gastrointestinal and Metabolic Function in GPR39-Obestatin Receptor-Knockout Mouse, Gastroenterology, Moechars et al., Oct, 2006, Vol. 131, Issue 4, pp. 1131-1141, GPR39 receptor antagonists are shown to inhibit functional dyspepsia, Conclusions are disclosed that it may be useful in disorders affecting colonic motility, including diabetic gastric atony and/or irritable bowel syndrome, diarrhea or chronic constipation.

The role of obestatin/GPR39 system in human gastric adenocarcinoma, Alen et al., Oncotarget 2016, 7:5957-5971 describes the role of obestatin/GPR39 system in controlling motility, EMT and invasion of gastric adenocarcinoma cells. There is.

GPR39 antagonists are used 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 discuss its use in the treatment of breast cancer, particularly ER-negative breast cancer.

The use of GPR39 antagonists in the treatment of various cancers is described in US Patent Application Publication No. 2004/0071708 (Claassen et al.).

Inge Depoortere published the paper “GI functions of GPR39: novel biology, Current Opinion
in Pharmacology, 2012, 12:647-652, discloses the use of GPR39 antagonists for movement disorders such as functional dyspepsia, hypokinesia and chronic constipation.

Paper The zinc sensing receptor, ZnR/GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in colon, Cohen et al., Cell Death and Disease (2014) 5, e1307 has been shown to be effective in ulcerative colon diseases such as ulcerative colitis. The potential use of GPR antagonists in promoting or enhancing colonic epithelial function and tight junction barrier integrity, including in the treatment of diseases and conditions of diarrhea, is discussed.

式中、
Ｘ_１は、以下の群から選択され：
ｎ_ａは、０、１および２の群から選択された整数であり；
ｎ_ｂは、０、１、２、３および４の群から選択された整数であり；
ただし、ｎ_ａ＋ｎ_ｂの和が２以上４以下であり；
またはＸ_１とＺ_１が共に式（Ｉａ）の縮合環系を形成しており：

Ｒ_ａは、水素およびＣ_１－Ｃ_３アルキルの群から選択され；
Ｘ_２は、以下の群から選択され：
各例における波線
[化４-2]

は、各Ｘ_１およびＸ_２部分が結合している結合を表し；
Ｙ_１は、ＣおよびＮの群から選択され；
Ｙ_２は、Ｃ、Ｎ、ＳおよびＯの群から選択され、ただし、Ｙ_２がＯの場合Ｒ_４は存在せず、Ｙ_２がＳの場合Ｒ_４は存在しないかまたは１回もしくは２回存在し；
ただし、Ｙ_１およびＹ_２のうち１つだけがＣであり；
Ｚ_１、Ｚ_２およびＺ_３は、それぞれ独立してＣおよびＮの群から選択され、ただし、Ｚ_１、Ｚ_２およびＺ_３のうち２つだけがＮであってもよく、さらに、Ｒ_２と結合した場合はＺ_１、Ｚ_２およびＺ_３はＣであり；
Ｒ_１は、Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、－ＮＲ^ｘＲ^ｙ、フェニルおよびベンジルの群から選択され、ここで、前記Ｃ_１－Ｃ_６アルキル基と前記－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、フェニルおよびベンジル基の環は、ハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立してＨならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２
または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
ｎ１は、０、１、２および３の群から選択された整数であり；
Ｒ_２は、フェニルならびに窒素ヘテロ原子を介して結合し、３、４、５、６、７または８個の環炭素原子と、ＮおよびＯの群から選択された０、１、２、３または４個の追加の環ヘテロ原子とを含む単環式複素環または二環式もしくはスピロ環状複素環系の群から選択され、Ｒ_２の単環式環または二環式もしくはスピロ環状環系は、Ｃ_１－Ｃ_６アルキル、－Ｏ－Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、－ＣＦ_３、ハロゲンおよびフェニルの群から選択された０、１、２または３個の置換基で置換されており；
Ｒ_３は１回または複数回存在し、独立して以下の群から選択され：
ａ）水素；
ｂ）－ＣＯ_２Ｈまたは－ＣＯ_２－（Ｃ_１－Ｃ_６アルキル）；
ｃ）ハロゲン、ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されたＣ_１－Ｃ_６アルキル；
ｄ）フェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキルであって、フェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキルの群のそれぞれの環は、ＯＨ、ハロゲンおよびＣ_１－Ｃ_６アルキルから選択された０、１、２または３個の置換基で置換されており、前記Ｃ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されたフェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキル；
ｅ）Ｏ、ＳおよびＮから独立して選択された１、２または３個の環ヘテロ原子を含む５員または６員の複素環であって、前記５員または６員の複素環は、ＯＨ、ハロゲン、ベンジルおよびＣ_１－Ｃ_６アルキルから選択された０、１、２または３個の置換基で置換されており、前記Ｃ_１－Ｃ_６アルキル基はさらに、ハロゲンおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換された５員または６員の複素環；
Ｒ_４は１回または２回存在し、独立してＨ、オキソ、Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、－Ｏ－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、－Ｃ（＝Ｏ）－Ｏ－Ｃ_１－Ｃ_６アルキル、－Ｓ（＝Ｏ）_２－Ｃ_１－Ｃ_６アルキル、－Ｃ（＝Ｏ）－ＮＲ^ｘＲ^ｙ、フェニル、ベンジルまたは３、４、５、６、７、８、９もしくは１０個の環原子を有する複素環で、そのうち１、２、３もしくは４個の環原子がＮ、ＯおよびＳの群から選択される複素環の群から選択され、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルから選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
Ｙ_２が炭素である場合、Ｒ_４は－Ｏ－Ｃ_１－Ｃ_６アルキルであってもよく、または、２つのＲ_４が炭素環または複素環を形成していてもよく；
前記Ｒ_４のＣ_１－Ｃ_６アルキル、－Ｃ（＝Ｏ）－Ｏ－Ｃ_１－Ｃ_６アルキルおよび－Ｏ－Ｃ_１－Ｃ_６アルキル基と、－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキルおよび－Ｏ－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、フェニルおよびベンジル基の環は、それぞれ独立してハロゲン、ＣＦ_３、ＯＨ、３、４、５、６、７、８、９または１０個の環原子を有する複素環であって、そのうち１、２、３または４個の環原子がＮ、ＯおよびＳの群から選択された複素環、置換または非置換のフェニル、ならびに－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されており、ただし、Ｙ_１が窒素でＹ_２が炭素の場合は、Ｒ_４は非置換ベンジルではなく、かつＹ_１が窒素でＹ_２が窒素の場合は、Ｒ_４は非置換ピリジニルまたは置換もしくは非置換フェニルではなく；
Ｒ_５は、ＨおよびＣ_１－Ｃ_６アルキルの群から選択され、前記Ｒ_５のＣ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３、－ＮＲ^ｘＲ^ｙおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
Ｒ_６は、Ｈ、Ｃ_１－Ｃ_６アルキル、３、４、５、６、７、８、９または１０個の環原子を有する複素環であって、そのうち１、２、３または４個の環原子がＮ、ＯおよびＳの群から選択された複素環、フェニル、ならびにベンジルの群から選択され、前記Ｒ_６のＣ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３、－ＮＲ^ｘＲ^ｙおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、前記Ｒ_６のフェニル基およびベンジル基の環ならびに複素環の環は、Ｃ_１－Ｃ_６アルキル、－Ｏ－Ｃ_１－Ｃ_６アルキル、ハロゲン、－ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルから選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
各例においてｎ_２は、０、１、２および３の群から選択された整数であり；
ただし、Ｒ_２がＸ_２に対してオルトの非置換アゼパニル環であり、Ｘ_１が以下の部分

であり、Ｒ_ａがＨであり、Ｒ_１が非置換シクロプロピルであり、Ｘ_２が

であり、Ｙ_１がＮであり、かつａ）Ｙ_２がＯである、ｂ）Ｙ２がＮであり、Ｒ４がＨまたはアルキルである、ｃ）Ｙ_２がＣであり、Ｒ４がＨ、アルキルまたは－Ｃ（＝Ｏ）－Ｃ_１－Ｃ_６アルキルであるいずれかの場合、Ｒ_３はＨではない）。 A compound of formula (I) or a pharmaceutically acceptable salt thereof is provided:

During the ceremony,
X ₁ is selected from the following group:
n _a is an integer selected from the group of 0, 1 and 2;
n _b is an integer selected from the group 0, 1, 2, 3 and 4;
However, the sum of n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ 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 following group:
Wavy line in each example
[C4-2]

represents the bond between each X ₁ and X ₂ moiety;
Y ₁ is selected from the group C and N;
_Y2 is selected from the group C, N, S and O, with the proviso that if _Y2 is O then _R4 is absent and if _Y2 is S then _R4 is absent or once or twice Exists;
However, only one of Y ₁ and Y ₂ is C;
Z ₁ , Z ₂ and Z ₃ are each independently selected from the group of C and N, with the proviso that only two of Z ₁ , Z ₂ and Z ₃ may be N, and further R ₂ When combined with Z ₁ , Z ₂ and Z ₃ are C;
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, where said C ₁ -C ₆ The alkyl group and the ring of the -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, phenyl and benzyl group are 0 selected from the group of halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl. , 1, 2 or 3 substituents, and R ^x and R ^y are each independently selected from the group of H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl 0, 1, 2
or selected from the group of C ₁ -C ₆ alkyl substituted with 3 substituents;
n1 is an integer selected from the group 0, 1, 2 and 3;
R ₂ is bonded via phenyl and a nitrogen heteroatom, with 3, 4, 5, 6, 7 or 8 ring carbon atoms and 0, 1, 2, 3 or 4 additional ring heteroatoms, and the monocyclic ring or bicyclic or spirocyclic ring system of R ₂ is selected from the group of monocyclic heterocycles or bicyclic or spirocyclic heterocyclic ring systems comprising 4 additional ring heteroatoms; 0, 1, 2 selected from the group of C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen and phenyl or substituted with 3 substituents;
R ₃ occurs one or more times and is independently selected from the following groups:
a) Hydrogen;
b) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
c) C 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, wherein 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 and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl group being Furthermore, phenyl, benzyl, C ₃ -C ₆ cycloalkyl and -CH ₂ - substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF ₃ and OH. C ₃ -C ₆ cycloalkyl;
e) a 5- or 6-membered heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, wherein the 5- or 6-membered heterocycle is OH , halogen, benzyl and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl group being further substituted with 0, 1, 2 or 3 substituents selected from the group of halogen and OH. 5- or 6-membered heterocycle substituted with 0, 1, 2, 3, 4 or 5 substituents;
R ₄ occurs once or twice and is independently H, 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)-O-C ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , phenyl, benzyl or a heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are from the group N, O and S; selected from the group of heterocycles, R ^x and R ^y are each independently 0, 1, 2 or selected from H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with 3 substituents;
When Y ₂ is carbon, R ₄ may be -O-C ₁ -C ₆ alkyl, or the two R ₄ may form a carbocycle or a heterocycle;
The C ₁ -C ₆ alkyl, -C(=O)-O-C ₁ -C ₆ alkyl and -O-C ₁ -C ₆ alkyl groups of R ₄ and -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl and -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, phenyl and benzyl rings each independently represent halogen, CF ₃ , OH, 3, 4, 5, 6, 7, Heterocycle having 8, 9 or 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 -O-C ₁ -C ₃ alkyl, with the proviso that when Y ₁ is nitrogen and Y ₂ is carbon, R ₄ is not unsubstituted benzyl, and when Y ₁ is nitrogen and Y ₂ is nitrogen, R ₄ is not unsubstituted pyridinyl or substituted or unsubstituted phenyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group of said R ₅ is further selected from the group of halogen, -CF ₃ , -NR ^x R ^y and OH. and R ^x and R ^y are each independently substituted with H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 substituents selected from the group of alkyl;
R ₆ is H, C ₁ -C ₆ alkyl, heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 The ring atoms are selected from the group of heterocycles selected from the group of N, O and S, phenyl, and benzyl, and the C ₁ -C ₆ alkyl group of R ₆ further comprises halogen, -CF ₃ , -NR ^x is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of R ^y and OH, and the ring of the phenyl group and benzyl group and the ring of the heterocycle of R ₆ are C substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, halogen, -CF ₃ and OH, R ^x and R ^y are each independently H and C 1 substituted with 0, 1, 2 or 3 substituents selected from halogen, OH _, CF ₃ and -O-C ₁ -C ₃ alkyl - selected from the group of C ₆ alkyl;
In each example n ₂ is an integer selected from the group 0, 1, 2 and 3;
However, R ₂ is an unsubstituted azepanyl ring ortho to X ₂ , and X ₁ is the following moiety:

, R _a is H, R ₁ is unsubstituted cyclopropyl, and X ₂ is

and Y ₁ is N, and a) Y ₂ is O, b) Y 2 is N and R 4 is H or alkyl, c) Y ₂ is C and R 4 is H, alkyl or -C(=O)-C ₁ -C ₆ alkyl, R ₃ is not H).

Wild type (WT) mice (n = 5; circles) and GPR39 KO mice (n = 10; squares) on normal (0.4%), low (0.1%) and high salt diets (4. 0%) blood pressure (BP) recording. BP was recorded continuously using implantable pressure sensing telemetry. Data was collected for 10 seconds every 5 minutes for at least 96 hours for each experimental condition. BP was reported as 24-hour, daytime and nighttime mean arterial pressure (MAP). FIG. 4 is a diagram of data showing the dose-dependent effects of GPR39 antagonist Example 34 on BP in spontaneously hypertensive rats (SHR). BP reduction was expressed as percent of baseline BP (*p<0.05) FIG. 3A is a diagram depicting the timeline of the experimental design. Example 34 was given as a single dose 15 minutes after left coronary artery occlusion, during 45 minutes of occlusion followed by 2 hours of reperfusion. Figure 3B depicts the coronary capillary bed from the area at risk (AAR) and normally perfused area of WT and GPR39 KO mice. Endothelium was immunolabeled with CD31 and pericytes with NG2. Within the AAR, KO animals had less capillary constriction. FIG. 3C depicts the infarct size (TTC staining) of WT (n=6) and GPR39 KO (n=6), showing that the infarct size is significantly reduced in the latter. FIG. 3D depicts data from WT animals (n=6) treated with Example 34, showing a significant reduction in infarct size compared to vehicle-treated animals (n=5). Infarct size in both Fig. 3C and Fig. 3D is expressed as percent of AAR defined by Evans blue. Summary data is depicted to the right of the actual image from a single representative animal. FIG. 4A shows no reflow data from WT, GPR39 KO and Example 34 mice. Thioflavin-S and Evans blue were injected during life and no-reflow measurements were made (region without Evans blue in right panel). GPR39 KO mice depict an example of almost no reflow while WT animals show large areas of no reflow. FIG. 4B shows no-reflow data from WT, GPR39 KO and Example 34 mice. Summary data depicting a significant decrease in no-reflow/AAR ratio in GPR39 mice (N=4) compared to WT (N=4). FIG. 4C shows no-reflow data from WT, GPR39 KO and Example 34 mice. Example 34-treated mice depict an example of almost no reflow while vehicle-treated WT animals show large areas of no reflow. FIG. 4D shows no-reflow data from WT, GPR39 KO and Example 34 mice. Summary data is depicted showing a significant reduction in no-reflow/AAR ratio in mice treated with Example 34 (n=4) compared to vehicle-treated mice (n=5). Example 34 was given 15 minutes after coronary artery occlusion, which lasted a total of 45 minutes, followed by 2 hours of reperfusion.

Detailed description of the invention

ここで、各例において、存在する場合は、Ｘ_１、Ｘ_２、Ｒ_２、Ｚ_１、Ｚ_２、Ｚ_３、ならびに他のすべての変数およびただし書きは、上記の式（Ｉ）について定義されたとおりである。 Within the scope of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (IA) or a pharmaceutically acceptable salt thereof and a compound of formula (IB) or a pharmaceutically acceptable salt thereof. There are two additional embodiments, each containing a salt that can:

where in each example, if present, X ₁ , X ₂ , R ₂ , Z ₁ , Z ₂ , Z ₃ and all other variables and proviso are as defined for formula (I) above That's right.

Also, within the scope of formula (I) and based on the definitions of X ₁ and X ₂ above, figures (I-1), (I-2), (I-3), (I-4) and It will be appreciated that there are separate and independent embodiments each comprising a compound of (I-5) or a pharmaceutically acceptable salt thereof:

Here, X ₁ , R _a , R ₁ , R ₂ , R ₃ , R ₄ , Y ₁ , Y ₂ , Z ₁ , Z ₂ , Z ₃ , _na , n _b , n1, n2 and the proviso are those is as defined above for formula (I).

Furthermore, within the scope of formula (I) and based on the definitions of X ₁ and X ₂ above, compounds of the following formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof It is understood that there are separate and independent embodiments each comprising;
Here, R _a , R _{1 ,} R ₂ , R ₃ , R 4 , R ₅ , R ₆ , Y ₁ , Y ₂ , Z ₁ , Z ₂ , Z ₃ , _na , n _b , n1, n2 and the proviso are, in each instance in which they occur, as defined above for formula (I).

Other separate embodiments include compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or their pharmaceutically acceptable 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 (I) to (I-hh).

Other separate embodiments include compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or their pharmaceutically acceptable 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 (I) to (I-hh).

Additional separate embodiments provide compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or pharmaceutically acceptable compounds thereof. 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 the proviso are as defined above for the corresponding formulas (I) to (I-hh).

Additional separate embodiments provide compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or pharmaceutically acceptable compounds thereof. 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 the proviso are as defined above for the corresponding formulas (I) to (I-hh).

Additional separate embodiments provide compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or pharmaceutically acceptable compounds thereof. 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 the proviso are as defined above for the corresponding formulas (I) to (I-hh).

Additional separate embodiments provide compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or pharmaceutically acceptable compounds thereof. 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 the proviso are as defined above for the corresponding formulas (I) to (I-hh).

Additional separate embodiments provide compounds of each of Formula (I), Formulas (I-1) to (I-5), and Formulas (I-a) to (I-hh) above, or pharmaceutically acceptable compounds thereof. 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 the proviso are as defined above for the corresponding formulas (I) to (I-hh).

Within each embodiment herein, there are further embodiments in which R ₂ is selected from the group:

where R ₇ and R ₈ are independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -CF ₃ and phenyl in each instance, with the proviso that R Only one of ₇ and R ₈ may be phenyl. In embodiments herein, in instances where the _R group is _bicyclic or spirocyclic, R and _R are bonded to any available ring carbon or nitrogen atom on either of the rings. It is understood that R ₇ and R ₈ may be attached to ring atoms of the same or different rings.

Within each embodiment herein, there are further embodiments in which R ₂ is selected from the group:



wherein R ₇ and R ₈ are selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -CF ₃ and phenyl, with the proviso that R ₇ and only one of R ₈ may be phenyl.

Further, separate compounds each containing a compound of formula (I), formulas (I-1) to (I-5), and formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof, respectively. Embodiments are provided, which further embodiments include compounds of each formula where R ₂ is defined as each group a) to r) above.
For example, a compound of formula (1) or a pharmaceutically acceptable salt thereof is provided, wherein R ₂ is the azepane ring of group a) substituted with the variables R ₇ and R ₈ . Another embodiment includes compounds of formula (I) where R ₂ is an azabicyclo[3.10.0]hexanyl ring of group b) substituted with variables R ₇ and R ₈ . This pattern continues to define the remaining embodiments, each having R ₂ groups referenced separately from the list above.

Within each of the above embodiments regarding each compound of formula (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof , and each variable including Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , _na , n _b , n1, n2, and The proviso is as defined above for the corresponding formulas (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh), and R ₂ is a group of: There are also embodiments selected from:


wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, halogen and -CF ₃ .

Within each of the above embodiments regarding each compound of formula (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof , and each variable including Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , _na , n _b , n1, n2, and The proviso is as defined above for the corresponding formulas (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh), and R ₂ is a group of: There are also embodiments selected from:

wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl and -CF ₃ .

Within each of the above embodiments regarding each compound of formula (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof , and each variable including Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , _na , n _b , n1, n2, and The proviso is as defined above for the corresponding formulas (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh), and R ₂ is a group of: There are also embodiments selected from:

wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl and -CF ₃ .

Within each of the above embodiments regarding each compound of formula (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh) or a pharmaceutically acceptable salt thereof , and each variable including Z ₁ , Z ₂ , Z ₃ , R _a , R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , Y ₁ , Y ₂ , _na , n _b , n1, n2, and The proviso is as defined above for the corresponding formulas (I), formulas (I-1) to (I-5) and formulas (I-a) to (I-hh), and R ₂ is a group of: There are also embodiments selected from:

wherein R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C 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 further embodiments, hydrogen, F, Cl, -CF ₃ , C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy.

Within each embodiment of compounds and salts herein that include an R ₃ moiety, there are further embodiments in which the range is the same except that R ₃ occurs from 1 to 3 times. Within each embodiment of compounds and salts herein that include an R ₃ moiety, there are further embodiments in which the range is the same except that R ₃ occurs one to two times. Within each embodiment of compounds and salts herein that include an R ₃ moiety, there are further embodiments that are of the same scope except that R ₃ occurs only once. Within each embodiment of the compounds and salts herein that include an R ₃ moiety, R ₃ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , -C ₁ -C There are further embodiments that are the same except that they are selected from the group of ₄ alkyl-OH, phenyl, pyrazolyl and thiophenyl, where the phenyl, pyrazolyl and thiophenyl rings are halogen, OH, _-CF3 , C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy.

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

In addition, for each compound of formula (I) and all other formulas and specifically named compounds herein, pharmaceutically acceptable salts, pharmaceutically acceptable co-crystals, pharmaceutical pharmaceutically acceptable esters, pharmaceutically acceptable solvates, hydrates, isomers (including optical isomers, racemates or other mixtures), tautomers, isotopes, polymorphs and Acceptable prodrugs are included.

Compounds of the present disclosure may have asymmetric centers and can be prepared as racemic mixtures or as individual enantiomers. Individual enantiomers can be obtained by asymmetric synthesis or by resolving racemic or non-racemic mixtures of intermediates at some appropriate stage of the synthesis. The individual enantiomers can also be obtained by resolution of the compound by conventional means, such as crystallization in the presence of a resolving agent or chromatography using, for example, 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, all of which are intended to be included within the structures depicted herein, unless explicitly indicated otherwise. There is.

〔how to use〕
Hypertension is the most common chronic disease, affecting 1.13 billion people worldwide and causing 10 million deaths each year. Despite antihypertensive drugs that have successfully lowered blood pressure (BP) in millions of patients, significant unmet needs remain. Only half of hypertensive patients have their BP under control, and current antihypertensive drugs are unable to return BP to normal in a significant proportion of patients. Treatment-resistant hypertension (TRH), also known as resistant hypertension, is on the rise due to increases in diabetes and obesity. Diabetes and obesity account for 75% of the risk of hypertension and are involved in most cases of TRH. Identifying new targets and developing new strategies to prevent and treat hypertension and its complications remains a high public health and medical priority.

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

式Ｉ’：
式中：
Ｘ_１は、以下の群から選択され：

ｎ_ａは、０、１および２の群から選択された整数であり；
ｎ_ｂは、０、１、２、３および４の群から選択された整数であり；
ただし、ｎ_ａ＋ｎ_ｂの和が２以上４以下であり；
またはＸ_１とＺ_１が一緒になって式（Ｉａ）の縮合環系を形成し：

Ｒ_ａは、水素およびＣ_１－Ｃ_３アルキルの群から選択され；
Ｘ_２は、以下の群から選択され：

各例における波線
[化１９-２]

は、Ｘ_１およびＸ_２部分のそれぞれが結合している結合を表し；
Ｙ_１は、ＣおよびＮの群から選択され；
Ｙ_２は、Ｃ、Ｎ、ＳおよびＯの群から選択され、ただし、Ｙ_２がＯの場合Ｒ_４は存在せず、Ｙ_２がＳの場合Ｒ_４は存在しないかまたは１回もしくは２回存在し；
ただし、Ｙ_１およびＹ_２の１つのみがＣであり；
Ｚ_１、Ｚ_２およびＺ_３は、それぞれ独立してＣおよびＮの群から選択され、ただし、Ｚ_１、Ｚ_２およびＺ_３のうち２つのみがＮであってもよく、さらに、Ｒ_２と結合した場合はＺ_１、Ｚ_２およびＺ_３はＣであり；
Ｒ_１は、Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、－ＮＲ^ｘＲ^ｙ、フェニルおよびベンジルの群の一つから選択され、ここで、前記Ｃ_１－Ｃ_６アルキル基と前記－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、フェニルおよびベンジル基の環は、ハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から独立して選択された０、１、２または３個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立してＨならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
ｎ１は０、１、２および３から選択された整数であり；
Ｒ_２は、フェニルならびに窒素ヘテロ原子を介して結合し、３、４、５、６、７または８個の環炭素原子と、ＮおよびＯの群から選択された０、１、２、３または４個の追加の環ヘテロ原子とを含む単環式複素環または二環式もしくはスピロ環状複素環系の群から選択され、Ｒ_２の単環式環または二環式もしくはスピロ環状環系は、Ｃ_１－Ｃ_６アルキル、－Ｏ－Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ１－Ｃ_３－Ｃ_６シクロアルキル、－ＣＦ_３、ハロゲンおよびフェニルの群から選択された０、１、２または３個の置換基で置換されており；
Ｒ_３は１回または複数回存在し、以下の群から選択され：
ａ）水素；
ｂ）－ＣＯ_２Ｈまたは－ＣＯ_２－（Ｃ_１－Ｃ_６アルキル）；
ｃ）ハロゲン、ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されたＣ_１－Ｃ_６アルキル；
ｄ）フェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキルであって、該フェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキル基のそれぞれの環は、ＯＨ、ハロゲンおよびＣ_１－Ｃ_６アルキルから選択された０、１、２または３個の置換基で置換されており、Ｃ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されたフェニル、ベンジル、Ｃ_３－Ｃ_６シクロアルキルおよび－ＣＨ_２－Ｃ_３－Ｃ_６シクロアルキル；
ｅ）Ｏ、ＳおよびＮから独立して選択された１、２または３個の環ヘテロ原子を含む５員または６員の複素環であって、前記５員または６員の複素環は、ＯＨ、ハロゲン、ベンジルおよびＣ_１－Ｃ_６アルキルから選択された０、１、２または３個の置換基で置換されており、前記Ｃ_１－Ｃ_６アルキル基はさらに、ハロゲンおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換された５員または６員の複素環；
Ｒ_４は１回または２回存在し、独立してＨ、オキソ、Ｃ_１－Ｃ_６アルキル、－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、－Ｏ－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、－Ｃ（＝Ｏ）－Ｏ－Ｃ_１－Ｃ_６アルキル、－Ｓ（＝Ｏ）_２－Ｃ_１－Ｃ_６アルキル、－Ｃ（＝Ｏ）－ＮＲ^ｘＲ^ｙ、フェニル、ベンジルまたは３、４、５、６、７、８、９もしくは１０個の環原子を有する複素環であって、そのうち１、２、３もしくは４個の環原子がＮ、ＯおよびＳの群から選択される複素環の群から選択され、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルから選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
Ｙ_２が炭素である場合、Ｒ_４は－Ｏ－Ｃ_１－Ｃ_６アルキルであってもよく、または、２つのＲ_４が炭素環または複素環を形成していてもよく；
前記Ｒ_４のＣ_１－Ｃ_６アルキル、－Ｃ（＝Ｏ）－Ｏ－Ｃ_１－Ｃ_６アルキルおよび－Ｏ－Ｃ_１－Ｃ_６アルキル基と、前記－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキルおよび－Ｏ－（ＣＨ_２）_ｎ２－Ｃ_３－Ｃ_６シクロアルキル、フェニルおよびベンジル基の環は、それぞれ独立して、ハロゲン、ＣＦ_３、ＯＨ、３、４、５、６、７、８、９または１０個の環原子を有する複素環であって、そのうち１、２、３または４個の環原子がＮ、ＯおよびＳの群から選択された複素環、置換または非置換のフェニル、ならびに－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されており；
Ｒ_５は、ＨおよびＣ_１－Ｃ_６アルキルの群から選択され、前記Ｒ_５のＣ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３、－ＮＲ^ｘＲ^ｙおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルの群から選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
Ｒ_６は、Ｈ、Ｃ_１－Ｃ_６アルキル、３、４、５、６、７、８、９または１０個の環原子を有する複素環であって、そのうち１、２、３または４個の環原子がＮ、ＯおよびＳの群から選択された複素環、フェニル、ならびにベンジルの群から選択され、前記Ｒ_６のＣ_１－Ｃ_６アルキル基はさらに、ハロゲン、－ＣＦ_３、－ＮＲ^ｘＲ^ｙおよびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、前記Ｒ_６のフェニル基およびベンジル基の環ならびに複素環の環は、Ｃ_１－Ｃ_６アルキル、－Ｏ－Ｃ_１－Ｃ_６アルキル、ハロゲン、－ＣＦ_３およびＯＨの群から選択された０、１、２、３、４または５個の置換基で置換されており、Ｒ^ｘおよびＲ^ｙはそれぞれ独立して、Ｈならびにハロゲン、ＯＨ、ＣＦ_３および－Ｏ－Ｃ_１－Ｃ_３アルキルから選択された０、１、２または３個の置換基で置換されたＣ_１－Ｃ_６アルキルの群から選択され；
各例においてｎ_２は、０、１、２および３の群から選択された整数である。

Formula I':
During the ceremony:
X ₁ is selected from the following group:

n _a is an integer selected from the group of 0, 1 and 2;
n _b is an integer selected from the group 0, 1, 2, 3 and 4;
However, the sum of n _a + n _b is 2 or more and 4 or less;
or X ₁ and Z ₁ 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 following group:

Wavy line in each example
[Chem.19-2]

represents a bond between each of the X ₁ and X ₂ moieties;
Y ₁ is selected from the group C and N;
_Y2 is selected from the group C, N, S and O, with the proviso that if _Y2 is O then _R4 is absent and if _Y2 is S then _R4 is absent or once or twice Exists;
However, only one of Y ₁ and Y ₂ is C;
Z ₁ , Z ₂ and Z ₃ are each independently selected from the group of C and N, provided that only two of Z ₁ , Z ₂ and Z ₃ may be N, and further R ₂ When combined with Z ₁ , Z ₂ and Z ₃ are C;
R ₁ is selected from one of the group of C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -NR ^x R ^y , phenyl and benzyl, where said C ₁ The rings of the -C ₆ alkyl group and the -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, phenyl and benzyl groups are independent from the group of halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl. and R ^x and R ^y are each independently H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl. selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 substituents selected from the group of;
n1 is an integer selected from 0, 1, 2 and 3;
R ₂ is bonded via phenyl and a nitrogen heteroatom, with 3, 4, 5, 6, 7 or 8 ring carbon atoms and 0, 1, 2, 3 or 4 additional ring heteroatoms, and the monocyclic ring or bicyclic or spirocyclic ring system of R ₂ is selected from the group of monocyclic heterocycles or bicyclic or spirocyclic heterocyclic ring systems comprising 4 additional ring heteroatoms; 0, 1, 2 selected from the group of C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen and phenyl or substituted with 3 substituents;
R ₃ occurs one or more times and is selected from the following groups:
a) Hydrogen;
b) -CO ₂ H or -CO ₂ -(C ₁ -C ₆ alkyl);
c) C 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, wherein phenyl, benzyl, C ₃ -C ₆ cycloalkyl and -CH ₂ -C ₃ -C Each ring of the ₆ -cycloalkyl group is substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group is further substituted with , phenyl, benzyl, C ₃ -C ₆ cycloalkyl and -CH ₂ -C substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of , halogen, -CF ₃ and OH ₃ - _C6cycloalkyl ;
e) a 5- or 6-membered heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, wherein the 5- or 6-membered heterocycle is OH , halogen, benzyl and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl group being further substituted with 0, 1, 2 or 3 substituents selected from the group of halogen and OH. 5- or 6-membered heterocycle substituted with 0, 1, 2, 3, 4 or 5 substituents;
R ₄ occurs once or twice and is independently H, 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)-O-C ₁ -C ₆ alkyl, -S(=O) ₂ -C ₁ -C ₆ alkyl, -C(=O)-NR ^x R ^y , Phenyl, benzyl or a heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are N, O and S. and R ^x and R ^y are each independently selected from H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl; selected from the group of C ₁ -C ₆ alkyl substituted with 2 or 3 substituents;
When Y ₂ is carbon, R ₄ may be -O-C ₁ -C ₆ alkyl, or the two R ₄ may form a carbocycle or a heterocycle;
The C ₁ -C ₆ alkyl, -C(=O)-O-C ₁ -C ₆ alkyl and -O-C ₁ -C ₆ alkyl groups of R ₄ and the -(CH ₂ ) _n2 -C ₃ - The rings of C ₆ cycloalkyl and -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, phenyl and benzyl groups each independently represent halogen, CF ₃ , OH, 3, 4, 5, 6, Heterocycle having 7, 8, 9 or 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 0, 1, 2 or 3 substituents selected from the group -O-C ₁ -C ₃ alkyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, and the C ₁ -C ₆ alkyl group of said R ₅ is further selected from the group of halogen, -CF ₃ , -NR ^x R ^y and OH. and R ^x and R ^y are each independently substituted with H and halogen, OH, CF ₃ and -O-C ₁ -C ₃ selected from the group of C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 substituents selected from the group of alkyl;
R ₆ is H, C ₁ -C ₆ alkyl, heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 The ring atoms are selected from the group of heterocycles selected from the group of N, O and S, phenyl, and benzyl, and the C ₁ -C ₆ alkyl group of R ₆ further comprises halogen, -CF ₃ , -NR ^x is substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of R ^y and OH, and the ring of the phenyl group and benzyl group and the ring of the heterocycle of R ₆ are C substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, halogen, -CF ₃ and OH, R ^x and R ^y are each independently H and C 1 substituted with 0, 1, 2 or 3 substituents selected from halogen, OH _, CF ₃ and -O-C ₁ -C ₃ alkyl - selected from the group of C ₆ alkyl;
In each example n ₂ is an integer selected from the group 0, 1, 2 and 3.

Thus, in certain embodiments, the method comprises administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula (I), a compound of any subformula of formula (I), as specified herein. or a pharmaceutically acceptable salt of any of the foregoing.

A method for treating hypertension in a human in need thereof, comprising a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subformula of formula (I). , any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing, to said human. In one embodiment, the hypertension treated is primary hypertension, which may also be referred to as essential hypertension.

In another embodiment, the hypertension treated is secondary hypertension, including but not limited to sleep apnea, blocked renal arteries, abnormal levels of hormones, enzymes, growth factors, or systemic or local hypertension. Other drugs that control blood pressure (renin, angiotensin I and II and aldosterone, angiotensin converting enzyme, catecholamines, thrombin, prostaglandins, natriuretic peptides, vasopressin, adreomedulin, substance P, calcitonin gene-related peptide, kallikrein, (including but not limited to kininogen, kinin, kinin-degrading enzymes, fosdocin, adipokines and leptin), adrenal disease, thyroid abnormalities (hyperthyroidism, hypothyroidism, Cushing's disease, pheochromocytoma and growth hormone excess). (including coarctation) as well as hypertension caused by constriction of the aorta, including coarctation.

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

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

In another embodiment, the hypertension treated is malignant hypertension, which may also be referred to as hypertensive emergency or hypertensive crisis.

In additional embodiments, the hypertension treated is isolated systolic hypertension.

In further embodiments, the hypertension treated is salt-sensitive hypertension.

In another embodiment, the hypertension treated is pulmonary hypertension.

Current stroke treatment involves dissolving or removing thrombi that cause vascular occlusion. However, despite opening the large vessels, the small vessels remain compromised in a significant proportion of patients, 30-50%, which may not lead to effective treatment. The compounds described herein can be combined with current stroke treatments to improve prognosis for many patients.

Accordingly, a method for treating stroke in a human in need thereof, comprising a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), any subformula of formula (I). , any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing, to said human.

Vascular dementia is a disease of the small blood vessels in the brain that impairs blood flow and oxygen supply to brain cells, causing nerve cell dysfunction. Dementia due to small vessel disease is the second largest cause of dementia after Immer's disease, and is the main cause in people over 70 years of age and in developing countries. Provided is a method of treating dementia due to small vessel disease in a human in need thereof, the method comprising: a pharmaceutically effective amount of a compound of formula (I'); ), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing, to said human. including.

In view of their microvascular relaxing and protective effects, the compounds and compositions herein can also be used in methods of treating conditions associated with microvascular dysfunction and microvascular disease, each method comprising: administering to a subject in need thereof a pharmaceutically effective amount of a compound of formula (I') or a compound of formula (I), any sub-formula of formula (I) as specifically named herein; or a pharmaceutically acceptable salt of any of the foregoing. This includes methods of treating microvascular complications associated with or caused by diabetes. In one embodiment, the diabetes in question is type I diabetes. In another embodiment, the diabetes in question is type II diabetes. This also includes methods of treating microvascular complications associated with or caused by the condition of prediabetes, also known as prediabetes.

Also provided is a method of treating heart failure in a human, comprising administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), any of the compounds of formula (I). A method is provided comprising administering a compound of the partial formula, any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

Methods of 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 included.

Peripheral artery disease is mostly small vessel disease, and surgery and stent placement that target large vessels and do not treat small vessel disease are generally ineffective.

Provided herein is a method of treating peripheral arterial disease in humans, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I'), I), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

The compounds herein can also be used to treat preeclampsia, a pregnancy complication characterized by high blood pressure and signs of damage to other organ systems, most often the liver and kidneys. Provided herein is a method of treating pre-eclampsia in humans, which method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I'), I), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing. .

The compounds herein are useful in the treatment of myocardial infarction, particularly when a no-reflow phenomenon is present. No-reflow phenomenon exists when destruction or occlusion of coronary microvessels can significantly reduce blood flow to the infarcted area despite restoration of coronary blood flow to the myocardium. Flow into the microcirculation in such cases can occur in 1/3 of myocardial infarction patients.

Thus, there is provided a method for treating myocardial infarction in humans, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), or a compound of formula (I). A method is provided comprising administering a compound of any subformula, any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

The present invention also provides a method for treating myocardial infarction accompanied by the presence of a no-reflow phenomenon in humans, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of formula (I), Methods are provided comprising administering a compound of any subformula of I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

The compounds of the invention may also be used to treat patients with chronic coronary artery disease, where approximately one-third of patients continue to have angina due to microvascular dysfunction, even though the aorta has been bypassed or stentd. It can be used in any situation.

Thus, there is provided a method for treating chronic coronary artery disease in humans, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), or a compound of formula (I). , any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

Also provided is a method for treating microvascular dysfunction associated with chronic coronary artery disease in humans, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I). , a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing. provided.

The compounds of the invention may be used to treat syndrome It can also be used for called states. Thus, there is provided a method of treating Syndrome X in humans, which method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

Provided is a method of treating breast cancer in a human in need thereof, the method comprising administering to said human a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I'), ), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the breast cancer treated with the method is an ER-negative breast cancer.

Also, a method for treating gastric adenocarcinoma in humans, comprising administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), or any of the compounds of formula (I). A method is provided comprising administering a compound of the subformula, any of the compounds specifically set forth herein, or a pharmaceutically acceptable salt of any of the foregoing.

There is also provided a method of promoting or enhancing colonic epithelial function and tight junction barrier integrity in a human, comprising: administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'); a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing. is provided.

Also provided is a method of treating ulcerative colon disease in a human, comprising administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I'), ), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing. In one embodiment, the ulcerative colon disease treated is ulcerative colitis. In another embodiment, the ulcerative colon disease treated is Crohn's disease or Crohn's disease. In yet another embodiment, the ulcerative colon disease treated is irritable bowel syndrome (IBS), which may also be referred to as colitis, enteritis, ileitis, or proctitis.

Also provided is a method for treating inflammatory bowel disease (IBD) in humans, comprising administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of formula (I), Methods are provided comprising administering a compound of any subformula of I), any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

Also provided is a method of treating diarrhea in a human, comprising administering to said human in need thereof a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), any of the compounds of formula (I). A method is provided comprising administering a compound of the partial formula, any of the compounds specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the compounds herein distribute local, regional, or systemic delivery of anesthetics and improve their effectiveness, since microvascular complications can inhibit uniform delivery of anesthetics. It can be used in any way. Thus, a method is also provided for enhancing the delivery of an anesthetic to a human experiencing microvascular complications, the method comprising administering to a human in need thereof a pharmaceutically effective amount of the formula (I' ), a compound of formula (I), a compound of any subformula of formula (I), any of the compounds specifically named herein, or a pharmaceutically acceptable compound of any of the foregoing. and a pharmaceutically effective amount of an anesthetic. In some embodiments, a compound of formula (I'), a compound of any subformula of formula (I), any of the compounds specifically set forth herein, or any of the foregoing pharmaceutical is administered to the human prior to administration of the anesthetic.

[Pharmaceutical composition]
Also provided herein is a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subformula of formula (I), a compound of formula (I), a compound of formula (I), a compound of formula (I), Pharmaceutical compositions are provided comprising any of the compounds, or a pharmaceutically acceptable salt or co-crystal of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. Additional pharmaceutical compositions include pharmaceutically effective amounts of Figures (I-1), (I-2), (I-3), (I-4), (I-5) and (I-a), respectively. ) through (I-hh) as well as the compounds specifically provided herein, and a pharmaceutically acceptable carrier or excipient.

Further provided herein are compounds of formula (I'), compounds of formula (I), compounds of any subformula of formula (I), specifically herein The use of a pharmaceutically acceptable salt or co-crystal of any of the named compounds or any of the foregoing. Additional uses include figures (I-1), (I-2), (I-3), (I-4), (I-5) of pharmaceutically effective amounts for use in the preparation of pharmaceutical products. ) and (I-a) through (I-hh), respectively, as well as compounds specifically named herein.

The term "carrier" refers to an excipient or vehicle with which a compound is administered, including, but not limited to, diluents, disintegrants, suspending agents, surfactants, lubricants, binders, lubricants, etc. is included. Pharmaceutically acceptable carriers are described generally herein and also in "Remington's Pharmaceutical Sciences" by EW Martin. Examples of carriers include aluminum monostearate, aluminum stearate, carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxyoctacosa hydroxystearate. Nil, hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, Examples include, but are not limited to, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. However, it is to be understood that the carrier selected for a pharmaceutical composition and the amount of such carrier in the composition can vary depending on the method of formulation (e.g., dry granulation, solid dispersion formulation).

Some examples of suitable excipients in oral formulations include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl Includes pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations may further contain: lubricants such as talc, magnesium stearate, mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable vehicle, including, but not limited to, any and all carriers, solvents, dispersion media, coatings. , antibacterial and antifungal agents, isotonic agents and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Its use in therapeutic compositions is contemplated unless conventional vehicles or agents are incompatible with the active ingredient. Supplementary active ingredients can also be incorporated into the compositions.

The pharmaceutical compositions may be administered by any of the recognized modes of administration of agents of similar efficacy, such as rectal, buccal, intranasal and intranasal, as described, for example, in the patents and patent applications incorporated by reference. via the skin route, intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via impregnated or coated devices such as stents or arterially inserted cylindrical polymers. , can be administered in either a single dose or multiple doses.

One mode of administration is parenterally, particularly by injection. Forms in which a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, may be incorporated for administration by injection include aqueous or oily suspensions or emulsions and sesame oil, corn oil, cottonseed oil, or peanut oil; and elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles. Aqueous solutions in saline are also conventionally available for injection. Further, ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and appropriate mixtures thereof), cyclodextrin derivatives, vegetable oils, etc. can also be employed. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size when dispersing, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal.

Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients such as those enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying techniques to obtain the powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution. In some embodiments, a sterile injectable solution is prepared for parenteral administration containing a therapeutically effective amount, e.g., 0.1 to 1000 mg, of a compound of Formula I or a pharmaceutically acceptable salt or co-crystal thereof. be done. However, 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 this will be determined by the physician in light of the relevant circumstances, including weight, etc.

Oral administration is another route of administration of a compound of Formula I or a pharmaceutically acceptable salt or co-crystal thereof. Administration can be via capsules or enteric coated tablets and the like. In preparing pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt or co-crystal thereof, the active ingredient is usually diluted with excipients and/or in the form of a capsule, sachet, paper or other container. Encapsulated in any possible carrier. When an excipient functions as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above) that functions as a vehicle, carrier or medium for the active ingredient. The compositions may therefore be tablets, pills, powders, troches, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), e.g. ointments, ointments containing up to 10% by weight of the active compound. and can be in the form of hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

In some embodiments, for parenteral administration, each dosage unit contains 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of a compound of formula (I) or a pharmaceutically acceptable compound thereof. Contains salts or co-crystals. In some embodiments, the therapeutically effective amount or pharmaceutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises from about 0.1 mg to about 500 mg per dose, per day. Administered once or twice. In some embodiments, the individual doses are selected from 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, 350 mg, 400 mg, and 500 mg per dose. be done.

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

[Manufactured articles and kits]
Compositions (including, e.g., formulations and unit doses) containing a compound of Formula I' or I, or a pharmaceutically acceptable salt or co-crystal thereof, are prepared and placed in a suitable container for the treatment of an indicated condition. Labels can be attached. Accordingly, also provided are articles of manufacture, such as containers comprising a unit dosage form of a compound of Formula I' or I, or a pharmaceutically acceptable salt or co-crystal thereof, and a label containing instructions for use of the compound. In some embodiments, the article of manufacture is a container containing a unit dosage form of a compound of Formula I' or I, or a pharmaceutically acceptable salt or co-crystal thereof, and at least one pharmaceutically acceptable vehicle. The article of manufacture may be a bottle, vial, ampoule, single-use disposable applicator, etc. containing a pharmaceutical composition provided in this disclosure. The container may be formed from a variety of materials, such as glass or plastic, and in one aspect includes a label on or associated with the container indicating its use in treating cancer or inflammatory conditions. is also possible. It should be understood that the active ingredient may be packaged in any material that can improve chemical and physical stability, such as an aluminum foil bag. In some embodiments, the disease or condition indicated on the label can include, for example, treatment of cancer.

[Definition]
Terms such as "microvascular tone,""microcirculatorytone,""microcirculatory vascular tone," and "arteriolar tone" refer to the degree of constriction experienced by microcirculatory vessels relative to their maximally dilated state. The microcirculation is anatomically defined as blood vessels having a diameter of about 250 μm to about 100 μm, especially about 200 μm to about 150 μm, and includes arterioles, capillaries and veins (postcapillary veins). These blood vessels may be collectively referred to as "microvessels", "microcirculation blood vessels", etc. Embodiments herein relax the subject's microvessels, reduce vascular resistance, protect the microvessels themselves, and prevent end organ damage associated with microvascular resistance, particularly seen in the eyes, kidneys, and heart; It is a goal to provide compounds, compositions, and methods that reduce or eliminate nerve sheath damage associated with microvessels. In some embodiments, microcirculation is defined as blood vessels <200 μm in diameter. In the human body, approximately 90% of the blood volume resides in these blood vessels, including arterioles, capillaries, and veins. The diameter of arterioles ranges from 50 to 200 μm. Some of the veins contain vascular smooth muscle, and some of the capillaries are surrounded by pericytes, both of which are contractile cells that constrict and relax these blood vessels to release blood and oxygen. It is possible to supply more or less to cells and remove cellular waste products. The size of these arterioles is tightly regulated to match the oxygen needs of the cells they serve.

"Coronary microvascular disease" is a heart disease that affects the walls and inner walls of small blood vessels that branch from large coronary arteries. Coronary microvascular disease is also sometimes referred to as "cardiac syndrome X" or "non-obstructive coronary artery disease." In the heart or elsewhere, it may also be called "arteriolar disease," "small vessel disease," or "arteriolosclerosis."

Such small vessel diseases are often seen in primary hypertension, stroke, and hypertensive kidney disease. Renal manifestations typically involve the afferent arterioles and interlobular arteries, with intimal thickening, vascular smooth muscle cell proliferation, and extracellular matrix deposition, which can increase the media-to-lumen ratio. be. Areas of vascular smooth muscle cells may then be replaced by fibrosis and cell loss.

"Microvascular angina" is chest pain caused by abnormalities in the microvessels of the heart, including, but not limited to, abnormal relaxation and spasms of the microvessels.

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

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

Examples of 4-membered heterocycles as seen in the definitions of R ₃ and R ₄ herein include, by way of example and not limitation, azetidinyl, dihydro-1λ ⁴ -azetyl, azetyl, 1,3 -diazetidinyl and oxetanyl groups.

Examples of the 5-membered heterocycle as seen in the definitions of R ₃ and R ₄ herein include, but are not limited to, thiazolyl, tetrahydrothiophenyl, sulfurized tetrahydrothiophenyl, furanyl, Thienyl, pyrrolyl, dihydropyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, pyrrolidinyl, 2-pyrrolidonyl, dihydropyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, triazinyl, thienyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, imidazolinyl, pyrazolidinyl, pyrazolinyl and oxazolidinyl groups can be mentioned.

Examples of 6-membered heterocycles as seen in the definitions of R ₃ and R ₄ herein include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), pyrimidinyl, piperidinyl. , thiadiazinyl, thiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, pyrazinyl, pyridazinyl, piperazinyl, thienyl, thiopyran, ditanyl, morpholinyl, and thiomorpholinyl groups.

Examples of 7-membered heterocycles herein include, by way of example and without limitation, vorepinyl, azepanyl, azepinyl, oxepanyl, oxepinyl, teipinyl, thiepanyl, diazepanyl, diazepinyl, and thiazepinyl groups.

Examples of the 8-membered heterocycle herein include, by way of example and not limitation, an azosinyl group, an azosinyl group, an oxocanyl group, an oxocinyl group, a thiocanyl group, and a thiocinyl group.

Examples of 9-membered heterocycles herein include, by way of example and not limitation, monocyclic heterocycles such as azonanyl, azoninyl, oxonanyl, thionanyl and thioninyl groups, and indolyl, indolinyl, isoindolyl, Indolizinyl, indazolyl, azaindolyl, benzimidazolyl, azaindazolyl, pyrazolopyrimidinyl, purinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzo[d]isoxazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[c] Included are fused heterocycles such as [1,2,5]thiadiazolyl, benzo[d]thiazolyl, benzisothiazolyl, adeninyl and guaninyl groups.

Examples of the 10-membered heterocycle in this specification include, but are not limited to, decahydroisoquinolinyl, decahydroquinolinyl, tetrahydroquinolinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, Quinoxaline, quinolidinyl, phthalazinyl, quinazolinyl, sinolinyl, 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 (thieno[3, 2-d]pyrimidinyl) and isoquinolinonyl groups.

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

Similarly, the common heterocycle designation includes each variation 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 hydrocarbon. For example, an alkyl group can have a 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 include, but are not limited to, 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 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 ).

The term "alkoxy" refers to a group having the formula "-O-alkyl" where the alkyl group, as defined above, is attached to the parent molecule through an oxygen atom. The alkyl portion of an alkoxy group can have a specified number of carbon chain atoms, such as from 1 to 6 carbon atoms (ie, C ₁ -C ₆ alkoxy or C _1-6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O _- CH or --OMe), ethoxy ( _-OCH CH _or --OEt), t-butoxy (--O- --C(CH ₃ ) ₃ or --OtBu).

The term "cycloalkyl" refers to a saturated ring having from 3 to 6 carbon atoms as a single ring and includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

The term "halogen" refers to atoms selected from the group of elements chlorine, fluorine, bromine and iodine.

The term "oxo" refers to a double-bonded oxygen "=O".

The terms "therapeutically effective amount" and "pharmaceutically effective amount" refer to a therapeutically effective amount that, when administered to a subject (e.g., a mammal, such as a human), in need of such treatment, as defined below. Refers to the amount sufficient to carry out a specific task. A therapeutically or pharmaceutically effective amount will vary depending on the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the method of administration, etc., and can be readily determined by one of ordinary skill in the art. It is possible to do so. For example, a "therapeutically effective amount" or "pharmaceutically effective amount" of a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, antagonizes the expression or activity of GPR39, thereby afflicting an indication. An amount sufficient to treat a subject (eg, a human) or ameliorate or alleviate existing symptoms of the indication. For example, a therapeutically or pharmaceutically effective amount can 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 obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) suppressing the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition; (ii) delaying or preventing the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, reducing the scope of the disease or condition); preventing or slowing the deterioration or progression of the condition and/or preventing or slowing the spread of the disease (e.g. metastasis); and/or (iii) palliating the disease, i.e. causing regression of clinical symptoms (e.g. improving the condition, providing partial or total amelioration of the disease or condition, enhancing the effect of another drug, slowing the progression of the disease, increasing quality of life and/or prolonging 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" means inhibition of GPR39 activity as a direct or indirect response to the presence of a compound of formula I or a pharmaceutically acceptable salt or co-crystal thereof; Refers to the reduction in activity of GPR39 in the absence of co-crystals. Decreased activity may be due to direct interaction of the compound with GPR39 or between a compound described herein and one or more other factors that affect GPR39 expression and/or activity. It may also be due to interaction. For example, the presence of a compound can be inhibited by directly binding to GPR39, by causing (directly or indirectly) another factor that reduces GPR39 expression or activity, or by the amount of GPR39 protein present in a cell or organism. (directly or indirectly) may reduce GPR39 activity. In some embodiments, inhibition of GPR39 activity can be compared in the same subject before treatment or in other subjects who do not receive treatment. The term "inhibitor" is understood to refer to a compound or agent that provides the desired inhibitory activity when administered to a human in need thereof in a pharmaceutically or therapeutically effective dose.

"Delaying" the onset of a disease or condition means postponing, preventing, delaying, delaying, and/or postponing the onset of the disease or condition. This delay can be of varying lengths of time depending on the history of the disease or condition and/or the subject being treated. A method of "delaying" the occurrence of a disease or condition is one that reduces the probability of the occurrence of the disease or condition in a given time frame and/or reduces the probability of the disease or condition occurring in a given time frame compared to not using the method. This is a method of reducing the severity. Such comparisons are typically made based on clinical studies using statistically significant numbers of subjects. The occurrence of a disease or condition can be detected using standard methods such as routine physical exams, mammography, diagnostic imaging or biopsies. Onset can also refer to the progression of a disease or condition that may not be initially detectable, and includes occurrence, recurrence, and onset.

As used herein, the singular terms "a," "an," and "the" refer to the plural unless the context clearly dictates otherwise. Contains reference words. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. Also, as used herein, the term "comprises" means "includes." Therefore, "comprising A or B" means including A, B or A and B.

Numerical values in the specification and claims are the same when reduced to the same significant figures and conventional methods of the type described herein for determining that value from the recited value. It should be understood that numerical values that differ by less than experimental errors of measurement techniques are included.

All ranges disclosed and/or claimed herein are inclusive of the recited endpoints and are independently combinable (for example, the ranges "from 2 to 10" and "from 2 to 10" are inclusive of the recited endpoints). endpoints 2 and 10, including all intermediate values 3, 4, 5, 6, 7, 8 and 9).

"Significant" means any detectable change that is statistically significant at p<0.05 in a standard parametric test such as the Student's T-test.

"Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Examples of salts include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate. Acid salt, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesulfonate (besylate), p-toluenesulfonate (tosylate), 2-hydroxyethylsulfone Examples include acid salts, benzoates, salicylates, stearates and alkanoates (acetate, HOOC--(CH ₂ ) _n --COOH (n is 0 to 4), etc.). Additionally, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from basic compounds. In particular, pharmaceutically acceptable addition salts can be prepared. 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 "crystalline form" and related terms include, but are not limited to, polymorphs, solvates, hydrates, co-crystals and other molecular complexes, as well as salts, solvates of salts. Refers to various crystalline modifications of a given substance, such as compounds, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystalline forms of a substance can be obtained by several methods, as known in the art. Such methods include melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces, e.g. within nanopores or capillaries, e.g. on surfaces such as polymers or on templates. Recrystallization, recrystallization in the presence of additives, such as co-crystal pair molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, milling and milling by solvent dropwise addition. but not limited to.

As used herein, the term "cocrystal" or "cocrystal salt" refers to a crystalline material consisting of two or more distinct solids at room temperature, each with a structure, physical properties such as melting point and heat of fusion, and moisture absorption. It means a substance that is characterized by its properties, 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 refers to a multicomponent system in which a host API (active pharmaceutical ingredient) molecule or molecules, such as a compound of formula I, and a guest (or coformer) molecule or molecules are present. It can also refer to In certain embodiments, the pharmaceutically acceptable co-crystals of a compound of Formula I or a compound of Formula II and a coformer molecule include malonic acid co-crystals, succinic acid co-crystals, decanoic acid co-crystals, salicylic acid co-crystals, vanillic acid co-crystals. in the form of a crystal selected from co-crystals, maltol co-crystals or glycolic acid co-crystals. Co-crystals can have improved properties compared to the parent form (ie, free molecule, zwitterion, etc.) or a salt of the parent compound. Improved properties include increased solubility, increased degree of decomposition, increased bioavailability, increased dose response, decreased hygroscopicity, crystalline forms for normally amorphous compounds, and difficult or non-salting out properties. This may include crystalline forms of the compound, reduced diversity of forms, more desirable forms, and the like.

As used herein, the terms "isotope" and "isotopic" with respect to compounds as disclosed herein mean that one or more atoms of the compound are It means that it is replaced by an isotope of an atom. "Isotope" refers to any of two or more forms of a chemical element that have 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) are replaced with one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and when a hydrogen atom is replaced (at one or more positions) with deuterium, the resulting compound becomes an isotopic compound. For example, and referring to formula (I), replacing the two methyl groups (-CH(CH ₃ ) ₂ ) of the isopropyl moiety with fully deuterated methyl groups (-CH(CD ₃ ) ₂ ) gives the formula ( It becomes an isotopic compound of I). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotope substitutions include replacing carbon-12 with carbon-13, and unstable (radioactive) isotopes include: Examples include replacing hydrogen with tritium, replacing carbon-12 with carbon-14, and replacing iodine-127 with iodine-123 or iodine-125. Accordingly, all references herein to isotopic compounds of formula (I) and to its various embodiments refer to the substitution of one or more hydrogen atoms with one or more deuterium atoms. Refers to compounds with one or more isotopic substitutions, including but not limited to, and any occurrence in such compounds. To this end, the isotopic compounds disclosed herein offer improved advantages compared to their non-isotopic forms. To this end, isotopic modification provides a means of improving existing drugs and/or a tool in the design of new drugs. For example, isotope drug design has proven successful in the context of deuterium (D) dynamic isotope effects. Because D is twice as large in mass compared to H, the CD bond is more resistant to oxidative processes (such as its ability to be catalyzed by CYP450 or other enzymes involved in metabolism), yet very similar Retains three-dimensional properties. Thus, HD isotope substitutions typically preserve the pharmacodynamics of the compound while improving the half-life and/or area under the curve values, and thus the pharmacokinetics, which affects the dose and/or administration regimen. For example, drug exposure can be enhanced by isotopic modification and/or decreased clearance. Such advantages are provided to the compounds disclosed herein through isotopic derivatization.

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 can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is human; in some embodiments, the subject is selected from cats and dogs. A "subject in need thereof" or a "human being in need thereof" would benefit from a particular treatment; e.g., treatment with a compound of Formula I or a pharmaceutically acceptable salt or co-crystal thereof as described herein. Refers to a subject, such as a human, who has or is suspected of having a disease or condition that they may suffer from. This includes subjects who can be determined to be at risk or susceptible to a disease or condition whose occurrence can be prevented by treatment.

The term "prediabetes" or "prediabetic state" refers to a condition in which blood sugar levels are not high enough to be considered diabetes, but may be a precursor to type 2 diabetes. A prediabetic state can be defined in a subject whose fasting blood glucose level is 100 mg/dl or more and less than 126 mg/dl (a value that serves as a diagnostic criterion for diabetes). Hemoglobin A1c (HbA1c) level is another laboratory test for diabetes. An HbA1c value of 6.5% or higher is characteristic of diabetes, and a value of 5.7% to 6.4% suggests pre-diabetes.

Measurement of intracellular calcium responsiveness in PC3 cells expressing endogenous human GPR39 receptors

Human prostate adenocarcinoma (PC3) cells endogenously expressing the human GPR39 receptor were cultured in DMEM (low glucose) with 10% heat-inactivated fetal calf serum and 1% Pen/Strep. The cells were plated in a Clear Base 384-well plate at a density of 7500 cells/well and cultured overnight at 37°C and 5% CO2. Assay buffer (20mM HEPES, 137mM NaCl, 5.4mM KCl, 10mM glucose, 0.8mM MgSO4, 1.3mM CaCl2, 0.3mM Na2HPO4, 0.4mM KH2PO4 4.2
After washing with (mM NaHCO3, pH 7.4), the cells were incubated with calcium 6 probe (Molecular Devices) for 2 h at 37°C and equilibrated on a metal block for 30 min at RT. Fluorescence was measured in real time using a Fluorometric Imaging Plate Reader (FLIPRTETRA, Molecular Devices) (excitation wavelength 470-495 nm, emission wavelength 515-575 nm).

Compounds of the invention were serially diluted at 1000-fold concentrations in neat DMSO and plated in 384-well plates, followed by 200 μM in assay buffer containing 150 μM ZnCl (final concentration 30 μM) and 1.1% DMSO (final concentration 0.32%). Diluted twice.

Compounds diluted 1:200 in assay buffer containing 150 μM ZnCl2 and 1.1% DMSO were first added and 10 min later a submaximal concentration of hGPR39 receptor agonist C3 (Tocris, TC-G1008) was added at EC90 (90% of maximal response). A dual-addition FLIPR protocol was used, with a second addition at a concentration of 1.5 μM (concentration) yielding a concentration of 1.5 μM.

Fluorescence was monitored throughout the run assay. The peak of Ca2+ stimulation (baseline subtracted) was expressed as the maximum percent inhibition of the EC90 C3 response and plotted against the concentration of test compound. Curve fitting and IC50 estimation were performed with a 4-parameter logistic model using XLfitSoftware.

Compound efficacy was reported as the function 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 50% of the maximal response. The concentration of agonist required to induce % (obtained in each experimental plate).

The fpKi data is shown in Table 1 below. fpKi less than 5.2 is reported as "+/-". fpKi between 5.2 and 5.9 is reported as "+". fpKi between 6.0 and 6.5 is reported as "++". fpKi between 6.6 and 7.2 is reported as "+++". fpKi greater than or equal to 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.

Variants of the moiety at the _R2 position can be prepared using synthetic route 1 below.

Synthesis route 1

Synthetic route 1 - Reagents and conditions: a) N-propylpiperazine, HATU, DIPEA, DMF, rt, 2h; b) Zn, AcOH, rt, 1h; c) cyclopropanecarbonyl chloride, TEA, DCM, rt, overnight ;y=62%;d) Buckwald, Suzuki or Stille conditions.

Preparation: 1-(2-bromo-4-nitrobenzoyl)-4-propylpiperazine

2-bromo-4-nitrobenzoic acid (5.0 g, 20.32 mmol) in DMF (50 mL) and HATU: [dimethylamino o(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium; To a solution of hexafluorophosphate (8.5 g, 22.36 mmol) was added N,N-diisopropylethylamine (5.31 mL, 30.49 mmol) and the mixture was stirred at RT for 30 min. This was followed by the addition of a solution of 1-propylpiperazine dihydrobromide (5.9 g, 20.32 mmol) and N,N-diisopropylethylamine (7.08 mL, 40.65 mmol) in DMF (25 mL). The resulting solution was stirred at RT for 2 h. The mixture was diluted with _NaHCO3 s. s. and extracted three times with AcOEt. The organic layer was washed with brine, dried, filtered, and concentrated under vacuum. The crude product was purified by FC on silica gel (eluting with 100% DCM to DCM/MeOH 9:1) to yield a product of formula (1-(2-bromo-4-nitrobenzoyl)-4-propylpiperazine). Ta.
Yield: 7g

-
¹ H NMR (400 MHz, Chloroform-d) δ 8.48 (d, 1H), 8.24 (dd, 1H), 7.46 (d, 1H), 3.91 - 3.83 (m, 2H), 2.63 - 2.45 (m, 4H) , 2.40 - 2.31 (m, 4H), 1.57 - 1.46 (m, 2H), 0.93 (t, 3H); LC-MS: m/z 356.11, 358.14 (MH+).

Preparation: 3-bromo-4-(4-propylpiperazine-1-carbonyl)aniline

Dissolve (2-bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl)methanone (6.63 g, 18.61 mmol) in acetic acid (51.13 mL), and dissolve zinc (6.08 g, 93.06 mmol). ) was added to the solution. The resulting suspension was stirred for 60 minutes at RT. After this time, the suspension was filtered and the solution was concentrated under vacuum. The residue was dissolved in _NaHCO3 s. s. and extracted three times with AcOEt. _The organic layers were collected, washed with brine, dried over _Na2SO4 , filtered, and concentrated under vacuum. The resulting material was purified by FC on a NH column (DCM to DCM/AcOEt7:) to yield a product of formula (4-amino-2-bromophenyl)-(4-propylpiperazin-1-yl)methanone. Ta.
Yield: 3.2g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.91 (d, 1H), 6.78 (d, 1H), 6.56 (dd, 1H), 5.58 (s, 2H), 3.57 (s, 2H), 3.15 ( s, 2H), 2.44 - 2.21 (m, 6H), 1.49 - 1.39 (m, 2H), 0.85 (t, 3H); LC-MS: m/z 326.44, 328.44 (MH+)

Preparation: N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

A solution of (4-amino-2-bromophenyl)-(4-propylpiperazin-1-yl)methanone (2.2 g, 6.74 mmol) in DCM (30 mL) was added with triethylamine (2.82 mL, 20.23 mmol). was added and the resulting mixture was cooled to 0°C. A solution of cyclopropanecarbonyl chloride (1.53 mL, 16.86 mmol) in DCM (5 mL) was then added dropwise and the reaction was stirred at RT overnight. The next day, the reaction mixture was diluted with DCM and s.c. of _NaHCO3 . s. and washed with brine. The organic phase was dried on a phase separator and the solvent was removed under vacuum. The resulting material was purified by FC on silica gel (eluted from DCM to DCM/MeOH 95:5) to give a compound of formula N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide. of product was obtained.
Yield: 2.15g

¹ H NMR (400 MHz, Chloroform-d) δ 8.28 (bs, 1H), 7.73 (d, 1H), 7.35 (dd, 1H), 7.10 (d, 1H), 3.88 - 3.79 (m, 2H), 3.37 LC-MS: m/ z 394.09, 396.11 (MH+)

Preparation: N-(4-(4-propylpiperazine-1-carbonyl)-3-(6-azaspiro[3.4]octan-6-yl)phenyl)cyclopropanecarboxamide

A vial contained N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.250 mmol), sodium tert-butoxide (48.74 mg, 0.510 mmol), and Dry toluene (1.5 mL) was then added. The suspension was degassed by Schlenkline method and 6-aza-spiro[3.4]octane (42.29 mg, 0.380 mmol) was added. Next, (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone; palladium (11.61 mg, 0.010 mmol) and [1-(2-diphenylphosphino-1-naphthalenyl) -2-Naphthalenyl]-diphenylphosphine (15.79 mg, 0.030 mmol) was added to the suspension and degassed again by Schlenck line method over 10 minutes. The resulting mixture was heated to 120°C ON. The next day, the reaction mixture was diluted with water and extracted three times with AcOEt. _The organic layer was collected, washed with brine, dried over _Na2SO4 , filtered and the solvent was removed under vacuum. The resulting material was purified by FC on RP using basic conditions (elution from 100% aqueous ammonium bicarbonate to 100% CH ₃ CN adjusted to pH 10 with ammonia) to give the formula N-(4- A product of (4-propylpiperazine-1-carbonyl)-3-(6-azaspiro[3.4]octan-6-yl)phenyl)cyclopropanecarboxamide was obtained.
Yield: 11mg

¹ H NMR (500 MHz, METHANOL-d4 ) δ ppm 7.14 (d, 1 H), 7.01 (d, 1 H), 6.87 (dd, 1 H), 3.98 - 3.86 (m, 1 H), 3.69 - 3.57 (m, 1 H), 3.38 - 3.30 (m, 2 H), 3.29 -
3.11 (m, 4 H), 2.66 - 2.58 (m, 1 H), 2.53 - 2.42 (m, 2 H), 2.40 - 2.26 (m, 3 H)
, 2.11 - 1.86 (m, 8 H), 1.79 - 1.71 (m, 1 H), 1.61 - 1.50 (m, 2 H), 0.98 - 0.81 (m, 7 H); LC-MS: m/z 425.3 ( MH) ⁺

Preparation: (S)-N-(3-(3-isopropylpyrrolidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using (3S)-3-propan-2-ylpyrrolidin-1-ium chloride in place of 6-aza-spiro[3.4]octane to the compound of Example 1 (N-( The synthesis of 4-(4-propylpiperazine-1-carbonyl)-3-(6-azaspiro[3.4]octan-6-yl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 6.5% (7.3 mg).

1H NMR (500 MHz, METHANOL-d4 ) δ ppm 7.18 - 7.11 (m, 1 H), 7.06 - 6.94 (m, 1
H), 6.92 - 6.85 (m, 1 H), 4.07 - 3.29 (m, 4 H), 3.37 - 3.26 (m, 2 H), 3.38 - 2.90 (m, 2 H), 2.38 - 2.32 (m, 2 H), 2.71 - 2.18 (m, 4 H), 2.17 - 2.07 (m, 1 H), 1.98 - 1.83 (m, 1 H), 1.79 - 1.72 (m, 1 H), 1.64 - 1.47 (m, 4 H), 0.94 - 0.82 (m,
4 H), 1.05 - 0.80 (m, 9 H); LC-MS: (m/z) 427.6 (MH+).

Preparation: N-(3-(1,4-oxazepan-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (50.0 mg, 0.130 mmol) [1-(2-diphenylphosphino-1-naphthalenyl)-2- Naphthalenyl]-diphenylphosphine (15.79 mg, 0.030 mmol) and Cs ₂ CO ₃ (123.95 mg, 0.380 mmol) were suspended in dry toluene (1.5 mL) and the mixture was fluxed with N ₂ for 10 min. . Next, [1,4]oxazepane (64.13 mg, 0.630 mmol) and (1E,4E)-1,5-diphenyl-3-penta-1,4-dienone; palladium (11.61 mg, 0.010 mmol) ) was added and the mixture was heated to 120° C. for 48 hours. The reaction mixture was cooled to RT, diluted with water and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered, and the solvent was removed under reduced _pressure . The resulting material was purified by FC on RP using basic conditions (eluting with 100% aqueous ammonium bicarbonate adjusted to pH 10 with ammonia to 100% CH ₃ CN) to give the formula N-[3- The product (1,4-oxazepan-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was obtained as a white solid.
Yield: 2.2mg

¹ H NMR (400 MHz, DMSO-d6 ) δ ppm 10.18 (s, 1 H), 7.37 (d, 1 H), 7.09 (dd, 1 H), 6.96 (d, 1 H), 3.78 - 3.58 (m , 4 H), 3.61 - 3.02 (m, 8 H), 2.27 - 2.20 (m, 2 H), 2.46 - 2.06 (m, 4 H), 1.85 (quin, 2 H), 1.80 - 1.71 (m, 1 LC-MS: m/z 415.3 (MH+)

Preparation: N-(4-(4-propylpiperazine-1-carbonyl)-3-(7-oxa-
2-Azaspiro[3.5]nonan-2-yl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 7-oxa-2-azaspiro[3.5]nonane hydrochloride in place of 6-aza-spiro[3.4]octane to synthesize the compound of Example 1 (N-(4 The synthesis of -(4-propylpiperazine-1-carbonyl)-3-(6-azaspiro[3.4]octan-6-yl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 6.5% (7.3 mg).

¹ H NMR (500 MHz, DMSO-d6 ) δ ppm 10.22 - 10.06 (m, 1 H), 7.00 - 6.79 (m, 3 H), 3.66 - 3.47 (m, 10 H), 3.24 - 3.10 (m, 2 H), 2.46 - 2.18 (m, 6 H), 1.76 (t, 1 H), 1.72 - 1.67 (m, 4 H), 1.48 - 1.38 (m, 2 H), 0.85 (t, 3 H), 0.80 - 0.75 (m, 4
H); LC-MS: m/z 441.4 (MH+).

Preparation: N-(3-(3-phenylpyrrolidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 3-phenyl-pyrrolidine in place of [1,4]oxazepane to synthesize the compound of Example 3 (N-(3-(1,4-oxazepan-4-yl)-4-( The synthesis was carried out analogously to the synthesis of 4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 7.7% (9 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 7.42 - 7.20 (m, 5H), 7.12 (d, 1H),
6.93 (d, 2H), 3.74 - 3.10 (m, 4H), 3.28 - 3.06 (m, 6H), 2.42 - 2.01 (m, 7H), 1.76 (d, 1H), 1.46 - 1.38 (m, 2H), 0.93 - 0.74 (m, 7H); LC-MS: m/z 461.4 (MH+).

Preparation: N-(4-(4-propylpiperazine-1-carbonyl)-3-(2-oxa-6-azaspiro[3.5]nonan-6-yl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 2-oxa-6-azaspiro[3.5]nonane in place of [1,4]oxazepane to synthesize the compound of Example 3 (N-(3-(1,4-oxazepane- The synthesis was carried out analogously to the synthesis of 4-(4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 6% (4.8 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.48 (d, 1H), 7.27 (dd, 1H), 7.03 (d, 1H), 4.32 (d, 1H), 4.28 - 4.21 ( m, 3H), 3.71 (d, 1H), 3.49 (d, 1H), 3.17 - 2.85 (m, 5H), 2.62 (d, 1H), 2.48 - 2.41 (m, 1H), 2.37 - 2.21 (m, 4H), 2.16 - 2.10
(m, 1H), 1.76 (dd, 3H), 1.60 - 1.51 (m, 2H), 1.42 (q, 2H), 0.91 - 0.77 (m, 7H);
LC-MS: m/z 441.4 (MH+)

Preparation: N-(3-(4,4-difluoropiperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 4,4-difluoropiperidine in place of [1,4]oxazepane to synthesize the compound of Example 3 (N-(3-(1,4-oxazepan-4-yl)-4- The synthesis of (4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was carried out analogously. The title compound was obtained in a yield of 22% (12.3 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.28 (s, 1 H), 7.46 (d, 1 H), 7.25 (dd, 1 H), 7.06 (d, 1 H), 3.75 - 2.99 (m, 4 H), 3.21 - 2.85 (m, 4 H), 2.26 - 2.19 (m, 2
H), 2.45 - 2.12 (m, 4 H), 2.11 - 1.95 (m, 4 H), 1.84 - 1.71 (m, 1 H), 1.42 (sxt, 2 H), 0.84 (t, 3 H), 0.81 - 0.76 (m, 4 H); LC-MS: m/z 435.3 (MH+).

Preparation: N-(3-(3-methyl-1H-pyrazol-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.250 mmol), tripotassium phosphate (114.66 mg, 0.530 mmol), 3-Methyl-1H-pyrazole (0.02 mL, 0.300 mmol) and dry toluene (0.254 mL) were added sequentially. The resulting suspension was degassed for 15 min while bubbling with _N2 and then treated with copper(I) iodide (2.43 mg, 0.010 mmol) and N,N'-dimethylcyclohexane-1,2-diamine ( 0.0 mL, 0.030 mmol) was added under nitrogen flux and degassed again by Schlenkline method. The vial was sealed and stirred at 120° C. overnight. The next day, the reaction mixture was diluted with AcOEt and filtered through a pad of Celite. The organic layer was evaporated under reduced pressure and purified by FC on RP using basic conditions (elution: 100% aqueous ammonium bicarbonate to CH3CN 100% adjusted to pH 10 with ammonia), followed by semi-preparative chiral chromatography. Further purification was done by HPLC.

Preparation: N-[3-(3-methylpyrrol-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-methyl-1H-pyrrole in place of 3-methyl-1H-pyrazole to synthesize the compound of Example 8 (N-(3-methyl-1H-pyrazol-1-yl)- The synthesis was carried out analogously to the synthesis of 4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 4% (3.6 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.50 (s, 1 H), 7.75 (d, 1 H), 7.48 (dd, 1 H), 7.26 (d, 1 H), 6.80 (t, 1 H ), 6.69 (s, 1 H), 6.12 - 6.02 (m, 1 H), 3.87 - 2.66 (m, 4 H), 2.11 - 2.06 (m, 2 H), 2.05 (s, 3 H), 1.79 ( quin, 1 H), 2.41 - 1.37(
m, 4 H), 1.36 - 1.30 (m, 2 H), 0.82 (d, 4 H), 0.79 (t, 3 H); LC-MS: m/z 395.3 (MH+).

Preparation: N-(6-(4-propylpiperazine-1-carbonyl)-[1,1'-biphenyl]-3-yl)cyclopropanecarboxamide

N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (100.25 mg, 0.250 mmol), phenylboronic acid (31.0 mg, 0.250 mmol), sodium carbonate ( 188.63 mg, 1.78 mmol) was suspended in a mixture of toluene (1.112 mL), ethanol (1.112 mL) and water (0.318 mL). After the resulting suspension was degassed by Schlenkline method, palladium tetrakistriphenylphosphine (5.89 mg, 0.010 mmol) was added under nitrogen flux. The mixture was degassed again and heated to 140° C. for 60 minutes under microwave conditions. The reaction mixture was cooled to room temperature, diluted with H ₂ O, and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and the solvent was removed under vacuum _. The raw material was purified by FC on a NH column (eluted from cHex/AcOEt 95:5 to 100% AcOEt) and was purified with the formula (N-(6-(4-propylpiperazine-1-carbonyl)-[1,1'-biphenyl] -3-yl)cyclopropanecarboxamide) product was obtained.
Yield: 34mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.40 (s, 1 H), 7.74 (d, 1 H), 7.61 (dd, 1 H), 7.51 - 7.33 (m, 5 H), 7.25 (d, 1 H), 3.63 - 2.61 (m, 4 H), 2.02 - 1.97 (m, 2
LC-MS: m/z 392.7 ( MH+).

Preparation: N-(4-(4-propylpiperazine-1-carbonyl)-3-(pyridin-2-yl)phenyl)cyclopropanecarboxamide

N-[3-Bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.250 mmol) was dissolved in dry DMF (1.569 mL) and tributyl (2-pyridinyl) ) Stannane (0.1 mL, 0.300 mmol) was added and the solution was degassed by Schlenkline method for 15 minutes. Palladium tetrakis triphenylphosphine (14.51 mg, 0.010 mmol) was then added under a nitrogen flux and the reaction was stirred at 120° C. overnight. The next day, the reaction mixture was cooled to RT, diluted with 10% aqueous KF and extracted three times with AcOEt. The combined organic fractions were then washed with water, brine, dried over _Na2SO4 , filtered and the solvent was evaporated under reduced _pressure . The resulting material was purified by FC on an NH column (eluted from cHex/AcOEt 95:5 to AcOEt 100%) and further purified by FC on RP using basic conditions (aqueous ammonium bicarbonate solution adjusted to pH 10 with ammonia). 100% to CH ₃ CN 100%), a compound of formula (N-[4-(4-propylpiperazine-1-carbonyl)-3-pyridin-2-ylphenyl]cyclopropanecarboxamide) was obtained.
Yield: 10.5mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.44 (s, 1 H), 8.62 (dd, 1 H), 8.00 (d, 1 H
), 7.87 (td, 1 H), 7.69 (dd, 1 H), 7.54 (d, 1 H), 7.41 - 7.36 (m, 1 H), 7.25 (d,
1 H), 3.62 - 2.75 (m, 4 H), 2.18 - 2.05 (m, 2 H), 1.88 - 1.74 (m, 1 H), 2.41 -
1.58 (m, 4 H), 1.35 (sxt, 2 H), 0.87 - 0.73 (m, 7 H); LC-MS: m/z 265.3 (MH+).

Synthesis route 2

Synthetic route 2 - Reagents and conditions: a) cyclopropanecarbonyl chloride, TEA, DCM, 0°C to RT; b) LiOHH ₂ O, THF/MeOH/H ₂ O 40°C, 5 h; c) 1-propylpiperazine, HATU, DIPEA, DMF, RT, ON; d) Appropriate amine, Δ.

Preparation: N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

To a cooled solution of methyl 4-amino-2-fluorobenzoate (2.1 g, 12.42 mmol) and trimethylamine (5.19 mL, 37.25 mmol) in DCM (40 mL) at 0 °C was added cyclopropylene in DCM (22 mL). A solution of propanecarbonyl chloride (2.82 mL, 31.04 mmol) was added slowly. The mixture was warmed to RT and stirred overnight. The next day, the reaction mixture was diluted with DCM, washed with _NaHCO3 , brine, dried on a phase separator, and concentrated under reduced pressure. The residue was purified by FC on silica gel (eluting with cHex/AcOEt 95:5 to 3:7) to give the product of formula (methyl 4-(cyclopropanecarbonylamino)-2-fluorobenzoate).
Yield: 1.8g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.2 (bs, 1H), 10.65 (s, 1H), 7.81 (t, 1H), 7.65 (d, 1H), 7.33 (s, 1H), 1.84 - 1.73 (m, 1H), 0.92 - 0.81 (m, 4H); LC-MS: m/z 224.0 (MH+)

Preparation: 4-cyclopropanamido-2-fluorobenzoic acid

Methyl 4-(cyclopropanecarbonylamino)-2-fluorobenzoate (1.8 g, 7.72 mmol) in a mixture of THF (6.432 mL)/methanol (3.216 mL) was dissolved in lithium hydroxide (0.37 g) in water. , 15.44 mmol) (6.432 mL) was added, and the reaction was stirred at 40° C. for 5 h. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was taken up with HCl 1N and the suspension was filtered. The resulting solid was washed with H ₂ O and dried under vacuum to yield the product of formula (4-(cyclopropanecarbonylamino)-2-fluorobenzoic acid).
Yield: 6.9g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.2 (bs, 1H), 10.65 (s, 1H), 7.81 (t, 1H), 7.65 (d, 1H), 7.33 (s, 1H), 1.84 - 1.73 (m, 1H), 0.92 - 0.81 (m, 4H); LC-MS: m/z 224.0 (MH+)

Preparation: N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

A solution of 4-(cyclopropanecarbonylamino)-2-fluorobenzoic acid (1.5 g, 6.95 mmol) in DCM (35 mL) was added with 1-hydroxybenzotriazole; hydrate (2.2 g, 14.36 mmol). ), 3-(ethyliminomethylideneamino)-N,N-dimethyl-1-propanamine hydrochloride (2.2 g, 11.49 mmol) and N,N-diisopropylethylamine (2.0 mL, 11.49 mmol). and the resulting mixture was stirred for 30 minutes at RT. A solution of 1-propylpiperazine (1.5 g, 11.49 mmol) in DCM (7 mL) was then added and the mixed reaction was stirred at RT overnight. The next day, the mixture was diluted with DCM and s.c. s. of NaHCO ₃ , brine, dried on a phase separator and the solvent was removed under reduced pressure. The residue was purified by FC on a NH column (eluted from 100% DCM to DCM/MeOH 95:5) to give the formula (N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide ) product was obtained.
Yield: 1.95g

¹ H NMR (400 MHz, Chloroform-d) δ 7.62 (d, 1H), 7.34 (t, 1H), 7.13 (dd, 1H), 3.83 (d, 2H), 3.37 (s, 2H), 2.52 (t , 2H), 2.46 - 2.28 (m, 4H), 1.62 (s, 1H), 1.57
- 1.49 (m, 3H), 1.17 - 1.09 (m, 2H), 0.97 - 0.87 (m, 5H), LC-MS: m/z 334.17 (MH+)

Preparation: N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cylopropanecarboxamide

3-azabicyclo[3.1.0]hexane hydrochloride (358.7 mg, 3 mmol), potassium carbonate (207.27 mg, 1.5 mmol) N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl) ) phenyl]cyclopropanecarboxamide (100 mg, 0.3 mmol) was mixed in DMF (0.500 mL) and the reaction was heated at 120° C. for 1 week. The reaction was then cooled to RT and purified by FC on RP using basic conditions (eluted from 100% aqueous ammonium bicarbonate solution adjusted to pH 10 with ammonia to 100% CH ₃ CN), with the formula (N-[ A product of 3-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide) was obtained.
Yield: 5mg

¹ H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.05 (d, 1H), 6.97 (dd, 1H), 6.85 (d, 1H), 3.76 - 3.66 (m, 1H), 3.51 - 3.43 (m, 1H), 3.41 - 3.34 (m, 2H), 3.21 - 3.09 (m, 4H), 2.46 - 2.42 (m, 1H), 2.33 - 2.29 (m, 2H), 2.27 - 2.22 (m, 2H), 2.21
- 2.14 (m, 1H), 1.76 (p, 1H), 1.65 - 1.59 (m, 2H), 1.43 (h, 2H), 0.86 (d, 3H), 0.82 - 0.75 (m, 4H), 0.62 (td , 1H), 0.26 (q, 1H); LC-MS: m/z 397.6 (MH) ⁺

Preparation: N-(3-(3-methylpyrrolidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The title compound was synthesized using 3-methylpyrrolidine hydrochloride in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0]). The title compound was obtained in 15% yield (18 mg).

¹ H NMR (500 MHz, METHANOL-d4 ) δ ppm 7.19 - 7.10 (m, 1 H), 7.07 - 6.98 (m, 1 H), 6.93 - 6.87 (m, 1 H), 4.10 - 3.12 (m, 7 H), 2.95 - 2.80 (m, 1 H), 2.51 - 2.42 (m, 2 H), 2.79 - 2.29 (m, 4 H), 2.40 - 2.28 (m, 1 H), 2.15 - 2.04 (m, 1 H), 1.80 - 1.71 (m, 1 H), 1.65 - 1.51 (m, 3 H), 1.18 - 1.06 (m, 3 H), 1.00 - 0.80 (m,
7 H); LC-MS: m/z 399.6 (MH) ⁺

The racemic mixture was then separated into single enantiomers by preparative HPLC.

Preparation: Syn/Anti N-(3-((-3,5-dimethylpiperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 3,5-dimethylpiperidine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3 Syn/Anti Obtained as a mixture of diastereoisomers.

The mixture of syn/anti isomers was then separated into single isomers by preparative chiral HPLC.

Preparation: N-(3-(4-methylpiperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-methylpyrrolidine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3.1 The title compound was obtained in 26% yield (32 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.21 (s, 1 H), 7.37 (d, 1 H), 7.18 (dd, 1
H), 7.01 (d, 1 H), 3.71 - 3.03 (m, 4 H), 3.40 - 2.31 (m, 4 H), 2.28 - 2.20 (m, 2 H), 2.46 - 2.05 (m, 4 H) , 1.80 - 1.69 (m, 1 H), 1.43 (sxt, 3 H), 1.89 - 1.13 (m, 4 H), 0.93 (d, 3 H), 0.84 (t, 3 H), 0.81 - 0.75 (m , 4 H); LC-MS: m/z 413.3 (MH+).

Preparation: N-[4-(4-propylpiperazine-1-carbonyl)-3-(pyrrolidin-1-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using pyrrolidine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0]hexane). -3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 30% (28 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 7.39 (s, 1H), 7.18 (s, 1H), 7.06 (d, 1H), 6.66 (dd, 1H), 4.01 (d, 1H), 3.60 (t , 1H), 3.47 - 3.14 (m, 6H), 2.66 - 2.17 (m, 6H), 1.93 (t, 4H), 1.52 (p, 3H), 1.11 (p, 2H), 0.94 (d, 3H), 0.91 - 0.84 (m, 2H); LC-MS: m/z 385.5 (MH+)

Preparation: N-(3-(4,4-dimethylpiperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

N-(3-(4-methylpiperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 4,4-dimethylpiperidine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[ 3.1.0]hexan-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 24% (37 mg).

¹ H NMR (400 MHz, DMSO-d6 ) δ ppm 10.22 (s, 1 H), 7.44 (d, 1 H), 7.17 (dd, 1 H), 7.01 (d, 1 H), 3.70 - 3.47 (m , 2 H), 3.20 - 2.68 (m, 6 H), 2.47 - 2.14 (m, 6 H), 1.82 - 1.70 (m, 1 H), 1.51 - 1.34 (m, 6 H), 0.95 (s, 6 H), 0.84 (t, 3 H), 0.81 - 0.76 (m, 4 H); LC-MS: m/z 427.3 (MH+).

Preparation: N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting 1,
Using 2,3,4-tetrahydroisoquinoline, the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(4-propylpiperazine-1 -carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 12% (8 mg).

¹ H NMR (400 MHz, DMSO-d6 ) δ ppm 10.28 (s, 1 H), 7.49 (d, 1 H), 7.24 (dd, 1 H), 7.20 - 7.03 (m, 5 H), 4.25 (d , 1 H), 4.01 (d, 1 H), 3.36 (br d, 2 H), 3.66 - 3.04 (m, 4 H), 2.94 - 2.78 (m, 2 H), 2.36 - 2.06 (m, 4 H) ), 2.02 (t, 2 H), 1.84 -
1.72 (m, 1 H), 1.35 - 1.19 (m, 2 H), 0.89 - 0.62 (m, 7 H); LC-MS: m/z 447.3 (MH+).

Preparation: N-(3-(piperidin-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using piperidine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0] The synthesis of hexan-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 41% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm, 10.22 (s, 1 H), 7.37 (d, 1 H), 7.19 (dd, 1
H), 7.02 (d, 1 H), 3.82 - 2.93 (m, 4 H), 3.07 - 2.68 (m, 4 H), 2.28 - 2.20 (m, 2 H), 2.47 - 2.03 (m, 4 H) , 1.81 - 1.71 (m, 1 H), 1.69 - 1.46 (m, 6 H), 1.46 - 1.37 (m, 2 H), 0.84 (t, 3 H), 0.81 - 0.74 (m, 4 H); LC -MS: m/z 399.3 (MH+).

Preparation: N-[3-(cyclopentylamino)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using cyclopentanamine in place of 3-azabicyclo[3.1.0]hexane hydrochloride to synthesize the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0) ]Hexan-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 26% (23 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 7.10 (d, 1H), 6.96 (d, 1H), 6.84 (dd, 1H), 5.38 (d, 1H), 3.70 - 3.60 (m, 1H), 3.51 - 3.41 (m, 4H), 2.34 (t, 4H), 2.25 (d, 2H), 1.97 (dt, 2H), 1.82 - 1.75 (m, 1H), 1.72 - 1.54 ( LC-MS: m/z 399.50 (MH+).

_X2 groups or moieties bridged through carbonyl linkers can be prepared using Synthetic Scheme 3.

Synthesis scheme 3
Example 21

Synthesis Scheme 3 - Reagents and conditions: a) azepane, CH ₃ CN, 100 °C, 2 days; b) Pd-C 10%, EtOH, rt, 2 h; c) cyclopropane carbonyl chloride, TEA, DCM, rt, overnight ; d) LiOH, THF/ _H2O4 :1, 50<0>C, overnight; e) appropriate amine, HATU, DIPEA, DMF, RT, ON; f) TFA, DCM, RT, 2h; g) appropriate aldehyde. , STAB, DCM, RT, ON.

Preparation: Methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate

A mixture of methyl 2-fluoro-4-nitrobenzoate (3.0 g, 15.06 mmol) and 3,5-dimethylpiperidine (6.0 mL, 45.19 mmol) in MeCN (25.11 mL) was stirred at RT for 2 h. Stirred. After this time, the reaction mixture was concentrated under reduced pressure. The residue was taken up with AcOEt and washed with water and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by FC on silica gel (eluted from cHex 100% to cHex/AcOEt 7:3) to give a product of formula 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate methyl Obtained as a mixture of anti-isomers. This product was used directly in the next step.
Yield: 4g
LC-MS: m/z 293.1 (MH+)

Preparation: Methyl 2-(azepan-1-yl)-4-nitrobenzoate

The title compound was synthesized according to the synthesis of methyl 3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate, using homopiperidine in place of 3,5-dimethylpiperidine, and 2- The synthesis of methyl (3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate was carried out analogously. The title compound was obtained in a yield of 93% (2.6 g).

¹ H NMR (400 MHz, Chloroform-d) δ 7.78 (d, 1H), 7.62 (d, 1H), 7.51 (dd, 1H), 3.93 (s, 3H), 3.42 - 3.36 (m, 4H), 1.90 - 1.79 (m, 4H), 1.63 (t, 4H); LC-MS: m/z 278.7 (MH+).

Preparation: Methyl 4-nitro-2-pyrrolidin-1-ylbenzoate

The synthesis of the title compound was carried out analogously to the synthesis of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate using pyrrolidine in place of 3,5-dimethylpiperidine. Ta. The title compound was obtained in a yield of 94% (5.9 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+).

Preparation: Methyl 2-(6-azaspiro[3.4]octan-6-yl)-4-nitrobenzoate

6-aza-spiro[ 3.4] octane (502.47 mg, 4.52 mmol) was added and the reaction was stirred at 80° C. overnight. The reaction was cooled to RT and water was added. The mixture was extracted three times with AcOEt. The combined organics were washed with brine, dried on a phase separator, and concentrated under vacuum. The crude material was purified by FC on silica gel (elution from cHex 100% to cHex/AcOEt 9:1) to yield methyl 2-(6-azaspiro[3.4]octan-6-yl)-4-nitrobenzoate of formula I got something.
Yield: 792mg

1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.51 - 7.36 (m, 2H), 3.86 (s, 3H), 3.24 (t, 2H), 3.18 (s, 2H), 2.08 - 1.74 (m, 8H); LC-MS: m/z 291.1 (MH+).

Preparation: Methyl 2-(3-methylpyrrolidin-1-yl)-4-nitrobenzoate

The synthesis of the title compound was carried out using 2-(3,5-dimethylpiperidine The synthesis of methyl-1-yl)-4-nitrobenzoate was carried out analogously. The title compound was obtained in a yield of 92% (2.45 g).

1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, 1H), 7.47 (d, 1H), 7.43 (dd, 1H), 3.86 (s, 3H), 3.38 - 3.19 (m, 3H), 2.88 ( dd, 1H), 2.31 (dq, 1H), 2.07 (dtd, 1H), 1.64 - 1.49 (m, 1H), 1.06 (d, 3H); LC-MS: m/z 265.28 (MH+).

Preparation: Methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate

To a solution of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate (4.0 g, 13.68 mmol) in ethanol (54.73 mL) was added palladium (1456.16 mg, 1. 37 mmol) was added and the reaction was stirred at RT under H2 atmosphere for 2 hours. After this time, the mixture was filtered through a pad of Celite, washed with AcOEt, and the solution was concentrated under vacuum to obtain methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate of formula Obtained as a mixture of syn/anti isomers. This crude material was used in the next step without further purification.
Yield: 3.5g
LC-MS: m/z 264.1 (MH+)

Preparation: Methyl 4-amino-2-pyrrolidin-1-ylbenzoate

The synthesis of the title compound was carried out using methyl 4-nitro-2-pyrrolidin-1-ylbenzoate in place of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. The synthesis of methyl -amino-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out analogously. The title compound was obtained in a yield of 92% (5 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+).

Preparation: Methyl 4-amino-2-(6-azaspiro[3.4]octan-6-yl)benzoate

The synthesis of the title compound was modified by substituting 2-(6-azaspiro[3.4]octan-6-yl)-4 for methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. -The synthesis of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out using methyl nitrobenzoate. The title compound was obtained in a yield of 95% (672 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, 1H), 5.98 - 5.87 (m, 2H), 5.47 (s, 2H), 3.67 (s, 3H), 3.10 (t, 2H), 3.04 ( s, 2H), 2.01 - 1.74 (m, 8H); LC-MS: m/z 261.1 (MH+).

Preparation Methyl 4-amino-2-(3-methylpyrrolidin-1-yl)benzoate

The synthesis of the title compound was carried out using methyl 2-(3-methylpyrrolidin-1-yl)-4-nitrobenzokosan in place of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. The synthesis of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out using the following methods. The title compound was obtained in a yield of 99% (1.5 g).

¹ H NMR (400 MHz, DMSO-d6) δ 7.28 (d, 1H), 6.00 - 5.88 (m, 2H), 5.46 (s, 2H), 3.67 (s, 3H), 3.25 (td, 1H), 3.14 - 2.97(m, 2H), 2.80 (dd, 1H), 2.28 - 2.14 (m, 1H), 1.98 (dtd, 1H), 1.53 - 1.40 (m, 1H), 1.03 (d, 3H); LC-MS : m/z 245.72 (MH+)

Preparation: Methyl 4-amino-2-(azepan-1-yl)benzoate

A mixture of methyl 2-(azepan-1-yl)-4-nitrobenzoate (6.3 g, 22.18 mmol) and 10% palladium on carbon (2.36 g, 2.22 mmol) in ethanol (100 mL) Stirred overnight at RT under an atmosphere of _H2 . The next day, the reaction was filtered through a pad of Celite and concentrated under vacuum to give the formula 4-amino-2-(azepan-1-yl).
The product of methyl benzoate was obtained.
Yield: 5.4g

¹ H NMR (400 MHz, Chloroform-d) δ 7.53 (d, 1H), 6.22 (d, 1H), 6.10 (dd, 1H), 3.84 (s, 3H), 3.39 - 3.29 (m, 4H), 1.83 - 1.71 (m, 4H), 1.67 - 1.55 (m, 6H); LC-MS: m/z 249.1 (MH+)

Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate

Methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate (3.5 g, 13.34 mmol) and N,N-diisopropylethylamine (5.58 mL) in DCM (66.7 mL). 40.02 mmol) was cooled to 0° C. and cyclopropanecarbonyl chloride (2.42 mL, 26.68 mmol) was added dropwise. The mixture was stirred at RT/ON. The next day, the reaction mixture was diluted with DCM and s.c. s. of NaHCO ₃ , washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give formula 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl). Methyl benzoate was obtained as a mixture of syn/anti isomers, which was used in the next step without further purification.
Yield: 4.2g
LC-MS: m/z 331.15 (MH+).

Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate

The synthesis of the title compound was modified using methyl 4-amino-2-pyrrolidin-1-ylbenzoate in place of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. The synthesis of methyl (cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out analogously. The title compound was obtained in a yield of 99% (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+).

Preparation: Methyl 2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoate

The synthesis of the title compound was carried out using 4-amino-2-(6-azaspiro[3.4]octan-6-yl instead of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. ) The synthesis of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out using methyl benzoate. The title compound was obtained in a yield of 88% (742 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 7.41 (d, 1H), 7.22 (d, 1H), 6.87 (dd, 1H), 3.75 (s, 3H), 3.12 (t , 2H), 3.06 (s, 2H), 2.04 - 1.70 (m, 9H), 0.87 - 0.73 (m, 4H); LC-MS: m/z 329.11 (MH+).

Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoate

The synthesis of the title compound was carried out using methyl 4-amino-2-(3-methylpyrrolidin-1-yl)benzoate instead of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. The synthesis of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate was carried out using the following methods. The title compound was obtained in a yield of 99% (1.7 g).
LC-MS: m/z 303.05 (MH+)

Preparation: Methyl 2-(azepan-1-yl)-4-cyclopropanamide benzoate

A solution of methyl 4-amino-2-(azepan-1-yl)benzoate (5.4 g, 21.75 mmol) and N,N-diisopropylethylamine (7.58 mL, 43.49 mmol) in DCM (45 mL) After 5 minutes of cooling to 0° C., cyclopropanecarbonyl chloride (2.96 mL, 32.62 mmol) was added dropwise. The reaction was stirred at RT overnight. The next day, the reaction was diluted with DCM and diluted with NaHCO3s. s. and washed with brine. The organic phase was dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on an NH column (elution from cHex/AcOEt 95:5 to cHex/AcOEt 50:50) to yield methyl 2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoate of formula I got something.
Yield: 6.5g.

¹ H NMR (400 MHz, Chloroform-d) δ 7.55 (d, 2H), 7.45 (s, 1H), 6.66 (dd, 1H), 3.87 (s, 3H), 3.38 - 3.32 (m, 4H), 1.83 - 1.75 (m, 4H), 1.60 (h, 4H), 1.58 - 1.43
(m, 1H), 1.17 - 1.09 (m, 2H), 0.87 (dt, 2H); LC-MS: m/z 317.2 (MH+).

Preparation: 2-(6-Azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid

Methyl 2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoate (742.0 mg, 2.26 mmol) in a mixture of THF (16 mL)/methanol (19 mL) ) was added a solution of lithium hydroxide (974 mg, 40.68 mmol) in water (8 mL). The reaction was stirred at 80°C for 24 hours. After this time, the reaction was cooled to RT and observed for formation of a precipitate. The suspension was filtered and the mother liquor was concentrated under vacuum. The residue was taken up with _H2O and washed 3 times with DCM. The aqueous phase was acidified with HCl 3N to pH=1 and extracted three times with AcOEt. The organic phase was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a compound of formula 2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropane). The product carbonylamino)benzoic acid was obtained.
Yield: 330mg

1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.23 (s, 1H), 7.49 (d, 1H), 7.30 (d, 1H), 6.92 (dd, 1H), 3.23 - 3.13 ( LC-MS: m/z 315.16 (MH+).

Preparation: 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoic acid

A solution of 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoic acid (2.46 g, 5.86 mmol) in a mixture of THF (11 mL)/methanol (4 mL) was added with water ( A solution of lithium hydroxide (1.5 g, 62.63 mmol) in 4 mL) was added and the reaction mixture was stirred at 50° C. for 60 hours. The reaction was cooled to RT, acidified with HCl 3N to pH=1 and concentrated under vacuum. The residue was directly purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 7:3 + 0.1% formic acid), A product of formula 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoic acid was obtained.
Yield: 1.06g
1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.22 (s, 1H), 7.49 (d, 1H), 7.30 (d, 1H), 6.94 (dd, 1H), 3.30 (td, 2H), 3.20 - 3.12 (m, 1H), 3.10 (ddd, 1H), 2.27
(dt, 1H), 2.10 - 1.98 (m, 1H), 1.78 (tt, 1H), 1.52 (dq, 1H), 1.06 (d, 3H), 0.86
- 0.73 (m, 4H); LC-MS: m/z 289.12 (MH+).

Preparation: 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid

表題化合物の合成を、４－（シクロプロパンカルボニルアミノ）－２－（３－メチルピロリジン－１－イル）安息香酸メチルの代わりに４－（シクロプロパンカルボニルアミノ）－２－ピロリジン－１－イル安息香酸メチルを用いて、４－（シクロプロパンカルボニルアミノ）－２－（３－メチルピロリジン－１－イル）安息香酸の合成に類似して行った。表題化合物を収率４９％（３ｇ）で得た。

The synthesis of the title compound was carried out using 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoate instead of methyl 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoate. The synthesis of 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoic acid was carried out analogously using methyl acid. The title compound was obtained in a yield of 49% (3 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+).

Preparation: syn/anti-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid

Methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (2.6 g, 7 To a solution of lithium hydroxide (392.81 mg, 15.74 mmol) in water (3.14 mL) was added. The resulting mixture was heated to 50°C overnight. The next day, the reaction was cooled to RT, brought to pH 2 with HCl 3N and concentrated under reduced pressure. The resulting solid was taken up with H ₂ O, filtered, washed with H ₂ O and dried under vacuum to give the formula 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidine-1- The product of benzoic acid was obtained as a mixture of syn/anti isomers.
Yield: 2.37g
LC-MS: m/z 317.19 (MH+).

Preparation: Syn-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid and anti-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidine) -1-yl)benzoic acid

Methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (2.6 g, 7 .87 mmol) was added a solution of lithium hydroxide (392.81 mg, 15.74 mmol) in water (3.14 mL). The resulting mixture was heated to 50°C overnight. The next day, the reaction was cooled to RT, brought to pH 2 with HCl 3N and concentrated under reduced pressure. The resulting solid was taken up with H ₂ O, filtered, washed with H ₂ O and dried under vacuum to give the formula 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidine-1- The product of benzoic acid was obtained as a mixture of syn/anti isomers [2.37 g, LC-MS: m/z
317.19 (MH+)].

The mixture of isomers was then separated into single isomers using a semi-preparative MDAP method.

Preparation: 2-(azepan-1-yl)-4-cyclopropanamide benzoic acid hydrochloride

A solution of methyl 2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoate (6.5 g, 20.54 mmol) in THF (24 mL) and methanol (8 mL) in water (8 mL) A solution of lithium hydroxide (0.98 g, 41.09 mmol) was added. The reaction was stirred at 50C overnight. The next day, the reaction was cooled to RT and concentrated under vacuum. The residue was taken up with HCl 1N and stirred at 0C for 10 minutes. After this time, a solid was observed, so the mixture was filtered and the solid was washed with H ₂ O and dried under vacuum to give the formula 2-(azepan-1-yl)-4-(cyclopropanecarbonyl The product of amino)benzoic acid hydrochloride was obtained.
Yield: 6.45g

¹ H NMR (400 MHz, Chloroform-d) δ 10.04 (s, 1H), 8.51 (d, 1H), 8.07 (d, 1H), 7.64 (dd, 1H), 3.49 (s, 4H), 2.07 - 2.02 (m, 7H), 1.86 (s, 4H), 1.14 - 1.06 (m, 2H), 0.94 (dt, 2H). LC-MS: m/z 303.2 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-cyclopropanamidobenzoyl]piperazine-1-carboxylate

2-(Azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoic acid hydrochloride (1.0 g, 2.95 mmol) in DCM (20 mL), 1-hydroxybenzotriazole; hydrate (0. N,N-diisopropylethylamine (1.93 g, 6.09 mmol) and 3-(ethyliminomethylideneamino)-N,N-dimethyl-1-propanamine; hydrochloride (0.93 g, 4.87 mmol). 03 mL, 5.9 mmol) was added and the reaction was stirred for 30 min at RT. After this time, 1-piperazinecarboxylic acid tert-butyl ester (0.91 g, 4.87 mmol) was added and the reaction was stirred at RT overnight. The next day, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. , brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from cHex/AcOEt 9:1 to cHex/AcOEt 1:1) to give the formula 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl] A product of tert-butyl piperazine-1-carboxylate was obtained.
Yield: 1.18g

¹ H NMR (400 MHz, Chloroform-d) δ 7.53 - 7.49 (m, 1H), 7.40 - 7.35 (m, 1H), 7.12 (d, 1H), 6.74 (dd, 1H), 4.04 - 3.94 (m, 1H), 3.68 - 3.60 (m, 1H), 3.57 - 3.49
(m, 4H), 3.42 - 3.10 (m, 6H), 1.53 (d, 18H), 1.12 (h, 2H), 1.00 - 0.84 (m, 2H);
LC-MS: m/z 471.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(piperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

of tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]piperazine-1-carboxylate (1.18 g, 2.51 mmol) in DCM (12.54 mL). Trifluoroacetic acid (0.96 mL, 12.54 mmol) was added to the solution. The reaction was stirred at RT for 2 hours. After this time, the mixture was concentrated in vacuo and the residue was purified by SCX washing first with MeOH and then with _1M NH3 in MeOH to give the formula (N-[3-(azepane-1- yl)-4-(piperazine-1-carbonyl)phenyl]cyclopropanecarboxamide) was obtained.
Yield: 0.8g

¹ H NMR (400 MHz, Chloroform-d) δ 7.59 - 7.44 (m, 2H), 7.10 (d, 1H), 6.86 - 6.63 (m, 1H), 4.02 (dt, 1H), 3.56 - 3.47 (m, 1H), 3.37 - 3.19 (m, 6H), 3.00 - 2.87
(m, 2H), 2.80 - 2.63 (m, 2H), 1.81 - 1.73 (m, 4H), 1.61 - 1.47 (m, 5H), 1.16 - 1.05 (m, 2H), 0.91 - 0.81 (m, 2H) .LC-MS: m/z 371.3 (MH+)

Preparation: N-(3-(azepan-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(piperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (50.0 mg, 0.130 mmol) was suspended in MeCN (3 mL), and N,N-diisopropyl Ethylamine (0.05 mL, 0.270 mmol) was added followed by 1,2-oxazolo-3-carbaldehyde (14.41 mg, 0.150 mmol). After stirring the reaction mixture for 15 minutes, sodium triacetoxyborohydride (57.21 mg, 0.270 mmol) was added. The resulting mixture was stirred at room temperature overnight, then the mixture was diluted with EtOAc and _H2O and the organic phase was separated. The aqueous phase was back-extracted twice with AcOEt, then the combined organic fractions were 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 from 100% cHex to 100% EtOAc) to give the formula N-[3-(azepan-1-yl)-4-[4-(1,2-oxazol-3-ylmethyl) ) Piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was obtained.
Yield: 20 mg.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 8.87 (d, 1H), 7.34 (d, 1H), 7.01 (dd, 1H), 6.91 (d, 1H), 6.55 ( d, 1H), 3.73 - 3.54 (m, 4H), 3.18 (td, 6H), 2.46 - 2.23 (m, 4H), 1.83 - 1.40 (m, 9H), 0.86 - 0.63 (m, 4H). LC- MS: m/z 452.4 (MH+)

Preparation: N-[3-(azepan-1-yl)-4-[4-[(1H-pyrazol-3-yl)methyl]piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using pyrazole-3-carbaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4 -(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 21% (13 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.62 (d, 1H), 10.13 (s, 1H), 7.33 (d, 2H), 7.01 (dd, 1H), 6.90 (d, 1H), 6.14 ( s, 1H), 3.66 - 3.48 (m, 4H), 3.21 - 3.11 (m, 6H), 2.45 - 2.16 (m, 4H), 1.87 - 1.32 (m, 9H), 0.83 - 0.67 (m, 4H). LC-MS: m/z 451.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(oxazol-2-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-oxazolecarboxaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4- The synthesis was carried out analogously to the synthesis of (4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 37% (22.5 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 8.08 (d, 1H), 7.34 (d, 1H), 7.18 (d, 1H), 7.01 (dd, 1H), 6.91 ( d, 1H), 3.72 (s, 2H), 3.59 (d, 2H), 3.24 - 3.08 (m,
6H), 2.42 - 2.31 (m, 4H), 1.79 - 1.41 (m, 9H), 0.83 - 0.74 (m, 4H); LC-MS: m/z 452.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-methoxybenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 46% (30.5 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.12 (s, 1 H), 7.32 (d, 1 H), 7.23 (t, 1 H), 7.06 - 6.97 (m, 1 H), 6.94 - 6.77 ( m, 4 H), 3.73 (s, 3 H), 3.47 (d, 4 H), 3.25
- 3.08 (m, 6 H), 2.45 - 2.17 (m, 4 H), 1.80 - 1.43 (m, 9 H) 0.82 - 0.71 (m, 4 H); LC-MS: m/z 491.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-fluorobenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 40% (25 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.13 (s, 1 H), 7.33 (d, 2 H), 7.18 - 6.98 (m, 4 H), 6.91 (d, 1 H), 3.53 (d, LCMS: m/z 479.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(2-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-methoxybenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 59% (58 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.19 - 10.05 (m, 1 H), 7.37 - 7.19 (m, 3 H), 6.90 (d, 4 H), 3.75 (s, 3 H), 3.62 - 3.49 (m, 4 H), 3.25 - 3.09 (m, 6 H), 2.46
- 2.20 (m, 4 H), 1.75 - 1.49 (m, 9 H), 0.83 - 0.71 (m, 4 H); LC-MS: m/z 491.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-fluorobenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 42% (41 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.16 - 10.04 (m, 1 H), 7.43 - 7.36 (m, 1 H), 7.32 (d, 2 H), 7.20 - 7.13 (m, 2 H), 7.03 - 6.97 (m, 1 H), 6.90 (d, 1 H), 3.57 (s, 4 H), 3.23 - 3.05 (m, 6 H), 2.45 - 2.21 (m, 4 H), 1.78 - 1.43 ( m, 9 H), 0.82 - 0.73 (m, 4 H); LC-MS: m/z 479.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-fluorobenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 65% (56 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.12 (s, 1 H), 7.39 - 7.27 (m, 3 H), 7.19 - 7.08 (m, 2 H), 7.00 (dd, 1 H), 6.90 ( d, 1 H), 3.52 - 3.43 (m, 2 H), 3.25 - 3.06 (m, 4 H), 3.70 - 3.06 (m, 4 H), 2.46 - 2.16 (m, 4 H), 1.81 - 1.71 ( m, 1 H), 1.70 - 1.43 (m, 8 H), 0.85 - 0.69 (m, 4 H); LC-MS: m/z 479.5 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-methoxybenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 56% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm, 10.12 (br s, 1 H), 7.32 (d, 1 H), 7.19 (d,
2 H), 7.00 (dd, 1 H), 6.88 (dd, 3 H), 3.73 (s, 3 H), 3.67 - 3.47(m, 2 H), 3.42 (d, 2 H), 3.24 - 3.06 ( m, 6 H), 2.43 - 2.16 (m, 4 H), 1.82 - 1.71 (m, 1 H), 1.69
- 1.40 (m, 8 H), 0.88 - 0.70 (m, 4 H); LC-MS: m/z 491.5 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(2-chlorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-chlorobenzaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-(4 -(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 66% (52 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.13 (s, 1 H), 7.49 (dd, 1 H), 7.43 (dd, 1
H), 7.43 (dd, 1 H), 7.37 - 7.24 (m, 3 H), 7.04 - 6.97 (m, 1 H), 6.92 (d, 1 H),
3.26 - 3.09 (m, 4 H), 3.74 - 3.07 (m, 4 H), 2.49 - 2.25 (m, 4 H), 1.83 - 1.45 (m, 9 H), 0.85 - 0.71 (m, 4 H); LC-MS: m/z 495.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 3-pyridinecarboxaldehyde in place of 1,2-oxazolo-3-carbaldehyde to synthesize the compound of Example 22 (N-(3-(azepan-1-yl)-4-( The synthesis of 4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 34% (25 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.12 (s, 1 H), 8.49 (d, 1 H), 8.47 (dd, 1 H), 7.71 (dt, 1 H), 7.35 (dd, 1 H ), 7.32 (d, 1 H), 7.00 (dd, 1 H), 6.91 (d, 1 H), 3.53 (br d, 2 H), 3.27 - 3.06 (m, 4 H), 3.72 - 3.06 (m , 4 H), 2.46 - 2.16 (m, 4 H), 1.80 - 1.71 (m, 1 H), 1.73 - 1.41 (m, 8 H), 0.85 - 0.69 (m, 4 H); LC-MS:
m/z 462.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(piperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (75.0 mg, 0.200 mmol) and N,N-diisopropylethylamine ( 0.05 mL, 0.300 mmol) was added 7-chlorothieno[2,3-C]pyridine (41.21 mg, 0.240 mmol) and the reaction was stirred at 120 °C overnight and treated under microwave conditions. It was heated to 150°C for 2 hours. The reaction was concentrated to dryness and the residue was taken up with AcOEt. The organic phase _was washed with water, brine, dried over _Na2SO4 , filtered and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% AcOEt to AcOEt/MeOH 8:2), with formula N-[3-(azepan-1-yl)-4-(4-thieno[2,3-c] A product of pyridin-7-ylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 9mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.11 - 10.19 (m, 1 H) 8.09 (d, 1 H) 8.01 (d, 1 H) 7.49 (d, 1 H) 7.39 (d, 2 H) 7.01 (s, 2 H) 3.82 - 3.90 (m, 1 H) 3.34 - 3.80 (m, 7 H) 3.21 - 3.27 (m, 4 H) 1.45 - 1.81 (m, 9 H) 0.80 (d, 4 H); LC-MS: m/z 504.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-thieno[3,2-d]pyrimidin-4-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-chlorothieno[2,3-D]pyrimidine in place of 7-chlorothieno[2,3-C]pyridine to synthesize the compound N-[3-(azepan-1- yl)-4-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide. The title compound was obtained in a yield of 85% (86 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.13 - 10.19 (m, 1 H) 8.51 (s, 1 H) 8.23 (d, 1 H) 7.41 - 7.48 (m, 1 H) 7.33 - 7.40 (m, 1 H) 6.96 - 7.07 (m, 2 H) 3.65 - 4.14 (m, 6 H) 3.32 - 3.45 (m, 2 H) 3.16 - 3.26 (m, 4 H) 1.43 - 1.82 (m, 9 H) 0.74 -
0.85 (m, 4 H); LC-MS: m/z 505.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide

2-(Azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoic acid hydrochloride (50.0 mg, 0.150 mmol), HATU: [dimethylamino(3-triazolo[4,5-b]pyridinyloxy) methylidene]-dimethylammonium; hexafluorophosphate (67.33 mg, 0.180 mmol) and N,N-diisopropylethylamine (76.29 mg, 0.590 mmol) were mixed in DMF (1.5 mL) and stirred for 5 minutes. , piperidine (14.45 mg, 0.170 mmol) was added. The reaction mixture was stirred at RT for 2 hours. After this time, the reaction was concentrated under vacuum and the residue was purified by SCX cartridge, washing first with MeOH and then eluting with NH ₃ 1M in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluting with 100% cHex to cHex/AcOEt 70:30), giving the formula N-[3-(azepan-1-yl)-4-( A product of piperidine-1-carbonyl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 46mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 7.32 (d, 1H), 7.01 (dd, 1H), 6.90 (d, 1H), 3.80 - 3.38 (m, 2H), 3.25 - 3.10 (m, 6H), 1.82 - 1.25 (m, 15H), 0.84 - 0.73 (m, 4H); LC-MS: m/z 370.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was performed using azepane in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The synthesis was carried out analogously. The title compound was obtained in a yield of 77.2% (470 mg).

NMR: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 7.34 (d, 1H), 7.01 (dd, 1H), 6.92 (s, 1H), 3.70 - 3.62 (m, 1H) ), 3.55 - 3.46 (m, 1H), 3.26 - 3.08 (m, 6H), 2.45 - 2.12 (m, 6H), 1.81 - 1.36 (m, 11H), 0.85 (t, 3H), 0.80 - 0.76 (m , 4H); LC-MS: m/z 413.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 1,2-dimethyl-piperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl). ) was performed analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 48% (42 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.34 (d, 1H), 7.01 (dd, 1H), 6.92 (s, 1H), 3.70 - 3.62 (m, 1H), 3.55 - 3.46 (m, 1H), 3.26 - 3.08 (m, 6H), 2.45 - 2.12 (m, 6H), 1.81 - 1.36 (m, 11H), 0.85 (t, 3H), 0.80 - 0.76 (m, 4H); LC-MS: m/z
399.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(trifluoromethyl)piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 4-(trifluoromethyl)piperidine hydrochloride in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 54% (35 mg).

1H NMR (400 MHz, DMSO-d6 ) d ppm 10.19 - 10.06 (m, 1 H), 7.41 - 7.30 (m, 1 H),
6.98 - 6.88 (m, 2 H), 6.90 (s, 1 H), 4.69 - 4.54 (m, 1 H), 3.51 - 3.37 (m, 1 H), 3.25 - 3.12 (m, 4 H), 3.08 - 2.89 (m, 1 H), 2.76 - 2.53 (m, 2 H), 1.96 - 1.09
(m, 12 H), 0.79 (m, 4 H); LC-MS: m/z 438.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1,2,3,4-tetrahydroisoquinoline in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 68% (42 mg).

1H NMR (400 MHz, DMSO-d6 ) d ppm 10.16 (s, 1 H), 7.37 (dd, 1 H), 7.28 - 6.92 (m, 6 H), 4.90 - 4.25 (m, 2 H), 4.05 - 3.93 (m, 1 H), 3.40 (d, 1 H), 3.25 - 3.01
(m, 4 H), 2.93 - 2.69 (m, 2 H), 1.82 - 1.24 (m, 9 H), 0.87 - 0.71 (m, 4 H); LC-MS: m/z 418.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-2-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl) -4-(Piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 70% (42 mg).

1H NMR (400 MHz, DMSO-d6 ) d ppm 10.16 (s, 1 H), 7.38 (dd, 1 H), 7.08 - 6.94 (m, 2 H), 6.66 (d, 1 H), 6.07 - 5.94 ( m, 1 H), 5.92 - 5.63 (m, 1 H), 4.96 - 4.22 (m, 2 H), 4.07 - 3.76 (m, 3 H), 3.51 (s, 1 H), 3.20 (t, 4 H) ), 1.81 - 1.26 (m, 9 H), 0.88 - 0.69 (m, 4 H); LC-MS: m/z 407.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-{octahydropyrrolo[1,2-a]pyrazine-2-carbonyl}phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out in Example 35 (N-(3- (azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 65% (65 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 7.56 - 7.38 (m, 2H), 7.17 - 7.00 (m, 1H), 6.71 (ddd, 1H), 4.83 (ddd, 1H), 3.71 - 2.46 (m, 9H), 2.30 - 1.23 (m, 18H), 1.17 - 1.05 (m, 2H); LC-MS: m/z 411.5 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a ]Pyrazine-7-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out in Example 35 using 5,6,7,8-tetrahydro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine in place of piperidine. The synthesis of (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 72% (51 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.30 - 10.12 (m, 1 H), 7.53 - 7.36 (m, 1 H), 7.18 - 6.97 (m, 2 H), 5.31 - 4.46 (m, 2 H ), 4.35 - 3.61 (m, 4 H), 3.26 - 3.02 (m, 4 H), 1.77 (quin, 1 H), 1.69 - 1.30 (m, 8 H), 0.87 - 0.73 (m, 4 H); LC-MS: m/z 477.4 (MH+).

Preparation: 2-(azepan-1-yl)-4-cyclopropanamide-N-[(pyridin-2-yl)methyl]benzamide

The synthesis of the title compound was modified using 2-pyridinylmethanamine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl). ) was performed analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 43% (50 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 10.11 (t, 1H), 8.53 (ddd, 1H), 7.78 (td, 1H), 7.68 (d, 1H), 7.61 ( d, 1H), 7.39 (d, 1H), 7.35 - 7.26 (m, 1H), 7.23 (dd, 1H), 4.60 (d, 2H), 3.16 - 3.00 (m, 4H), 1.84 - 1.76 (m, 1H), 1.69 (s, 4H), 1.53 (p, 4H), 0.81 (dt, 4H); LC-MS: m/z 393.4 (MH+).

Preparation: 2-(azepan-1-yl)-N-benzyl-4-cyclopropanamide benzamide

The synthesis of the title compound (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) of Example 35 was carried out using benzylamine in place of piperidine. The synthesis was carried out analogously to that of The title compound was obtained in a yield of 69% (66 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 10.86 (s, 1H), 8.22 (d, 1H), 7.94 (s, 1H), 7.52 (s, 1H), 7.43 - 7.29 (m, 5H), 6.98 (dd, 1H), 4.67 (d, 2H), 3.11 - 3.03 (m, 4H), 1.60 - 1.56 (m, 4H), 1.54 - 1.51 (m, 1H), 1.47 (p, 4H), 1.12 (dd , 2H), 0.96 - 0.85 (m, 2H); LC-MS: 392.4 (MH+).

Preparation: 2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)-N-(pyridin-3-ylmethyl)benzamide

The synthesis of the title compound was modified using 3-pyridinylmethanamine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl). ) was performed analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 72% (69 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 11.13 (s, 1H), 8.68 - 8.64 (m, 1H), 8.55 (dd, 1H), 8.21 (d, 1H), 7.97 (s, 1H), 7.76 (dd, 1H), 7.54 (d, 1H), 7.28 (s, 1H), 7.00 (dd, 1H), 4.69 (d, 2H), 3.24 - 2.96 (m, 4H), 1.59 (s, 9H), 1.24 - 1.10 (m, 2H), 0.91 (dd, 2H); LC-MS: 393.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(morpholine-4-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was performed using morpholine in place of piperidine to prepare the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The synthesis was carried out analogously. The title compound was obtained in a yield of 60% (66 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (s, 1H), 7.35 (d, 1H), 7.03 (dd, 1H), 6.95 (d, 1H), 3.76 - 3.40 (m, 6H), 3.26 - 3.07 (m, 6H), 1.81 - 1.44 (m, 9H), 0.81 - 0.74 (m, 4H); LC-MS: m/z 372.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(pyridin-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The title compound was synthesized using 1-(2-pyridinyl)piperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl) (phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 60% (77 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 8.12 (ddd, 1H), 7.55 (ddd, 1H), 7.37 (d, 1H), 7.08 - 6.96 (m, 2H), 6.87 - 6.81 (m, 1H), 6.67 (ddd, 1H), 3.84 - 3.47 (m, 5H), 3.39 - 3.13 (m, 6H), 1.81 - 1.39 (m, 10H), 0.82 - 0.75 (m, 4H) ); LC-MS
: m/z 448.4 (MH+)

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperidine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-ethyl-N-methylhexan-1-amine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine- The synthesis of 1-carbonyl)phenyl)cyclopropanecarboxamide) was carried out analogously to the synthesis of 1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 45% (55 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.11 (s, 1 H), 7.31 (dd, 1 H), 7.03 - 6.97 (m, 1 H), 6.95 - 6.81 (m, 1 H), 3.27 - 3.09 (m, 4 H), 4.61 - 2.54 (m, 4 H), 1.79 - 1.39 (m, 12 H), 1.36 - 1.23 (m, 2 H), 1.22 - 0.82 (m, 4 H), 0.90 - 0.82 (m,
3 H), 0.81 - 0.72 (m, 4 H); LC-MS: m/z 412.5 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-ethoxypiperidine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 4-ethoxypiperidin-1-ium chloride in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl) (phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 61% (75 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.12 (s, 1 H), 7.32 (d, 1 H), 7.04 - 6.96 (m, 1 H), 6.91 (dd, 1 H), 4.17 - 3.39 ( m, 5 H), 3.31 - 2.87 (m, 6 H), 1.80 - 1.7 (m, 1 H), 2.11 - 1.16 (m, 12 H), 1.17 - 1.02 (m, 3 H), 0.83 - 0.72 ( m, 4 H); LC-MS: m/z 414.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-methylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The title compound was synthesized using 1-methylpiperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropane. Carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 76% (86 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.13 (s, 1 H), 7.33 (d, 1 H), 7.01 (dd, 1 H), 6.91 (d, 1 H), 3.88 - 2.96 (m, 8 H), 2.42 - 2.07 (m, 7 H), 1.83 - 1.42 (m, 9 H), 0.85 - 0.72 (m, 4 H); LC-MS: m/z 385.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-benzylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The title compound was synthesized using 1-benzylpiperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropane. Carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 23% (31 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.13 (s, 1 H), 7.37 - 7.27 (m, 5 H), 7.27 -
7.22 (m, 1 H), 7.00 (dd, 1 H), 6.90 (d, 1 H), 3.49 (d, 2 H), 3.69 - 3.08 (m, 4
H), 3.26 - 3.08 (m, 4 H), 2.46 - 2.02 (m, 4 H), 1.79 -1.71 (m, 1 H), 1.71 - 1.44 (m, 8 H), 0.86 - 0.70 (m, 4 H); LC-MS: m/z 461.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-(pyridin-3-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified using 1-pyridin-3-yl-piperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidin-1-carbonyl)). ) phenyl) cyclopropane carboxamide). The title compound was obtained in a yield of 20% (26 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.16 (s, 1 H), 8.31 (d, 1 H), 8.02 (dd, 1 H), 7.37 (d, 1 H), 7.33 (ddd, 1 H ), 7.22 (dd, 1 H), 7.08 - 7.01 (m, 1 H), 7.00 - 6.94 (m, 1 H), 3.24 - 3.19 (m, 4 H), 3.89 - 3.00 (m, 8 H), 1.81 - 1.73 (m, 1 H),
1.73 - 1.60 (m, 4 H), 1.60 - 1.43 (m, 4 H), 0.83 - 0.75 (m, 4 H); LC-MS: m/z 448.4 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-phenylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1-phenylpiperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropane. Carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 28% (21 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.15 (s, 1 H), 7.36 (d, 1 H), 7.28 - 7.16 (m, 2 H), 7.08 - 7.01 (m, 1 H), 6.97 ( d, 1 H), 6.94 (d, 2 H), 6.80 (t, 1 H), 3.91 - 3.26 (m, 4 H), 3.26 - 2.91 (m, 8 H), 1.84 - 1.72 (m, 1 H) ), 1.67 (br s, 4 H), 1.60 - 1.39 (m, 4 H), 0.91 - 0.64 (m, 4 H); LC-MS: m/z 447.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-cyclopentylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1-cyclopentylpiperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropane. Carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 68% (73 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 7.46 (s, 1H), 7.40 (s, 1H), 7.11 (d, 1H), 6.72 (dd, 1H), 4.11 (d, 1H), 3.53 (t , 1H), 3.31 (tt, 6H), 2.77 - 2.11 (m, 6H), 1.96 - 1.61 (m, 12H), 1.52 - 1.34 (m, 4H), 1.11 (q, 2H), 0.88 (dt, 2H) ); LC-MS: m/z
439.5 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[2-(1-benzyltetrazol-5-yl)piperidine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-(1-benzyltetrazol-5-yl)piperidine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine)). -1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 60% (64 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 7.51 - 7.34 (m, 6H), 7.13 - 6.96 (m, 1H), 5.81 - 5.69 (m, 2H), 5.19 - 4.59 (m, 1H), 3.76 - 3.53 (m, 0H), 3.45 - 3.17 (m, 4H), 3.11 - 2.77 (m, 1H), 2.55 - 2.36 (m, 1H), 2.07 - 1.91 (m, 0H), 1.90 - 1.25 (m,
19H), 1.10 (dq, 0H), 0.85 (tt, 2H); LC-MS: m/z 528.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(3,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 1,2-dimethyl-piperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl). ) was performed analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 48% (42 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (d, 1H), 7.35 (dd, 1H), 7.05 - 6.86 (m, 2H), 4.42 - 4.12 (m, 1H), 3.25 - 2.90 (m , 6H), 2.88 - 2.57 (m, 2H), 2.17 (t, 3H), 2.10 - 1.37 (m, 11H), 0.94 (ddd, 3H), 0.82 - 0.75 (m, 4H); LC-MS: m /z 399.3 (MH+).

Preparation: 2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)-N-[4-(4-methylpiperazin-1-yl)phenyl]methyl]benzamide

The synthesis of the title compound was carried out using [4-(4-methylpiperazin-1-yl)phenyl]methanamine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4 -(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 59% (64 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.27 (s, 1 H), 9.83 - 9.70 (m, 1 H), 7.66 - 7.50 (m, 2 H), 7.18 (d, 3 H), 6.89 ( d, 2 H), 4.35 (d, 2 H), 3.15 - 2.97 (m, 8
H), 2.47 - 2.38 (m, 4 H), 2.21 (s, 3 H), 1.81 - 1.70 (m, 1 H), 1.63 - 1.50 (m, 4 H), 1.44 (d, 4 H), 0.85 - 0.72 (m, 4 H); LC-MS: 490.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-pyridin-4-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1-pyridin-4-ylpiperazine in place of piperidine to synthesize the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidin-1-carbonyl) (phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 24% (32 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 8.27 - 7.99 (m, 2H), 7.37 (d, 1H),
7.07 - 6.96 (m, 2H), 6.85 - 6.79 (m, 2H), 3.81 (dd, 1H), 3.62 (dd, 1H), 3.46 (dd, 1H), 3.41 - 3.34 (m, 3H), 3.22 ( LC-MS: m/z 448.4 (MH+)

Preparation: N-[4-(3-phenylthiomorpholine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

4-(Cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (229.52 mg, 0.840 mmol) in MeCN (2.4 mL) and HATU: b] Pyridinyloxy)methylidene]-dimethylammonium; In a solution of hexafluorophosphate (477.2 mg, 1.26 mmol), N,N-diisopropylethylamine (324.4 mg, 2.51 mmol) and 3-phenylthiomorpholine ( 150.0 mg, 0.840 mmol) was added. The reaction mixture was heated to 70°C and stirred overnight. After the reaction was complete, the mixture was cooled to RT and treated s. with NaHCO ₃ (30 mL) and AcOEt (45 mL). s. I poured it inside. The phases were separated and the organic layer was washed with a saturated solution of NH ₄ Cl, dried over Na ₂ SO ₄ and concentrated to dryness under vacuum. The residue was purified by FC on silica gel (eluted from cHex/AcOEt 8:2 to cHex/AcOEt 2:8) to give the formula N-[4-(3-phenylthiomorpholin-4-carbonyl)-3-pyrrolidin-1-yl. A product of phenyl]cyclopropanecarboxamide was obtained.
Yield: 180mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 - 10.01 (m, 1H), 7.58 - 7.19 (m, 5H), 7.19
- 6.76 (m, 3H), 6.17 - 4.52 (m, 1H), 3.83 - 3.65 (m, 1H), 3.29 - 3.21 (m, 4H), 3.16 - 2.58 (m, 4H), 2.46 - 2.29 (m, 1H), 2.03 - 1.62 (m, 5H), 0.89 - 0.61 (m, 4H); LC-MS: m/z 436.17 (MH+).

Preparation: N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

実施例５９

Example 59

4-(Cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (100.0 mg, 0.360 mmol), N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) in DMF (1.823 mL). ) and HATU:([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (207.91 mg, 0.550 mmol) solution was stirred at RT for 15 min. Then, 4,4-difluoropiperidine (53.43 mg, 0.440 mmol) was added and the reaction mixture was stirred at 80 °C for 2 h. After this time, a saturated solution of _NaHCO was added. The reaction was dissolved in AcOEt The organic fractions were collected, washed with brine, dried over _Na2SO4 , filtered and the solvent was evaporated under reduced _pressure.The residue was purified by FC on RP using acidic conditions. Purified (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid) to give a compound of formula N-[4-(4,4-difluoropiperidine) A product of -1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained.
Yield: 58mg

1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.07 (d, 1H), 7.00 (d, 1H), 6.94 (dd, 1H), 4.00 - 3.84 (m, 1H), 3.29 ( s, 1H), 3.55 - 3.39 (m, 2H), 3.23 - 2.98 (m,
4H), 2.14 - 1.82 (m, 8H), 1.77 (tt, 1H), 0.85 - 0.72 (m, 4H); LC-MS: m/z 378.17
(MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by using 1,4-thiazine 1,1-dioxide hydrochloride in place of 4,4-difluoropiperidine to synthesize the compound of Example 59 (N-[4-(4,4-difluoropiperidine -1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 46% (66 mg).

¹ H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 6.95 (dd, 1H), 4.38 (d, 1H), 3.78 (d , 1H), 3.62 (dt, 2H), 3.25 - 2.98 (m, 8H), 1.93 - 1.81 (m, 4H), 1.82 - 1.71 (m, 1H), 0.88 - 0.71 (m, 4H); LC-MS : m/z 390.17 (MH+).

Preparation: N-[3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 4-(trifluoromethyl)piperidine; The synthesis was carried out analogously to the synthesis of 1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 70% (52 mg).

1H NMR (400 MHz, DMSO-d6) δ,10.10 (d, 1H), 7.08 (d, 1H), 7.01 - 6.83(m, 2H), 4.61 (t, 1H), 3.60 (t, 1H), 3.22 - 3.09 (m, 3H), 2.98 (dd, 2H), 2.72 (q, 1H), 2.60 (s, 1H), 1.87 (d, 5H), 1.81 - 1.68 (m, 2H), 1.47 - 1.21 (m , 2H), 0.87 - 0.71 (m, 4H); LC-MS: m/z 410.20 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 1-methyl-3-phenylpiperazine in place of 4,4-difluoropiperidine to synthesize the compound of Example 59 (N-[4-(4,4-difluoropiperidine-1-carbonyl )-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 49% (38.7 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.16 - 10.06 (m, 1 H), 7.78 - 7.16 (m, 5 H), 7.16 - 6.75 (m, 3 H), 5.85 - 4.63 (m, 1 H), 4.51 - 3.11 (m, 4 H), 4.51 - 3.11 (m, 4 H), 3.08 - 2.57 (m, 4 H), 2.28 - 2.16 (m, 3 H), 2.40 - 1.95 (m, 2 H), 1.79 - 1.71 (m, 1 H), 1.94 - 1.56 (m, 4 H), 0.83 -
0.69 (m, 4 H); LC-MS: m/z 433.27 (MH+).

The racemic mixture (Example 62c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: 2R or 2SN-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide hydrochloride

(2R or 2S)N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (enantiomer 1, Example 62a, 10 mg) was dissolved in MeOH (1 mL). ) and treated with 1 eq. The hydrochloride product was obtained.
Yield: 10mg

LC-MS: m/z 433.32 (MH+)

Preparation: N-[3-(3-methylpyrrolidin-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting 4,4-difluoropiperidine and 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid for 4-(trifluoromethyl)piperidine hydrochloride and 4-( The compound of Example 59 (N-[4-(4,4-difluoropiperidin-1-carbonyl)-3- pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 67% (98 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 - 10.05 (m, 1H), 7.11 (d, 1H), 6.98 - 6.84 (m, 2H), 4.78 - 3.40 (m, 1H), 3.27 - 2.53 (m, 6H), 2.37 - 1.66 (m, 5H), 1.60 - 1.15 (m, 5H), 1.10 - 1.01 (m, 3H), 0.86 - 0.73 (m, 4H); LC-MS: m/z 424.16 (MH+).

The racemic mixture (Example 63c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-methylpyrrolidin-1-yl)phenyl]cyclopropanecarboxamide

4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidin-1-yl)benzoic acid (200.0 mg, 0.690 mmol) in DMF (7.291 mL), N,N-diisopropylethylamine (0 A stirred solution of HATU ([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (395.61 mg, 1.04 mmol) was stirred at RT. 1-methyl-3-phenylpiperazine (146.71 mg, 0.830 mmol) was then added and the reaction mixture was stirred at RT overnight. The next day, a saturated solution of _NaHCO was added to the reaction mixture. and the aqueous phase was extracted three times with AcOEt. The organic portion was collected, washed with brine, dried over Na _SO and the solvent was evaporated under _reduced pressure. The residue was purified by FC on a NH column. (eluting from 100% cHex to 100% AcOEt), formula N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-methylpyrrolidin-1-yl)phenyl]cyclopropanecarboxamide The product was obtained as a mixture of diastereoisomers.
Yield: 150mg

LC-MS: m/z 447.23 (MH+)

The mixture of diastereoisomers was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: N-[3-(6-Azaspiro[3.4]octan-6-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

Example 65

2-(6-Azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid (112.0 mg, 0.360 mmol), HATU: [dimethylamino(3-triazolo[4, 5-b]pyridinyloxy)methylidene]-dimethylammonium; hexafluorophosphate (162.55 mg, 0.430 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.43 mmol) were mixed in DMF (3 mL). Stir for 5 minutes and add thiomorpholine 1,1-dioxide (48.16 mg, 0.360 mmol). The reaction mixture was stirred at RT overnight. The next day, water was added and the mixture was extracted three times with AcOEt. The combined organics were washed with brine, dried on a phase separator, and then concentrated under vacuum. The residue was purified by FC on RP using basic conditions (eluted from 100% water + 0.1% NH ₄ OH to water + 0.2% NH ₄ OH/CH ₃ CN 6:4), giving the formula The product of (N-[3-(6-azaspiro[3.4]octan-6-yl)-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide Obtained.
Yield: 26.8mg

1H NMR (600 MHz, DMSO-d6 ) δ ppm 10.12 (s, 1 H), 7.16 - 7.03 (m, 2 H), 6.90 (dd, 1 H), 4.33 - 4.45 (m, 1 H), 3.71 - 3.83 (m, 1 H), 3.70 - 3.60 (m, 1 H), 3.59
- 3.48 (m, 1 H), 3.36 - 2.97 (m, 8 H), 2.04 - 1.80 (m, 8 H), 1.79 - 1.72 (m, 1 H), 0.90 - 0.65 (m, 4 H); LC -MS: m/z 432.2 (MH+).

Preparation: N-[3-(6-Azaspiro[3.4]octan-6-yl)-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1-methyl-3-phenylpiperazine in place of thiomorpholine 1,1-dioxide to synthesize the compound of Example 65 (N-[3-(6-azaspiro[3.4]octane- The synthesis of the compound 6-yl)-4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)phenyl])cyclopropanecarboxamide) was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 20% (30 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.18 - 10.00 (m, 1 H), 7.16 - 6.99 (m, 1 H), 6.99 - 6.92 (m, 1 H), 6.92 - 6.84 (m, 1 H ), 7.84 - 6.66 (m, 5 H), 5.87 - 4.60 (m, 1 H), 3.28 - 3.20 (m, 2 H), 3.06 - 2.61 (m, 2 H), 4.48 - 2.29 (m, 6 H) ), 2.27
- 2.10 (m, 3 H), 1.80 - 1.69 (m, 1 H), 2.09 - 1.53 (m, 8 H), 0.84 - 0.67(m, 4 H); LC-MS: m/z 473.2 (MH+) .

The racemic mixture (Example 66c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: Syn N-[3-[-3,5-dimethylpiperidin-1-yl]-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting syn-4-(cyclopropanecarbonylamino)-2-[ Using (3,5-dimethylpiperidin-1-yl)benzoic acid, the compound of Example 65 (N-[3-(6-azaspiro[3.4]octan-6-yl)-4-(1 , 1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 20% (21 mg).

¹ H NMR (400 MHz, DMSO-d6 ) δ ppm 10.27 (s, 1 H), 7.42 (d, 1 H), 7.26 (dd, 1 H), 7.15 (d, 1 H), 4.29 - 3.39 (m , 4 H), 3.30 - 3.00 (m, 2 H), -3.61 - 2.97 (m, 4
H), 2.38 - 1.88 (m, 2 H), 1.84 - 1.72 (m, 2 H), 1.71 - 1.48 (m, 2 H), 0.82 - 0.74 (m, 4 H), 0.99 - 0.71 (m, 6 H), 0.62 (q, 1 H); LC-MS: m/z 434.2 (MH+)

Preparation: Syn N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting syn-4-(cyclopropanecarbonylamino)-2-[ Using (3,5-dimethylpiperidin-1-yl)benzoic acid, the compound of Example 66 (N-[3-(6-azaspiro[3.4]octan-6-yl)-4-(4- The synthesis was carried out analogously to the synthesis of methyl-2-phenylpiperazine-1-carbonyl)phenyl])cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 62% (92 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.31- 10.06 (m, 1 H), 7.81 - 6.94 (m, 8 H),
5.74 (br s, 1 H), 2.94 - 2.22 (m, 4 H), 2.17 (s, 2 H), 1.82 - 1.76 (m, 1 H), 4.43 - 1.69 (m, 6 H), 2.01 - 1.53 (m, 3 H), 2.07 - 1.03 (m, 1 H), 0.82 - 0.74 (m,
4 H), 0.71 - 0.41 (m, 1 H), 0.99 - 0.38 (m, 6 H); LC-MS: m/z 475.3 (MH+).

The racemic mixture (Example 68c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: Anti-N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid (50.0 mg, 0.160 mmol) and N,N-diisopropylethylamine in DMF (1.58 mL) (0.07 mL, 0.400 mmol) was added HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (60.09 mg, 0.160 mmol). was added and the mixture was stirred at RT for 30 minutes. After this time, 1-methyl-3-phenylpiperazine (32.03 mg, 0.180 mmol) was added and the reaction was stirred at room temperature overnight. The next day, H ₂ O was added and the formation of a precipitate was observed. The solids were filtered and washed with _H2O . The resulting solid was first purified by FC on RP using acidity (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 6:4 + 0.1% formic acid) and further Purified by semi-preparative MDAP Method:

Preparation: Syn 2R or 2SN-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide hydrochloride

Syn 2R or 2SN-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (enantiomer 1, Example 68a, 14 mg ) was dissolved in MeOH (1 mL) and treated with 1 eq HCl in dioxane and after evaporation, the formula syn2R or 2SN-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl A product of -2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide hydrochloride was obtained.
Yield: 10.1mg

LC-MS: 475.33 (MH+)

Preparation: N-[4-(2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-phenylpiperazine-1-carboxylate (156.0 mg, 0.300 mmol) in DCM (3 mL). Trifluoroacetic acid (1.0 mL, 23.77 mmol) was added to the solution and the reaction was allowed to stand overnight at RT. The solvent was removed under vacuum and the residue was purified by SCX, washing with MeOH and eluting with 1N _NH3 in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluted from 100% DCM to DCM/MeOH 95:5) to give the formula N-[4-(2-phenylpiperazine-1-carbonyl) as a racemic mixture. )-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide product was obtained.
Yield: 85 mg.

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.18 - 9.98 (m, 1 H), 7.15 - 7.02 (m, 1 H),
6.99 - 6.70 (m, 1 H), 7.98 - 6.57 (m, 6 H), 5.71 - 4.57 (m, 1 H), 3.31 - 2.76 (m, 4 H), 2.84 - 2.54 (m, 2 H), 4.49 - 2.54 (m, 4 H), 1.79 - 1.74 (m, 1 H), 2.01 - 1.54 (m, 4 H), 0.84 - 0.65 (m, 4 H); LC-MS: 419.2 (MH+).

Preparation: N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate (200.0 mg, To the solution (0.370 mmol) was added trifluoroacetic acid (0.29 mL, 3.73 mmol) and the reaction was stirred at RT for 2 hours. The solvent was removed under vacuum and the residue was purified by SCX, washing with MeOH and eluting with 1N _NH3 in MeOH. The basic fractions were evaporated to yield the product of formula N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide as a racemic mixture. Ta.
Yield: 95mg

LC-MS: m/z 437.17 (MH+)

Preparation: N-[4-[2-(4-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[ The synthesis was carried out analogously to the synthesis of 4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemate in a yield of 95% (85 mg).

LC-MS: m/z 437.18 (MH+).

Preparation: N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(3-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[ The synthesis was carried out analogously to the synthesis of 4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemate in a yield of 99% (75 mg).

LC-MS: m/z 437.18 (MH+).

Preparation: N-[3-(6-Azaspiro[3.4]octan-6-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. Using tert-butyl [2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophen-2-ylpiperazin-1-carboxylate, The synthesis of the compound of Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide) was performed analogously. The title compound was obtained as a racemic mixture in a yield of 60% (14 mg).

LC-MS: m/z 465.18 (MH+).

Preparation: N-[3-pyrrolidin-1-yl-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[4 -[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemate in a yield of 99% (170 mg).

LC-MS: m/z 425.12 (MH+).

Preparation: N-[4-[2-(1-methylpyrazol4-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 was prepared using tert-butyl [4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate. Synthesis of (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide) was carried out in the same manner. The title compound was obtained as a racemic mixture in a yield of 88% (88 mg).

LC-MS: m/z 425.12 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[2-(thiophen-2-yl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophen-2-ylpiperazin-1-carboxylate (145.0 mg, 0.260 mmol) Dissolved in DCM (4 mL) and added trifluoroacetic acid (0.2 mL, 2.62 mmol). After stirring the mixture overnight at RT, the volatiles were removed under vacuum and the residue was loaded onto an SCX, washed with MeOH and eluted with 1N _NH3 in MeOH. Evaporation of the basic fraction yielded a compound of formula (N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide). and was used in the next step without further purification.
Yield: 94mg

LC-MS: 453.2 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-thiophen-3-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N The synthesis of -(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 96% (51 mg).

LC-MS: m/z 453.2 (MH+)

Preparation: N-[3-(azepan-1-yl)-4-[2-(1-methylpyrazol-4-yl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using Example using tert-butyl -[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate The synthesis of compound No. 35 (N(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) was carried out in the same manner. The title compound was obtained in a yield of 92% (53 mg).

LC-MS: m/z 451.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N- The synthesis was carried out analogously to the synthesis of (3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 91% (60 mg).

LC-MS: m/z 448.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[2-(trifluoromethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N -(3-(azepan-1-yl)
-4-(Piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in 90% yield (33 mg).

LC-MS: m/z 439.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-benzylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The title compound was synthesized using tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophen-2-ylpiperazine-1-carboxylate. The compound of Example 35 (N-(3 -(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 80% (65 mg).

LC-MS: m/z 461.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[2-(hydroxymethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N- The synthesis was carried out analogously to the synthesis of (3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 86% (72 mg).

LC-MS: m/z 401.6 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-methylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N-(3- (azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 80% (70 mg).

LC-MS: m/z 385.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-propan-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N The synthesis of -(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 83% (80 mg).

LC-MS: m/z 413.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using The compound of Example 35 (N-(3- (azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 83% (80 mg).

LC-MS: m/z 447.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The title compound was synthesized using tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophen-2-ylpiperazine-1-carboxylate. The compound of Example 35 (N The synthesis of -(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 92% (60 mg).

LC-MS: 448.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide (94.0 mg, 0.210 mmol) in methanol (5 mL) and To a mixture of 37% formaldehyde in _H2O (0.15 mL, 2.08 mmol) at 0<0>C was added sodium triacetoxyborohydride (264.1 mg, 1.25 mmol). The reaction was allowed to warm to RT and stirred overnight. The next day, the reaction was concentrated under vacuum, AcOEt and water were added and the organic phase was separated. The aqueous phase was back-extracted twice with AcOEt, then the combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from cHex 100% to cHex/AcOEt 10:90), which was further purified by FC on RP using basic conditions (100% water + 0.2% _NH4OH ). to water + 0.2% NH4OH/ _CH3CN6 :4), formula N-[3-(azepan-1-yl)-4-(4-methyl-2-thiophen-2-ylpiperazine-1-) The product carbonyl)phenyl]cyclopropane carboxamide was obtained.
Yield: 36mg

1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 - 10.06 (m, 1 H), 7.47 - 7.24 (m, 2 H),
7.23 -6.55 (m, 4 H), 6.01 - 4.27(m, 1 H), 2.27 - 2.19 (m, 3 H), 4.40 - 1.84 (m,
10 H), 1.81 - 1.67 (m, 1 H), 1.85 - 1.17 (m, 8 H), 0.86 - 0.69 (m, 4 H); LC-MS: 467.21 (MH+).

The racemic mixture (Example 69c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-(3-(azepan-1-yl)-4-(4-methyl-2-(thiophen-3-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide. azepan-1-yl)-4-(2-thiophen-3-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide). -yl)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide. The title compound was synthesized in 32% yield (17 mg). I got it.

1H NMR (400 MHz, DMSO-d6 ) d ppm 10.06 - 10.27 (m, 1 H) 6.73 - 7.68 (m, 6 H) 4.29 - 5.77 (m, 1 H) 3.35 - 3.41 (m, 1 H) 2.57 - 3.26 (m, 5 H) 2.09 - 2.38 (m, 4 H) 1.05 - 2.01 (m, 12 H) 0.66 - 0.86 (m, 4 H); LC-MS: m/z 467.3 (MH+).

The racemic mixture (Example 70c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-(3-(azepan-1-yl)-4-(4-methyl-2-(1-methyl-1H-pyrazol-3-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound consisted of replacing N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane carboxamide with Compounds of Example 69a-c (N-(3-( Synthesis of azepan-1-yl)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide was carried out analogously. The title compound was obtained in 40% yield. (21 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.27 - 9.96 (m, 1 H), 7.78 -7.49 (m, 1 H), 7.48 - 7.20 (m, 2 H), 7.05 - 6.75 (m, 2 H ), 5.74 - 4.39(m, 1 H), 3.86 - 3.67 (m,
3 H), 2.22 - 2.16 (m, 3 H), 4.37 - 1.83 (m, 10 H), 1.81 - 1.27 (m, 9 H), 0.86
- 0.68 (m, 4 H); LC-MS: m/z 465.5 (MH+).

The racemic mixture was then separated into single enantiomers by preparative HPLC.

Preparation: N-(3-(azepan-1-yl)-4-(2-phenyl-4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide. Compounds of Example 69a-c (N-(3-(azepan-1-yl)-4- The synthesis of (4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 70% (80 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.27 - 9.95 (m, 1H), 7.81 - 6.76 (m, 8H), 5.89 - 4.49 (m, 1 H), 3.39 - 2.87 (m, 4 H), 2.15 (br s, 3 H), 4.46 - 1.86 (m, 6H), 1.83 - 1.67 (m, 1H), 1.84 - 1.25 (m, 8 H), 0.88 - 0.67 (m, 4H); LC-MS: m/z 461.4 (MH+).

The racemic mixture was then separated into single enantiomers by preparative HPLC.

Preparation: N-[3-(azepan-1-yl)-4-(2-phenyl-4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (110.0 mg, 0.250 mmol) in MeCN (1.5 mL) and N, To a solution of N-diisopropylethylamine (0.06 mL, 0.370 mmol) was added 1-bromopropane (45.44 mg, 0.370 mmol) and the reaction was stirred at 60° C. overnight. The next day, the reaction was concentrated to dryness and the residue was taken up in AcOEt. The organic phase was soaked with _NaHCO3 s. s. , brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified with FCNH (eluted from 100% cHex to cHex/AcOEt 6:4), which was further purified by FC on RP (eluted from water/ _CH3CN 95:5 to water/ _CH3CN 5:95). , a product of formula (N-[3-(azepan-1-yl)-4-(2-phenyl-4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide) was obtained.
Yield: 72mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.36 - 9.79 (m, 1 H), 8.12 - 6.60 (m, 8 H),
5.93 - 4.45 (m, 1 H), 3.62 - 3.35 (m, 1 H) 3.35 - 2.83 (4 H), 4.44 - 2.82 (m, 2
H), 2.81 - 2.62 (m, 1 H), 2.43 - 2.28 (m, 1 H), 2.29 - 2.19 (m, 2 H), 2.11 - 1.87 (m, 1 H), 1.80 - 1.66 (m, 1 LC-MS: m/z 489.4 (MH+).

The racemic mixture (Example 73c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(Azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cycloprophane carboxamide. Azepan-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide was used to prepare the compound of Example 69a-c The synthesis was carried out analogously to the synthesis of cyclopropanecarboxamide)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 70% (21 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.28 - 9.92 (m, 1 H), 8.70 - 8.37 (m, 1 H),
7.88 - 7.65 (m, 1 H), 7.55 - 6.68 (m, 5 H), 5.72 - 4.54 (m, 1 H), 2.10 (s, 3 H), 4.53 - 1.86 (m, 10 H), 1.85 - 1.36 (m, 9 H), 0.92 - 0.63 (m, 4 H); LC-MS: m/z 462.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[4-methyl-2-(trifluoromethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(Azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cycloprophane carboxamide. azepan-1-yl)-4-[2-(trifluoromethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was used to prepare the compound of Example 69a-c The synthesis was carried out analogously to the synthesis of cyclopropanecarboxamide)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 13% (4.4 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.31 - 10.07 (m, 1H), 7.52 - 7.33 (m, 1H), 6.98 (br s, 1H), 6.98 - 6.79 (m, 1H), 5.34 - 3.86 (m, 1H), 3.32 (s, 2H), 3.27
- 3.18 (m, 4H), 2.23 - 2.14 (m, 3H), 2.50 (s, 4 H), 1.77 - 1.40 (m, 9 H), 0.89 - 0.72 (m, 4 H); LC-MS: m /z 453.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2-benzyl-4-methylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed using N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cycloprophane carboxamide. (Azepan-1-yl)-4-(2-benzylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was used to prepare the compound of Example 69a-c (N-(3-(azepan-1-yl)- The synthesis of 4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 40% (27 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.23 - 9.99 (m, 1H), 7.46 - 6.21 (m, 8 H), 4.89 - 3.40 (m, 1H), 3.25 - 3.17 (m, 4 H) 2.20 - 2.10 (m, 3 H), 4.49 - 1.79 (m, 8 H), 1.78 - 1.36 (m, 9 H), 0.97 - 0.69 (m, 4H); LC-MS: 475.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[2-(hydroxymethyl)-4-methylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using N-[3-(azepan-1-yl)-4-(2-thiophene-2
-ylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide instead of N-[3-(azepan-1-yl)-4-[2-(hydroxymethyl)piperazine-1-carbonyl]phenyl]cyclopropanecarboxamide The compound of Example 69a-c (N-(3-(azepan-1-yl)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclo Propane carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 12.3% (9.2 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.19 - 10.05 (M, 1 H), 7.39 - 7.27 (m, 1H), 7.08 - 6.80 (m, 2 H), 4.90 - 4.56 (m, 1H), 4.90 - 4.56 (m, 1H), 3.84 - 3.38 (m, 2H), 4.51 - 3.32 (m, 1H) 4.33 - 3.18 (m, 1H), 3.27 - 3.17 (m, 4H), 3.11 - 2.83 ( m, 1H), 2.23 - 2.08 (m, 3H), 3.14 - 1.77 (m, 4H), 1.75 - 1.43 (m, 9H), 0.85
- 0.71 (m, 4 H); LC-MS: 415.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(2,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide. Compounds of Example 69a-c (N-(3-(azepan-1-yl)-4- The synthesis of (4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 60% (24 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 7.37 - 7.29 (m, 1H), 7.05 - 6.98 (m, 1H), 6.95 - 6.73 (m, 1H), 4.73 - 3.47 (m, 1H), 3.28 - 3.11 (m, 6H), 3.02 - 2.57 (m, 2H), 2.22 - 1.95 (m, 4H), 1.85 - 1.42 (m, 10H), 1.27 - 1.04 (m, 3H) , 0.84
- 0.74 (m, 4H); LC-MS: m/z 399.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-2-propan-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide. The compound of Example 69a-c (N-(3-(azepan-1-yl) )-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 53% (22 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.14 (d, 0H), 7.41 - 7.33 (m, 1H), 7.02 (ddd, 1H), 6.94 - 6.79 (m, 1H), 4.41 - 4.07 (m LC -MS: 427.1 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(Azepan-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cycloprophane carboxamide. Azepan-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide was used to prepare the compound of Example 69a-c The synthesis was carried out analogously to the synthesis of cyclopropanecarboxamide)-4-(4-methyl-2-(thiophen-2-yl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 70% (21.5 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.28 - 9.92 (m, 1 H), 8.70 - 8.37 (m, 1 H),
7.88 - 7.65 (m, 1H), 7.55 - 6.68 (m, 5H), 5.72 - 4.54 (m, 1H), 4.53 - 1.86 (m,
10 H), 2.10 (s, 3 H), 1.85 - 1.36 (m, 9 H), 0.92 - 0.63 (m, 4 H); LC-MS: m/z 462.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl] phenyl] cyclopropane carboxamide

To a solution of N-[3-(azepan-1-yl)-4-(2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (55.0 mg, 0.120 mmol) in MeCN (3.5 mL) N,N-diisopropylethylamine (0.04 mL, 0.250 mmol) was added followed by 3,5-dimethyl 4-isoxazole carbaldehyde (23.12 mg, 0.180 mmol). After stirring the reaction mixture for 15 minutes, sodium triacetoxyborohydride (52.2 mg, 0.250 mmol) was added. The resulting mixture was stirred at RT overnight. The next day, the mixture was diluted with AcOEt, washed with brine, dried over _Na2SO4 , filtered, and concentrated under vacuum _. The residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 3:7) and was given the formula N-[3-(azepan-1-yl)-4-[4-[(3,5- A product of dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide was obtained.
Yield: 32mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (t, 1H), 7.71 - 7.40 (m, 1H), 7.37 - 7.18 (m, 4H), 7.13 - 7.00 (m, 1H), 6.96 - 6.85 (m, 1H), 5.75 (d, 1H), 4.90 - 4.17 (m, 1H), 3.50 - 3.19 (m, 4H), 3.11 - 2.61 (m, 4H), 2.44 - 1.95 (m, 9H), 1.86 - 1.22 (m, 10H), 0.78 (d, 4H); LC-MS: m/z 556.4 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[4-(1,2-oxazol-3-ylmethyl)-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 1,2-oxazole-3-carbaldehyde in place of 3,5-dimethyl-4-isoxazolecarbaldehyde to synthesize the compound of Example 81 (N-[3-(azepane-1 cyclopropanecarboxamide) I went. The title compound was obtained in a yield of 20% (7 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (t, 1H), 8.93 - 8.83 (m, 1H), 7.77 - 6.82 (m, 8H), 6.62 - 6.31 (m, 1H), 5.82 - 5.67 (m, 1H), 4.62 - 3.44 (m, 3H), 3.30 - 3.27 (m, 2H), 3.21 - 2.66 (m, 4H), 2.45 - 2.05 (m, 2H), 1.86 - 1.16 (m, 10H) , 0.85
- 0.62 (m, 4H); LC-MS: m/z 528.3 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-[4-(1,3-oxazol-2-ylmethyl)-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 2-oxazolecarboxaldehyde in place of 3,5-dimethyl-4-isoxazolecarbaldehyde to synthesize the compound of Example 81 (N-[3-(azepan-1-yl)-4 -[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 42% (15 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 - 10.06 (m, 1H), 8.21 - 8.04 (m, 1H), 7.83 - 7.11 (m, 7H), 7.07 - 6.84 (m, 2H), 5.85 - 4.28 (m, 1H), 3.87 - 3.37 (m, 2H), 3.28 - 3.23 (m, 2H), 3.19 - 2.61 (m, 4H), 2.39 - 2.16 (m, 1H), 1.92 - 1.28 (m, 11H), 0.78 (d, 5H); LC-MS: m/z 528.3 (MH+)

Preparation: N-[4-[2-(2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

Solution of N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (95.0 mg, 0.220 mmol) in methanol (5 mL) Formaldehyde (176.63 mg, 2.18 mmol) and sodium triacetoxyborohydride (276.75 mg, 1.31 mmol) were added to the mixture. The reaction was stirred at room temperature overnight. The next day, the reaction was concentrated to dryness under reduced pressure, washed with MeOH, and purified by SCX eluting with 1N _NH3 in MeOH. The basic fractions were evaporated and the residue was purified by FC on an NH column (eluted from 100% cHex to cHex/AcOEt 1:1) to give the formula N-[4-[2-(2-fluorophenyl)-4- The product methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained as a racemic mixture.
Yield: 54mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.36 - 9.83 (m, 1 H), 8.06 - 7.40 (m, 1 H),
7.39 - 7.25 (m, 1 H), 7.24 - 6.41 (m, 5 H), 6.07 - 4.84 (m, 1 H), 4.65 - 2.64 (m, 8 H), 2.42 - 2.23 (m, 1 H), 2.21 - 2.09 (m, 3 H), 1.80 - 1.71 (m, 1 H), 2.06 - 1.42 (m, 5 H), 0.87 - 0.66 (m, 4 H); LC-MS: 451.19 (MH+).

The racemic mixture (Example 84c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[3-(6-Azaspiro[3.4]octan-6-yl)-4-(4-methyl-2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-(6- Compounds of Example 84a-c (N-[4 -[2-(2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 17% (2.5 mg).

H NMR (500 MHz, METHANOL-d4 ) δ ppm 7.40 - 7.27 (m, 2 H), 7.07 - 7.03 (m, 1 H), 6.90 - 6.82 (m, 1 H), 7.19 - 6.59 (m, 1 H ), 7.48 - 6.56 (m, 1 H), 6.17 - 4.97
(m, 1 H), 4.55 - 3.35 (m, 2 H), 3.06 - 3.02 (m, 1 H), 3.00 - 2.86 (m, 1 H), 2.85 - 2.73 (m, 1 H), 2.67 - 2.57 (m, 1 H), 4.64 - 2.39 (m, 2 H), 2.51 - 2.38 (m, 1
H), 2.35 - 2.26 (m, 3 H), 2.12 - 1.94 (m, 1 H), 1.81 - 1.65 (m, 1 H), 2.22 - 1.58 (m, 8 H), 1.00 - 0.81 (m, 4 H), LC-MS: m/z 479.2 (MH+).

Preparation: N-[4-(4-methyl-2-thiophen-2-ylpiperazin-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[3-pyrrolidine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. Compounds of Example 84a-c (N-[4-[2-(2-fluorophenyl) )-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 5.3% (15.9 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.26 - 10.01 (m, 1 H), 7.45 - 7.32 (m, 1 H), 7.27 - 6.55 (m, 5 H), 6.05 - 4.83 (m, 1 H ), 4.39 - 2.61 (m, 8 H), 2.40 - 2.16 (m, 4 H), 2.06 - 1.82 (m, 3 H), 1.80 - 1.71 (m, 1 H), 1.71 - 1.52 (m, 2 H) ), 0.83
- 0.72 (m, 4 H); LC-MS: m/z 437.25 (MH+).

The racemic mixture (Example 86c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[4-[4-methyl-2-(1-methylpyrazol-4-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by replacing N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide with (1-Methylpyrazol-4-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was used to prepare the compound of Example 84a-c (N-[4-[2-( The synthesis was carried out analogously to the synthesis of 2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl])cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 30% (27 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.23 - 9.99 (m, 1 H), 7.80 - 7.50 (m, 1 H),
7.48 - 7.01 (m, 1 H), 7.15 - 6.68 (m, 3 H), 5.70 - 4.50 (m, 1 H), 3.89 - 3.67 (m, 3 H), 4.38 - 2.57 (m, 8 H), 2.29 - 2.07 (m, 4 H), 2.04 - 1.57 (m, 6 H), 0.87 - 0.68 (m, 4 H), LC-MS: m/z 437.23 (MH+).

Preparation: N-[4-[2-(3-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (72.0 mg, 0.160 mmol) in DMF (1 mL) and carbonic acid To a mixture of potassium (42.86 mg, 0.310 mmol) was added a solution of 4-methylbenzenesulfonic acid methyl ester (28.87 mg, 0.160 mmol) in DMF (0.500 mL) and the reaction was allowed to cool at RT. It was stirred overnight. The next day, the reaction was treated s.c. with _NaHCO3 and AcOEt. s. poured into. The two phases were separated and the organic was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness under vacuum. The residue was washed with MeOH and purified by SCX eluting with 1N _NH3 in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 1:1) with formula N-[4-[2-(3-fluorophenyl)-4 -Methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide product was obtained.
Yield: 31mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.20 - 10.05 (m, 1 H), 7.59 - 6.99 (m, 2 H), 7.18 - 6.79 (m, 2 H), 7.61 - 6.76 (m, 3 H ), 5.83 - 4.65 (m, 1 H), 4.50 - 3.25 (m, 1 H), 3.30 - 2.94 (m, 4 H), 2.82 - 2.57 (m, 1 H), 3.48 - 2.54 (m, 2 H) ), 2.39
- 2.22 (m, 1 H), 2.27 - 2.13 (m, 3 H), 2.05 - 1.85 (m, 1 H), 1.80 - 1.71 (m, 1 H), 1.98 - 1.59 (m, 4 H), 0.86 - 0.68 (m, 4 H); LC-MS: m/z 451.16(MH+).

The racemic mixture (Example 88c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[4-[2-(4-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by replacing [N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide with N-[4-[ Compounds of Examples 88a-c (N-[4-[2-(3- The synthesis of fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide) was performed analogously. The title compound was obtained as a racemic mixture in a yield of 48% (42 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.10 (d, 1H), 7.90 - 7.37 (m, 1H), 7.28 - 7.12 (m, 3H), 7.02 - 6.76 (m, 3H), 5.89 - 4.25 (m , 1H), 3.09 - 2.63 (m, 8H), 2.38 - 2.15 (m, 3H), 1.91 (s, 4H), 1.68 (d, 3H), 0.76 (d, 4H); LC-MS: m/z 451.24 (MH+)

Examples of compounds in which the R1 group is varied can be prepared using Synthetic Scheme 4.

Synthesis scheme 4

Synthesis Scheme 4 - Reagents and conditions: a) azepane, CH ₃ CN, 80° C., 3 days; b) 1-propylpiperazine dihydrobromide, HATU, DIPEA, DMF, rt, overnight; c) H ₂ 1 atm _, Pd-C10%, EtOH, rt, 2h; d) Coupling

Preparation: 2-(azepan-1-yl)-4-nitrobenzoic acid hydrochloride

A mixture of 2-fluoro-4-nitrobenzoic acid (4.0 g, 21.61 mmol) and homopiperidine (12.18 mL, 108.04 mmol) in MeCN (40 mL) was stirred at 80° C. for 4 days. The reaction was concentrated under vacuum, the residue was taken up with HCl 1N and the suspension was filtered. The solid was then washed with H ₂ O and dried under vacuum to yield the product of formula 2-(azepan-1-yl)-4-nitrobenzoic acid hydrochloride. This product was used in the next step without further purification.
Yield: 5.14g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 14.11 (bs, 1H), 7.81 (d, 1H), 7.72 (d, 1H), 7.59 (dd, 1H), 3.71 (bs, 1H), 3.44 - 3.32 (m, 4H), 1.79 (s, 4H), 1.57 (dq, 4H); LC-MS: m/z 265.1 (MH+)

Preparation: 1-[5-nitro-2-(4-propylpiperazine-1-carbonyl)phenyl]azepane

2-(azepan-1-yl)-4-nitrobenzoic acid hydrochloride (650 mg, 2.16 mmol) and [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene in DMF (21.8 mL). ]-Dimethylammonium; To a mixture of hexafluorophosphate (821.8 mg, 2.16 mmol) was added N,N-diisopropylethylamine (0.38 mL, 2.16 mmol). The reaction was stirred at RT for 30 min, after this time N,N-diisopropylethylamine (0.75 mL, 4.32 mmol) and 1-propylpiperazine dihydrobromide (626. A solution of 87 mg, 2.16 mmol) was added. The reaction mixture was stirred at RT overnight. The next day, the reaction was washed s.c. with _NaHCO3 . s. and extracted three times with AcOEt. The organic phase was then washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on a NH column (eluting from cHex/AcOEt 95:5 to cHex/AcOEt 1:1) and was purified with the formula ([2-(azepan-1-yl)-4-nitrophenyl]-(4-propylpiperazine). -1-yl)methanone) was obtained.
Yield: 870mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 (d, 1H), 7.57 (dd, 1H), 7.28 (d, 1H), 3.72 -
3.52 (m, 2H), 3.42 - 3.31 (m, 2H), 3.22 - 3.14 (m, 2H), 2.46 - 2.38 (m, 2H), 2.35 - 2.20 (m, 4H), 1.76 - 1.70 (m, 4H) ), 1.65 - 1.48 (m, 4H), 1.48 - 1.39 (m, 4H), 0.86 (t, 3H); LC-MS: m/z 375.3 (MH+)

Preparation: 3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)aniline

Pd-C ( 341.02 mg, 0.320 mmol) was added. The reaction was stirred at RT under _H2 atmosphere for 2 hours. After this time, the reaction was filtered through a pad of celite and concentrated under vacuum to produce a compound with the formula [4-amino-2-(azepan-1-yl)phenyl]-(4-propylpiperazin-1-yl). The product of methanone was obtained.
Yield: 1g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.68 (d, 1H), 6.15 (d, 1H), 6.03 (dd, 1H), 5.10 (s, 2H), 3.54 (d, 2H), 3.23 - 3.08 (m, 6H), 2.45 - 2.10 (m, 6H), 1.74 - 1.32 (m, 10H), 0.85 (t, 3H); LC-MS: m/z 345.3 (MH+)

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclobutanecarboxamide

4-amino-2-(azepan-1-yl)phenyl]-(4-propylpiperazin-1-yl)methanone (100 mg, 0.290 mmol) in DMF (2 mL), cyclobutanecarboxylic acid (0.03 mL, 0 N,N-diisopropylethylamine (.350 mmol) and [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium; 56.27 mg, 0.440 mmol) was added and the reaction was allowed to stir at RT overnight. The next day, s.c. of _NaHCO3 . s. was added to the reaction, which was extracted three times with AcOEt. The combined organic phases were then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% DCM to DCM/MeOH 9:1) and further purified by FC on a NH column (eluted from cHex/AcOEt 8:2 to AcOEt 100%), giving the formula N-[ A compound of 3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclobutanecarboxamide was obtained.
Yield: 75mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 9.66 (s, 1 H), 7.33 (d, 1 H), 7.05 (dd, 1 H), 6.90 (d, 1 H), 3.24 - 3.17 (m, 5 H), 3.73 - 3.06 (m, 4 H), 2.25 - 2.13 (m, 5 H), 2.44 - 2.13 (m, 4 H), 2.09 (dtd, 2 H), 2.01 - 1.88 (m, 1 H) ), 1.85 - 1.75 (m, 1 H), 1.74 - 1.61 (m, 4 H), 1.60 - 1.47 (m, 4 H), 1.42 (sxt, 2 H), 0.84 (t, 3 H); LC- MS: m/z 427.32 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)benzamide

The synthesis of the title compound was modified using benzoic acid in place of cyclobutanecarboxylic acid to synthesize the compound of Example 90 (N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl ) was performed analogously to the synthesis of cyclobutanecarboxamide). The title compound was obtained in a yield of 66% (85 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 7.99 - 7.91 (m, 2H), 7.63 - 7.45 (m, 4H), 7.31 (dd, 1H), 6.98 (d, 1H) ), 3.59 (d, 2H), 3.27 - 3.13 (m, 6H), 2.43 - 2.13 (m, 6H), 1.79 - 1.67 (m, 4H), 1.58 (dd, 4H), 1.49 - 1.39 (m, 2H) ), 0.86 (t, 3H); LC-MS: m/z 449.3 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)-2,2-difluorocyclopropane-1-carboxamide

The synthesis of the title compound was carried out using 2,2-difluoro-1-cyclopropanecarboxylic acid in place of cyclobutanecarboxylic acid to prepare the compound of Example 90 (N-(3-(azepan-1-yl)-4-( The synthesis was carried out analogously to the synthesis of 4-propylpiperazine-1-carbonyl)phenyl)cyclobutanecarboxamide). The title compound was obtained in a yield of 45% (30 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 7.30 (d, 1H), 7.07 - 6.91 (m, 2H),
3.74 - 3.48 (m, 2H), 3.27 - 3.14 (m, 6H), 2.93 - 2.72 (m, 1H), 2.43 - 2.17 (m, 6H), 2.06 - 1.92 (m, 2H), 1.74 - 1.66 (m , 4H), 1.63 - 1.50 (m, 4H), 1.43 (q, 2H), 0.85 (t, 3H); LC-MS: m/z 449.6 (MH+).

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)isobutyramide

The synthesis of the title compound was modified using 2-methylpropanoic acid in place of cyclobutanecarboxylic acid to synthesize the compound of Example 90 (N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1- The synthesis was carried out analogously to the synthesis of carbonyl)phenyl)cyclobutanecarboxamide). The title compound was obtained in a yield of 63% (76 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.77 (s, 1H), 7.36 (d, 1H), 7.05 (dd, 1H), 6.91 (d, 1H), 3.74 - 3.46 (m, 2H), 3.26 - 3.10 (m, 6H), 2.61 - 2.55 (m, 1H), 2.45 - 2.10 (m, 6H), 1.76 - 1.63 (m, 4H), 1.61 - 1.52 (m, 4H), 1.43 (q, 2H) ), 1.09 (d, 6H), 0.85 (t, 3H); LC-MS: m/z 415.4 (MH+)

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)propionamide

[4-amino-2-(azepan-1-yl)phenyl]-(4-propylpiperazin-1-yl)methanone (50.0 mg, 0.150 mmol) in 1,4-dioxane (1 mL) and N, A solution of N-diisopropylethylamine (0.05 mL, 0.290 mmol) was cooled to 0° C. and after 10 minutes propanoyl chloride (0.02 mL, 0.220 mmol) was added. The reaction was warmed to RT and stirred overnight. The next day, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. , brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 2:8), giving the formula N-[3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl) ) phenyl]propanamide was obtained.
Yield: 40.7mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 7.32 (d, 1H), 7.04 (dd, 1H), 6.91 (d, 1H), 3.79 - 3.42 (m, 2H), 3.24 - 3.11 (m, 6H), 2.43 - 2.14 (m, 8H), 1.68 (s,
4H), 1.60 - 1.53 (m, 4H), 1.43 (q, 2H), 1.08 (d, 3H), 0.85 (t, 3H); LC-MS: m/z 401.3 (MH+)

Preparation: N-(3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)acetamide

[4-Amino-2-(azepan-1-yl)phenyl]-(4-propylpiperazin-1-yl)methanone (70.0 mg, 0.200 mmol) and N,N-diisopropylethylamine in DCM (2 mL). (0.07 mL, 0.410 mmol) was added acetic anhydride (0.02 mL, 0.200 mmol) and the reaction was stirred at RT overnight. The next day, the reaction _was diluted with DCM, dried over _Na2SO4 , filtered, and concentrated under vacuum. The residue was purified by FC on NH (eluted from cHex/AcOEt 8:2 to cHex/AcOEt 2:8), giving the formula N-[3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl) ) phenyl]acetamide product was obtained.
Yield: 60mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 7.26 (d, 1H), 7.04 (dd, 1H), 6.91 (d, 1H), 3.73 - 3.46 (m, 2H), 3.25 - 3.04 (m, 6H), 2.44 - 2.13 (m, 6H), 2.02 (s, 3H), 1.75 - 1.62 (m, 4H), 1.63 - 1.51 (m, 4H), 1.43 (q, 2H), 0.85 (t, 3H); LC-MS: m/z 387.3 (MH+).

Preparation: [3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]urea

Potassium cyanate (111.95 mg, 1.38 mmol) was dissolved in warm water (0.459 mL) and dissolved in [4-amino-2-(azepane-1) in a mixture of water (0.919 mL) and acetic acid (0.100 mL). -yl)phenyl]-(4-propylpiperazin-1-yl)methanone (50.0 mg, 0.140 mmol). The reaction was stirred at RT for 1 hour. The reaction mixture was diluted with water and extracted three times with AcOEt. The organic phase was washed with brine, dried over _Na2SO4 , filtered and concentrated _under reduced pressure. The residue was purified by FC on RP under acidic conditions (eluted from _CH3CN / _H2O5 :95+0.1% formic acid to _CH3CN / _H2O95 :5+0.1% formic acid). Fractions containing the desired product were pooled together and concentrated under vacuum. The resulting material was dissolved in DCM and s.c. of _NaHCO3 . s. and dried by filtering through a phase separator. The solvent was removed under vacuum to give formula [3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]urea.
Yield: 6mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 8.54 (s, 1 H), 7.07 (s, 1 H), 6.91 - 6.77 (m, 2 H), 5.81 (s, 2 H), 3.18 (br t , 4 H), 3.72 - 3.03 (m, 4 H), 2.22 (br t, 2 H), 2.45 - 2.09 (m, 4 H), 1.76 - 1.47 (m, 8 H), 1.42 (sxt, 2 H) ), 0.84 (t, 3 H); LC-MS: m/z 388.6 (MH+).

Preparation: (2-(azepan-1-yl)-4-((5-cyclopropyl-4H-1,2,
4-triazol-3-yl)amino)phenyl)(4-propylpiperazin-1-yl)methanone

Step a:

A mixture of potassium thiocyanate (193.75 mg, 1.99 mmol) and cyclopropanecarbonyl chloride (0.18 mL, 1.99 mmol) in MeCN (8 mL) was stirred at 80° C. for 2 hours. After this time, a solution of [4-amino-2-(azepan-1-yl)phenyl]-(4-propylpiperazin-1-yl)methanone (300.0.870 mmol) in MeCN (2 mL) was added. , and the reaction was stirred at the same temperature for 1 hour. The reaction was then cooled to RT, filtered and the supernatant was concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% DCM to DCM/MeOH 9:1) to yield intermediate 1-[3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl). phenyl]-3-cyclopropanecarbonylthiourea was obtained.
Yield: 316mg

LC-MS: m/z 472.3 (MH+)

step b

Intermediate 1-[3-(azepan-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]-3-cyclopropanecarbonylthiourea (316.0 mg, 0.670 mmol) was dissolved in EtOH (12 mL). Hydrazine hydrate (0.7 mL, 9.21 mmol) was added and the reaction was stirred at RT for 24 h. After this time, the reaction was concentrated under vacuum and the residue was purified by FC on RP using basic conditions (elution: 100% aqueous ammonium bicarbonate adjusted to pH 10 with ammonia to _CH3CN100 %). ), which was further purified by FC on silica gel (eluted from DCM 100% to DCM/MeOH 9:1) to give the formula 2-(azepan-1-yl)-4-((5-cyclopropyl-4H-1,2 ,4-triazol-3-yl)amino)phenyl(4-propylpiperazin-1-yl)methanone was obtained.
Yield: 13mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 13.25 - 12.46 (m, 1 H), 9.31 - 8.76 (m, 1 H), 7.31 (s, 1 H), 6.97 - 6.73 (m, 2 H), 3.24 - 3.18 (m, 4 H), 3.79 - 3.02 (m, 4 H), 2.25 - 2.20 (m, 1 H), 2.43 - 2.10 (m, 4 H), 1.97 - 1.86 (m, 1 H), 1.80 - 1.48 (m, 8 H), 1.42 (sxt, 2 H), 0.98 (br d, 2 H), 0.89 - 0.78 (m, 5 H); LC-MS: m/z 452.34 (MH+).

The synthesis of a compound in which X2 is an imidazo[1,5-a]pyrazine group is shown in Scheme 5 below.

Scheme 5

Scheme 5 - Reagents and conditions: a) 2-aminomethylpyrazine, HATU, DIPEA
ON, RT; b) _POCl3 , _CH3CN ; 85°C, 2 days; c) azepane, DIPEA, DMF, 80°C, 4h; d) _{H21atm ,} Pd-C10%, EtOH, rt, 2h; e ) Cbz-Cl, TEA, DCM, rt, 2h; f) cyclopropanecarbonyl chloride, TEA, DCM, rt, ON; g) H ₂ 1 atm _, Pd-C10%, EtOH, rt, 3h; h) Popaldehyde, DIPEA ,STAB,DCM,rt,ON.

Preparation: 2-fluoro-4-nitro-N-[(pyrazin-2-yl)methyl]benzamide

2-Fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol), HATU (4.93 g, 12.97 mmol) and N,N-diisopropylethylamine (7.53 mL, 43.22 mmol) were dissolved in DMF (50 mL). After mixing and stirring for 30 min at 0° C., 2-aminomethylpyrazine (1.41 g, 12.97 mmol) in DMF (5 mL) was added. The reaction mixture was warmed to RT and stirred at the same temperature overnight. The next day, the reaction was concentrated to dryness, the residue was taken up in AcOEt, and the organic _phase was washed s. s. , washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated under vacuum. The residue was taken up in DCM and filtered. The solid was washed with DCM and dried under vacuum to give a product of formula 2-fluoro-4-nitro-N-(pyrazin-2-ylmethyl)benzamide, which was carried on in the next step without further purification. used.
Yield: 1.9g

1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.68 (d, 1H), 8.62 (dd, 1H), 8.57 (d, 1H), 8.24 (dd, 1H), 8.15 (dd, 1H), 7.92 (dd, 1H), 4.65 (d, 2H); LC-MS: m/z 277.04 (MH+).

Preparation: 3-(2-fluoro-4-nitrophenyl)imidazo[1,5-a]pyrazine

2-Fluoro-4-nitro-N-(pyrazin-2-ylmethyl)benzamide (1.9 g, 6.88 mmol) was dissolved in CH ₃ CN (95 mL) and phosphorus(V) oxychloride (6.41 mL, 68 mmol) was dissolved in CH 3 CN (95 mL). .79 mmol) was added dropwise and the reaction mixture was stirred at 85° C. for 48 hours. The reaction mixture was cooled to RT and evaporated. The residue was taken up in DCM and filtered. The solid was washed with DCM and dried under vacuum to give a product of formula 3-(2-fluoro-4-nitrophenyl)imidazo[1,5-a]pyrazine.
Yield: 1g

1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, 1H), 8.40 (dd, 1H), 8.29 (dd, 1H), 8.24 - 8.18 (m, 2H), 8.11 (dd, 1H), 7.74 ( d, 1H); LC-MS: m/z 259.02 (MH+).

Preparation: 3-[2-(azepan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine

A solution of N,N-diisopropylethylamine (0.62 mL, 3.56 mmol) and homopiperidine (1.2 mL, 10.69 mmol) in DMF (9 mL) was treated with 3-(2-fluoro-4-nitrophenyl)imidazo. [1,5-a]pyrazine (920.0 mg, 3.56 mmol) was added and the reaction was stirred at 80° C. for 4 hours. After this time, the reaction was cooled to RT, diluted with _H2O , and the mixture was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified on a FCNH column (elution from cHex to cHex/AcOEt 1:1). Fractions containing the desired product were combined and evaporated. The residue was triturated with pentane to give a product of formula 3-[2-(azepan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine.
Yield: 800mg

¹ H NMR (400 MHz, Chloroform-d) δ 9.09 (d, 1H), 8.02 (dd, 2H), 7.84 (dd, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.35 (ddd , 1H), 3.01 (s, 4H), 1.45 (s, 9H); LC-MS: m/z 338.2 (MH+).

Preparation: 3-(4-nitro-2-pyrrolidin-1-ylphenyl)imidazo[1,5-a]pyrazine

The synthesis of the title compound was carried out analogously to the synthesis of 3-[2-(azepan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine using pyrrolidine in place of homopiperidine. Ta. The title compound was obtained in a yield of 99% (600 mg).

1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, 1H), 8.06 (d, 1H), 7.72 - 7.55 (m, 5H), 2.72 - 2.62 (m, 4H), 1.73 - 1.60 (m, 4H) ); LC-MS: 310.12 (MH+).

Preparation: syn/anti 3-[2-(3,5-dimethylpiperidin-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine

The synthesis of the title compound was changed to the synthesis of 3-[2-(azepan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine using 3,5-dimethylpiperidine in place of homopiperidine. It was done similar to. The title compound was obtained as a mixture of stereoisomers in a yield of 87% (475 mg).

LC-MS: m/z 352.15 (MH+)

Preparation: 3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

3-[2-(azepan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine (380.0 mg, 1.13 mmol) and acetic acid (67.64 mg, 1 20% palladium(2+) hydroxide (395.43 mg, 0.560 mmol) was added to the mixture of 0.13 mmol) and the reaction was stirred at RT under _H2 atmosphere for 2 h. The reaction mixture was then filtered through Celite and the solvent was removed under vacuum. The residue was purified by SCX washing first with MeOH and then with NH ₃ 1M in MeOH to give the formula 3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[ A product of 1,5-a]pyrazin-3-yl)aniline was obtained.
Yield: 300mg

¹ H NMR (400 MHz, Chloroform-d) δ 7.10 (d, 1H), 6.87 - 6.84 (m, 1H), 6.36 (d, 1H), 6.28 (dd, 1H), 3.83 - 3.63 (m, 4H) , 3.15 (t, 2H), 3.11 - 3.04 (m, 4H), 1.58
- 1.43 (m, 9H); LC-MS: m/z 312.2 (MH+).

Preparation: 3-pyrrolidin-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

3-(4-nitro-2-pyrrolidin-1-ylphenyl)imidazo[1,5-a]pyrazine (597.0 mg, 1.93 mmol) in methanol (15 mL), acetic acid (0.33 mL, 5.79 mmol) ) and 20% palladium(2+) hydroxide (271.04 mg, 0.390 mmol) was stirred at RT under _H2 atmosphere for 1 h. After this time, the mixture was filtered through a pad of Celite and the solvent was removed under vacuum. The residue was purified by SCX cartridge, first washed with MeOH and then eluted with _1M NH in MeOH, giving the formula 3-pyrrolidin-1-yl-4-(5,6,7,8-tetrahydroimidazo[1 ,5-a]pyrazin-3-yl)aniline product was obtained.
Yield: 358mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.81 - 6.50 (m, 2H), 6.11 - 5.86 (m, 1H), 5.02 (d, 1H), 3.96 - 3.78 (m, 2H), 3.63 - 3.41 (m, 2H), 3.31 - 3.21 (m, 2H), 2.98 - 2.83 (m, 0H), 2.81 - 2.65 (m, 4H), 1.70 (q, 4H), LC-MS: 284.0

Preparation: syn/anti 3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

The synthesis of the title compound was modified by substituting syn/anti 3-[2-(3,5-dimethylpiperidine- 3-pyrrolidin-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a] ] Pyrazin-3-yl)aniline was carried out analogously to the synthesis. The title compound was obtained as a mixture of stereoisomers in a yield of 47% (120 mg).

LC-MS: m/z 326.1 (MH+)

Preparation: Benzyl 3-[4-amino-2-(azepan-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline (300.0 mg, 0.0 mg) in DCM (16 mL). A solution of triethylamine (0.27 mL, 1.93 mmol) was cooled to 0° C. and after 5 minutes Cbz-Cl (0.12 mL, 0.870 mmol) was added dropwise. The reaction was stirred at the same temperature for 2 hours. HCl 1N was added and the organic phase was separated. The aqueous phase was then diluted with _NaHCO3 s. s. to pH 8 and extracted three times with DCM. The organic phase was dried _{over Na2SO4} , filtered and evaporated. The residue was purified by FC on a NH column (eluted from 100% AcOEt to AcOEt/MeOH 9:1) to give the formula 3-[4-amino-2-(azepan-1-yl)phenyl]-6,8-dihydro A product of benzyl -5H-imidazo[1,5-a]pyrazine-7-carboxylate was obtained.
Yield: 165mg

¹ H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.35 (m, 5H), 7.12 (d, 1H), 6.92 (s, 1H), 6.36 (d, 1H), 6.29 (dd, 1H), 5.21 (s, 2H), 4.81 - 4.69 (m, 2H), 3.86 - 3.68
(m, 4H), 3.03 (t, 4H), 1.58 - 1.37 (m, 8H); LC-MS: m/z 446.3 (MH+).

Preparation: Benzyl 3-(4-amino-2-pyrrolidin-1-ylphenyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

The synthesis of the title compound was modified by substituting 3-pyrrolidine for 3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline. 3-[4-amino-2-(azepan-1- The synthesis of benzyl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate was carried out analogously. The title compound was obtained in a yield of 43% (126 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.43 - 7.26 (m, 5H), 6.81 - 6.73 (m, 2H),6.07 - 5.98 (m, 2H), 5.13 (s, 2H), 5.09 (s, 2H) ), 4.73 - 4.55 (m, 2H), 3.78 - 3.56 (m, 4H), 2.76 - 2.59 (m, 4H), 1.75 - 1.59 (m, 4H); LC-MS: m/z 418.2 (MH+).

Preparation: Benzyl 3-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

Benzyl 3-[4-amino-2-(azepan-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate (165 A solution of .0 mg, 0.370 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.740 mmol) was cooled to 0 °C, and after 5 minutes, cyclopropanecarbonyl chloride (0.05 mL, 0.560 mmol) was added dropwise. and added. The reaction was stirred at RT overnight. The next day, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. , washed with brine. The organic phase was dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was eluted by FC on an NH column (elution from cHex/AcOEt 95:5 to cHex/AcOEt 40:60), with formula 3-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)phenyl] A product of benzyl -6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate was obtained.
Yield: 175mg

LC-MS: m/z 514.3 (MH+)

Preparation: Benzyl 3-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylphenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

The synthesis of the title compound was performed in place of benzyl 3-[4-amino-2-(azepan-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate. The compound of Example 99 was prepared using benzyl 3-(4-amino-2-pyrrolidin-1-ylphenyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate. (benzyl 3-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1.5-a]pyrazine-7-carboxylate) The synthesis was performed analogously. The title compound was obtained in a yield of 88% (130 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 7.44 - 7.26 (m, 5H), 7.19 (d, 1H),
7.07 - 6.93 (m, 2H), 6.82 (s, 1H), 5.13 (s, 2H), 4.67 (s, 2H), 3.68 (s, 4H), 2.73 (s, 4H), 1.84 - 1.62 (m, 5H), 0.84 - 0.71 (m, 4H); LC-MS: m/z 486.2 (MH+).

Preparation: syn/anti 3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a] Benzyl pyrazine-7-carboxylate

3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline (119) in DCM (7 mL). A solution of triethylamine (0.0 mg, 0.370 mmol) and triethylamine (0.1 mL, 0.730 mmol) was cooled to 0 °C and after 10 minutes, chlorocarbonic acid (phenylmethyl) ester (0.05 mL, 0.330 mmol) was added dropwise. added. The reaction was stirred at the same temperature for 2 hours. After this time, more triethylamine (0.1 mL, 0.730 mmol) was added followed by cyclopropanecarbonyl chloride (0.04 mL, 0.400 mmol). The reaction was stirred at RT/ON. The next day, the mixed reaction was diluted with DCM and the organic phase was washed with _NaHCO3 s. s. , washed with brine, dried on a phase separator and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% cHex to 100% AcOEt), giving the formula 3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl] The product of benzyl -6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate was obtained as a syn/anti isomer mixture.
Yield: 121mg

LC-MS: 528.23 (MH+)

Preparation: N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide

3-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7- in ethanol (7 mL) 10% palladium on carbon (36.26 mg, 0.030 mmol) was added to a mixture of benzyl carboxylate (175.0 mg, 0.340 mmol) and acetic acid (0.35 mL, 6.13 mmol) and the reaction mixture was placed in an atmosphere of _H2. The mixture was stirred at RT for 3 hours. The reaction was then filtered through a pad of Celite and concentrated under vacuum. The residue was purified by SCX, washing first with MeOH and then with _1M NH in MeOH, giving the formula N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydro A product of imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 95mg

LC-MS: m/z 380.3 (MH+).

Preparation: N-[3-pyrrolidin-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 3-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylphenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid instead of benzyl carboxylate of N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide using benzyl. The synthesis was performed analogously. The title compound was obtained in a yield of 87% (81 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 7.15 (s, 1H), 6.97 (s, 2H), 6.65 (d, 1H), 3.88 (s, 2H), 3.47 (s, 2H), 2.92 (t, 2H), 2.75 (s, 4H), 1.84 - 1.65 (m, 5H), 0.85 - 0.71 (m, 4H); LC-MS: 352.1 (MH+).

Preparation: syn/anti N-[3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl ]Cyclopropanecarboxamide

The synthesis of the title compound was carried out using Syn/anti 3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1. N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine- The synthesis of 3-yl)phenyl]cyclopropanecarboxamide was carried out analogously. The title compound was obtained as a mixture of syn/anti isomers in 80% yield (72 mg).

LC-MS: m/z 394.26 (MH+)

Preparation: N-[3-(azepan-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-3-yl}phenyl]cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide in methanol (2 mL) (45.0 mg, 0.120 mmol) and 37% formaldehyde in H2O (0.09 mL, 1.19 mmol) at 0<0>C was added sodium triacetoxyborohydride (150.79 mg, 0.710 mmol). The reaction was warmed to RT and stirred overnight. The solvent was evaporated, AcOEt and water were added and the organic phase was separated and dried. The aqueous phase was back-extracted twice with AcOEt, then the combined organic fractions were 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 from 100:0 Cy/EtOAc to 10:90) to give the formula N-[3-(azepan-1-yl)-4-(7-methyl-6,8 -dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 21.5mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 7.47 (d, 1H), 7.08 (dd, 1H), 7.03 (d, 1H), 6.70 (d, 1H), 3.64 ( s, 2H), 3.54 (s, 2H), 2.98 (t, 4H), 2.65 (t, 2H), 2.35 (s, 3H), 1.78 (qd, 1H), 1.46 (s, 8H), 0.87 - 0.74 (m, 4H); LC-MS: m/z 394.3 (MH+).

Preparation: N-[4-(7-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound involves N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide carried out using N-[3-pyrrolidin-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide instead of Compound of Example 102 (N-[3-(azepan-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-3-yl}phenyl]cyclo Propane carboxamide) was carried out analogously to the synthesis. Yield of the title compound: 64
% (54 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.12 (br s, 1 H), 7.22 - 7.13 (m, 1 H), 7.05 - 6.94 (m, 2 H), 6.69 (s, 1 H), 3.65 - 3.56 (m, 2 H), 3.53 (s, 2 H), 2.79 - 2.70 (m, 4 H), 2.64 (br t, 2 H), 2.34 (s, 3 H), 1.83 - 1.76 (m, 1 H), 1.75 - 1.69 (m, 4 H), 0.84 - 0.73 (m, 4 H); LC-MS: m/z 355.2 (MH+).

Preparation: syn/anti N-[3-(3,5-dimethylpiperidin-1-yl)-4-(7-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-3- yl) phenyl] cyclopropane carboxamide

The synthesis of the title compound was performed using N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide syn/anti N-[3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1.5-a]pyrazin-3-yl) instead of ) phenyl]cyclopropanecarboxamide to prepare the compound of Example 102 (N-[3-(azepan-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5- a] pyrazin-3-yl}phenyl)cyclopropanecarboxamide). The title compound was obtained as a mixture of syn/anti isomers in 99% yield (75 mg).

LC-MS: m/z 409.9 (MH+).

Thereafter, the mixed isomers were separated into isomers using a semi-preparative MDAP method.

Preparation: N-[3-(azepan-1-yl)-4-(7-propyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide

N-[3-(azepan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide in MeCN (2 mL) Sodium triacetoxyborohydride (39.09 mg, 0.180 mmol) was added to a mixture of (35.0 mg, 0.090 mmol) and propanal (6.43 mg, 0.110 mmol) at 0°C. The reaction was warmed to RT and stirred overnight. The mixture was directly purified by SCX washing first with MeOH and then with _NH3 1M in MeOH, and further purified by FC on a NH column (elution from cHex 100% to cHex/AcOEt 1:1). Formation of formula N-[3-(azepan-1-yl)-4-(7-propyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide I got something.
Yield: 15mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 7.48 (d, 1H), 7.09 (dd, 1H), 7.03 (d, 1H), 6.71 (d, 1H), 3.69 - 3.56 (m, 4H), 2.98 (t, 4H), 2.71 (t, 2H), 2.45 - 2.40 (m, 2H), 1.82 - 1.75 (m, 1H), 1.56 - 1.37 (m, 10H), 0.89 ( t, 3H), 0.83 - 0.77 (m, 4H); LC-MS: m/z 422.0 (MH+).

Scheme 6

Synthesis Scheme 6 - Reagents and conditions: a) 2,4-dimethoxybenzylamine, CsF, DMSO, 60 °C, 2 h; b) TFA, DCM, rt, 30 min; c) azepane, DMF, 80 °C, 4 h; d ) Cyclopropane carbonyl chloride, pyridine, 80°C, overnight; e) LiOH H ₂ O, MeOH/THF/H ₂ O, 40°C, overnight; f) 1-propylpiperazine dihydrobromide, DIPEA; DMF, rt, overnight.

Preparation: Methyl 3-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}pyrazine-2-carboxylate

A solution of methyl 3,5-dichloropyrazine-2-carboxylate (1.0 g, 4.83 mmol) in DMSO (16.1 mL) was added with (2,4-dimethoxyphenyl)methanamine (0.73 mL, 4.83 mmol). and cesium fluoride (0.73 g, 4.83 mmol) were added. The reaction was stirred at 60°C for 2 hours. After this time, the reaction was cooled to rt and diluted with _H2O . The reaction was extracted three times with AcOEt. The organic phase was then washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on a NH column (100% cHex to cHex/AcOEt 1:1) to give methyl 3-chloro-5-[(2,4-dimethoxyphenyl)methylamino]pyrazine-2-carboxylate. The product was obtained.
Yield: 1.4g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (s, 1H), 7.95 (s, 1H), 7.18 (d, 1H), 6.59 (d, 1H), 6.50 (dd, 1H), 4.39 ( d, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 2.55 (s, 3H); LC-MS: m/z 338.3 (MH+).

Preparation: Methyl 5-amino-3-chloropyrazine-2-carboxylate

A mixture of methyl 3-chloro-5-[(2,4-dimethoxyphenyl)methylamino]pyrazine-2-carboxylate (400.0 mg, 1.18 mmol) and trifluoroacetic acid (0.95 mL, 12.39 mmol) Stirred for 30 minutes at rt. After this time, the reaction was concentrated under vacuum. The residue was directly purified by SCX washing first with MeOH and then with _1M NH in MeOH to give a product of formula methyl 5-amino-3-chloropyrazine-2-carboxylate, which was further purified by Used in the next step without purification.
Yield: 220mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.85 (s, 1H), 7.69 (s, 2H), 3.79 (s, 3H); LC-MS: m/z 186.11 (MH)

Preparation: Methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate

To a suspension of methyl 5-amino-3-chloropyrazine-2-carboxylate (220.0 mg, 1.17 mmol) in pyridine (6 mL) was added cyclopropanecarbonyl chloride (0.32 mL, 3.52 mmol); Stirred at 80°C overnight. The next day, the reaction was concentrated under vacuum. The residue was dissolved in AcOEt and s.c. of _NaHCO3 . s. , washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give a product of formula methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate. . This product was used in the next step without further purification.
Yield: 220mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.75 (s, 1H), 9.32 (s, 1H), 3.90 (s, 3H), 2.04 (tt, 1H), 0.95 - 0.88 (m, 4H).

Preparation: Methyl 3-(azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate

Methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate (222.0 mg, 0.870 mmol) in DMF (2.22 mL) and N,N-diisopropylethylamine (0.15 mL, 0.5 mL). Homopiperidine (0.29 mL, 2.61 mmol) was added to a solution of 870 mmol), and the reaction was stirred at 80° C. for 4 hours. After this time, the reaction was cooled to RT, diluted with _H2O , and the mixture was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on an NH column (elution from cHex to cHex/AcOEt 1:1) to yield methyl 3-(azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate. I got something.
Yield: 240mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 8.52 (s, 1H), 3.81 (s, 3H), 3.43 (t, 4H), 2.08 (p, 1H), 1.76 ( s, 4H), 1.46 (p, 4H), 0.85 (d, 4H); LC-MS: m/z 319.4
(MH+)

Preparation: 3-(azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid

Methyl 3-(azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate (240 mg, 0.7
A solution of lithium hydroxide hydrate (63.26 mg, 1.51 mmol) in water (0.500 mL) was added to the mixture. The reaction was stirred at 40°C overnight. The next day, the reaction was cooled to RT and acidified with HCl 1N to pH=1. The mixture was concentrated under vacuum. The residue was taken up with _H2O and filtered. The solid was dried under vacuum to yield a product of formula 3-(azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid. This product was used in the next step without further purification.
Yield: 230mg

LC-MS: m/z 305.33 (MH+)

Preparation: N-[6-(azepan-1-yl)-5-(4-propylpiperazine-1-carbonyl)pyrazin-2-yl]cyclopropanecarboxamide

実施例１０６

Example 106

3-(Azepan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid (230.0 mg, 0.790 mmol) and [dimethylamino(3-triazolo[4, 5-b]pyridinyloxy)methylidene]-dimethylammonium; To a solution of hexafluorophosphate (299.85 mg, 0.790 mmol) was added N,N-diisopropylethylamine (0.14 mL, 0.790 mmol) and the mixture was brought to RT. The mixture was stirred for 10 minutes. After this time, a solution of 1-propylpiperazine dihydrobromide (228.72 mg, 0.790 mmol) and N,N-diisopropylethylamine (0.28 mL, 1.58 mmol) in DMF (3 mL) was added. , the reaction was stirred at RT overnight. The next day, the reaction was washed s.c. with _NaHCO3 . s. and extracted three times with AcOEt. _The organic phase was washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum. The residue was purified by SCX washing first with MeOH and then with _NH3 1M in MeOH, then by FC on C18 (5:95 of _CH3CN /aqueous solution adjusted to pH 10 with ammonia). to a 95:5 CH ₃ CN/aqueous solution adjusted to pH 10 with ammonia), formula N-[6-(azepan-1-yl)-5-(4-propylpiperazine-1-carbonyl)pyrazine-2- [yl]cyclopropanecarboxamide product was obtained.
Yield: 20mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.54 (s, 1 H), 8.44 (s, 1 H), 3.60 (br s, 2
H), 3.53 - 3.43 (m, 4 H), 3.37 (br t, 2 H), 2.37 (br s, 2 H), 2.34 - 2.28 (m, 2
H), 2.28 - 2.21 (m, 2 H), 2.10 - 1.97 (m, 1 H), 1.73 (br s, 4 H), 1.54 - 1.36 (m, 6 H), 0.90 - 0.79 (m, 7 H) ); LC-MS: m/z 415.4 (MH+).

Scheme 7

Preparation: Methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate

2,6-dichloro-3-pyridinecarboxylic acid methyl ester (1.2 g, 5.82 mmol), (2,4-dimethoxyphenyl)methanamine (0.88 mL, 5.82 mmol) in DMF (19.41 mL) and A mixture of cesium fluoride (0.88 g, 5.82 mmol) was stirred at 80° C. for 3 hours. After this time, the reaction was cooled to RT, diluted with _H2O , and extracted three times with AcOEt. The organic phase was washed with brine, dried, filtered and concentrated under vacuum. The residue was purified by FC on an NH column (elution from cHex to cHex/AcOEt 1:1) to yield methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate of formula I got something.
Yield: 726mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 7.93 (br s, 1 H), 7.87 (br d, 1 H), 7.13 (br
d, 1 H), 6.57 (d, 1 H), 6.54 - 6.45 (m, 1 H), 6.48 (dd, 1 H), 4.36 (br s, 2 H),
3.80 (s, 3 H), 3.75 (s, 3 H), 3.74 (s, 3 H); LC-MS: m/z 337.2 (MH+).

Preparation: Methyl 2-(azepan-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate

Methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (726.0 mg, 2.16 mmol), N,N-diisopropylethylamine (1. A mixture of 12 mL, 4.31 mmol) and homopiperidine (0.5 mL, 3.80 mmol) was stirred at 120° C. for 5 hours. After this time, the reaction was cooled to RT and _H2O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, filtered and concentrated under vacuum. The crude product was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 1:1) and purified with 2-(azepan-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino ] A product of methyl pyridine-3-carboxylate was obtained.
Yield: 543mg

1H NMR (400 MHz, DMSO-d6) δ 7.54(d, 1H), 7.14- 7.06 (m, 2H), 6.53 (d, 1H), 6.44(dd, 1H), 5.84(d, 1H), 4.38( d, 2H), 3.78(s, 3H), 3.72(s, 3H), 3.64(s, 3H), 3.31- 3.28 (m, 4H), 1.73 -1.63 (m, 4H), 1.41- 1.36 (m, 4H); LC-MS: m/z 400.22 (MH+).

Preparation: Methyl 6-[(2,4-dimethoxyphenyl)methylamino]-2-pyrrolidin-1-ylpyridin-3-carboxylate

Methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (820.0 mg, 2.43 mmol) in DMF (16.4 mL), N
, N-diisopropylethylamine (0.85 mL, 4.08 mmol) and pyrrolidine (0.41 mL, 4.87 mmol) was heated to 80° C. for 5 hours. After this time, the reaction was cooled to RT and _H2O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 3:7) to give formula 6-[(2,4-dimethoxyphenyl)methylamino]-2-pyrrolidin-1-ylpyridin-3 - A compound of methyl carboxylate was obtained.
Yield: 900 mg.

LC-MS: 372.2 (MH+).

Preparation: [6-(azepan-1-yl)-5-methoxycarbonylpyridin-2-yl]azanium; 2,2,2-trifluoroacetate

A mixture of methyl 2-(azepan-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (200.0 mg, 0.500 mmol) in DCM (2 mL) Trifluoroacetic acid (0.19 mL, 2.5 mmol) was added. The reaction was stirred at RT for 2 hours. After this time, the reaction was concentrated under vacuum to obtain a product of formula [6-(azepan-1-yl)-5-methoxycarbonylpyridin-2-yl]azanium; 2,2,2-trifluoroacetate. Obtained.
Yield: 200mg

LC-MS: m/z 250.10 (MH+).

Preparation: (5-methoxycarbonyl-6-pyrrolidin-1-ylpyridin-2-yl)azanium; 2,2,2-trifluoroacetate

Trifluoroacetic acid ( 0.93 mL, 12.12 mmol) was added. The reaction was stirred at RT overnight. The next day after the reaction, it was concentrated under vacuum to obtain a product of formula (5-methoxycarbonyl-6-pyrrolidin-1-ylpyridin-2-yl)azanium; 2,2,2-trifluoroacetate.
Yield: 800mg

LC-MS: m/z 222.0 (MH+)

Preparation: Methyl 2-(azepan-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate

[6-(azepan-1-yl)-5-methoxycarbonylpyridin-2-yl]azanium in pyridine (2.752 mL); 2,2,2-trifluoroacetate (200.0 mg, 0.550 mmol) and cyclopropanecarbonyl chloride (0.05 mL, 0.550 mmol) was heated to 80° C. for 3 h, after which time the reaction was cooled to RT, H ₂ O was added and the mixture was filtered. The solid was washed with H ₂ O and dried under vacuum to yield a product of formula methyl 2-(azepan-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate, which was Used in next step without further purification.
Yield: 165mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 7.78 (d, 1H), 7.32 (d, 1H), 3.75 (s, 3H), 3.40 (t, 4H), 2.13 - 2.00 (m, 1H), 1.76 (s, 4H), 1.45 (q, 4H), 0.80 (d, 4H).

Preparation: Methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylpyridin-3-carboxylate

(5-methoxycarbonyl-6-pyrrolidin-1-ylpyridin-2-yl)azanium in pyridine (11.01 mL); 2,2,2-trifluoroacetate (800.0 mg, 2.39 mmol) and cyclopropane A mixture of carbonyl chloride (0.22 mL, 2.39 mmol) was heated to 80° C. for 3 h, after which time the reaction was cooled to RT and H ₂ O was added and the suspension so obtained Filtered. The solid was washed with H ₂ O and dried under vacuum to yield a product of formula methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylpyridin-3-carboxylate, which was purified without further purification. used in the next step.
Yield: 275mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 7.82 (d, 1H), 7.35 (d, 1H), 3.50 -
3.28 (m, 7H), 2.14 - 2.04 (m, 1H), 1.93 - 1.77 (m, 4H), 0.86 - 0.71 (m, 4H); LC-MS: m/z 290.0 (MH+).

Preparation: N-[6-pyrrolidin-1-yl-5-[4-(trifluoromethyl)piperidine-1-carbonyl]pyridin-2-yl]cyclopropanecarboxamide

A solution of 4-(trifluoromethyl)piperidine (0.19 mL, 0.380 mmol) in toluene (2 mL) was cooled to 0C and after 10 minutes a 2M solution of trimethylalmane (0.19 mL, 0.380 mmol) in toluene was added. Added under N2. The mixture was stirred at the same temperature for 30 minutes and then dissolved in a mixture of methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylpyridin-3-carboxylate (100.0 mg, 0.350 mmol) in toluene (2 mL). added. The reaction was heated to reflux for 72 hours. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was purified by FC on a NH column (100% DCM to DCM/MeOH 95:5) and further purified on RP using basic conditions (100% water + 0.1% _NH4OH to 100% % CH ₃ CN) to give formula N-[6-pyrrolidin-1-yl-5-[4-(trifluoromethyl)piperidine-1-carbonyl]pyridin-2-yl]cyclopropanecarboxamide.
Yield: 9.5mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.37 - 10.18 (m, 1 H), 7.40 - 7.27 (m, 2 H), 4.69 - 3.54 (m, 2 H), 3.51 - 3.16 (m, 4 H ), 3.18 - 2.68 (m, 2 H), 2.68 - 2.51 (m, 1 H), 2.13 - 2.01 (m, 1 H), 1.94 - 1.60 (m, 6 H), 1.46 - 1.22 (m, 2 H) ), 0.88
- 0.70 (m, 4 H); LC-MS: m/z 411.2 (MH+).

Preparation: 6-amino-2-(azepan-1-yl)pyridine-3-carboxylic acid; formic acid

Solution of 2-(azepan-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate (165.0 mg, 0.520 mmol) in THF (1.752 mL)/methanol (0.701 mL) To this was added a solution of lithium hydroxide hydrate (43.63 mg, 1.04 mmol) in water (0.701 mL). The reaction was stirred at 50° C. overnight. The reaction was cooled to RT, acidified with HCl 1N to pH=1 and concentrated under vacuum. The residue was purified by FC on a C18 column (eluted from H ₂ O/ _CH CN 95:5 + 0.1% formic acid to H ₂ O/CH _CN 5:95 + 0.1% FA) to give formula 6-amino-2 A product of -(azepan-1-yl)pyridine-3-carboxylic acid formic acid was obtained.
Yield: 180mg

LC-MS: m/z 236.10 (MH+).

Preparation: [6-amino-2-(azepan-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl)methanone

[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (270.33 mg, 0.710 mmol), 6-amino-2-(azepane-) in DMF (6 mL). N,N-diisopropylethylamine was added to a mixture of 1-yl)pyridine-3-carboxylic acid formic acid (200.0 mg, 0.710 mmol) and 1-propylpiperazine dihydrobromide (412.41 mg, 1.42 mmol). (0.74 mL, 4.27 mmol) was added and the reaction was stirred at RT overnight. The next day, the mixed reaction was purified by FC on RP under acidic conditions (5:95 _CH3CN / _H2O +0.1% formic acid to 95:5 _CH3CN / _H2O +0.1% (elution to formic acid) and further purified by FC on RP using basic conditions (from CH 3 CN/aq 5:95 adjusted to pH 10 _{with ammonia to CH 3 CN} /aq 95:5 adjusted to pH 10 with ammonia). elution), a product of formula [6-amino-2-(azepan-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl)methanone was obtained.
Yield: 33mg

LC-MS: m/z 346.28 (MH+).

Preparation: N-[6-(azepan-1-yl)-5-(4-propylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

In a solution of [6-amino-2-(azepan-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl)methanone (33.0 mg, 0.100 mmol) in pyridine (2 mL) , cyclopropanecarbonyl chloride (0.01 mL, 0.100 mmol) was added and the reaction was stirred at 80° C. for 2 hours, after which time the reaction was cooled to RT and concentrated under vacuum. The residue was purified by SCX washing first with MeOH and then with 1M NH3 in MeOH, then by FC on RP using acid conditions (5:95 _CH3CN / _H2O +1% formic acid to 95:5 CH ₃ CN/H ₂ O + 1% FA), which was further purified by SCX washing first with MeOH and then with 1M NH in MeOH to give the formula N-[6-( Azepan-1-yl)-5-(4-propylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide product was obtained.
Yield: 14mg

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.22 (s, 1 H), 7.37 - 7.23 (m, 2 H), 3.58 (br t, 2 H), 3.54 - 3.35 (m, 4 H), 3.26 (br t, 2 H), 2.42 - 2.18 (m, 6 H), 2.05 (quin, 1 H), 1.82 - 1.62 (m, 4 H), 1.58 - 1.35 (m, 6 H), 0.85 (t, 3 H), 0.81 - 0.75 (m, 4 H); LC-MS: m/z 414.28 (MH+).

Scheme 8

Synthesis Scheme 8 - Reagents and conditions: a) Hydrazine hydrate, EtOH, reflux, overnight; b) Methyl isothiocyanate, THF, MW 130°C, after 8 min, s.c. of NaHCO ₃ . s. , MW 100°C, 3 min; c) CH ₃ I, NaOH, EtOH, 30 min, RT or iodobenzene, CuI, K ₂ CO ₃ , DMF, 120°C, overnight or (2-bromomethyl)dimethylamine hydrogen bromide. acid salt, K ₂ CO ₃ , acetone, 65° C., overnight; d) Zn, AcOH, RT, 1 h; e) cyclopropane carbonyl chloride, TEA, DCM, RT, overnight.

Preparation: 2-(azepan-1-yl)-4-nitrobenzohydrazide

To a solution of methyl 2-(azepan-1-yl)-4-nitrobenzoate (1.89 g, 6.79 mmol) in ethanol (15.79 mL) was added hydrazine hydrate (2.56 mL, 33.96 mmol). and the reaction was heated to reflux and stirred overnight. The next day, the reaction mixture was cooled to RT and concentrated under reduced pressure. The resulting material was purified by FC on a NH column (eluted from DCM/AcOEt 95:5 to DCM/AcOEt 6:4) to yield a product of formula 2-(azepan-1-yl)-4-nitrobenzohydrazide. Ta.
Yield: 690mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 7.57 (d, 1H), 7.48 (dd, 1H), 7.31 (d, 1H), 4.47 (d, 2H), 3.37 ( dd, 4H), 1.73 (p, 4H), 1.51 (p, 4H); LC-MS: m/z 279.13 (MH+).

Preparation: 5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazole-3-thiol

To a solution of 2-(azepan-1-yl)-4-nitrobenzohydrazide (550.0 mg, 1.98 mmol) in THF (10 mL) was added methyl isothiocyanate (0.15 mL, 2.17 mmol) and the mixture was The mixture was stirred at 130° C. for 8 minutes under MW conditions. Concentrate the organic solution and add 12.5 ml of _NaHCO3 s. s. was added and the mixed reaction was stirred at 100° C. for 3 minutes under MW conditions. The aqueous solution was then neutralized with HCl 2M and extracted three times with AcOEt. The organic fraction was washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 7:3), giving the formula 5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1, A product of 2,4-triazole-3-thiol was obtained.
Yield: 420mg

¹ H NMR (400 MHz, Chloroform-d) δ 11.14 (s, 1H), 7.95 (d, 1H), 7.76 (dd, 1H), 7.45 (d, 1H), 3.39 (s, 3H), 3.28 - 3.22 (m, 4H), 1.68 (q, 4H), 1.63 - 1.59 (s, 4H); LC-MS: m/z 334.12 (MH+)

Preparation: 1-[2-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)-5-nitrophenyl]azepane

5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazole-3-thiol (250.0 mg, 0.750 mmol), sodium hydroxide (1. 57 mL, 1.57 mmol) 1M solution and iodomethane (0.07 mL, 1.2 mmol) were combined in ethanol (0.375 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was diluted with _NaHCO3 and extracted three times with EtOAc. The organic layers were collected together, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to give the formula 1-[2-(4-methyl-5-methylsulfanyl-1,2, A product of 4-triazol-3-yl)-5-nitrophenyl]azepane was obtained. This product was used in the next step without further purification.
Yield: 224mg

¹ H NMR (400 MHz, Chloroform-d) δ 7.92 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 3.34 (s, 3H), 3.21 - 3.14 (m, 4H), 2.81 (s, 3H), 1.65 - 1.41 (m, 8H); LC-MS: m/z
348.15 (MH+)

Preparation: 1-[2-(4-methyl-5-phenylsulfanyl-1,2,4-triazol-3-yl)-5-nitrophenyl]azepane

Iodobenzene (0.03 mL, 0.240 mmol), copper(I) iodide (1.9 mg, 0.010 mmol) and potassium carbonate (35.57 mg) in dry DMF (2 mL)
, 0.260 mmol) of 5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazole-3- in DMF (0.2 mL). Thiol (66 mg, 0.198 mmol) was added. The resulting mixture was degassed by Schlenkline method and stirred at 120° C. overnight. The next day, the reaction mixture was cooled to RT, diluted with ss of _NaHCO3 , extracted with AcOEt _, washed with brine, dried over _Na2SO4 , filtered and concentrated under reduced pressure to give formula 1-[ The product of 2-(4-methyl-5-phenylsulfanyl)-1,2,4-triazol-3-yl]-5-nitrophenyl]azepane was obtained, which was used in the next step without further purification. .
Yield: 40mg

LC-MS: m/z 410.14 (MH+)

Preparation: 2-[[5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-yl]sulfanyl]-N,N-dimethylethane amine

5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazole-3-thiol (100.0 mg, 0.300 mmol) in acetone (3 mL), To the mixture of (2-bromoethyl)dimethylamine hydrobromide was added potassium carbonate (82.91 mg, 0.600 mmol). The reaction was stirred at 65°C overnight. After this time, the reaction mixture was cooled to RT and treated with _NaHCO3 s. s. and extracted three times with DCM. The organic phase was washed with brine, filtered over Na ₂ SO ₄ and concentrated under vacuum to give the formula 2-[[5-[2-(azepan-1-yl)-4-nitrophenyl]-4-methyl -1,2,4-triazol-3-yl]sulfanyl]-N,N-dimethylethanmine was obtained, which was used in the next step without further purification.
Yield: 120mg

LC-MS: m/z 405.15 (MH+).

Preparation: 3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)aniline

1-[2-(4-Methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)-5-nitrophenyl]azepane (100.0 mg, 0.290 mmol) in dry acetic acid (3 mL) Zinc (94.09 mg, 1.44 mmol) was slowly added to the solution. The resulting suspension was stirred at room temperature for 1 hour. The reaction mixture was filtered, washed with AcOEt and the organic phase was concentrated under reduced pressure. The resulting material was dissolved in _NaHCO3 s. s. and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the formula 3-(azepan-1-yl)-4-(4-methyl-5- The product methylsulfanyl-1,2,4-triazol-3-yl)aniline was obtained, which was used in the next step without further purification.
Yield: 60mg

LC-MS: m/z 318.20 (MH+)

Preparation: 3-(azepan-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2,4-triazol-3-yl)aniline

The synthesis of the title compound was carried out by substituting 1-[2-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)-5-nitrophenyl]azepane. 3-(azepan-1-yl)-4-(4-methyl-5- The synthesis was carried out analogously to the synthesis of methylsulfanyl-1,2,4-triazol-3-yl)aniline. The title compound was obtained in a yield of 71% (80 mg).

LC-MS: m/z 380.18 (MH+)

Preparation: 3-(azepan-1-yl)-4-[5-[2-(dimethylamino)ethylsulfanyl]-4-methyl-1,2,4-triazol-3-yl]aniline

The synthesis of the title compound was carried out by substituting 2-[[5-[ Using 2-(azepan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-yl]sulfanyl]-N,N-dimethylethanamine, 3-(azepane -1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)aniline. The title compound was obtained with a yield of 67% (50 mg).

LC-MS: m/z 375.27 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

3-(Azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)aniline (60.0 mg, 0.0 mg) in DCM (0.945 mL). A solution of triethylamine (0.08 mL, 0.570 mmol) was cooled to 0° C. and cyclopropanecarbonyl chloride (0.04 mL, 0.470 mmol) was added. The mixture was brought to room temperature and stirred overnight. The next day, the reaction mixture was diluted with DCM and s.c. of _NaHCO3 . s. , dried on a phase separator and concentrated under reduced pressure. The resulting material was purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid). ), yielding a product of formula N-[3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide. Ta.
Yield: 16.8mg

¹ H NMR (400 MHz, Chloroform-d) δ 7.76 (s, 1H), 7.62 (s, 1H), 7.28 (s, 1H), 6.79 (dd, 1H), 3.34 (s, 3H), 3.12 (t , 4H), 2.77 (s, 3H), 1.54 (s, 9H), 1.18 - 1.09
(m, 2H), 0.90 (dt, 2H); LC-MS: m/z 386.20 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting 3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)aniline. The compound of Example 109 (N-[3-(azepan-1-yl) )-4-(4-Methyl-5-methylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide). The title compound was obtained with a yield of 12% (19 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 7.73 (d, 2H), 7.48 - 7.43 (m, 2H), 7.39 - 7.30 (m, 4H), 6.79 (dd, 1H), 3.33 (s, 3H) , 3.03 (d, 4H), 1.57 (s, 1H), 1.45 - 1.32
(m, 8H), 1.16 - 1.05 (m, 2H), 0.89 (dt, 2H); LC-MS: m/z 448.17.

Preparation: N-[3-(azepan-1-yl)-4-[5-[2-(dimethylamino)ethylsulfanyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]cyclo propane carboxamide

The synthesis of the title compound was carried out by substituting 3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl)1,2,4-triazol-3-yl)aniline. The compound of Example 109 (N-[ The synthesis of 3-(azepan-1-yl)-4-(4-methyl-5-methylsulfanyl-1,2.4-triazol-3-yl)phenyl]cyclopropanecarboxamide) was carried out analogously. The title compound was obtained with a yield of 9% (6.3 mg).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.73 (br s, 1 H), 7.58 - 7.47 (m, 1 H), 7.28 (s, 1 H), 6.78 (dd, 1 H), 3.45 (t , 2 H), 3.32 (s, 3 H), 3.19 - 3.04 (m, 4 H), 2.74 (s, 2 H), 2.31 (s, 6 H), 1.52 (br s, 9 H), 1.19 - 1.05 (m, 2 H), 0.96 - 0.83 (m, 3 H); LC-MS: 443.18 (MH+).

Synthesis scheme 9

Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide

A solution of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (1.5 g, 4.54 mmol) in ethanol (10.56 mL) was added with hydrazine water. (3.43 mL, 45.4 mmol) was added. The resulting solution was stirred at 85°C for 4 hours. After this time, the reaction was cooled to ambient temperature and concentrated under reduced pressure to produce a compound of the formula N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide. was obtained as a mixture of syn/anti isomers.
Yield: 1.5g

LC-MS: 331.22(MH+).

Preparation: N-[3-(azepan-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide

HATU=[dimethyl Amino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (308.6 mg, 0.810 mmol) and hydrazine hydrochloride (252.74 mg, 3.69 mmol) were added. The solution was stirred at room temperature for 30 minutes, then a solution of N,N-diisopropylethylamine (333.75 mg, 2.58 mmol) in DMF (2 mL) was slowly added and stirred at room temperature overnight. The next day, the reaction mixture was diluted with DCM and s.c. of _NaHCO3 . s. 3 times, brine, dried through a phase separator and concentrated under vacuum. The residue was purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid), giving the formula The product N-[3-(azepan-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 60mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.98 (s, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.11 (dd, 1H), 4.41 ( LC-MS: m/z 317.23 (MH+)

Preparation: N-[4-(hydrazinecarbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-yl instead of 2-(azepan-1-ium-1-yl)-4-(cyclopropanecarbonylamino)benzoic acid chloride. The synthesis of N-[3-(azepan-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide was carried out analogously using benzoic acid. The title compound was obtained with a yield of 99% (1 g).

1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.23 (s, 1H), 7.07 - 7.00 (m, 2H),
6.89 (dd, 1H), 3.20 - 3.09 (m, 4H), 1.91 - 1.81 (m, 4H), 1.77 (tt, 2H), 0.83 - 0.72 (m, 4H); LC-MS: m/z 289.16 ( MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

A solution of N-methylbenzamide (25.63 mg, 0.190 mmol) and 2,6-dimethylpyridine (0.04 mL, 0.380 mmol) in dry DCM (0.948 mL) was cooled to 0 °C and after 10 min. Oxalyl dichloride (0.02 mL, 0.190 mmol) was carefully added under _N2 atmosphere and the resulting mixture was stirred at the same temperature for 30 min. After this time, N-[3-(azepan-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide (60.0 mg, 0.190 mmol) was added and the reaction mixture was brought to room temperature and stirred for 2 hours. did. After this time, the reaction mixture was concentrated, the residue was taken up with 5 mL of _NaHCO3 , and the mixture was refluxed overnight. The next day, the reaction mixture was acidified with HCl 1N to pH=2 and concentrated under vacuum. The residue was purified by FC on RP using basic conditions (eluting with 100% water + 0.1% NH ₄ OH to 100% CH ₃ CN) to give the compound of formula.
Yield: 5.8mg

1H NMR (400 MHz, DMSO-d6) δ ppm 10.36 - 10.27 (m, 1H), 7.77- 7.71 (m, 2H), 7.62- 7.54 (m, 4H), 7.22- 7.18 (m, 2H), 3.44 - 3.38(m, 3H), 3.07 - 2.99(m, 4H), 1.85- 1.74 (m, 1H), 1.53- 1.39 (m, 8H), 0.86- 0.76 (m, 4H); LC-MS: m/z 416.27 (MH+).

Preparation: N-[3-(azepan-1-yl)-4-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

A solution of N-methylacetamide (36.96 mg, 0.510 mmol) and 2,6-dimethylpyridine (0.12 mL, 1.01 mmol) in DCM (2.528 mL) was cooled to 0 °C and after 10 min nitrogen Oxalyl dichloride (0.04 mL, 0.510 mmol) was carefully added under atmosphere. After stirring the resulting mixture at the same temperature for 30 minutes, N-[3-(azepan-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide (160.0 mg, 0.510 mmol) was added. . The reaction was warmed to RT and stirred for 3.5 hours. The volatiles were removed under reduced pressure and the resulting material was dissolved in 3.5 mL of NaHCO ₃ s. s. The mixture was taken out and stirred at 100°C for 45 minutes. After this time, the reaction was cooled to rt and extracted three times with DCM. The combined organic fractions were dried through a phase separator and concentrated under vacuum. The resulting material was purified twice by FC on RP using acidic conditions (CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid ), yielding a product of formula N-[3-(azepan-1-yl)-4-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide. .
Yield: 4.8mg

H NMR (500 MHz, METHANOL-d4 )δ ppm 7.65 (d, 1H), 7.23- 7.16 (m, 1H), 7.16- 7.09 (m, 1H), 3.40 (s, 3H), 3.09(t, 4H) , 2.48(s, 3H), 1.83- 1.73 (m, 1H), 1.63- 1.41 (m, 8H), 0.97(quin, 2H), 0.92- 0.82 (m, 2H); LC-MS: m/z 354.26 (MH+).

Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

To a solution of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide (1.3 g, 3.93 mmol) in THF (23.36 mL) Methylimino(sulfanylidene)methane (0.316 g, 4.33 mmol) was added and the reaction was stirred at 130° C. for 8 minutes under MW irradiation. The reaction was then cooled to RT and added 30 mL of _NaHCO3 s. s. added. The resulting mixture was heated to reflux overnight. The next day, the reaction was cooled to RT and acidified with HCl 2N to pH=1. The aqueous solution was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 7:3) to give the formula N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl- A compound of 5-sulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 1.1g

LC-MS: m/z 386.2 (MH+)

Preparation: N-[4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-(hydrazinecarbonyl)-3 for N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide. -pyrrolidin-1-ylphenyl]cyclopropanecarboxamide to produce N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-sulfanyl-1,2,4- The synthesis of triazol-3-yl)phenyl]cyclopropane carboxamide was carried out analogously. The title compound was obtained in a yield of 18% (405 mg).

1H NMR (400 MHz, DMSO-d6) δ 13.73 (s, 1H), 10.25 (s, 1H), 7.28 (d, 1H), 7.12 (d, 1H), 7.04 (dd, 1H), 3.21 (s, 3H), 2.89 (d, 4H), 1.89 - 1.71 (m, 5H), 0.88 - 0.71 (m, 4H); LC-MS: m/z 344.16 (MH+)

Preparation: N-[4-[2-(dimethylamino)ethyl]-5-sulfanyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl] cyclopropane carboxamide

To a solution of bis(1-imidazolyl)methanethione (177.98 mg, 1 mmol) in THF (7.566 mL) was added N',N'-dimethylethane-1,2-diamine (0.09 mL, 0.830 mmol). , and stirred for 15 minutes. To this solution was added N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropanecarboxamide (250.0 mg, 0.760 mmol), and the resulting solution was Heated to 130° C. for 10 minutes under irradiation. After this time, the reaction was concentrated under vacuum and added 10 mL of _NaHCO3 s. s. added. The resulting mixture was further stirred at 100° C. for 1 hour under MW irradiation. The reaction mixture was brought to pH 2 with HCl 2N and concentrated under reduced pressure. The raw material was purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid) with the formula N-[4-[2-(dimethylamino)ethyl]-5-sulfanyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl]cyclopropane A carboxamide product was obtained.
Yield: 70mg

LC-MS: 443.5 (MH+).

Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide

Copper(I) iodide (6.21 mg, 0.030 mmol), 1,10-phenanthroline (11.69 mg, 0.060 mmol), potassium carbonate (116.51 mg, 0.840 mmol) in dry DMF (4.323 mL) ) was added iodobenzene (0.09 mL, 0.780 mmol). This solution was added to N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-sulfanyl-1,2,4-triazole- A solution of 3-yl)phenyl]cyclopropanecarboxamide (250.0 mg, 0.650 mmol) was added and the resulting mixture was degassed using the Schlenkline method. The mixture was heated to 120°C overnight. The next day, the reaction mixture was diluted with water and extracted three times with AcOEt. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The raw material was purified by FC on RP using basic conditions (eluted from 100% water + 0.1% NH ₄ OH to water + 0.1% NH ₄ OH/CH ₃ CN 6:4), formula N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide Obtained as a mixture of anti-isomers.
Yield: 70mg

LC-MS: m/z 462.03 (M + Na)

The mixture of syn/anti isomers (Example 114c) was then separated into single isomers by semi-preparative chiral HPLC.

Preparation: N-[4-[4-[2-(dimethylamino)ethyl]-5-phenylsulfanyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1- yl) phenyl] cyclopropane carboxamide

The synthesis of the title compound was carried out using N-[4-[4-[2-(dimethylamino)ethyl]-5-sulfanyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidine- The compound of Example 114a, b (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylsulfanyl) -1,2,4-triazol-3-yl)phenyl]cyclopropanecarboxamide). The title compound was obtained in 41% yield (35 mg) as a mixture of syn/anti isomers.

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.37 (s, 1 H), 7.53 (d, 1 H), 7.40 - 7.30 (m, 6 H), 7.24 (d, 1 H), 3.99 (t, 2 H), 3.00 - 2.75 (m, 2 H), 2.07 (t, 2 H), 2.04
- 1.86 (m, 2 H), 1.82 (s, 6 H), 1.80 - 1.75 (m, 1 H), 1.52 (br d, 1 H), 1.35 -
0.95(m, 2 H), 0.84 - 0.79 (m, 4 H), 0.77 - 0.54 (m, 6 H), 0.47 (q, 1 H); LC-MS:
m/z 519.3 (MH+)

Preparation: N-[4-(4-methyl-5-pyridin-2-ylsulfanyl-1,2,4-triazol-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed using N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)phenyl] N-[4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide and 2 instead of cyclopropanecarboxamide and iodobenzene. The compound of Example 114a, b (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2, The synthesis of 4-triazol-3-yl)phenyl]cyclopropanecarboxamide was carried out analogously. The title compound was obtained in a yield of 27% (43 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.35 (ddd, 1H), 7.79 (ddd, 1H), 7.34 (dt, 1H), 7.31 (d, 1H), 7.27 (ddd, 1H), 7.14 (d, 1H), 7.06 (dd, 1H), 3.29 (s,
3H), 2.93 - 2.84 (m, 4H), 1.84 - 1.77 (m, 5H), 0.87 - 0.75 (m, 4H); LC-MS: m/z 421.15 (MH+).

Preparation: N-[4-(4-methyl-5-pyridin-3-ylsulfanyl-1,2,4-triazol-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed using N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)phenyl] N-[4-(4-methyl-5-sulfanyl-1,2,4-triazol-3-yl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide and 3 instead of cyclopropanecarboxamide and iodobenzene. The compound of Example 114a, b (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylsulfanyl-1,2,4 -triazol-3-yl)phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 88% (140 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.57 (dd, 1H), 8.54 (dd, 1H), 7.78
(ddd, 1H), 7.44 (ddd, 1H), 7.28 (d, 1H), 7.13 (d, 1H), 7.06 (dd, 1H), 3.32 (s, 3H), 2.78 - 2.65 (m, 4H), 1.80 (tt, 1H), 1.77 - 1.61 (m, 4H), 0.87 - 0.73 (m, 4H); LC-MS: m/z 421.17 (MH+).

Scheme 10

Scheme 10 - Reagents and conditions: a) azepane, CH ₃ CN, RT, overnight; b) NH ₂ OHHCl, TEA, tBuOH, 80° C., overnight, then Cs ₂ CO ₃ , Cu(OAc) ₂ , cyclo propanecarbonitrile, Na ₂ SO ₄ , DMSO, 120°C, overnight; c) LiOH, MeOH/THF/H ₂ O, 50°C, overnight, then HATU, DIPEA, 1-propylpiperazine, DMF, RT; One night.

Preparation: Methyl 2-(azepan-1-yl)-4-cyanobenzoate

A mixture of methyl 4-cyano-2-fluorobenzoate (1.2 g, 6.7 mmol) and homopiperidine (3.77 mL, 33.49 mmol) in MeCN (11 mL) was stirred at RT overnight. The reaction was concentrated in vacuo and the residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 9:1) to give formula 2-(azepan-1-yl)-4-cyanobenzoic acid. A methyl product was obtained.
Yield: 1.3g

¹ H NMR (400 MHz, Chloroform-d) δ 7.56 (d, 1H), 7.19 (d, 1H), 6.97 (dd, 1H), 3.92 (s, 3H), 3.40 - 3.23 (m, 4H), 1.86 - 1.77 (m, 4H), 1.62 (dt, 4H); LC-MS: m/z
258.8 (MH+).

Preparation: Methyl 2-(azepan-1-yl)-4-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)benzoate

of methyl 2-(azepan-1-yl)-4-cyanobenzoate (317.65 mg, 1.23 mmol), hydroxylamine hydrochloride (94.0 mg, 1.35 mmol) and triethylamine (0.34 mL, 2.46 mmol). The mixture in tert-butanol (3.5 mL) was stirred at 80° C. overnight. After this time, the reaction was cooled to RT and cyclopropanecarbonitrile (165.0 mg, 2.46 mmol), copper diacetate (45.17 mg, 0.250 mmol), dicesium carbonate (1.21 g, 3.69 mmol) ) and anhydrous Na ₂ SO ₄ (1.2 g, 8.61 mmol) and DMSO (3 mL) were added and the reaction was stirred at 120° C. overnight. The reaction was cooled to RT and concentrated. The residue was purified by FC on an NH column (eluted from 100% cHex to cHex/AcOEt 70:30) to give the formula 2-(azepan-1-yl)-4-(3-cyclopropyl-1H-1,2,4- A product of methyl triazol-5-yl)benzoate was obtained.
Yield: 30mg

LC-MS: m/z 341.2 (MH+)

Preparation: [2-(azepan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-propylpiperazin-1-yl)methanone

Methyl 2-(azepan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)benzoate in THF (0.111 mL) and methanol (0.037 mL) (30.0 mg, 0.090 mmol) was added a solution of lithium hydroxide (4.22 mg, 0.180 mmol) in water (0.037 mL). The reaction was stirred at 50° C. overnight. The next day, the reaction was cooled to RT, acidified with HCl 1N to pH=5, and concentrated under vacuum to give the formula 2-(azepan-1-yl)-4-(5-cyclopropyl-4H-1,2 ,4-triazol-3-yl)benzoic acid intermediate was obtained, which was used in the next step without further purification. LC-MS: m/z 327.1 (MH+).

Intermediate 2-(azepan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)benzoic acid (25.0 mg, 0.075 mmol) was dissolved in DMF (0.0 mg, 0.075 mmol). 5 mL), then N,N-diisopropylethylamine (0.05 mL, 0.310 mmol) and HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophos Fart (69.9 mg, 0.180 mmol) was added. The mixture was stirred at RT for 10 min, then a solution of 1-propylpiperazine (51.1 mg, 0.180 mmol) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was purified by SCX washing first with MeOH and then with NH ₃ 1M in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluted from 100% AcOEt to AcOEt/MeOH 9:1). The product was further purified by FC on fresh P using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 95:5 + 0.1% formic acid. ), formula [2-(azepan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-propylpiperazin-1-yl)methanone of product was obtained.
Yield: 15mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 14.26 (m, 1 H) - 13.34, 7.54 (br s, 1 H), 7
.38 (br d, 1 H), 7.08 (br d, 7.3 Hz, 1 H), 3.26 (t, 4 H), 3.55 - 3.10 (m, 2 H), 3.75 - 3.10 (m, 2 H), 2.27 - 2.21 (m, 2 H), 2.48 - 2.13 (m, 4 H), 2.06 (br s, 1 H), 1.77 - 1.48 (m, 8 H), 1.42 (sxt, 2 H), 1.10 - 0.87 (m, 4 H), 0.84 (t, 3 H); LC-MS: m/z 437.4 (MH+).

Synthesis scheme 11

Preparation: Methyl 4-bromo-2-pyrrolidin-1-ylbenzoate

To a solution of methyl 4-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol) in DMF (7.122 mL) was added pyrrolidine (1.43 mL, 17.17 mmol) and stirred at 80 °C for 8 h. . After this time, the reaction was cooled to RT and _H2O was added. The mixture was stirred for 10 minutes and filtered. The resulting solid was washed with H ₂ O and dried under vacuum to yield a product of formula methyl 4-bromo-2-pyrrolidin-1-ylbenzoate.
Yield: 1g

1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, 1H), 6.92 (d, 1H), 6.82 (dd, 1H), 3.79 (s, 3H), 3.19 - 3.12 (m, 4H), 1.92 - 1.84 (m, 4H); LC-MS: m/z 284.03, 286.01 (MH+).

Preparation: 4-bromo-2-pyrrolidin-1-ylbenzoic acid

Lithium hydroxide hydrate ( 147.67 mg, 3.52 mmol) was added and the reaction was stirred at 50° C. overnight. The next day, HCl 3N was added until pH=1 and the reaction was extracted with AcOEt. The organic phase was then washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to yield a product of formula 4-bromo-2-pyrrolidin-1-ylbenzoic acid, This was used in the next step without further purification.
Yield: 387mg

1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.38 (dd, 1H), 6.91 (t, 1H), 6.81 (dt, 1H), 3.17 (q, 4H), 1.88 (h, 4H); LC-MS: m/z 269.99, 271.97 (MH+).

Preparation: (4-bromo-2-pyrrolidin-1-ylphenyl)-(4-propylpiperazin-1-yl)methanone

4-bromo-2-pyrrolidin-1-ylbenzoic acid (389.0 mg, 1.44 mmol
), HATU: [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (657.08 mg, 1.73 mmol) and N,N-diisopropylethylamine (0.5 mL, 1-propylpiperazine dihydrobromide (480.34 mg, 1.66 mmol) in DMF (2 mL) and N,N- A solution of diisopropylethylamine (0.5 mL, 2.88 mmol) was added. The reaction mixture was stirred at RT overnight. The next day, the solvent was removed under vacuum. The residue was purified by SCX cartridge, first washing with MeOH and then eluting with NH ₃ 1M in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 7:3), giving the formula (4-bromo-2-pyrrolidin-1-ylphenyl)-( A product of 4-propylpiperazin-1-yl) methanone was obtained.
Yield: 430mg

1H NMR (400 MHz, DMSO-d6) δ 6.94 - 6.85 (m, 1H), 6.84 - 6.73 (m, 2H), 3.72 - 3.62 (m, 1H), 3.49 (ddd, 1H), 3.26 - 3.02 (m , 6H), 2.44 - 2.16 (m, 6H), 1.92 - 1.80 (m, 4H), 1.42 (h, 2H), 0.84 (t, 3H); LC-MS: m/z 380.10, 382.10 (MH+).

Preparation: (4-propylpiperazin-1-yl)-[4-(pyridin-2-ylamino)-2-pyrrolidin-1-ylphenyl]methanone

(4-bromo-2-pyrrolidin-1-ylphenyl)-(4-propylpiperazin-1-yl)methanone (0.2 g, 0.530 mmol), (1E,4E)-1,5-diphenyl-3- Penta-1,4-dienone; palladium (24.08 mg, 0.030 mmol), dicesium carbonate (257.01 mg, 0.790 mmol), 2-pyridineamine (59.39 mg, 0.630 mmol) and [1-(2 -diphenylphosphino-1-naphthalenyl)-2-naphthalenyl]-diphenylphosphine (32.74 mg, 0.050 mmol) was suspended in toluene (2.815 mL). The reaction was degassed with _N2 for 10 minutes and then stirred at 100 °C overnight. The next day, it was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by FC on RP using basic conditions (eluted from H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 95:5 to H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 5:95). ), a product of formula (4-propylpiperazin-1-yl)-[4-(pyridin-2-ylamino)-2-pyrrolidin-1-ylphenyl]methanone was obtained.
Yield: 5.8mg

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.14 (d, 1H), 7.54 (t, 1H), 7.15 - 6.93 (m, 2H), 6.85 (dd, 2H), 6.79 - 6.69 (m, 1H), 3.53 (s, 4H), 3.27 - 2.97 (m, 6H), 2.24 (t, 4H), 1.88 (d, 4H), 1.43 (q, 2H), 0.85 (t, 3H); LC-MS: m/z 394.3 (MH+).

Preparation: (4-bromo-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using 1-methyl-3-phenylpiperazine in place of 1-propylpiperazine dihydrobromide (4-bromo-2-pyrrolidin-1-ylphenyl).
The synthesis of -(4-propylpiperazin-1-yl)methanone was performed analogously. The title compound was obtained in a yield of 66% (1.04 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 - 7.15 (m, 5H), 7.09 - 6.67 (m, 3H), 5.85 - 4.30 (m, 1H), 3.31 - 3.21 (m, 2H), 3.06 (d, 2H), 2.81 - 2.64 (m, 2H), 2.45 - 2.11 (m, 5H), 2.07 - 1.80 (m, 4H), 1.75 - 1.54 (m, 2H), LC-MS: m/z 428.08 , 430.10 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidin-1-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) phenyl] methanone

4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (311.22 mg, 1.23 mmol), (4-bromo-2-pyrrolidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (500.0 mg, 1.17 mmol) and potassium acetate (347. A mixture of 19 mg, 3.5 mmol) in 1,4-dioxane (22 mL) was degassed by 5 cycles of nitrogen/vacuum. Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (19.11 mg, 0.020 mmol) was added and again after 5 cycles of nitrogen/vacuum degassing. , the reaction mixture was heated at 100° C. for 2 hours. After this time, the reaction mixture was cooled to RT, filtered through a pad of Celite, and washed with AcOEt. The organic solution was concentrated under reduced pressure to give a product with the formula (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidin-1-yl-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl]methanone was obtained, which was used in the next step without further purification.
Yield: 559mg

LC-MS: m/z 476.22 (MH+).

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

Palladium tetrakis triphenylphosphine (6.08 mg, 0.010 mmol), a 2M aqueous solution of sodium carbonate (0.16 mL, 0.320 mmol) and (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidine- 1-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (50.0 mg, 0.110 mmol) in 1,2-dimethoxyethane ( The mixture in 1 mL) was degassed by 5 cycles of nitrogen/vacuum. Next, 2-bromo-1-methylimidazole (0.01 mL, 0.120 mmol) was added and the vessel was sealed. The reaction mixture was again degassed with 5 cycles of nitrogen/vacuum and then heated to 95° C. overnight. The next day, the reaction was cooled to RT and the mixture was purified directly by FC on RP using acid conditions ( _CH3CN / _H2O 5:95+0.1% formic acid to _CH3CN / _H2O5 :5+0 .1% formic acid). Appropriate fractions were pooled together and concentrated under vacuum. The residue was further purified by FC on RP using basic conditions (H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 95:5 to H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 2:8 elution), the product of formula [4-(1-methylimidazol-2-yl)-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone as a racemic mixture. Obtained.
Yield: 11.6mg

1H NMR (400 MHz, DMSO-d6) δ 7.81 - 7.69 (m, 1H), 7.49 (d, 1H), 7.44 - 6.89 (m, 8H), 5.90 - 4.74 (m, 1H), 3.83 - 3.68 (m LC -MS: m/z 430.22 (MH+)

Preparation: [4-(2-Methyl-1H-imidazol-5-yl)-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using 4-bromo-2-methylimidazole in place of 2-bromo-1-methylimidazole to synthesize the compound of Example 121 ([4-(1-methylimidazol-2-yl)-2 -pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone). The title compound was obtained in a yield of 38.3% (17.3 mg).

1H NMR (400 MHz, DMSO-d6) δ 11.94 (d, 1H), 8.08 - 6.54 (m, 9H), 5.89 - 4.68 (m, 1H), 3.55 - 2.59 (m, 8H), 2.42 - 2.11 (m , 7H), 1.95 (s, 3H), 1.77 - 1.59 (m, 2H); LC-MS: 430.20 (MH+).

Preparation: [4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using 2-bromo-5-methyl-1,3,4-oxadiazole in place of 2-bromo-1-methylimidazole to synthesize the compound of Example 121 ([4-(1- The synthesis was carried out analogously to the synthesis of methylimidazol-2-yl)-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone). The title compound was obtained as a racemic mixture in a yield of 16.5% (7.5 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.03 - 6.97 (m, 8H), 5.86 - 4.62 (m, 1H),3.53 - 3.26 (m, 2H), 3.30 - 2.54 (m, 9H), 2.37 - 1.87 (m, 8H), 1.79 - 1.60 (m, 1H); LC-MS: m/z 432.26 (MH+).

Scheme 12

Synthesis Scheme 12 - Reagents and conditions: a) Palladium tetrakistriphenylphosphine, appropriate boronate ester, Na ₂ CO ₃ 2M, 1,2 dimethoxyethane, 95°C, 1
．． 5 h or; b) PtO ₂ , EtOH, RT, 1 atm, 3 h; c) Boc ₂ O, TEA, DCM, 0° C. to RT, overnight.

Preparation: 2-thiophen-2-ylpyrazine

A 2M aqueous solution of 2-chloropyrazine (2.6 mL, 29.13 mmol), thiophen-2-ylboronic acid (4.1 g, 32.04 mmol) and sodium carbonate in 1,2-dimethoxyethane (100 mL) (43.69 mL) , 87.38 mmol) was degassed by 5 cycles of nitrogen/vacuum. Palladium tetrakistriphenylphosphine (1.7 g, 1.46 mmol) was then added and the vessel was sealed. The reaction mixture was again degassed by 5 cycles of nitrogen/vacuum and then heated to 95° C. overnight. The reaction was cooled to RT, diluted with _H2O , and the reaction was extracted with EtOAc (x3). The organic portion was collected, washed with brine, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by FC on an NH column (eluted from cHex 100% to cHex/AcOEt 8:2) to obtain 2-thiophen-2-ylpyrazine.
Yield: 3.9g

LC-MS: m/z 162.85 (MH+).

Preparation: 3-thiophen-2-ylpyrazine

The synthesis of the title compound was carried out analogously to the synthesis of 2-thiophen-2-ylpyrazine using 3-thiophenylboronic acid in place of thiophen-2-ylboronic acid. The title compound was obtained in a yield of 85% (3 g).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.94 (d, 1 H) 8.57 (dd, 1 H) 8.45 (d, 1 H) 8.01 (dd, 1 H) 7.71 (dd, 1 H) 7.46 (dd , 1 H); LC-MS: m/z 162.9 (MH+)

Preparation: 2-(1-methylpyrazol-4-yl)pyrazine

The title compound was synthesized in a similar manner to the synthesis of 2-thiophen-2-ylpyrazine, using 1-methylpyrazole-4-boronic acid pinacol ester in place of thiophen-2-ylboronic acid. The title compound was obtained with a yield of 96% (0.8 g).

1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, 1H), 8.55 (dd, 1H), 8.41 (s, 1H), 8.40 (s, 1H), 8.10 (d, 1H), 3.91 (s, 3H); LC-MS: m/z 160.95 (MH+).

Preparation: 2-pyridin-2-ylpyrazine

A mixture of 2-chloropyrazine (250.0 mg, 2.18 mmol) and tributyl(2-pyridinyl)stannane (0.85 mL, 2.62 mmol) in dry toluene (10 mL), the solution was degassed and palladium tetrakis triphenyl Phosphine (126.12 mg, 0.110 mmol) was added under nitrogen flux. The suspension was degassed again and stirred at 115°C overnight. The next day, the reaction mixture was diluted with a 10 mol% KF aqueous solution and extracted three times with EtOAc. The organic fraction was washed with _water , brine, dried over _Na2SO4 , filtered and the solvent was evaporated under reduced pressure. The resulting material was purified by FC on silica gel (eluted from cHex 100% to cHex/AcOEt 60:40) to yield a product of formula 2-pyridin-2-ylpyrazine.
Yield: 350mg

¹ H NMR (400 MHz, Chloroform-d) δ 9.66 (d, 1H), 8.75 (ddd, 1H), 8.66 - 8.61 (m, 2H), 8.39 (dt, 1H), 7.87 (td, 1H), 7.43 - 7.38 (m, 1H); LC-MS: m/z 158.1 (MH+)

Preparation: 2-thiophen-2-ylpiperazine

A mixture of 2-thiophen-2-ylpyrazine (275.0 mg, 1.7 mmol) and platinum (IV) oxide (192.49 mg, 0.850 mmol) in ethanol (5 mL) and AcOH (1 mL) was added under an atmosphere _{of H2} . , 1 atm, RT for 3 hours, and the next day the reaction was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by SCX washing first with MeOH and then with NH ₃ 1M in MeOH to give the product of formula 2-thiophen-2-ylpiperazine.
Yield: 240mg

LC-MS: m/z 169.0 (MH+).

Preparation: 2-(1-methylpyrazol-4-yl)piperazine

The synthesis of the title compound was similar to that of 2-thiophen-2-ylpiperazine, using 2-(1-methylpyrazol-4-yl)pyrazine in place of the synthesis of 2-thiophen-2-ylpiperazine. went. The title compound was obtained with a yield of 53% (550 mg).

LC-MS: m/z 167.0 (MH+)

Preparation: 2-thiophen-3-ylpiperazine

A mixture of 2-thiophen-3-ylpyrazine (315.0 mg, 1.94 mmol) and platinum (IV) oxide (220.49 mg, 0.970 mmol) in ethanol (8 mL) and AcOH (1 mL) under an atmosphere of _H2 , 6 bar, RT overnight. The reaction was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by SCX washing first with MeOH and then with NH ₃ 1M in MeOH to give the product of formula 2-thiophen-3-ylpiperazine.
Yield: 150mg

LC-MS: m/z 169.0 (MH+)

Preparation: 2-pyridin-2-ylpiperazine

The synthesis of the title compound was carried out analogously to the synthesis of 2-thiophen-3-ylpiperazine, substituting 2-pyridin-2-ylpyrazine for the synthesis of 2-thiophen-3-ylpiperazine. The title compound was obtained with a yield of 83% (130 mg).

¹ H NMR (400 MHz, Chloroform-d) δ 8.57 (ddd, 1H), 7.67 (td, 1H), 7.37 (dt, 1H), 7.19 (ddd, 1H), 3.93 (dd, 1H), 3.28 - 3.13 (m, 2H), 3.04 - 2.96 (m, 2H), 2.91 - 2.75 (m, 2H).

Preparation: tert-butyl 3-thiophen-2-ylpiperazine-1-carboxylate

2-thiophen-2-ylpiperazine (140.0 mg, 0.830 mmol), di-tert-butyl dicarbonate (181.59 mg, 0.830 mmol) and triethylamine (0.13 mL, 0.920 mmol) in DCM (4 mL). ) was stirred at room temperature for 3 hours. The reaction was diluted with DCM and washed with brine. The organic phase was dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 90:10) to give a product of the formula tert-butyl 3-thiophen-2-ylpiperazine-1-carboxylate.
Yield: 200mg

1H NMR (400 MHz, CHLOROFORM-d) d ppm 7.21 - 7.15 (m, 1 H), 7.04 - 6.99 (m, 2 H), 4.05 - 3.92 (m., 2 H), 2.90 (dd, 4 H) , 1.82 - 1.57 (m, 2 H), 1.48 (s, 9 H).

Preparation: tert-butyl 3-thiophen-3-ylpiperazine-1-carboxylate

Synthesis of the title compound analogously to the synthesis of tert-butyl 3-thiophen-2-ylpiperazine-1-carboxylate using 2-thiophen-3-ylpiperazine in place of 2-thiophen-2-ylpiperazine. I did it. The title compound was obtained with a yield of 20% (45 mg).

LC-MS: m/z 269.1 (MH+).

Preparation: 3-(1-methylpyrazol-4-yl)piperazine-1-carboxylic acid tert
-Butyl

Similar to the synthesis of tert-butyl 3-thiophen-2-ylpiperazine-1-carboxylate using 2-(1-methylpyrazol-4-yl)piperazine in place of 2-thiophen-2-ylpiperazine. The title compound was synthesized. The title compound was obtained in a yield of 99% (430 mg).
LC-MS: m/z 267.1 (MH+)

Preparation: tert-butyl 3-pyridin-2-ylpiperazine-1-carboxylate

Synthesis of the title compound analogously to the synthesis of tert-butyl 3-thiophen-2-ylpiperazine-1-carboxylate using 2-pyridin-2-ylpiperazine in place of 2-thiophen-2-ylpiperazine. I did it. The title compound was obtained with a yield of 46% (185 mg).

LC-MS: m/z 264.3 (MH+)

Preparation: tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate

A solution of 2-(3-fluorophenyl)piperazine (200.0 mg, 1.11 mmol) and triethylamine (0.17 mL, 1.22 mmol) in DCM (2.5 mL) was added with dicarbonate dicarbonate in DCM (1 mL). A solution of -tert-butyl (242.2 mg, 1.11 mmol) was added slowly and the reaction was stirred at RT for 1 h, diluted with more DCM and washed with H ₂ O. The organic phase was dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum to yield the product of formula tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate as a racemic mixture. This product was used in the next step without further purification.
Yield: 300mg

¹ H NMR (400 MHz, Chloroform-d) δ 7.36 - 7.30 (m, 1H), 7.24 - 7.11 (m, 2H), 7.03 - 6.93 (m, 1H), 4.06 (s, 2H), 3.73 (dd, 1H), 3.18 - 3.04 (m, 1H), 3.00 - 2.88
(m, 2H), 2.72 (s, 1H), 1.83 (s, 1H), 1.49 (s, 9H); LC-MS: m/z 281.1 (MH+)

Preparation: tert-butyl 3-(2-fluorophenyl)piperazine-1-carboxylate

tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate by using 2-(2-fluorophenyl)piperazine-1,4-dium dichloride in place of 2-(3-fluorophenyl)piperazine. The synthesis of the title compound was carried out analogously to the synthesis of . The title compound was obtained with a yield of 99% (220 mg).

LC-MS: m/z 281.1 (MH+).

Preparation: tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate

The title compound was synthesized analogously to the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate using 2-(4-fluorophenyl)piperazine in place of 2-(3-fluorophenyl)piperazine. was synthesized. The title compound was obtained in a yield of 90% (280 mg).

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 7.48 - 7.39 (m, 2H), 7.15 - 7.04 (m, 2H), 4.02 (ddt, 2H), 3.69 (dd, 1H), 3.10 - 2.70 (m , 4H), 1.47 (d, 10H), LC-MS: m/z 281.1
(MH+).

Preparation: tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate

The title compound was prepared analogously to the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate using 2-(2-chlorophenyl)piperazine in place of 2-(3-fluorophenyl)piperazine. Synthesis was performed. The title compound was obtained in a yield of 99% (752 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (dd, J=7.59, 1.87 Hz, 1 H), 7.44 (dd, J=7.81, 1.43 Hz, 1 H), 7.40 - 7.28 (m, 2 H) ), 4.03 (br d, J=12.10 Hz, 1 H), 3.97 - 3.81 (m, 2 H), 2.98 (br d, J=11.00 Hz, 1 H), 2.93 - 2.73 (m, 2 H), 2.73 - 2.63 (m, 2 H), 1.41 (s, 9 H); LC-MS: m/z 297.132 (MH+).

Preparation: tert-butyl 3-(3-chlorophenyl)piperazine-1-carboxylate

The title compound was prepared analogously to the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate using 2-(3-chlorophenyl)piperazine in place of 2-(3-fluorophenyl)piperazine. Synthesis was performed. The title compound was obtained in a yield of 99% (752 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (s, 1 H), 7.44 - 7.31 (m, 4 H), 3.81 (br
d, J=12.32 Hz, 2 H), 3.60 (dd, J=10.34, 2.86 Hz, 1 H), 3.03 - 2.73 (m, 2 H), 2.73 - 2.59 (m, 2 H), 1.41 (s, 9H); LC-MS: 297.16 (MH+).

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophen-2-ylpiperazine-1-carboxylate

2-thiophen-2-ylpiperazine-1-carboxylic acid tert instead of piperidine
Synthesis of the title compound analogously to the synthesis of the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide) using -butyl I did it. The title compound was obtained in a yield of 89% (145 mg).

LC-MS: m/z 553.4 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophen-3-ylpiperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis of the title compound was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 80% (65 mg).

LC-MS: m/z 553.4 (MH+).

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepane)-4-(piperidine-1 The synthesis of the title compound was carried out analogously to the synthesis of -carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 58% (70 mg).

LC-MS: m/z 551.4 (MH+).

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis of the title compound was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained with a yield of 50% (80 mg).

LC-MS: m/z 548.52

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(trifluoromethyl)piperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis of the title compound was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 40% (45 mg).

LC-MS: m/z 539.4 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-benzylpiperazine-1-carboxylate

Using tert-butyl 3-benzylpiperazine-1-carboxylate in place of piperidine, the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl) The synthesis of the title compound was carried out analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 88% (100 mg).

LC-MS: m/z 561.4 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(hydroxymethyl)piperazine-1-carboxylate

Using 1-boc-3-hydroxymethyl-piperidine in place of piperidine, the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropane The synthesis of the title compound was carried out analogously to the synthesis of carboxamide). The title compound was obtained in a yield of 72% (80 mg).

LC-MS: m/z 501.3 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-methylpiperazine-1-carboxylate

Using 3-methyl-1-piperazinecarboxylic acid tert-butyl ester in place of piperidine, the compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1-carbonyl)phenyl ) The synthesis of the title compound was carried out analogously to the synthesis of cyclopropanecarboxamide). The title compound was obtained in a yield of 98% (105 mg).

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-propan-2-ylpiperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis of the title compound was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained with a yield of 99% (120 mg).

LC-MS: m/z 513.4 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-phenylpiperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1 The synthesis of the title compound was carried out analogously to the synthesis of -carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 91% (145 mg).

LC-MS: m/z 547.5 (MH+)

Preparation: tert-butyl 4-[2-(azepan-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylate

The compound of Example 35 (N-(3-(azepan-1-yl)-4-(piperidine-1- The synthesis of the title compound was carried out analogously to the synthesis of carbonyl)phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 91% (145 mg).

LC-MS: m/z 548.5 (MH+)

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-phenylpiperazine-1-carboxylate

4-(Cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (100.0 mg, 0.360 mmol), HATU: [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethyl Ammonium hexafluorophosphate (166.33 mg, 0.440 mmol) and N,N-diisopropylethylamine (0.25 mL, 1.46 mmol) were mixed in DMF (3.5 mL) and stirred for 5 minutes, then 3- Phenylpiperazine, N1Coc protected (95.64mg, 0.360mmol) was added. The reaction mixture was stirred at RT for 2 hours. Stirred at 60°C overnight. the next day,
The reaction was cooled to RT, poured into _H2O and extracted three times with AcOEt. The organic fractions were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by FC on a NH column (eluted from 100% cHex to AcOEt/cHex 3:7) to give the formula 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl] as a racemic mixture. A product of tert-butyl-3-phenylpiperazine-1-carboxylate was obtained.
Yield: 156 mg.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 - 10.04 (m, 1H), 7.49 - 6.69 (m, 8H), 5.76 - 4.31 (m, 2H), 3.74 - 3.48 (m, 2H), 3.31 (s, 2H), 3.17 - 2.86 (m, 4H), 2.05 - 1.60 (m, 5H), 1.48 - 1.19 (m, 10H), 0.78 (d, 4H), LC-MS: 519.2 (MH+)

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate

4-(Cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (136.5 mg, 0.500 mmol) and HATU: [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethyl A solution of ammonium hexafluorophosphate (283.81 mg, 0.750 mmol) in DMF (3 mL) was sequentially added with N,N-diisopropylethylamine (0.26 mL, 1.49 mmol) and 3-(4-fluorophenyl)piperazine. Tert-butyl-1-carboxylate (150.0 mg, 0.500 mmol) was added. The reaction mixture was heated to 80° C. and allowed to react overnight. After the completion of the reaction, the mixture was cooled to RT and it was treated with NaHCO ₃ s. s. and poured into AcOEt. The phases were separated and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to dryness under vacuum to give the formula 4-[4-(cyclopropanecarbonylamino)-2 as a racemic mixture. A product of tert-butyl-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate was obtained. This product was used in the next step without further purification.
Yield: 110 mg.

¹ H NMR (400 MHz, Chloroform-d) δ 7.63 - 7.26 (m, 3H), 7.04 (ddtd, 5H), 6.82 -
5.15 (m, 2H), 4.87 - 4.35 (m, 1H), 4.20 - 3.66 (m, 2H), 3.59 - 2.68 (m, 6H), 1.88 (d, 4H), 1.57 - 1.43 (m, 9H), 1.29 (d, 1H), 1.15 - 1.02 (m, 2H), 0.94 - 0.75 (m, 2H), LC-MS: 537.18 (MH+)

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(3-fluorophenyl)piperazine-1-carboxylate

The compound of Example 136 (4-[ The synthesis of the title compound was carried out analogously to tert-butyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). The title compound was obtained as a racemic mixture in a yield of 52.2% (100 mg).

LC-MS: m/z 537.26 (MH+).

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate

The compound of Example 136 (4-[ The title compound was synthesized analogously to the synthesis of tert-butyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). . The title compound was obtained as a racemic mixture in a yield of 79% (200 mg).

LC-MS: m/z 537.26 (MH+).

Preparation: tert-butyl 4-[2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophen-2-ylpiperazine-1-carboxylate

The synthesis of the title compound was carried out by substituting tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate and 3-thiophene-1-ylbenzoic acid for 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid, respectively. The compound of Example 136 using tert-butyl 2-ylpiperazine-1-carboxylate and 2-(6-azaspiro[3.4]octan-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid The synthesis was carried out analogously to the synthesis of (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). The title compound was obtained as a racemic mixture in a yield of 22% (28 mg).

LC-MS: m/z 565.2 (MH+).

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-thiophen-2-ylpiperazine-1-carboxylate

The compound of Example 136 (4-[4 The synthesis of the title compound was carried out analogously to the synthesis of tert-butyl-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). . The title compound was obtained as a racemic mixture in a yield of 99% (28 mg).

LC-MS: m/z 525.19 (MH+)

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate

The synthesis of the title compound was carried out using tert-butyl 3-(1-methylpyrazol4-yl)piperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. Similar to the synthesis of the compound of Example 136 (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate) So I went. The title compound was obtained as a racemic mixture in a yield of 99% (28 mg).

LC-MS: m/z 523.24 (MH+).

Synthesis scheme 13

Preparation: (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

In a round bottom flask, 2,6-dichloro-3-pyridinecarboxylic acid (1.0 g, 5.21 mmol) and thionyl dichloride (3.8 mL, 52.08 mmol) were mixed. The suspension was heated to reflux and stirred for 30 minutes. After this time, the reaction mixture was stirred at r. t. and concentrated under reduced pressure. The resulting material was stripped three times with cHex. The residue was dissolved in DCM (9.091 mL), cooled to 0° C. and stirred for 10 minutes. After this time, a solution of N,N-diisopropylethylamine (2.48 mL, 14.26 mmol) and thiomorpholine 1,1-dioxide hydrochloride (642.34 mg, 4.75 mmol) in DCM (2 mL) was added for 10 min. added across the board. The resulting solution was warmed to RT and stirred for 30 minutes. _The reaction mixture was diluted with DCM, washed with water, dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 4:6) to give a compound of formula (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinamine). -4-yl) methanone product was obtained.
Yield: 1g

1H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (d, 1 H), 7.43 (d, 1 H), 4.48 - 4.65 (m, 1 H), 4.19 - 4.04 (m, 1 H), 3.92 - 3.70 (m, 2 H), 3.31 - 3.13 (m, 3 H), 3.05 -
2.90 (m, 1 H); LC-MS: 309.24 (MH+)

Preparation: (2,6-dichloropyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A suspension of 2,6-dichloro-3-pyridinecarboxylic acid (3.0 g, 15.63 mmol) in thionyl dichloride (11.33 mL, 156.25 mmol) was heated to reflux and stirred for 30 minutes. After this time, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was taken up with cHex and concentrated under vacuum. This operation was repeated three times. The residue was then suspended in DCM (25 mL) and N,N-diisopropylethylamine (2.37 mL, 13.62 mmol) was added. The reaction was cooled to 0° C. and 1-methyl-3-phenylpiperazine (2.0 g, 11.35 mmol) was added. The reaction was warmed to RT and stirred for 3 hours. After this time, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. Washed with. The organic phase was dried through a phase separator and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 1:1) and was purified with formula (2,6-dichloropyridin-3-yl)-(4-methyl-2-phenylpiperazine-1- The product of yl) methanone was obtained as a racemic mixture.
Yield: 3g

H NMR (400 MHz, DMSO-d6) δ 8.05 (dd, 1H), 7.88 - 7.45 (m, 3H), 7.43 - 7.13 (m, 3H), 4.75 - 4.30 (m, 1H), 3.54 - 3.36 (m , 1H), 3.24 - 2.61 (m, 3H), 2.44 - 2.14 (m, 4H), 2.09 - 1.90 (m, 1H); LC-MS: m/z 350.1

Preparation: [6-chloro-2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

To a solution of (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone (155.0 mg, 0.500 mmol) in DMF (1 mL) was added 3 -(Propan-2-yl)pyrrolidine hydrochloride and potassium carbonate (69.29 mg, 0.500 mmol) were added. The resulting mixture was stirred at 80°C overnight. The next day H ₂ O was added and the reaction was extracted three times with AcOEt. The combined organic fractions were dried over brine, Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by FC on silica gel (eluting from cHex/AcOEt 9:1 to cHex/AcOEt 6:4) and was purified with the formula [6-chloro-2-(3-propan-2-ylpyrrolidin-1-yl)pyridine-3] The product of -yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was obtained as a racemic mixture.
Yield: 79mg

LC-MS: m/z 386.1 (MH+)

Preparation: [2-(6-Azaspiro[3.4]octan-6-yl)-6-chloropyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was carried out using 6-azaspiro[3.4]octane in place of 3-(propan-2-yl)pyrrolidine hydrochloride. The synthesis of -1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 58% (112 mg).

1H NMR (400 MHz, CHLOROFORM-d), ¹ H NMR (400 MHz, Chloroform-d) δ 7.36 (d, 1H), 6.65 (d, 1H), 4.04 - 3.70 (m, 4H), 3.47 (s, 2H), 3.32 (s, 2H), 3.16 (s, 2H), 2.95 (s, 2H), 2.04 - 1.90 (m, 8H); LC-MS: 384.2 (MH+)

Preparation: (6-chloro-2-pyrrolidin-1-ylpyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. [6-chloro-2-(3-propane- The synthesis was carried out analogously to the synthesis of 2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone. The title compound was obtained as a racemic mixture in 60% yield (190 mg).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97- 7.03 (m, 6 H), 6.64 -6.32 (m, 1 H),6.08 - 4.74 (m, 1 H), 4.72 - 2.63 (m, 8 H) ), 2.54 - 2.36 (m, 1 H), 2.35 - 2.26 (m, 3 H), 2.12 - 2.02 (m, 1 H), 2.02 - 1.62 (m, 4 H); LC-MS: m/z 385.2 (MH+).

Preparation: [2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloropyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. using (2,6-dichloropyrrolidin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone and 3-azabicyclo[3.1.0]hexane hydrochloride in place of , respectively. Similar to the synthesis of [6-chloro-2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone So I went. The title compound was obtained as a racemic mixture in a yield of 53% (182 mg).

LC-MS: m/z 397.17

Preparation: [6-chloro-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. [6-chloro- The synthesis of 2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 44% (167 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 - 7.58 (m, 1H), 7.53 - 7.42 (m, 1H), 7.39 - 7.17 (m, 4H), 7.06 - 6.80 (m, 1H), 5.83 - 5.61 (m, 1H), 3.54 (d, 2H), 3.27 - 2.60 (m, 5H), 2.44 - 1.88 (m, 8H), 1.79 - 1.51 (m, 2H), LC-MS: m/z 435.16 (MH+).

Preparation: [6-chloro-2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. [6-chloro- The synthesis of 2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 35% (75 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 - 7.61 (m, 1H), 7.48 (dd, 1H), 7.43 - 7.16 (m, 4H), 6.86 (dd, 1H), 5.84 - 4.34 (m , 1H), 3.92 - 3.38 (m, 3H), 3.22 - 2.58 (m,
5H), 2.45 - 1.69 (m, 8H), 1.53 - 1.08 (m, 1H), LC-MS: m/z 435.16 (MH+).

Preparation: [6-chloro-2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. [6-chloropyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone and 3,3-difluoropyrrolidine hydrochloride were used instead of -2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously to the synthesis. . The title compound was obtained as a racemate in a yield of 30% (96 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 7.62 - 7.48 (m, 1 H), 7.96 - 7.11 (m, 5 H), 6.65 (br d, 1 H), 4.69 - 5.90 (m, 1 H) , 4.58 - 3.01 (m, 7 H), 2.84 - 2.57 (m, 1 H), 2.56 - 2.47 (m, 1 H), 2.46 - 2.27 (m, 1 H), 2.28 - 2.12 (m, 4 H) , 2.11 - 1.88 (m, 1 H); LC-MS: 421.1 (MH+).

Preparation: (6-chloro-2-piperidin-1-ylpyridin-3-yl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using (2,6-dichloropyridin-3-yl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone and 3-(propan-2-yl)pyrrolidine hydrochloride. [6-chloro-2-(3- The synthesis of propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained as a racemic mixture in 50% yield (170 mg).

LC-MS: m/z 399.1 (MH+)

1H NMR (500 MHz, DMSO-d6 ) δ ppm 7.57 - 7.39 (m, 1 H), 7.88 - 7.04 (m, 5 H), 6.91 - 6.69 (m, 1 H), 5.75 - 4.48 (m, 1 H ), 3.51 - 3.34 (m, 1 H), 4.46 - 2.88 (m, 2 H), 3.51 - 2.88 (m, 4 H), 2.85 - 2.64 (m, 1 H), 2.48 - 2.26 (m, 1 H) ), 2.25 -
2.10 (m, 3 H), 2.06 - 1.88 (m, 1 H), 1.78 - 1.13 (m, 6 H).

Preparation: N-[5-(1,1-dioxo-1,4-thiazine-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-1-yl)pyridin-2-yl]cyclopropanecarboxamide

[6-chloro-2-(3-propan-2-ylpyrrolidin-1-yl)pyridin-3-yl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone (66.35 mg , 0.170 mmol), cyclopropanecarboxamide (16.09 mg, 0.190 mmol), dicium carbonate (112.73 mg, 0.340 mmol) and XPHOS PD G3 (7.28 mg, 0.010 mmol) in dry 1,4-dioxane. The solution in (1.715 mL) was degassed by Schlenkline method. The resulting mixture was heated to 100°C and stirred for 3 hours. After this time, the reaction was cooled to ambient temperature and the reaction mixture was diluted with AcOEt and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and purified by FC on silica gel (eluted from cHex/AcOEt 8:2 to cHex/AcOEt 4:6), giving a product of formula N-[5-(1,1-dioxo-1,4-thiazinean- The product 4-carbonyl)-6-(3-propane2-ylpyrrolidin-1-yl)pyridin-2-yl]cyclopropanecarboxamide was obtained as a racemic mixture.

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.38 - 10.16 (m, 1 H), 7.60 - 7.47 (m, 1 H), 7.40 - 7.24 (m, 1 H), 4.60 - 3.44 (m, 4 H ), 3.77 - 2.90 (m, 4 H), 3.42 - 2.87 (m, 4 H), 2.17 - 1.96 (m, 2 H), 1.93 - 1.75 (m, 1 H), 1.57 - 1.39 (m, 2 H) ), 0.93
(d, 3 H), 0.91 (d, 3 H), 0.83 - 0.64 (m, 4 H); LC-MS: m/z 435.86 (MH+).

Preparation: N-[6-(6-Azaspiro[3.4]octan-6-yl)-5-(1,1-dioxo-1,4-thiazinean-4-carbonyl)pyridin-2-yl]cyclopropane Carboxamide

The synthesis of the title compound was performed using ) [2-(6-Azaspiro[3.4]octan-6-yl)-6-chloropyridin-3-yl]-(1,1-dioxo-1,4-thiazinean-4-yl) instead of methanone ) methanone to prepare the compound of Example 142 (N-[5-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-1-yl). ) pyridin-2-yl]cyclopropanecarboxamide). The title compound was obtained in a yield of 16.3% (20 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.31 (s, 1 H), 7.53 (d, 1 H), 7.30 (d, 1 H), 4.53 - 3.75 (m, 2 H), 3.61 (br t , 2 H), 3.47 - 3.15 (m, 4 H), 3.43 - 2.94 (m, 4 H), 2.09 - 2.03 (m, 1 H), 2.02 - 1.77 (m, 8 H), 0.84 - 0.70 (m , 4 H); LC-MS: 433.46 (MH+).

Preparation: N-[6-(3,3-difluoropiperidin-1-yl)-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) Using [6-chloro-2-(3,3-difluoropiperidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone instead of methanone, Compound of Example 142 (N-[5-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-2-yl)pyridin-2-yl ] Cyclopropane carboxamide). The title compound was obtained as a racemate in a yield of 47% (69 mg).

1H NMR (600 MHz, DMSO-d6 ) δ ppm 10.60 - 10.39 (m, 1 H), 7.62 - 7.39 (m, 2 H), 7.76 - 7.13 (m, 2 H), 7.48 - 7.11 (m, 3 H ), 5.95 - 4.45 (m, 1 H), 4.43 - 2.86
(m, 7 H), 2.85 - 2.58 (m, 1 H), 2.48 - 2.26 (m, 1 H), 2.25 - 1.04 (m, 9 H), 0.91 - 0.63 (m, 4 H); LC-MS : m/z 484.19 (MH+).

Preparation: N-[6-(3-azabicyclo[3.1.0]hexan-3-yl)-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) methanone instead of [2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-ccyclopyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl ) methanone to prepare the compound of Example 142 (N-[5-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-2-yl) )
[pyridin-2-yl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 61% (125 mg).

1H NMR (600 MHz, DMSO-d6 ) δ ppm 10.56 - 9.96 (m, 1 H), 7.86 - 6.90 (m, 7 H),
5.92 - 4.63 (m, 1 H), 4.56 - 2.93 (m, 7 H), 2.92 - 2.62 (m, 1 H), 2.45 - 2.25 (m, 1 H), 2.25 - 2.11 (m, 3 H), 2.09 - 1.82 (m, 2 H), 1.71 - 1.29 (m, 2 H), 0.84 - 0.72 (m, 4 H), 0.70 - 0.43 (m, 1 H), 0.26 - -0.23(m, 1 H) ; LC-MS: 446.2 (MH+).

Preparation: N-[6-(4,4-difluoropiperidin-1-yl)-5-(4-methyl-2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) using [6-chloro-2-(4,4-difluoropiperidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone instead of methanone, Compound of Example 142 (N-[5-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-2-yl)pyridin-2-yl ] Cyclopropane carboxamide). The title compound was obtained as a racemic mixture in a yield of 58% (106 mg).

1H NMR (600 MHz, DMSO-d6 ) δ ppm 10.51 (s, 1 H), 7.65 - 7.40 (m, 2 H), 7.80 -
7.13 (m, 2 H), 7.48 - 7.11 (m, 3 H), 5.88 - 4.50 (m, 1 H), 4.47 - 2.82 (m, 7 H), 2.84 - 2.63 (m, 1 H), 2.37 - 2.25 (m, 1 H), 2.25 - 1.56 (m, 9 H), 0.95 - 0.60 (m, 4 H); LC-MS: m/z 484.2 (MH+)

Preparation: N-[5-(4-methyl-2-phenylpiperazine-1-carbonyl)-6-piperidin-1-ylpyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) The compound of Example 142 ( N-[5-(1,1-dioxo-1,4-thiazine-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-1-yl)pyridin-2-yl]cyclopropanecarboxamide) The synthesis was carried out analogously. The title compound was obtained as a racemic mixture in 50% yield (95 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.56 - 10.26 (m, 1 H), 7.93 - 6.96 (m, 7 H), 5.75 - 4.48 (m, 1 H), 4.43 - 2.84 (m, 7 H ), 2.83 - 2.60 (m, 1 H), 2.57 - 2.26 (m, 1 H), 2.26 - 2.13 (m, 3 H), 2.13 - 1.86 (m, 2 H), 1.80 - 1.07 (m, 6 H) ), 0.78
(br d, 4 H); LC-MS: m/z 484.2 (MH+)

Preparation: N-[6-(3,3-difluoropyrrolidin-1-yl)-5-(4-methyl-
2-phenylpiperazine-1-carbonyl)pyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) Using [6-chloro-2-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-(4-methyl-2-phenylpiperazin-1-yl)methanone instead of methanone, Compound of Example 142 (N-[5-(1,1-dioxo-1,4-thiazine-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-1-yl)pyridin-2-yl ] Cyclopropane carboxamide). The title compound was obtained as a racemic mixture in a yield of 53% (65 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.52 - 10.34 (m, 1 H), 7.77 - 7.18 (m, 7 H), 5.90 - 4.67 (m, 1 H), 4.60 - 2.86 (m, 34 H ), 2.80 - 2.47 (m, 1 H), 2.69 - 2.45
(m, 1 H), 2.42 - 2.22 (m, 1 H), 2.29 - 2.17 (m, 3 H), 2.33 - 2.13 (m, 1 H), 2.09 - 1.98 (m, 1 H), 2.12 - 1.88 (m, 1 H), 0.88 - 0.72 (m, 4 H); LC-MS: m/z 470.1 (MH+).

The racemic mixture (Example 148c) was then separated into single enantiomers by semi-preparative chiral HPLC.

Preparation: N-[5-(4-methyl-2-phenylpiperazine-1-carbonyl)-6-pyrrolidin-1-ylpyridin-2-yl]cyclopropanecarboxamide

The synthesis of the title compound was performed using ) The compound of Example 142 (N -Synthesis of [5-(1,1-dioxo-1,4-thiazine-4-carbonyl)-6-(3-propan-2-ylpyrrolidin-1-yl)pyridin-2-yl]cyclopropanecarboxamide) It was done similar to. The title compound was obtained as a racemic mixture in a yield of 53% (65 mg).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 - 7.10 (m, 8 H), 6.24 - 4.84 (m, 1 H), 4.81 - 2.57 (m, 8 H), 2.53 - 2.36 (m, 1 H ), 2.35 - 2.26 (m, 3 H), 2.25 - 2.02 (m, 1 H), 2.02 - 1.63 (m, 4 H), 1.62 - 1.50 (m, 1 H), 1.09 (br d, 2 H) , 0.94 -
0.79 (m, 2 H); LC-MS: 434.2 (MH+).

The racemic mixture (Example 149c) was then separated into single enantiomers by chiral semipreparative HPLC.

Synthesis scheme 14

Preparation: 3-fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)benzonitrile

4-cyano-2-fluorobenzoic acid (500.0 mg, 3.03 mmol), N,N-diisopropylethylamine (2.64 mL, 15.14 mmol) and HATU: ([dimethylamino(3-triazolo[4,5- A stirred solution of b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (1727.06 mg, 4.54 mmol) in DMF (15.14 mL) was stirred for 15 minutes at RT. Then 1-methyl-3-phenylpiperazine (640.48 mg, 3.63 mmol) was added and the reaction mixture was stirred at RT for 2 hours. After this time, a saturated solution of _NaHCO3 was added to the reaction mixture and the aqueous phase was extracted three times with AOEt. The organic portion was collected, washed with brine, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (eluted from 100% cHEx to AcOEt/cHex 1:1) to give a product of formula 3-fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)benzonitrile. was obtained as a racemic mixture.
Yield: 887mg

LC-MS: m/z 324.20 (MH+)

Preparation: 3-fluoro-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was carried out using 4-(trifluoromethyl)piperidine; hydrochloride in place of 1-methyl-3-phenylpiperazine. The synthesis was carried out analogously to the synthesis of carbonyl)benzonitrile. The title compound was obtained in a yield of 98% (894 mg).

LC-MS: m/z 301.13 (MH+).

Preparation: 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylbenzonitrile

3-fluoro-4-(4-methyl-2-phenylpiperazine-1-carbonyl)benzonitrile (887.0 mg, 2.74 mmol) and pyrrolidine (0.68 mL, 8.23 mmol) in MeCN (5.486 mL) The mixture was stirred at RT overnight. The next day, the reaction was heated to reflux for 4 hours. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was purified by FC on a NH column (eluted from 100% cHex to AcOEt/cHex 6:4) to give the formula 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylbenzo. The nitrile product was obtained as a racemic mixture.
Yield 560mg

1H NMR (400 MHz, DMSO-d6) δ 7.80 - 6.86 (m, 8H), 5.88 - 4.35 (m, 1H), 3.48 - 3.33 (m, 2H), 3.30 - 3.20 (m, 1H), 3.16 - 2.58 (m, 4H), 2.47 - 2.01 (m, 5H), 2.01 - 1.86 (m, 3H), 1.81 - 1.48 (m, 2H), LC-MS: m/z 375.22 (MH+).

Preparation: 3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile

The synthesis of the title compound was modified by substituting 3-fluoro-4-[4-(trifluoromethyl)piperidine-1- The synthesis of 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylbenzonitrile was carried out analogously using benzonitrile. The title compound was obtained in a yield of 68% (715 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.27 - 6.98 (m, 3H), 4.61 (t, 1H), 3.52 (dd, 1H),
3.30 - 2.94 (m, 5H), 2.88 - 2.71 (m, 1H), 2.62 (t, 1H), 1.99 - 1.83 (m, 5H), 1.76 (d, 1H), 1.41 (dqd, 2H), LC- MS: m/z 352.18 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]methanone

4-(4-Methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylbenzonitrile (295.0 mg, 0.790 mmol) and N-hydroxyethanimidamide (92.22 mg, 1.18 mmol) ) in DMSO (2.626 mL) containing copper diacetate (28.93 mg, 0.160 mmol), cesium carbonate (774.78 mg, 2.36 mmol) and disodium sulfate (794.39 mg, 5.51 mmol). ) was added and the reaction mixture was stirred at 120°C overnight. The next day, the reaction was cooled to RT and purified directly by FC on RP using acidic conditions (CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 6:4 + 0.1 % formic acid) and further purified by SCX washing first with MeOH and then with _1M NH in MeOH to give the formula (4-methyl-2-phenylpiperazin-1-yl)-[4- The product (5-methyl-4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]methanone was obtained as a racemic mixture.
Yield: 9.1 mg.

1H NMR (400 MHz,DMSO-d6) δ 13.61 (s, 1H),8.03 - 6.72 (m, 8H), 5.91 - 4.61 (m,
1H), 4.55 - 3.40 (m, 3H), 3.32 (d, 3H), 3.15 - 2.60 (m, 4H), 2.46 - 2.12 (m, 6H), 1.96 (s, 2H), 1.80 - 1.60 (m, 2H); LC-MS: m/z 431.25 (MH+).

The racemic mixture (Example 150c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: [4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl) methanone

Using N-hydroxycyclopropanecarboximidamide in place of N-hydroxyethanimidamide, the compound of Example 150a, b ((4-methyl-2-phenylpiperazin-1-yl)-[4-(5-methyl The title compound was synthesized analogously to the synthesis of -4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]methanone). The title compound was obtained as a racemic mixture in a yield of 10% (30 mg).

1H NMR (600 MHz, DMSO-d6 ) δ ppm 13.74 (br s, 1 H), 7.83 - 7.44 (m, 2 H), 7.43 - 7.09 (m, 5 H), 7.16 - 6.93 (m, 1 H) , 5.95 - 4.62 (m, 1 H), 4.73 - 3.20 (m, 1
H), 3.35 - 2.23 (m, 9 H), 2.27 - 2.12 (m, 3 H), 2.10 - 1.98 (m, 1 H), 1.98 - 1.51 (m, 4 H), 1.08 - 0.76 (m, 4 H), LC-MS: m/z 457.27 (MH+).

The racemic mixture (Example 151c) was then separated into single enantiomers by chiral semipreparative HPLC.

Preparation: [4-(3-methyl-1,2,4-oxadiazol-5-yl)-2-pyrrolidin-1-ylphenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone

実施例１５２

Example 152

3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (100.0 mg, 0.280 mmol) and N-hydroxyethanimidamide (33.32 mg, 0.430 mmol) ) in DMF (0.569 mL) under nitrogen atmosphere was added anhydrous zinc chloride (11.81 mg, 0.090 mmol) and trifluoroacetic acid (0.01 mL) under _N2 . The reaction mixture was heated at 120° C. for 30 min under MW irradiation. After this time, a saturated solution of _NaHCO3 was added to the mixture and the aqueous phase was extracted three times with EtOAc. The organic portion was collected, washed with brine, dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The residue was purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 8:2 + 0.1% formic acid), giving the formula [4-(3-methyl-1,2,4-oxadiazole-5-
The product yl)-2-pyrrolidin-1-ylphenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone was obtained.
Yield: 10.4mg

1H NMR (500 MHz,DMSO-d6 ) δ ppm 7.54 -7.42 (m, 2 H), 7.37 - 7.19 (m, 1 H), 4.84 - 4.73 (m, 1 H), 3.80 - 3.63 (m, 1 H ), 3.42 - 3.34 (m, 2 H), 3.26 - 2.78 (m, 4 H), 2.60 - 2.47 (m, 1 H), 2.44 (s, 3 H), 2.13 - 1.42 (m, 8 H); LC-MS: m/z 409.19 (MH+).

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

3-pyrrolidin-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]benzonitrile (100.0 mg, 0.280 mmol) and N-hydroxyethanimidamide (33.32 mg, 0.430 mmol ) in DMSO (0.0949 mL) containing copper diacetate (10.45 mg, 0.060 mmol), cesium carbonate (279.91 mg, 0.850 mmol) and disodium sulfate (287.0 mg, 1.99 mmol). ) was added and the reaction mixture was stirred at 120°C overnight. The next day, more N-hydroxyethanimidamide (33.32 mg, 0.430 mmol) and copper diacetate (10.45 mg, 0.060 mmol) were added and the reaction was stirred at 120° C. for an additional 12 hours. The next day, the reaction was cooled to RT and purified directly by FC on RP using acidic conditions (CH ₃ CN/H ₂ O 5:95+0.1% formic acid to CH ₃ CN/H ₂ O 6:4+0. 1% formic acid), formula [4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]-[4-(trifluoromethyl) The product of piperidin-1-yl]methanone was obtained.
Yield: 5.7mg

1H NMR (400 MHz, DMSO-d6) δ 13.73 (s, 1H), 7.43 - 7.23 (m, 2H), 7.09 (dd, 1H), 4.64 (t, 1H), 3.60 (d, 1H), 3.28 - 2.93 (m, 5H), 2.89 - 2.65 (m, 2H), 2.38 (s,
3H), 1.90 (s, 5H), 1.77 (d, 1H), 1.39 (dq, 2H); LC-MS: m/z 408.18 (MH+).

Preparation: [4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)-2-pyrrolidin-1-ylphenyl]-[4-(trifluoromethyl)piperidin-1-yl] methanone

Example 153 ([4-(5-methyl-4H-1,2,4-triazol-3-yl)-2- The title compound was synthesized analogously to the synthesis of pyrrolidin-1-ylphenyl]-[4-(trifluoromethyl)piperidin-1-yl]methanone). The title compound was obtained in a yield of 6% (6.7 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 14.40 - 13.26 (m, 1 H), 7.97 - 6.54 (m, 3 H), 4.76 - 4.53 (m, 1 H), 3.76 - 3.45 (m, 1 H ), 3.29 - 2.91 (m, 5 H), 2.83 - 2.68
(m, 1 H), 2.66 - 2.56 (m, 1 H), 2.16 - 1.99 (m, 1 H), 1.97 - 1.67 (m, 6 H), 1.50
- 1.28 (m, 2 H), 1.15 - 0.83 (m, 4 H), LC-MS: m/z 434.21 (MH+).

Synthesis scheme 15

Preparation: Methyl 2-(3-methylpyrazol-1-yl)-4-nitrobenzoate

Methyl 2-bromo-4-nitrobenzoate (2 g, 7.69 mmol), 3-methyl-1H-pyrazole 3 (1.24 mL, 15.38 mmol), cesium carbonate (5042.92 mg, 15.38 mmol), N, N'-dimethylcyclohexane-1,2-diamine (0.24 mL, 1.54 mmol) and copper(I) iodide (73.63 mg, 0.380 mmol) in 1,4-dioxane (12.6 mL)/water ( The suspension in 0.200 mL) was degassed by the Schelln-Kline method and heated to 100° C. for 4 hours. After this time, the reaction mixture was diluted with H ₂ O, brought to pH 2 with HCl 3N, and 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 under reduced pressure to give a compound of formula methyl 2-(3-methylpyrazol-1-yl)-4-nitrobenzoate. The product was obtained and used in the next step without further purification.
Yield: 1.8g

LC-MS: m/z 262.08 (MH+)

Preparation: 2-(3-methylpyrazol-1-yl)-4-nitrobenzoic acid

To a solution of methyl 2-(3-methylpyrazol-1-yl)-4-nitrobenzoate (1.8 g, 6.89 mmol) in THF (8.05 mL) and methanol (2.68 mL) was added water (2. A solution of lithium hydroxide (384.38 mg, 15.4 mmol) in 68 mL) was added. The reaction was stirred at 50° C. overnight. The next day, the reaction was cooled to RT, brought to pH 2 with HCl 3N, and the mixture was extracted three times with AcOEt. The combined organic fractions were then washed with brine, dried over _Na2SO4 , filtered, and concentrated under vacuum _. The raw material was purified by semi-preparative MDAP method.

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[2-(3-methylpyrazol-1-yl)-4-nitrophenyl]methanone

DMF (3 mL) and N,N-diisopropylethylamine (78.42 mg, 0.01 mg).
HATU:[dimethylamino(3-triazolo[4,5-b] Pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (0.12 mL, 0.240 mmol) was added and the mixture was stirred at rt for 30 min. After this time, 1-methyl-3-phenylpiperazine (49.2 mg, 0.280 mmol) was added and the reaction was stirred at room temperature overnight. The next day, the reaction mixture was diluted with water and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to yield a compound of formula (4-methyl-2-phenylpiperazin-1-yl)-[2-( The product 3-methylpyrazol-1-yl)-4-nitrophenyl]methanone was obtained as a racemic mixture. This product was used in the next step without further purification.
Yield: 100mg

LC-MS: m/z 406.5 (MH+)

Preparation: [4-amino-2-(3-methylpyrazol-1-yl)phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

(4-Methyl-2-phenylpiperazin-1-yl)-[2-(3-methylpyrazol-1-yl)-4-nitrophenyl]methanone (100.0 mg, 0.250 mmol) in methanol (2.466 mL) ) Pd-C 10% (26.25 mg, 0.020 mmol) was added to the solution. The resulting solution was stirred at RT for 1 h under H ₂ atmosphere (1 atm). After this time, the reaction mixture was filtered through a pad of celite, concentrated under reduced pressure and of the formula [4-amino-2-(3-methylpyrazol-1-yl)phenyl]-(4-methyl-2-phenyl) The product of piperazin-1-yl) methanone was obtained, which was used in the next step without further purification.
Yield: 69mg

LC-MS: m/z 376.1 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-methylpyrazol-1-yl)phenyl]cyclopropanecarboxamide

4-Amino-2-(3-methylpyrazol-1-yl)phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone (68.9 mg, 0.180 mmol) (0.918 mL) and triethylamine (0.08 mL, 0.550 mmol) was added cyclopropanecarbonyl chloride (0.04 mL, 0.460 mmol) and the reaction was stirred at rt overnight. The next day, the reaction mixture was diluted with DCM and s.c. of _NaHCO3 . s. , dried through a phase separator and concentrated under reduced pressure. The raw material was purified by FC on RP using basic conditions (eluted from H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 95:5 to H ₂ O + 0.1% ammonium hydroxide/CH ₃ CN 5:95). ), the product of formula N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(3-methylpyrazol-1-yl)phenyl]cyclopropanecarboxamide was obtained as a racemic mixture.
Yield: 27.5mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.59 - 10.44 (m, 1 H), 7.89 (br d, 1 H), 7.88 - 7.67 (m, 1 H), 7.65 - 7.51(m, 1 H) , 7.47 - 7.19 (m, 6 H), 6.45 - 6.07 (m, 1
H), 5.78 - 4.38 (m, 1 H), 2.32 - 2.15 (m, 3 H), 2.20 - 2.00 (m, 3 H), 1.83 - 1.71 (m, 1 H), 4.36 - 1.17 (m, 6 H), 0.87 - 0.76 (m, 4 H); LC-MS: m/z 444.3 (MH+).

The racemic mixture (Example 155c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: 4-amino-2-(3-methylpyrazol-1-yl)benzoic acid

A solution of palladium on carbon (146.36 mg, 0.140 mmol) ( 10% w/w) was added and stirred for 3 hours under H ₂ atmosphere. After this time, the reaction mixture was filtered through a pad of Celite and washed with methanol. The organic phase was concentrated under reduced pressure to obtain a product of formula 4-amino-2-(3-methylpyrazol-1-yl)benzoic acid, which was used in the next step without further purification.
Yield: 290mg

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.10 (d, 1 H), 7.63 - 7.80 (m, 1 H), 6.64 - 6.77 (m, 1 H), 6.48 - 6.60 (m, 1 H), 6.28 - 6.37 (m, 1 H), 3.51 (s, 2 H), 2.41 (s, 3 H); LC-MS: m/z 218.0 (MH+)

Preparation: 4-(cyclopropanecarbonylamino)-2-(3-methylpyrazol-1-yl)benzoic acid

Cyclopropanecarboxylic acid (0.11 mL, 1.34 mmol), HATU: [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (507.63 mg) and N,N A solution of -diisopropylethylamine (0.58 mL, 3.34 mmol) in DMF (8.35 mL) was stirred at RT for 45 min. After this time, 4-amino-2-(3-methylpyrazol-1-yl)benzoic acid (290.0 mg, 1.34 mmol) dissolved in DMF (5 mL) was added to the solution and the resulting mixture was Stir overnight at RT. The next day, the reaction mixture was diluted with _H2O , the pH was adjusted to pH=10 with NaOH 3M, and the reaction was washed with DCM. The aqueous solution was then acidified with HCl 3N to pH=2 and it was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the compound of formula 4-(cyclopropanecarbonylamino)-2-(3-methylpyrazole-1- The product of yl)benzoic acid was obtained, which was used in the next step without further purification.
Yield: 340mg

LC-MS: m/z 286.10 (MH+)

Preparation: N-[3-(3-methylpyrazol-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting 4-(cyclopropanecarbonylamino)-2-(3-methylpyrazole-1) for 2-(3-methylpyrazol-1-yl)benzoic acid and 1-methyl-3-phenylpiperazine. -yl)benzoic acid and 4-(trifluoromethyl)piperidine hydrochloride, respectively, (4-methyl-2-phenylpiperazin-1-yl)-[2-(3-methylpyrazol-1-yl)- The synthesis was carried out analogously to the synthesis of 4-nitrophenyl]methanone. The title compound was obtained with a yield of 3.2% (16 mg).

1H NMR (400 MHz, DMSO-d6 ) δ ppm 10.52 (s, 1 H), 7.98 - 7.87 (m, 1 H), 7.87 -
7.75 (m, 1 H), 7.55 (dd, 1 H), 7.40 - 7.19 (m, 1 H), 6.29 (d, 1 H), 4.66 - 3.32
(m, 2 H), 3.08 - 2.62 (m, 2 H), 2.60 - 2.49 (m, 1 H), 2.28 - 2.16 (m, 3 H), 1.83 - 1.74 (m, 1 H), 0.86 - 0.80 (m, 4 H), 1.93 - 0.68 (m, 4 H); LC-MS: m/z 421.1 (MH+).

Preparation: N-[4-(4-propylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

In a vial were N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (150.0 mg, 0.380 mmol), tripotassium phosphate (171.99 mg, 0.800 mmol), 3-(Trifluoromethyl)pyrazole (62.12 mg, 0.460 mmol) was suspended in dry 1,4-dioxane (1.869 mL). The resulting suspension was degassed by bubbling N2 for 15 min and then treated with copper(I) iodide (3.64 mg, 0.020 mmol) and N,N'-dimethylcyclohexane-1,2-diamine. (6.0 uL, 0.040 mmol) was added under nitrogen flux and degassed again by Schlenkline method. The vial was sealed and stirred at 100°C for 48 hours. The next day, the reaction mixture was diluted with AcOEt and filtered through a pad of Celite. The organic layer _was washed with brine, dried over _Na2SO4 , filtered and the solvent was removed under reduced pressure. The residue was purified by FC on RP using acidic conditions (eluted from 5:95 _CH3CN / _H2O +0.1% formic acid to 30:70 _CH3CN / _H2O +1% FA). , a product of formula N-[4-(4-propylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide was obtained.
Yield: 69mg

1H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 8.21 (dd, J = 2.5, 1.1 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 3.62 (s, 2H), 3.17 - 2.90 (m, 2H), 2.33 (d, LC-MS : m/z 450.2.

Preparation: tert-butyl 3-(3-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

実施例１５９

Example 159

The synthesis of the title compound was repeated in Example 136 using tert-butyl 3-(3-chlorophenyl)piperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. The synthesis of the compound (tert-butyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylic acid) was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 55% (67 mg).

LC-MS: m/z 553.30 (MH+)

Preparation: tert-butyl 3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

The synthesis of the title compound was repeated in Example 136 using tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. The synthesis was carried out analogously to the synthesis of the compound (tert-butyl 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). The title compound was obtained as a racemic mixture in a yield of 37% (45 mg).

LC-MS: m/z 553.27 (MH+)

Preparation: tert-butyl 3-(5-chloropyridin-3-yl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

The synthesis of the title compound was carried out using tert-butyl 3-(5-chloropyridin-3-yl)piperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. , for the synthesis of the compound of Example 136 (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). I did something similar. The title compound was obtained as a racemic mixture in a yield of 44% (55 mg).

LC-MS: m/z 554.27 (MH+).

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-pyridin-3-ylpiperazine-1-carboxylate

The synthesis of the title compound was repeated in Example 136 using tert-butyl 3-pyridin-3-ylpiperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. Synthesis of the compound (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate) was performed analogously to . The title compound was obtained as a racemic mixture in a yield of 56% (64 mg).

LC-MS: m/z 520.26 (MH+).

Preparation: tert-butyl 3-(3-chloropyridin-4-yl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

The synthesis of the title compound was carried out using tert-butyl 3-(3-chloropyridin-4-yl)piperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. , for the synthesis of the compound of Example 136 (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). I did something similar. The title compound was obtained as a racemic mixture in a yield of 20% (25 mg).

LC-MS: m/z 554.26 (MH+).

Preparation: tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-pyrimidin-5-ylpiperazine-1-carboxylate

The synthesis of the title compound was repeated in Example 136 using tert-butyl 3-pyrimidin-5-ylpiperazine-1-carboxylate in place of tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate. Synthesis of the compound (tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate) was performed analogously to . The title compound was obtained as a racemic mixture in a yield of 46% (52 mg).

LC-MS: m/z 521.28 (MH+).

Preparation: tert-butyl 3-(4-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate

The synthesis of the title compound was carried out using 3-(4-fluorophenyl)piperazine-1-carboxylic acid.
The compound of Example 136 (4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1- The synthesis was carried out analogously to the synthesis of tert-butylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate). The title compound was obtained as a racemic mixture in a yield of 43% (52 mg).

Preparation: N-[3-pyrrolidin-1-yl-4-[2-(trifluoromethyl)morpholine-4-carbonyl]phenyl]cyclopropanecarboxamide

4-(Cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (50.0 mg, 0.180 mmol) and HATU([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methyllidene]-dimethyl To a stirred solution of ammonium; hexafluorophosphate (100.84 mg, 0.270 mmol) in DMF (1.13 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.06 mmol) and the mixture was allowed to stand at RT. The mixture was stirred for 15 minutes. After this time, a solution of 2-(trifluoromethyl)morpholine hydrochloride (40.65 mg, 0.210 mmol) and diisopropylethylamine (0.09 mL, 0.53 mmol) in (1 mL of DMF) was added and the reaction mixture Stirred at RT for 8 hours. A saturated solution of _NaHCO3 was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). _The organic portions were collected, washed with brine, dried over _Na2SO4 , filtered, and concentrated under vacuum. The residue was purified by FC on silica gel (eluted from 100% DCM to DCM/AcOEt 70/30) with the formula N-[3-pyrrolidin-1-yl-4-[2-(trifluoromethyl)morpholine-4- The product carbonyl]phenyl]cyclopropanecarboxamide was obtained.

Yield: 50 mg.

1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, J = 14.3 Hz, 1H), 7.22 - 6.86 (m, 3H), 4.56 - 3.81 (m, 3H), 3.71 - 3.45 (m, 2H), 3.15 (dd, J = 14.4, 7.1 Hz, 4H), 2.97 (d, J = 28.1 Hz, 2H), 1.89 (d, J = 13.2 Hz, 4H), 1.76 (qd, J = 7.2, 5.2 Hz, 1H ),
0.78 (dd, J = 6.2, 3.4 Hz, 4H); LC-MS: m/z 412.2 (MH+).

Preparation: N-[4-(3-phenylmorpholine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 3-phenylmorpholine in place of 2-(trifluoromethyl)morpholine hydrochloride to synthesize the compound of Example 166 (N-[3-pyrrolidin-1-yl-4-[2-( The synthesis of trifluoromethyl)morpholine-4-carbonyl]phenyl]cyclopropanecarboxamide) was performed analogously. The title compound was obtained as a racemic mixture in a yield of 98% (75 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.30 - 9.97 (m, 1 H), 7.69 - 7.18 (m, 5 H),
7.17 - 6.72 (m, 3 H, 5.73 - 4.55 (m, 1 H), 4.52 - 3.40 (m, 4 H), 4.40 - 3.07 (m, 2 H), 3.40 - 2.65 (m, 4 H), 2.03 - 1.52 (m, 5 H), 0.89 - 0.67 (m, 4 H); LC-MS:
m/z 420.47 (MH+).

Preparation: N-[4-(4-fluoropiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting 4-fluoropiperidine; The synthesis was carried out analogously to the synthesis of 2-(trifluoromethyl)morpholine-4-carbonyl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 35% (23 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 7.06 (d, 1H), 6.93 (d, 2H), 5.00 -
4.78 (m, 1H), 3.91 - 3.66 (m, 2H), 3.51 (d, 1H), 3.23 - 2.90 (m, 5H), 2.00 - 1.44 (m, 9H), 0.78 (ddd, 4H); LC- MS: m/z 360.2 (MH+).

Preparation: N-[4-(1-oxo-3-phenyl-1,4-thiazine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

A solution of N-[4-(3-phenylthiomorpholine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (40.0 mg, 0.090 mmol) in DCM (6 mL) with 3-chlorobenzene Carboperoxy acid (33.28 mg, 0.190 mmol) was added and the reaction was allowed to stir at room temperature overnight. After this time, the reaction was diluted with a saturated solution of _NaHCO3 and extracted with DCM. The organic phase was dried using a phase separator and concentrated to give the crude product, which was purified by FC on silica gel (elution: 100% AcOEt to AcOEt/MeOH 90:10) with formula N-[ The product 4-(1-oxo-3-phenyl-1,4-thiazine-4-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained as a racemic mixture.
Yield: 22.5mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.35 -10.00 (m, 1 H), 7.50 - 7.21 (m, 5 H),
7.22 - 7.06 (m, 1 H), 7.26 - 6.71 (m, 2 H), 6.38 - 5.11 (m, 1 H), 5.07 - 3.71 (m, 2 H), 3.66 - 2.53 (m, 8 H), 2.08 - 1.58 (m, 5 H), 1.00 - 0.55 (m, 4 H); LC-MS: m/z 452.24

Preparation: N-[4-[2-(2-chlorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed by substituting 3-tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[ The synthesis was carried out analogously to the synthesis of 4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 96% (35 mg).

Lc-MS: m/z 453.39 (MH+)

Preparation: N-[4-[2-(3-chlorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed by substituting 3-tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[4 -[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 84% (46 mg).

Preparation: N-[4-[2-(5-chloropyridin-3-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed by substituting 3-tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 was prepared using tert-butyl (5-chloropyridin-3-yl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate. The synthesis was carried out analogously to the synthesis of (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 87% (39 mg).

LC-MS: m/z 454.20 (MH+).

Preparation: N-[4-(2-pyridin-3-ylpiperazin-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[4-[2- (2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 91% (47 mg).

LC-MS: m/z 420.22 (MH+).

Preparation: N-[4-[2-(3-chloropyridin-4-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed by substituting 3-tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 was prepared using tert-butyl (3-chloropyridin-4-yl)-4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]piperazine-1-carboxylate. The synthesis was carried out analogously to the synthesis of (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in 100% yield (20 mg).

LC-MS: m/z 454.12 (MH+).

Preparation: N-[4-(2-pyrimidin-5-ylpiperazin-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[4 -[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in 100% yield (45 mg).

LC-MS: m/z 421.28 (MH+).

Preparation: N-[4-[2-(4-chlorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed by substituting 3-tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate. The compound of Example 157 (N-[ The synthesis was carried out analogously to the synthesis of 4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained as a racemic mixture in a yield of 76% (33 mg).

LC-MS: m/z 453.27 (MH+)

Preparation: N-[4-[2-(2-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide Compounds N-[4-[2-(3-fluorophenyl)- The synthesis was carried out analogously to the synthesis of 4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 78% (28 mg).

1H NMR (500 MHz, DMSO-d6) δ ppm 10.20 - 9.92 (m, 1 H), 7.95 - 6.41 (m, 7 H), 5.98 - 5.04 (m, 1 H), 4.65 - 3.38 (m, 2 H) ), 3.28 - 3.08(m, 4 H), 2.20 - 2.09 (m,
LC-MS: m/z 467.24 (MH+).

The racemic mixture (Example 170c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[4-[2-(3-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide Compounds N-[4-[2-(3-fluorophenyl)- The synthesis was carried out analogously to the synthesis of 4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 82% (39 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.25 - 10.00 (m, 1 H), 7.75 - 7.19 (m, 4 H), 7.18 - 7.02 (m, 1 H), 7.01 - 6.76 (m, 2 H ), 5.88 - 4.64 (m, 1 H), 4.50 - 3.13 (m, 4 H), 2.29 - 2.17 (m, 3 H), 3.11 - 2.12 (m, 6 H), 1.81 - 1.72 (m, 1 H) ), 2.10
- 1.58 (m, 4 H), 0.83 - 0.71 (m, 4 H); LC-MS: m/z 467.28 (MH+)

The racemic mixture (Example 171c) was then separated into single enantiomers by preparative HPLC.

Preparation: N-[4-[2-(5-chloropyridin-3-yl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (5-chloropyridin-3-yl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was used to prepare the compound N-[4-[2-(3 -fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 63% (25 mg).

1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 - 10.09 (m, 1 H), 8.82 (d, J=1.76 Hz, 1
H), 8.64 - 8.47 (m, 1 H), 8.33 - 8.08 (m, 1 H), 7.98 - 7.16 (m, 1 H), 7.16 (br s, 1 H), 7.12 - 6.78 (m, 1 H) ), 5.84 (br d, J=2.64 Hz, 1 H), 5.73 (d, J=3.52 Hz, 1 H), 3.43 (br dd, J=11.33, 2.97 Hz, 1 H), 3.27 - 3.17 (m , 2 H), 3.09 - 2.82 (m,
2 H), 2.82 - 2.59 (m, 2 H), 2.39 (dd, J=11.99, 4.29 Hz, 1 H), 2.34 - 2.16 (m, 3
LC-MS: m/z 468.30 (MH+).

Preparation: N-[4-(4-methyl-2-pyridin-3-ylpiperazin-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by replacing N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide Compounds N-[4-[2-(3-fluorophenyl) of Examples 88a-c The synthesis was carried out analogously to the synthesis of -4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 88% (43 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.11 (d, 1H), 8.93 - 8.27 (m, 2H), 8.16 - 7.61 (m, 1H), 7.53 - 7.29 (m, 1H), 7.24 - 6.76 (m , 3H), 5.93 - 4.18 (m, 1H), 3.31 (s, 4H), 3.08 - 2.59 (m, 4H), 2.46 - 2.12 (m, 4H), 1.98 (d, 3H), 1.85 - 1.54 (m , 3H), 0.78 (dd, 4H); LC-MS: m/z 434.26 (MH+).

Preparation: N-[4-[2-(3-chloropyridin-4-yl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. Compounds N-[4-[2-( The synthesis was carried out analogously to the synthesis of 3-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 73% (17 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.75 - 8.38 (m, 2H), 7.92 - 7.42 (m, 1H), 7.20 - 6.84 (m, 3H), 6.19 - 4.31 (m , 1H), 3.74 - 3.45 (m, 2H), 3.29 - 3.00 (m, 4H), 3.00 - 2.62 (m, 2H), 2.47 - 2.30 (m, 1H), 2.21 - 2.09 (m, 3H), 2.02 - 1.64 (m, 6H), 0.93 - 0.53 (m, 4H); LC-MS: m/z 468.25 (MH+).

Preparation: N-[4-(4-methyl-2-pyrimidin-5-ylpiperazin-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by replacing N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide Compounds N-[4-[2-(3-fluorophenyl) of Examples 88a-c The synthesis was carried out analogously to the synthesis of -4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 55% (26 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, 1H), 9.10 (d, 2H), 8.91 - 8.53 (m, 1H),
7.30 - 6.76 (m, 3H), 5.96 - 4.28 (m, 1H), 3.44 (d, 1H), 3.23 (s, 2H), 3.13 - 2.93 (m, 2H), 2.92 - 2.62 (m, 2H), 2.45 - 2.16 (m, 4H), 2.11 - 1.84 (m, 4H), 1.82 - 1.60 (m, 3H), 0.78 (td, 4H); LC-MS: m/z 435.21 (MH+).

Preparation: N-[4-[2-(4-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. -(4-chlorophenyl)piperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide to prepare compounds N-[4-[2-(3-fluorophenyl) of Example 88a-c. The synthesis was carried out analogously to the synthesis of -4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 88% (30 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.26 - 9.99 (m, 1 H), 7.79 - 7.17 (m, 4 H),
7.17 - 7.00 (m, 1 H), 7.02 - 6.75(m, 2 H), 5.88 - 4.61 (m, 1 H), 3.47 - 3.10 (m, 4 H), 2.27 - 2.15 (m, 3 H), 3.27 - 2.11 (m, 6 H), 1.79 - 1.73 (m, 1 H), 2.04 - 1.58 (m, 4 H), 0.83 - 0.71 (m, 4 H); LC-MS: m/z 467.25 (MH+ ).

Preparation: 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]benzonitrile

The synthesis of the title compound was carried out using 3-(trifluoromethyl)pyrrolidine hydrochloride in place of 3-pyrrolidine, 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylbenzo It was carried out analogously to the synthesis of nitriles. The title compound was obtained as a mixture of diastereoisomers in 60% yield (163 mg).

LC-MS: m/z 443.23 (MH+).

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

Dicesium carbonate (360.07 mg, 1.11 mmol), copper bromide (2.64 mg, 0.020 mmol), 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoro A mixture of methyl)pyrrolidin-1-yl]benzonitrile (163.3 mm, 0.370 mmol) and ethanimidoamide hydrochloride (52.24 mg, 0.550 mmol) in DMSO (2.709 mL) at 110° C. for 24 hours. Heated. After this time, the reaction was cooled to RT and purified by FC on a NH column (eluted from cHex/AcOEt 80:20 to cHex/AcOEt 40:60) with the formula (4-methyl-2-phenylpiperazine-1- diastereoisomers of diastereoisomers of It was obtained as a mixture of in a yield of 76% (140 mg).

LC-MS: m/z 499.2 (MH+)

The mixture of diastereoisomers was then separated into single enantiomers by chiral semi-preparative HPLC.

Synthesis scheme 16

Preparation: (2-bromo-4-nitrophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

A mixture of 2-bromo-4-nitrobenzoic acid (3.0 g, 12.19 mmol) and thionyl dichloride (17.79 mL, 243.89 mmol) was heated to reflux for 1 hour. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was dissolved in DCM (10.16 mL) and cooled to 0°C. After 10 minutes, a solution of 1,4-thiazinane 1,1-dioxide hydrochloride (2.09 g, 12.19 mmol) and triethylamine (6.8 mL, 48.78 mmol) in DCM (50.81 mL) was added. The reaction was stirred at RT for 1 hour. After this time, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. Washed 3 times with The organic phase is dried on a phase separator and concentrated under vacuum to yield a product of formula (2-bromo-4-nitrophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. I got it. This product was used in the next step without further purification.
Yield: 3.3g

1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.2 Hz, 1H), 8.36 (dd, J = 8.4, 2.2 Hz,
1H), 7.89 (d, J = 8.4 Hz, 1H), 4.50 - 4.36 (m, 1H), 3.74 (ddd, J = 13.6, 9.8, 2.9 Hz, 1H), 3.60 - 3.51 (m, 2H), 3.42 (d, J = 14.6 Hz, 1H), 3.28 - 3.23 (m, 1H),
3.07 (s, 2H); LC-MS: m/z 364.94 (MH+)

Preparation: (4-amino-2-bromophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

(2-bromo-4-nitrophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone (3.9 g, 10.74 mmol) and tin(III) chloride dihydrate (4 .89 g, 21.48 mmol) was dissolved in ethanol (53.69 mL) and the mixture was heated to reflux for 8 hours. After this time, the reaction was cooled to RT and evaporated under vacuum. The residue was purified by FC on a NH column (eluted from 100% DCM to DCM/MeOH 95:5) to give the formula (4-amino-2-bromophenyl)-(1,1-dioxo-1,4-thiazine-4). -yl) methanone product was obtained.
Yield: 2.96g

1H NMR (400 MHz, DMSO-d6) δ 7.10 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.57 (dd, J = 8.3, 2.1 Hz, 1H), 5.75 (s, 2H), 4.27 (s, 1H), 3.40 (d, J = 44.2
Hz, 7H); LC-MS: m/z 333.0 (MH+)

Preparation: N-[3-bromo-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide

(4-Amino-2-bromophenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone (3.0 g, 9 mmol) and N,N-diisopropyl in DCM (136.42 mL) To a mixture of ethylamine (2.3 mL, 13.51 mmol) at 0° C. was added dropwise cyclopropanecarbonyl chloride (0.74 mL, 8.1 mmol) and allowed to reach RT. After 1 h, the reaction was concentrated under vacuum and added s.c. of _NaHCO3 . s. added. The aqueous phase was extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na ₂ SO ₄ , filtered, and the solvent was removed under vacuum to give the formula N-[3-bromo-4-(1,1-dioxo- A product of 1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide was obtained. This product was used in the next step without further purification.
Yield: 1.6g

1H NMR (400 MHz, DMSO) δ 10.49 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.59 (dd, J
= 8.4, 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 4.35 (s, 1H), 3.75 (s, 1H), 3.56 (s, 3H), 3.23 (s, 2H), 3.06 (s, 1H), 1.78 (p, J = 6.3 Hz, 1H), 0.84 (d, J = 7.4 Hz, 4H); LC-MS: m/z 401.27, 403.27 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

N-[3-bromo-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide (150.0 mg, 0.370 mmol) and tripotassium phosphate (169.0 mg, 0.370 mmol) were placed in a vial. 0 mg, 0.780 mmol) and 3-methyl-5-(trifluoromethyl)-1H-pyrazole (67.33 mg, 0.450 mmol) were added and suspended in dry 1,4-dioxane (1.869 mL). I let it happen. The resulting suspension was degassed for 15 min by bubbling _N2 , then copper(I) iodide (3.58 mg, 0.020 mmol) and N,N'-dimethylcyclohexane-1,2-diamine ( 5.89 μL, 0.040 mmol) was added under nitrogen flux and degassed again using the Schlenkline method. The vial was sealed and stirred at 100°C for 48 hours. After this time, the reaction was cooled to RT, diluted with EtOAc, and filtered through a pad of Celite. The organic layer was washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on RP using acidic conditions (eluted from CH ₃ CN/H ₂ O 5:95 + 0.1% formic acid to CH ₃ CN/H ₂ O 50:50 + 0.1% formic acid), giving the formula Production of N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide I got something.
Yield: 19.5mg

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.67 (s, 1 H), 7.90 (d, J=2.1 Hz, 1 H), 7.70 (dd, J=8.4, 2.0 Hz, 1 H), 7.55 ( d, J=8.4 Hz, 1 H), 6.74 (s, 1 H), 4.08 - 3.60 (m, 4 H), 3.26 - 2.70 (m, 4 H), 2.26 (s, 3 H), 1.91 - 1.70 (m, 1H), 0.93 - 0.75
(m, 4 H); LC-MS: m/z471.39 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-(3-propan-2-ylpyrazol-1-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-propan-2-yl-1H-pyrazole in place of 3-methyl-5-(trifluoromethyl)-1H-pyrazole to synthesize the compound of Example 178 (N-[4- (1,1-dioxo-1,4-cyazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide) I did it. The title compound was obtained in a yield of 6.5% (7 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.91 (dd, J = 6.4, 2.2 Hz, 2H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 4.02 (s, 1H), 3.86 (t, J = 11.0 Hz, 1H), 3.66 - 3.43 (m, 2H), 3.30 ( s, 1 H), 3.10 (d, J = 13.4 Hz, 1H), 2.93 (dt, J = 13.8, 6.9 Hz, 2H), 2.83 (d, J = 10.5 Hz,
LC-MS: 431.3 (MH+)

Preparation: N-[3-(3-cyclopropylpyrazol-1-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 3-cyclopropyl-1H-pyrazole in place of 3-methyl-5-(trifluoromethyl)-1H-pyrazole to synthesize the compound of Example 178 (N-[4-(1, The synthesis was carried out analogously to the synthesis of 1-dioxo-1,4-cyazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 13% (14 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.55 (s, 1 H), 7.92 (d, J=2.5 Hz, 1 H), 7.88 (d, J=1.8 Hz, 1 H), 7.55 (dd, J=8.4, 1.9 Hz, 1 H), 7.39 (d, J=8.4 Hz, 1 H), 6.21 (d, J=2.5 Hz, 1 H), 3.51 - 4.23 (m, 4 H), 2.94 - 3.31 (m, 4 H), 1.87 - 1.98 (m, 1 H), 1.80 (quin, J=6.2 Hz, 1 H), 0.88 - 0.96 (m, 2 H), 0.77 - 0.87 (m, 4 H),
0.60 - 0.75 (m, 2 H); m/z 429.2 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 3-(trifluoromethyl)-1H-pyrazole in place of 3-methyl-5-(trifluoromethyl)-1H-pyrazole to synthesize the compound of Example 178 (N-[4- (1,1-dioxo-1,4-cyazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide) I did it. The title compound was synthesized with a yield of 18% (42 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.37 (dd, J = 2.5, 1.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 4.01 (s, 1H), 3.84 (s, 1H), 3.68 (t, LC-MS: m/z 457.4 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-(trifluoromethyl)-1H-pyrazole in place of 3-methyl-5-(trifluoromethyl)-1H-pyrazole to synthesize the compound of Example 178 (N-[4- (1,1-dioxo-1,4-cyazine-4-carbonyl)-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide) I did it. The title compound was obtained with a yield of 5% (11 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 8.02 (d, 1H), 7.65 - 7.60 (m, 1H), 7.52 ( d, 1H), 3.92 (s, 2H), 3.62 (s, 2H), 3.11 (d, 4H), 1.81 (p, 1H), 0.84 (dd, 4H); LC-MS: m/z 457.10 (MH+ )

Synthesis scheme 17

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-3-methyl-4-nitrophenyl)methanone

2-Fluoro-3-methyl-4-nitrobenzoic acid (145.0 mg, 0.730 mmol) and thionyl dichloride (1.06 mL, 14.56 mmol) were stirred at 80° C. for 2 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 residue was dissolved in dry DCM (20 mL) and cooled to 0°C. After 10 minutes, a solution of 1,4-thiazinane 1,1-dioxide hydrochloride (124.98 mg, 0.730 mmol) and triethylamine (0.3 mL, 2.18 mmol) in dry DCM (10 mL) was added. The reaction mixture was allowed to reach RT and stirred overnight. The next day, the reaction was diluted with DCM and s.c. of NaHCO3. s. Washed 3 times with The organic phase was collected, washed with brine, dried on a phase separator and concentrated under vacuum to give the formula (1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-3- A product of methyl-4-nitrophenyl)methanone was obtained. This product was used in the next step without further purification.
Yield: 193 mg.

1H NMR (400 MHz, DMSO) δ 7.95 (dd, J = 8.4, 1.2 Hz, 1H), 7.80 - 7.54 (m, 1H),
4.34 (d, J = 39.6 Hz, 2H), 3.65 (s, 4H), 2.98 (d, J = 65.2 Hz, 2H), 2.41 (d, J = 2.2 Hz, 3H); LC-MS: 317.09 (MH+ ).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone

(1,1-dioxo-1,4-thiazinan-4-yl)-(2-fluoro-4-nitrophenyl)methanone (216.0 mg, 0.710 mmol) and 3-( To a solution of trifluoromethyl)pyrrolidine hydrochloride (250.93 mg, 1.43 mmol) was added N,N-diisopropylethylamine (0.5 mL, 2.86 mmol). The reaction was stirred at 120°C for 48 hours. After this time, the reaction was cooled to RT and diluted with water. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on silica gel (eluting with cHex/AcOEt 90:10 to 50:50) and was purified with formula (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[ A product of 3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was obtained.
Yield: 209mg

1H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.62 (m, 2H), 7.47 (dd, J = 6.8, 1.9 Hz, 1H), 4.48 (t, J = 7.3 Hz, 1H), 3.78 - 3.49 ( m, 4H), 3.44 - 3.31(m, 5H), 3.30 - 3.15 (m, 2H), 3.12 - 2.97 (m, 1H), 2.25 (dt, J = 12.8, 6.7 Hz, 1H), 2.07 (dt, J = 11.7, 7.6 Hz, 1H); LC-MS: 422.1 (MH+).

Preparation: [2-(3,3-difluoropyrrolidin-1-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was carried out using 3,3-difluoropyrrolidine; The synthesis of [4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanol was performed analogously. The title compound was obtained in a yield of 32% (62 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 1.2 Hz, 2H), 7.48 (d, J = 1.3 Hz, 1H), 4.48 (d, J = 14.1 Hz, 1H), 3.80 - 3.59 (m, 5H), 3.52 (dtd, J = 16.5, 9.6, 7.2
Hz, 2H), 3.45 - 3.36 (m, 1H), 3.30 - 3.21 (m, 2H), 3.12 - 3.02 (m, 1H), 2.46 (d, J = 7.3 Hz, 2H); LC-MS: 390.0 ( MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methanone

The synthesis of the title compound was carried out using 3-(trifluoromethyl)piperidine hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinan-4-yl). The synthesis of -[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was performed analogously. The title compound was obtained in a yield of 60% (254 mg).

1H NMR (400 MHz, Chloroform-d) δ 8.00 (dd, J = 8.3, 2.1 Hz, 1H), 7.97 - 7.86 (m, 1H), 7.49 - 7.38 (m, 1H), 4.60 - 4.45 (m, 1H) ), 4.15 - 3.99 (m, 1H), 3.66 (q,
J = 5.8 Hz, 3H), 3.44 (dd, J = 66.7, 11.8 Hz, 1H), 3.18 (dq, J = 10.2, 5.4 Hz, 3H), 3.08 - 2.96 (m, 2H), 2.87 (ddt, J = 19.9, 12.6, 6.3 Hz, 1H), 2.69 - 2.59 (m, 1H), 2.46 - 2.20 (m, 1H), 2.06 (dd, J = 22.8, 10.4 Hz, 2H), 1.71 - 1.58 (m, 1H) ); LC-MS: m/z 436.1 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[2-(trifluoromethyl)morpholin-4-yl]phenyl]methanone

The synthesis of the title compound was carried out using 2-(trifluoromethyl)morpholine hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinan-4-yl). The synthesis of -[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was performed analogously. The title compound was obtained in a yield of 15% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.01 (ddd, J = 8.4, 2.2, 1.2 Hz, 1H), 7.92 (dd, J
= 5.5, 2.2 Hz, 1H), 7.67 (dd, J = 8.3, 2.5 Hz, 1H), 4.56 - 4.28 (m, 2H), 4.14 -
3.93 (m, 1H), 3.81 - 3.42 (m, 5H), 3.29 - 3.07 (m, 5H), 2.99 - 2.71 (m, 2H); LC-MS: m/z 438.1 (MH+).

Preparation: [2-(3-azabicyclo[2.2.1]heptan-3-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was carried out using 2-azabicyclo[2.2.1]heptane in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinan-4-yl). )-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanol. The title compound was obtained in a yield of 73% (273 mg).

LC-MS: m/z 380.2 (MH+).

Preparation: [2-[(anti)-2,6-dimethylmorpholin-4-yl]-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The title compound was synthesized using trans-2,6-dimethylmorpholine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (1,1-dioxo-1,4-thiazinan-4-yl)-[ The synthesis of 4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 87% (344 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.95 (ddd, J = 20.0, 8.3, 2.1 Hz, 1H), 7.81 (dd, J = 13.0, 2.2 Hz, 1H), 7.69 (t, J = 8.9 Hz, 1H), 4.70 (t, J = 14.9 Hz, 1H), 4.01
(q, J = 7.2, 4.9 Hz, 2H), 3.61 - 3.32 (m, 4H), 3.26 - 3.11 (m, 2H), 3.03 - 2.87
(m, 4H), 2.65 (dd, J = 11.7, 5.9 Hz, 1H), 1.16 (dd, J = 11.8, 6.3 Hz, 6H); LC-MS: m/z 398.4 (MH+).

Preparation: [2-(5-Azaspiro[2.5]octan-5-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was carried out using 5-azaspiro[2.5]octane hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinan-4-yl). )-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously to the synthesis. The title compound was obtained in a yield of 90% (234 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J = 8.3, 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 14.2 Hz, 1H), 3.83 (dd, J = 13.7, 9.0 Hz, 1H), 3.55 - 3.36 (m, 3H), 3.30 - 3.07 (m, 4H), 2.95 (d, J = 11.5 Hz, 1H), 2.90 - 2.80 (m, 1H), 2.60 (d, J = 11.5 Hz, 1H), 1.68 (s, 2H), 1.48 - 1.29 (m, 2H), 0.35 (ddt, J = 13.2, 8.8, 5.1 Hz, 4H); LC-MS: m/z 394.2 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)phenyl]methanone

The synthesis of the title compound was carried out using 4-oxa-7-azaspiro[2.5]octane hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinamine). The synthesis of -4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained in a yield of 88% (231 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J = 8.4, 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 4.35 (d, J = 14.4 Hz, 1H), 3.83 - 3.69 (m, 3H), 3.61 - 3.35 (m, 4H), 3.25 - 3.04 (m, 4H), 2.96 - 2.82 (m, 2H), 0.78 - 0.45 (m, 4H); LC-MS: m/z 396.1 (MH+).

Preparation: [2-(3,3-difluoropiperidin-1-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was carried out using 3,3-difluoropiperidine; The synthesis of [4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was performed analogously. The title compound was obtained in a yield of 26% (106 mg).

1H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 8.3, 2.2 Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 4.31 - 4.23 (m, 1H), 3.82 (t, J = 11.1 Hz, 1H), 3.57 - 3.43 (m, 2H), 3.30 (s, 2H), 3.24 - 3.10 (m, 4H), 3.00 (ddd, J LC-MS: 404.1 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl ] Methanone

The title compound was synthesized using 2-oxa-5-azabicyclo[2.2.1]heptane in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4- The synthesis of thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained as a mixture of diastereoisomers in 81% yield (305 mg).

1H NMR (400 MHz, DMSO) δ 7.64 - 7.41 (m, 3H), 4.53 (dd, J = 39.7, 14.5 Hz, 3H), 3.97 - 3.37 (m, 6H), 3.19 - 2.62 (m, 3H), 2.04 - 1.75 (m, 2H), 1.33 - 1.05 (m, 2H); LC-MS: m/z 382.36 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl ] Methanone

The synthesis of the title compound was carried out using 6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4 -thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. The title compound was obtained in a yield of 25% (95 mg).

1H NMR (400 MHz, DMSO) δ 7.67 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 2.3 Hz, 2H), 4.60 (dd, J = 52.2, 10.7 Hz, 3H), 3.85 - 3.37 (m, 10H), 3.09 (d, J = 7.8 Hz, 2H)
, 1.16 (s, 1H); LC-MS: m/z 382.3 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl] methanone

The title compound was synthesized using 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4 -thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. The title compound was obtained in a yield of 25% (95 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.91 (dd, J = 8.3, 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 4.76 (d, J = 13.2 Hz, 1H), 4.35 (d, J = 39.1 Hz, 2H), 3.62 - 3.34 (m, 4H), 3.27 - 3.07 (m, 4H), 2.89 (td, J = 27.3, 24.1 , 12.7 Hz, 3H), 1.83 (s, 3H), 1.70 (d, J = 8.9 Hz, 1H); LC-MS: m/z 396.1 (MH+).

Preparation: [2-(3-azabicyclo[3.1.1]heptan-3-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was carried out using 3-azabicyclo[3.1.1]heptane hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride (1,1-dioxo-1,4-thiazinean-4 -yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained in a yield of 58% (145 mg).

LC-MS: m/z 380.36 (MH+).

Preparation: [2-(4,4-difluoropiperidin-1-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The title compound was synthesized using 4,4-difluoropiperidine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (1,1-dioxo-1,4-thiazinan-4-yl)-[4- The synthesis of nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was performed analogously. The title compound was obtained in a yield of 54% (215 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.96 (dd, J = 8.3, 2.2 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 4.49 (dd, J = 12.1, 6.8 Hz, 1H), 3.71 (ddd, J
LC-MS: m /z 404.1 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-(4-nitro-2-piperidin-1-ylphenyl)methanone

The title compound was synthesized using piperidine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[ The synthesis was carried out analogously to the synthesis of 3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. The title compound was obtained in a yield of 97% (177 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.91 (dd, 1H), 7.79 (d, 1H), 7.56 (d, 1H), 4.33 (d, 1H), 3.81 (dd, 1H), 3.55 - 3.47 ( LC-MS: 368.19 (MH+).

Preparation: (1,1-dioxo-1,4-thiazinan-4-yl)-(2-morpholin-4-yl-4-nitrophenyl)methanone

The title compound was synthesized using morpholine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[ The synthesis was carried out analogously to the synthesis of 3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. The title compound was obtained in a yield of 50% (121 mg).

1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 8.3, 2.2 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 4.35 (d, J = 13.9 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.74 - 3.62 (m, 4H), 3.55 (t, J = 5.7 Hz, 2H), 3.39 (t, J = 10.2 Hz, 1H), 3.25 - 3.11 (m, 4H), 3.09 - 3.01 (m, 1H), 2.94 - 2.83 (m, 2H); LC-MS: m/z 370.2 (MH+).

Preparation: [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

（１，１－ジオキソ－１，４－チアジンアン－４－イル）－［４－ニトロ－２－［３－（トリフルオロメチル）ピロリジン－１－イル］フェニル］メタノン（２０９．０ｍｇ、０．５００ｍｍｏｌ）およびＰｄ－Ｃ１０％（５２．７８ｍｇ、０．０５０ｍｍｏｌ）の混合物をＨ_２の雰囲気下（１ａｔｍ）で、ＲＴで一晩攪拌した。この時間の後、反応物をろ過し、真空下で濃縮した。残渣を、まずＭｅＯＨで洗浄し、次にＭｅＯＨ中のＮＨ_３ １Ｍで溶出するＳＣＸカートリッジで精製した。塩基性画分を蒸発させて、式［４－アミノ－２－［３－（トリフルオロメチル）ピロリジン－１－イル］フェニル］－（１，１－ジオキソ－１，４－チアジンアン－４－イル）メタノンの生成物を得た。
収率：１３６ｍｇ

(1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone (209.0 mg, 0.500 mmol ) and Pd-C 10% (52.78 mg, 0.050 mmol) was stirred at RT under an atmosphere of H ₂ (1 atm) overnight. After this time, the reaction was filtered and concentrated under vacuum. The residue was purified on an SCX cartridge, first washing with MeOH and then eluting with NH ₃ 1M in MeOH. The basic fraction was evaporated to give a compound of formula [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl). ) The product of methanone was obtained.
Yield: 136mg

1H NMR (400 MHz, DMSO-d6) δ 6.88 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 18.2 Hz, 2H), 5.24 (d, J = 7.5 Hz, 2H), 4.23 (s , 1H), 3.66 (s, 4H), 3.31 - 2.92(m, 8H), 2.17 (dq, J = 12.9, 6.2 Hz, 1H), 1.96 (dq, J = 13.9, 7.0 Hz, 1H);
LC-MS: m/z 392.1.

Preparation: [4-Amino-2-(3,3-difluoropyrrolidin-1-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone:

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. [4-Amino-2 The synthesis of -[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 87% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.91 (d, 1H), 6.10 (dd, 1H), 6.01 (d, 1H), 5.32 (s, 2H), 3.70 (d, 2H), 3.55 - 3.00 ( m, 8H), 2.45 - 2.31 (m, 2H), 1.77 (s, 2H); LC-MS: 360.1 (MH+).

Preparation: [4-amino-2-[3-(trifluoromethyl)piperidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)piperidin-1-yl]phenyl]methanone. [4-amino The synthesis of -2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 76% (181 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, 1H), 6.32 - 6.25 (m, 2H), 5.36 (s, 2H), 4.35 (s, 3H), 3.57 (s, 4H), 3.30 ( s, 4H), 2.37 (d, 1H), 1.83 (dd, 2H), 1.61 - 1.08 (m, 2H), 0.85 (d, 1H); LC-MS: 406.2 (MH+).

Preparation: [4-amino-2-[2-(trifluoromethyl)morpholin-4-yl]phenyl)-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. [4- The synthesis of amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 82% (38 mg).

LC-MS: m/z 370.2 (MH+).

Preparation: [4-amino-2-(3-azabicyclo[2.2.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Using [2-(3-azabicyclo[2,2,1]heptan-3-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone, [ The synthesis of 4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 78% (195 mg).

LC-MS: m/z 350.3 (MH+)

Preparation: [4-amino-2-[(anti)-2,6-dimethylmorpholin-4-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Using [2-[(anti)-2,6-dimethylmorpholin-4-yl]-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone, [4 The synthesis of -amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained as a racemic mixture in a yield of 47% (80 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.94 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 7.1 Hz, 2H), 5.33 (s, 2H), 4.59 (s, 1H), 3.94 (s, 2H), 3.66 (s, 1H), 3.24 - 2.62 (m, 10H),
1.14 (d, J = 6.5 Hz, 6H); LC-MS: m/z 368.4 (MH+).

Preparation: [4-amino-2-(5-azaspiro[2.5]octan-5-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. [4- The synthesis of amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously.
The title compound was obtained in a yield of 63% (136 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.85 (d, J = 7.9 Hz, 1H), 6.22 (d, J = 7.8 Hz, 2H), 5.30 (s, 2H), 4.08 (d, J = 5.9 Hz) , 2H), 3.55 (s, 2H), 3.12 (dd, J = 40.5, 16.0 Hz, 5H), 2.77 - 2.61 (m, 2H), 2.42 (d, J = 7.3 Hz, 1H), 1.63 (s, 2H), 1.34 (s,
2H), 0.31 (d, J = 10.0 Hz, 4H); LC-MS: m/z 364.2 (MH+).

Preparation: [4-amino-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Using (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)phenyl]methanone , carried out analogously to the synthesis of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Ta. The title compound was obtained in a yield of 11% (25 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.93 - 6.86 (m, 1H), 6.29 - 6.22 (m, 2H), 5.34 (d, J = 7.3 Hz, 2H), 4.13 (s, 1H), 3.85 ( LC-MS: m/ z 366.2 (MH+).

Preparation: [4-amino-2-(3,3-difluoropiperidin-1-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Using [2-(3,3-difluoropiperidin-1-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone, The synthesis of -[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 96% (94 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.6 Hz, 1H), 6.29 (dq, J = 4.3, 2.0 Hz, 2H), 5.37 (d, J = 7.2 Hz, 2H), 4.07 (d, J = 7.7 Hz, 1H), 3.83 (s, 1H), 3.51 (s, 2H), 3.24 (d, J = 49.7 Hz, 2H), 2.91 (d, J = 102.7 Hz, 6H), 1.97 (td, J = 13.8, 6.4 Hz, 2H), 1.70 (s, 2H); LC-MS: m/z 374.1 (MH+).

Preparation: [4-amino-2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl ) methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl]methanone similar to the synthesis of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone using I went. The title compound was obtained as a mixture of diastereoisomers in 100% yield (283 mg).

1H NMR (400 MHz, DMSO) δ 6.87 (d, J = 8.2 Hz, 1H), 6.18 - 5.83 (m, 2H), 5.18 (s, 2H), 4.49 (s, 1H), 4.22 (s, 2H) , 4.14 - 3.43 (m, 6H), 3.25 - 3.13 (m, 3H), 3.03 (s, 2H), 1.80 (s, 2H); LC-MS: m/z 352.36.

Preparation: [4-Amino-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl ) methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl]methanone similar to the synthesis of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone using I went. The title compound was obtained in a yield of 70% (58 mg).

1H NMR (400 MHz, DMSO) δ 6.94 (dd, J = 29.9, 8.2 Hz, 1H), 6.39 - 6.03 (m, 2H), 4.45 (dd, J = 99.7, 5.5 Hz, 3H), 3.83 (s, 1H), 3.69 - 3.51 (m, 3H), 3.24 - 2.93 (m, 9H), 2.08 (s, 2H); LC-MS: m/z 352.36 (MH+).

Preparation: [4-amino-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl) methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. (1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]methanone similar to the synthesis of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone using I went. The title compound was obtained in a yield of 68% (185 mg).

LC-MS: m/z 366.2 (MH+).

Preparation: [4-amino-2-(3-azabicyclo[3.1.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Using [2-(3-azabicyclo[3.1.1]heptan-3-yl)-4-nitrophenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone, [ The synthesis of 4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in 100% yield (140 mg).

1H NMR (400 MHz, DMSO) δ 6.85 (d, J = 8.1 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 6.03 (dd, J = 8.1, 1.9 Hz, 1H), 5.16 (s , 2H), 4.43 (s, 2H), 3.95 - 3.34 (m, 9H),
3.02 (d, J = 13.9 Hz, 1H), 2.46 (t, J = 6.1 Hz, 2H), 2.15 - 1.98 (m, 2H), 1.35 (dd, J = 6.3, 2.8 Hz, 2H); LC-MS : m/z 350.2 (MH+).

Preparation: [4-amino-2-(4,4-difluoropiperidin-1-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. [4-Amino-2 The synthesis of -[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 87% (174 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.93 (d, J = 8.1 Hz, 1H), 6.32 - 6.23 (m, 2H), 5.35 (d, J = 7.2 Hz, 2H), 4.44 - 4.10 (m, LC-MS: m/z 374.1 (MH+).

Preparation: (4-amino-2-piperidin-1-ylphenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. (1,1-dioxo-1,4-thiazinan-4-yl)-(4-nitro-2-piperidin-1-ylphenyl)methanone was used to The synthesis of methyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 92% (150 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.88 (d, 1H), 6.29 - 6.16 (m, 2H), 5.31 (s, 2H), 4.17 - 4.07 (m, 1H), 3.86 (s, 1H), 3.56 (s, 2H), 3.19 - 2.63 (m, 8H), 1.51 (d, 6H); LC-MS: m/z 338.17 (MH+).

Preparation: (4-amino-2-morpholin-4-ylphenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone

The synthesis of the title compound was performed by substituting 1,1-dioxo-1,4-thiazinan-4-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. [4-Amino-2-[3-( The synthesis of trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone was carried out analogously. The title compound was obtained in a yield of 56% (62 mg).

1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 8.6 Hz, 1H), 6.29 - 6.22 (m, 2H), 5.37 (s, 2H), 4.14 (s, 1H), 3.63 (s, 7H), 3.26 - 2.59 (m, 8H); LC-MS: m/z 340.4 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide

[4-Amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone (136.0 mg, 0.350 mmol ) and N,N-diisopropylethylamine (0.21 mL, 1.22 mmol) in DCM (3.892 mL) at 0 °C was added dropwise cyclopropanecarbonyl chloride (0.06 mL, 0.630 mmol). Ta. The reaction was allowed to reach RT and stirred at this temperature for 1 hour. After this time, the reaction was concentrated under vacuum and purified directly by FC on RP using basic conditions ( _H2O +0.1% ammonium hydroxide/CH3CN95:5 to _H2O +0.1% ammonium hydroxide/ _CH3CN 95:5). 1% ammonium hydroxide/CH ₃ CN 60:40), with formula N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(tri- A product of fluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide was obtained.
Yield: 95mg

1H NMR (400 MHz, DMSO-d6) δ 10.18 (d, 1H), 7.21 - 7.13 (m, 2H), 7.04 (dd, 1H), 4.36 (s, 1H), 3.64 (ddt, 3H), 3.31 ( s, 9H), 2.21 (s, 1H), 2.01 (dt, 1H), 1.75 (dt, 1H), 0.84 - 0.74 (m, 4H); LC-MS: 460.2 (MH+).

The racemic mixture (Example 183c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: N-[3-(3,3-difluoropyrrolidin-1-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

実施例１８４

Example 184

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Example 183a-c using [4-amino-2-(3,3-difluoropyrrolidin-1-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone Synthesis of the compound (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide) It was done similar to. The title compound was obtained in a yield of 43% (29 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 7.22 - 7.13 (m, 2H), 7.09 (dd, J =
8.3, 1.8 Hz, 1H), 4.32 (d, J = 14.2 Hz, 1H), 3.78 - 3.68 (m, 2H3.65 - 3.44 (m, 3H), 3.36 (t, J = 7.2 Hz, 3H), 3.19 (d, J = 10.5 Hz, 2H), 3.06 (d, J = 14.0 Hz, 1H), 2.43 (dd, J = 14.3, 7.2 Hz, 2H), 1.77 (tt, J = 7.1, 5.5 Hz, 1H) , 0.88 - 0.74 (m, 4H); LC-MS: m/z 428.2 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)piperidin-1-yl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. using N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)piperidin-1-yl]phenyl]cyclopropanecarboxamide. , the compound of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl] Synthesis of cyclopropanecarboxamide) was performed analogously to the synthesis of cyclopropanecarboxamide. The title compound was obtained as a racemate in a yield of 25% (50 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 5.7 Hz, 1H), 7.46 (d, J = 29.1 Hz, 1H), 7.34 - 7.28(m, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.38 (dd, J = 35.1, 13.8 Hz, 1H), 3.79 - 3.42 (m, 4H), 3.29 - 2.88 (m, 6H), 2.78 (t, J = 11.0 Hz, 1H), 2.50 (d, J = 2.1 Hz, 1H), 1.98 - 1.68 (m, 3H), 1.63 - 1.48 (m, 1H), 1.36 (td, J = 12.3, 8.4 Hz, 1H), 0.84 - 0.76 (m, 4H); LC-MS: m/z 474.1 (MH+)

The racemic mixture (Example 185c) was then separated into single enantiomers by chiral semipreparative HPLC.

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[2-(trifluoromethyl)morpholin-4-yl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Example 183a using [4-amino-2-(2-(trifluoromethyl)morpholin-4-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone -c compound (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide) The synthesis was carried out analogously to that of The title compound was obtained as a racemic mixture in a yield of 43% (20 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.33 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 28.3 Hz, 1H), 7.34 (d, J = 10.2 Hz, 1H), 7.25 (d , J = 8.2 Hz, 1H), 4.54 - 4.18 (m, 2H), 4.02 (dd, J = 50.7, 11.3 Hz, 1H), 3.64 (dd, J = 34.4, 18.7 Hz, 4H), 3.38 (d, J = 11.5 Hz, 1H), 3.26 - 2.83 (m, 6H), 2.72 - 2.54 (m, 1H), 1.77 (s, 1H), 0.80 (d, J
= 7.5 Hz, 4H); LC-MS: 476.2 (MH+).

Preparation: N-[3-(3-azabicyclo[2.2.1]heptan-3-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. using [4-amino-2-(3-azabicyclo[2.2.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone, Compounds of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclo Propane carboxamide) was carried out analogously to the synthesis. The title compound was obtained as a mixture of diastereoisomers in 23% yield (53 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.14 - 10.07 (m, 1 H), 7.14 - 7.04 (m, 1 H), 7.03 - 7.00 (m, 1 H), 6.97 - 6.88 (m, 1 H ), 4.53 - 4.26 (m, 1 H), 4.01 - 3.83 (m, 1 H), 4.01 - 3.37 (m, 3 H), 3.46 - 2.91 (m, 5 H), 2.54 - 2.44 (m, 1 H) ), 2.64
- 2.20 (m, 1 H), 1.81 - 1.72 (m, 1 H), 1.84 - 1.19 (m, 6 H), 0.87 - 0.70 (m, 4 H); LC-MS: m/z 418.2 (MH+) .

Preparation: N-[3-[(anti)-2,6-dimethylmorpholin-4-yl]-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. carried out using [4-amino-2-[(anti)-2-6-dimethylmorpholin-4-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Compounds of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropane Carboxamide) was carried out analogously to the synthesis. The title compound was obtained as a racemic mixture in a yield of 32% (57 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.45 - 7.37 (m, 1H), 7.34 - 7.28 (m, 1H), 7.24 (t, J = 8.9 Hz, 1H), 4.68 - 4.57 (m, 1H), 4.00 - 3.93 (m, 1H), 3.58
(d, J = 15.9 Hz, 1H), 3.47 (q, J = 13.8, 11.8 Hz, 2H), 3.34 (s, 2H), 3.22 - 2.91 (m, 4H), 2.75 (d, J = 4.7 Hz, 3H), 1.76 (tt, J = 6.7, 5.4 Hz, 1H), 1.14 (dd, J
= 11.2, 6.4 Hz, 6H), 0.83 - 0.74 (m, 4H); LC-MS: m/z 436.4 (MH+)

Preparation: N-[3-(5-Azaspiro[2.5]octan-5-yl)-4-(1,1-dioxo-1,4-thiazine-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Using [4-amino-2-(5-azaspiro[2.5]octan-5-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone, Example Compounds of 183a-c (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide ) was carried out analogously to the synthesis of The title compound was obtained in a yield of 40% (65 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 8.3, 1.8 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H),4.21 - 4.05 (m, 1H), 3.96 (d, J
= 8.1 Hz, 1H), 3.50 (s, 2H), 3.30 (s, 1H), 3.14 (dd, J = 23.5, 9.5 Hz, 5H), 2.88 - 2.62 (m, 2H), 1.83 - 1.55 (m, 3H), 1.36 (s, 2H), 0.89 - 0.66 (m, 4H), 0.32 (d, J = 11.8 Hz, 4H); LC-MS: m/z 432.4 (MH+)

Preparation: N-[4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)phenyl]cyclopropane Carboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. using [4-amino-2-(4-oxa-7-azaspiro[2.5]octan-7-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone. The compound of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl ] Cyclopropane carboxamide). The title compound was obtained in a yield of 64% (19 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8.3, 1.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.17 (s, 1H), 3.88 (t, J = 11.3 Hz, 1H), 3.70 (q, J = 4.4 Hz, 2H), 3.60 - 3.45 (m, 2H), 3.28 (s, 1H), 3.16 - 3.00 (m, 5H), 2.83 - 2.75 (m, 1H), 2.71 (d, J = 11.5 Hz, 1H), 1.77 (p, J = 6.2 Hz, 1H), 0.83 - 0.76 (m , 4H), 0.74 - 0.65 (m, 2H), 0.53 (q, J = 4.5, 4.1 Hz, 2H); LC-MS: m/z 434.2 (MH+).

Preparation: N-[3-(3,3-difluoropiperidin-1-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Example 183a-c using [4-amino-2-(3,3-difluoropiperidin-1-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone Synthesis of the compound (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide) It was done similar to. The title compound was obtained in a yield of 60% (66 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.3, 1.8 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.12 (t, J = 10.8 Hz, 1H), 3.91 (t, J = 10.8 Hz, 1H), 3.47 (q, J = 6.0 Hz, 2H), 3.30 (s, 2H), 3.10 - 2.99 (m, 5H), 2.85 (s, 1H), 2.00 (d, J = 7.1 Hz, 2H), 1.77 (p, J = 6.2 Hz, 3H), 0.83 - 0.76 (m, 4H); LC- MS: m/z 442.2 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-3-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl] cyclopropane carboxamide

The title compound was synthesized using [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. and [4-amino-2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl) Using methanone, the compound of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidine-1- yl]phenyl]cyclopropanecarboxamide). The title compound was obtained as a mixture of diastereoisomers in 66% yield (221 mg).

1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 7.29 - 6.86 (m, 3H), 4.52 (d, J = 9.9
Hz, 1H), 4.38 (s, 1H), 4.26 (s, 1H), 3.96 - 3.33 (m, 7H), 3.24 (s, 1H), 3.11 - 2.60 (m, 3H), 1.98 - 1.66 (m, 3H), 0.79 (dt, J = 7.9, 2.3 Hz, 4H); LC-MS: m/z 420.5 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl] cyclopropane carboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. to [4-amino-2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone The compound of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl ]Phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 12% (8 mg).

1H NMR (400 MHz, DMSO) δ 10.20 (s, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 8.3, 1.8 Hz , 1H), 4.61 (s, 2H), 4.46 (d, J = 14.5 Hz, 1H), 3.80 (d, J = 14.9 Hz, 1H), 3.59 (t, J = 12.1 Hz, 2H), 3.50 - 3.33 (m, 5H), 3.25 - 3.13 (m, 2H), 3.04 (q, J = 7.2 Hz, 2H), 1.93 (d, J = 8.4 Hz, 1H), 1.78
(p, J = 7.1 Hz, 1H), 0.80 (dt, J = 7.6, 2.2 Hz, 4H); LC-MS: m/z 420.47 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl] cyclopropane carboxamide

The title compound was synthesized using [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. and [4-amino-2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl) Using methanone, the compound of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidine-1- yl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 40% (88 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.29 (dd
, J = 8.3, 1.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 4.76 - 4.65 (m, 1H), 4.37 (s, 1H), 4.25 (s, 1H), 3.62 (d, J = 14.9 Hz, 1H), 3.47 (d, J = 11.6 Hz, 1H), 3.34 (d, J = 10.9 Hz, 2H), 3.19 (dd, J = 11.6, 3.7 Hz, 1H), 3.12 - 2.91 ( LC-MS: m/ z 434.2 (MH+).

Preparation: N-[3-(3-azabicyclo[3.1.1]heptan-3-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. using [4-amino-2-(3-azabicyclo[3.1.1]heptan-3-yl)phenyl]-(1,1-dioxo-1,4-thiazinean-4-yl)methanone, Compounds of Example 183a-c (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclo Propane carboxamide) was carried out analogously to the synthesis. The title compound was obtained in a yield of 6% (10 mg).

1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 8.3, 1.7 Hz , 1H), 4.51 (d, J = 14.1 Hz, 2H), 3.82 (d, J = 14.9 Hz, 2H), 3.51 (dd, J = 21.8, 10.7 Hz, 5H), 3.25 - 3.11 (m, 3H) , 3.03
(d, J = 13.6 Hz, 2H), 2.08 (s, 2H), 1.76 (q, J = 6.1 Hz, 1H), 1.35 (dd, J = 6.4, 2.8 Hz, 2H), 0.98 - 0.51 (m, 4H); LC-MS: m/z 418.2 (MH+).

Preparation: N-[3-(4,4-difluoropiperidin-1-yl)-4-(1,1-dioxo-1,4-thiazinean-4-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was replaced with [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. Example 183a- of the compound c (N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide) The synthesis was performed analogously. The title compound was obtained in a yield of 45% (93 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.3, 1.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 13.9 Hz, 1H), 3.79 (t, J = 11.6 Hz, 1H), 3.56 (d, J = 5.6 Hz, 2H), 3.32 (s, 1H), 3.21 - 3.03 (m, 4H), 3.02 - 2.87 (m, 3H), 2.03 (s, 4H), 1.76 (p, J = 6.2 Hz, 1H), 0.83 - 0.74 (m, 4H); LC-MS: m /z 442.4 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-piperidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. The compounds of Example 183a-c (N-[4 -(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide). The title compound was obtained in 75% yield (135 mg).

H NMR (500 MHz, DMSO-d6 ) δ ppm 10.29 (s, 1 H), 7.45 (d, J=1.8 Hz, 1 H), 7.25
(dd, J = 8.2, 1.8 Hz, 1 H), 7.14 (d, J = 8.2 Hz, 1 H), 4.30 - 3.43 (m, 4 H), 3.37 - 3.04 (m, 4 H), 3.05 - 2.67 (m, 4 H), 1.81 - 1.73 (m, 1 H), 1.66 - 1.43 (m, 6 H), 0.83 - 0.76 (m, 4 H); LC-MS: m/z 406.2 (MH+).

Preparation: N-[4-(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-morpholin-4-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out in place of [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(1,1-dioxo-1,4-thiazinan-4-yl)methanone. The compounds of Example 183a-c (N-[4 -(1,1-dioxo-1,4-thiazine-4-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 61% (45 mg).

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.32 (s, 1 H), 7.44 (d, J=1.8 Hz, 1 H), 7.30 (dd, J=8.2, 1.9 Hz, 1 H), 7.18 ( d, J=8.2 Hz, 1 H), 3.76 - 3.58 (m, 4 H), 4.30 - 3.45 (m, 4 H), 3.37 - 3.07 (m, 4 H), 3.07 - 2.70 (m, 4 H) , 1.81 - 1.72 (m, 1 H), 0.86 - 0.75 (m, 4 H); LC-MS: m/z 408.2 (MH+).

Synthesis scheme 18

Preparation: (2-fluoro-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 2-fluoro-4-nitrobenzoic acid (2.0 g, 10.8 mmol) and thionyl dichloride (7.84 mL, 108.04 mmol) was heated to reflux for 2 hours, after which time the reaction was quenched. Cool to RT and concentrate under vacuum. The residue was dissolved in DCM (3.0 mL) and cooled to 0°C. After 10 minutes, a solution of N,N-diisopropylethylamine (3.76 mL, 21.61 mmol) and 1-methyl-3-phenylpiperazine (1.9 g, 10.8 mmol) in DCM (20 mL) was added. The reaction was allowed to reach RT and stirred overnight. The next day, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. Washed with. The organic phase was washed with brine, dried on a phase separator, and concentrated under vacuum to give the formula (2-fluoro-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. The product was obtained. This product was used in the next step without further purification.
Yield: 3.46g

1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.09 (m, 2 H), 7.87 - 7.72 (m, 1 H), 7.49 (br d, J=7.48 Hz, 1 H), 7.44 - 7.19 (m , 4 H), 3.54 - 3.46 (m, 1 H), 3.24 - 3.06 (m, 1 H), 2.97 - 2.86 (m, 1 H), 2.86 - 2.75 (m, 1 H), 2.72 - 2.57 (m , 1H), 2.42
- 2.29 (m, 1 H), 2.26 - 2.12 (m, 3 H), 2.10 - 1.88 (m, 1 H); LC-MS: m/z 344.1 (MH+)

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone

3-(trifluoromethyl)pyrrolidine hydrochloride (204.55 mg, 1.16 mmol) and (2-fluoro-4-nitrophenyl)-(4-methyl-2-phenylpiperazine-1) in DMSO (2.566 mL) -yl) methanone (200.0 mg, 0.580 mmol) was heated to 120° C. for 12 hours, after this time the reaction was diluted with water and extracted with AcOEt (x3). The organic phase was washed three times with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to yield a compound of formula (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2 -[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was obtained as a mixture of distereoisomers. This product was used in the next step without further purification.
Yield: 214mg

LC:MS: m/z 463.21 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-(2-morpholin-4-yl-4-nitrophenyl)methanone

The title compound was synthesized using morpholine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-( The synthesis of trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained in a yield of 79% (0.94 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.01 - 7.74 (m, 3 H), 7.58 - 7.18 (m, 5 H), 5.82 - 5.72 (m, 1 H), 4.52 - 4.40 (m, 1 H), 3.93 - 3.71 (m, 2 H), 3.35 (br d, J=2
LC-MS: m/z 411.24 (MH+).

Preparation: (4-methyl-2-phenylpiperazin-1-yl)-(4-nitro-2-piperidin-1-ylphenyl)methanone

The title compound was synthesized using piperidine in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-( The synthesis of trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained in a yield of 92% (1.1 g).

1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 - 7.69 (m, 3 H), 7.54 - 7.16 (m, 5 H), 5.83 - 5.71 (m, 1 H), 4.50 - 4.34 (m, 1 H ), 3.33 (br s, 1 H), 3.28 - 3.12 (m, 1 H), 3.07 - 2.57 (m, 6 H), 2.43 - 2.29 (m, 1 H), 2.21 (br d, J=9.90 Hz , 3 H), 1.87 - 1.52 (m, 4 H), 1.41 - 1.23 (m, 2 H); LC-MS: m/z 409.23 (MH+).

Preparation: [2-(3,3-difluoropyrrolidin-1-yl)-4-nitrophenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out using 3,3-difluoropyrrolidine hydrochloride in place of 3-(trifluoromethyl)pyrrolidine hydrochloride, (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro The synthesis of -2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone was carried out analogously. The title compound was obtained in a yield of 33% (0.415 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.80 - 7.20 (m, 8 H), 5.86 - 5.69 (m, 1 H), 4.67 - 4.39 (m, 1 H), 3.83 (s, 3 H ), 3.26 - 3.01 (m, 2 H), 2.57 (br s, 2 H), 2.47
- 1.90 (m, 7 H); LC-MS: m/z 431.24 (MH+).

Preparation: 4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

(4-Methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone (214.0 mg, Pd-C10% (98.49 mg, 0.090 mmol) was added to a solution of 0.460 mmol). The reaction was stirred at RT under H2 atmosphere for 6 hours. After this time, the mixture was filtered, washed twice with ethanol and concentrated under vacuum, with the formula [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-( The product 4-methyl-2-phenylpiperazin-1-yl)methanone was obtained as a mixture of distereoisomers.
Yield: 180mg

LC-MS: m/z 433.25 (MH+)

Preparation: (4-amino-2-morpholin-4-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out by substituting (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Example compound 4-amino-2-[3-(trifluoromethyl)-methyl-2-phenylpiperazin-1-yl)-(2-morpholin-4-yl-4-nitrophenyl)methanone The synthesis of pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone was carried out analogously. The title compound was obtained in a yield of 99% (0.277 g).

LC-MS: m/z 381.16 (MH+)

Preparation: (4-amino-2-piperidin-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out by substituting (4-methyl-2-phenylpiperazin-1-yl)-[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]methanone. Example compound 4-amino-2-[3-(trifluoromethyl) The synthesis of pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone was carried out analogously. The title compound was obtained in a yield of 91% (0.253 g).

LC-MS: m/z 380.54 (MH+)

Preparation: [4-amino-2-(3,3-difluoropyrrolidin-1-yl)phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone

The synthesis of the title compound was carried out by substituting [2 The example compound 4-amino-2-[ The synthesis was carried out analogously to the synthesis of 3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone. The title compound was obtained in a yield of 95% (0.177 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.73 - 7.65 (m, 1 H), 7.44 - 7.20 (m, 5 H), 6
.88 - 6.68 (m, 1 H), 6.16 - 5.97 (m, 2 H), 5.28 - 5.19 (m, 2 H), 3.70 - 3.34 (m,
6 H), 3.16 - 2.61 (m, 4 H), 2.48 - 2.41 (m, 1 H), 2.37 - 1.89 (m, 4 H); LC-MS: m/z 401.27 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide

N,N-diisopropylethylamine (0.14 mL, 0.830 mmol) and [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazine- To a stirred solution of (1-yl) methanone (180.0 mg, 0.420 mmol) in DCM (4.557 mL) was added dropwise cyclopropanecarbonyl chloride (0.05 mL, 0.540 mmol) and the reaction mixture was brought to RT. The mixture was stirred overnight. The next day, the reaction was diluted with DCM and washed with a saturated solution of _NaHCO3 (x2). The organic phase was washed with water (x1) then brine, dried on a phase separator and the solvent was evaporated under reduced pressure to give the crude product, which was purified by FC on a NH column (cHex 100% cHex/AcOEt80), formula N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide The product was obtained as a mixture of distereoisomers.
Yield: 178mg

LC-MS: m/z 501.24 (MH+)

The mixture of diastereoisomers was then separated into single enantiomers by chiral semi-preparative HPLC.

Preparation: (2S,3R) or (2R,3S) or (2R,3R) or (2S,3S)N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3- (Trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide hydrochloride

(2S,3R) or (2R,3S) or (2R,3R) or (2S,3S)N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(tri- Fluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide (diester isomer 1 enantiomer 1, Example 198a, 20 mg) was dissolved in MeOH (1.5 mL) and treated with 1 eq HCl in dioxane and after evaporation. , formula (2S,3R) or (2R,3S) or (2R,3R) or (2S,3S)N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3- A product of (trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide hydrochloride was obtained.
Yield: 20.8mg

LC-MS: m/z 501.31 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-morpholin-4-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified by substituting (4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone). The compound of Example 199a-e (N-[4-(4-methyl- The synthesis was carried out analogously to the synthesis of 2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidine-1-]phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 64% (0.209 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.34 - 10.20 (m, 1 H), 7.79 - 7.71 (m, 1 H),
7.51 - 6.99 (m, 7 H), 5.82 - 5.72 (m, 1 H), 4.55 - 4.35 (m, 1 H), 3.93 - 3.44 (m, 3 H), 3.29 - 3.13 (m, 3 H), 3.10 -2.99 (m, 1 H), 2.95 - 2.55 (m, 5 H), 2.40 - 2.16 (m, 3 H), 2.12 - 1.95 (m, 1 H), 1.86 - 1.69 (m, 1 H), 0.85 - 0.73 (m, 4 H); LC-MS: m/z 450.01 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-piperidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting (4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(4-methyl-2-phenylpiperazin-1-yl)methanone). The compound of Example 199a-e (N-[4-(4-methyl- The synthesis was carried out analogously to the synthesis of 2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidine-1-]phenyl)cyclopropanecarboxamide). The title compound was obtained in a yield of 23.4% (0.072 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.28 -10.15 (m, 1 H), 7.78 - 6.98 (m, 8 H),
5.83 - 4.37 (m, 2 H), 3.51 - 3.33 (m, 1 H), 3.27 (s, 1 H), 3.19 - 2.98 (m, 2 H), 2.95 - 2.55 (m, 4 H), 2.41 - 1.97 (m, 5 H), 1.84 -1.51 (m, 4 H), 1.36 (br s, 2
H), 0.83 - 0.73 (m, 4 H); LC-MS: m/z 447.28 (MH+).

The racemic mixture (Example 201c) was then separated into single enantiomers by chiral semipreparative HPLC.

Preparation: N-[3-(3,3-difluoropyrrolidin-1-yl)-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out by substituting [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. The compound of Example 199a-e (N-[ The synthesis was carried out analogously to the synthesis of 4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 80.5% (0.167 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.29 - 10.15 (m, 1 H), 7.76 - 6.91 (m, 8 H),
5.82 - 4.34 (m, 1 H), 3.30 (s, 3 H), 2.41 - 1.66 (m, 13 H), 0.91 - 0.66 (m, 4 H); LC-MS: m/z 469.3 (MH+).

The racemic mixture (Example 202c) was then separated into single enantiomers by chiral semi-preparative HPLC.

Synthesis scheme 19

Preparation: (2-bromo-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

A mixture of 2-bromo-4-nitrobenzoic acid (1.05 g, 4.27 mmol) and thionyl dichloride (6.23 mL, 85.36 mmol) was heated to reflux for 1.30 hours. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was dissolved in DCM (3 mL) and cooled to 0°C. After 10 minutes, a solution of N,N-diisopropylethylamine (1.78 mL, 12.8 mmol) and 1-methyl-3-phenylpiperazine (0.75 g, 4.27 mmol) in DCM (20 mL) was added. The reaction was allowed to reach RT and stirred overnight. The next day, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. Washed with. The organic phase was washed with brine, dried on a phase separator and concentrated under vacuum to give the formula (2-bromo-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone. The product was obtained. This product was used in the next step without further purification.
Yield: 1.77g

H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.38 (s, 8 H), 5.83 - 4.36 (m, 2 H), 3.56 - 3.
33 (m, 1 H), 3.13 - 2.95 (m, 2 H), 2.87 - 2.58 (m, 1 H), 2.45 - 2.34 (m, 1 H), 2.29 - 1.92 (m, 3 H); LC- MS: m/z 405.96, 407.8 (MH+).

Preparation: (4-amino-2-bromophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone

To a solution of (2-bromo-4-nitrophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (1.0 g, 2.47 mmol) in acetic acid (40 mL) was added zinc (1.62 g). , 24.74 mmol) was added. The reaction mixture was stirred at room temperature. After 2 hours, the reaction was filtered through a Hirsch funnel, washed with EtOAc, and concentrated under vacuum. The crude product was dissolved in 2.5 ml of MeOH and applied to an SCX cartridge (20 g, washed with MeOH then eluted with NH ₃ IN in MeOH). The solvent was evaporated under reduced pressure and the product was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 20:80) with the formula (4-amino-2-bromophenyl)-(4-methyl- A product of 2-phenylpiperazin-1-yl)methanone was obtained.
Yield: 0.850g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.34 (br s, 8 H), 5.81 - 5.49 (m, 3 H), 3.54 - 3.35 (m, 1 H), 3.23 -2.55 (m, 3 H), 2.40 - 2.01 (m, 4 H), 1.89 (s, 1 H); LC-MS: m/z 374.09, 376.1 (MH+).

Preparation: N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide

(4-Amino-2-bromophenyl)-(4-methyl-2-phenylpiperazin-1-yl)methanone (0.85 g, 2.27 mmol) and N,N-diisopropylethylamine (0 To a stirred solution of cyclopropanecarbonyl chloride (0.27 mL, 2.95 mmol) at 0° C. was added dropwise and the reaction mixture was stirred at room temperature overnight. After this time, the mixture was diluted with _NaHCO3 and extracted with DCM (x3). The organic phase was washed with brine, dried on a phase separator and concentrated under vacuum. The crude product was purified by a chromatography column sfar Amino D 28 g (gradient from cHex/AcOEt 80:20 to cHex/AcOEt 10:90) with the formula N-[3-bromo-4-(4-methyl-2-phenylpiperazine- A product of 1-carbonyl)phenyl]cyclopropane carboxamide was obtained.
Yield: 0.850g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.57 - 10.37 (m, 1 H), 8.14 - 7.20 (m, 8 H),
LC -MS: m/z 442.11, 444.1 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide

In a 5 mL microwave vial, N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (100.0 mg, 0.230 mmol), sodium tert-butoxide ( 32.59 mg, 0.340 mmol), 2-oxa-6-azaspiro[3.4]octane (28.42 uL, 0.270 mmol) and dicyclohexyl-[2-[2,6-di(propan-2-yloxy)] Phenyl]phenyl]phosphine (26.37 mg, 0.060 mmol) and NMP (1.5 mL) were added. The resulting suspension was degassed using a Schlenkline method using a N ₂ -vacuum cycle. The reaction mixture was shaken at 120° C. for 4 hours in PLS. The crude product was dissolved in 0.5 ml MeOH and applied to an SCX cartridge (10 g, eluted with MeOH then washed with NH3 1N in MeOH). The solvent was evaporated under reduced pressure to obtain the crude product, which was purified by chromatography Sfar NH 11 g (gradient from cHex/AcOEt 70:30 to AcOEt 100%) with the formula N-[4-(4-methyl-2 -phenylpiperazine-1-carbonyl)-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide product was obtained.
Yield: 0.016g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.22 - 10.06 (m, 1 H), 7.83 - 6.84 (m, 8 H),
5.85 - 5.67 (m, 1 H), 4.71 - 4.21 (m, 6 H), 3.57 - 3.37 (m, 4 H), 3.17 - 2.58 (m, 4 H), 2.23 (s, 3 H), 2.03 - 1.69 (m, 3 H), 0.78 (br d, J=4.18 Hz, 4 H); LC-MS: m/z 475.49 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 2-oxa-6-azaspiro[3.3]heptane in place of 2-oxa-6-azaspiro[3.4]octane to synthesize the compound of Example 203 (N-[4- (4-Methyl-2-phenylpiperazine-1-carbonyl)-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide) . The title compound was obtained with a yield of 24% (0.025 g).

1H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.51 - 7.11
(m, 5H), 6.89 (dd, J = 45.0, 23.6 Hz, 3H), 5.72 (s, 1H), 4.74 (s, 3H), 4.57 - 4.28 (m, 2H), 4.01 (d, J = 13.2 Hz, 2H), 3.54 (dd, J = 102.7, 8.0 Hz, 3H), 2.68 (s, 1H), 2.22 (d, J = 7.9 Hz, 5H), 1.76 (s, 1H), 0.79 (s, 4H) ); LC-MS: m/z 461.26 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-(6-oxa-2-azaspiro[3.4]octan-2-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 6-oxa-2-azaspiro[3.4]octane in place of 2-oxa-6-azaspiro[3.4]octane to synthesize the compound of Example 203 (N-[4- (4-Methyl-2-phenylpiperazine-1-carbonyl)-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide) . The title compound was obtained in a yield of 7% (0.004 g).

1H NMR (500 MHz, DMSO-d6) δ ppm 10.28 - 10.04 (m, 1 H), 7.82 - 7.11 (m, 5 H),
7.11 - 6.70 (m, 3 H), 5.84 - 4.52 (m, 1 H), 2.46 - 2.25 (m, 1 H), 2.24 - 2.17 (m, 3 H), 2.00 - 1.83 (m, 2 H), 4.55 - 1.81 (m, 13 H), 1.83 - 1.64 (m, 1 H), 0.85
- 0.67 (m, 4 H); LC-MS: m/z 476.3 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

In a 5 mL microwave vial, N-[3-bromo-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide (200.0 mg, 0.450 mmol), tripotassium phosphate ( 204.41 mg, 0.950 mmol), 3-(trifluoromethyl)pyrazole (61.53 mg, 0.450 mmol) and dry 1,4-dioxane (0.507 mL) were added sequentially. The resulting suspension was degassed for 15 min by bubbling _N2 , then copper(I) iodide (4.33 mg, 0.020 mmol) and N,N'-dimethylcyclohexane-1,2-diamine ( 6.43 mg, 0.050 mmol) was added under nitrogen flux and degassed again by Schlenkline method. The vial was sealed and stirred at 120° C. overnight. The next day, the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The organic layer was evaporated under reduced pressure and purified by FC Sfar C18 (eluent: water/NH4OH0.1% 100% to water/NH4OH0.1%/MeCN 60:40) to give the formula N-[4-(4 -Methyl-2-phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide product was obtained.
Yield: 0.058g

1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.32 - 10.88 (m, 1 H), 7.87 - 8.37 (m, 2 H), 6.56 - 7.82 (m, 8 H), 4.43 - 5.74 (m, 1 H ), 3.07 - 4.34 (m, 2 H), 2.76 - 3.05
(m, 1 H), 2.39 - 2.78 (m, 1 H), 1.33 - 2.38 (m, 6 H), 0.72 - 0.95 (m, 4 H); LC-MS: m/z 498.20 (MH+).

Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-[4-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide

The synthesis of the title compound was modified using 4-(trifluoromethyl)-1H-pyrazole in place of 3-(trifluoromethyl)pyrazole to synthesize the compound of Example 206 (N-[4-(4-methyl-2- The synthesis of phenylpiperazine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]cyclopropanecarboxamide) was performed analogously. The title compound was obtained with a yield of 10% (0.023 g).

1H NMR (400 MHz, DMSO-d6) δ 10.60 (d, 1H), 8.69 (d, 1H), 8.33 - 7.91 (m, 2H),
7.76 - 7.12 (m, 7H), 5.89 - 4.10 (m, 1H), 3.42 (d, 1H), 3.17 - 2.60 (m, 4H), 2.41 - 1.58 (m, 5H), 0.84 (d, 4H); LC-MS: m/z 498.19 (MH+).

Synthesis scheme 20

Preparation: 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (841.11 mg, 2.21 mmol), 2-bromo-4-cyanobenzoic acid (0.5 g, 2 To a solution of 4,4-difluoropiperidine (267.95 mg, 2.21 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (1.18 mL, 6.64 mmol). The reaction was stirred at RT for 5 hours. After this time, the reaction was diluted with H2O. This mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by FC on silica gel (eluting from cHex to AcOEt/cHex 1:1) to give a product of formula 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile.
Yield: 0.530g

1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, 1H), 7.97 (dd, 1H), 7.66 (d, 1H), 3.86 (dt, 1H), 3.66 (ddd, 1H), 3.22 (t, 2H), 2.24 - 1.80 (m, 4H); LC-MS: m/z 329.06, 331.09 (MH+)

Preparation: 4-(4,4-difluoropiperidin-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile

In a vial were added 3-bromo-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile (150.0 mg, 0.460 mmol), tripotassium phosphate (206.04 mg, 0.960 mmol), and 3-(trifluoropiperidine-1-carbonyl). Fluoromethyl)pyrazole (74.42 mg, 0.550 mmol) was suspended in dry 1,4-dioxane (2.492 mL). The resulting suspension was degassed for 15 minutes while bubbling N2, and then copper(I) iodide (4.36 mg, 0.020 mmol) and N,N'-dimethylcyclohexane-1,2-diamine (6 .48 mg, 0.050 mmol) was added under nitrogen flux and degassed again by Schlenkline method. The vial was sealed and stirred at 120° C. overnight. The next day, the reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The organic layer was evaporated under reduced pressure and the residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 3:7) to give the formula 4-(4,4-difluoropiperidine-1-carbonyl)- A product of 3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile was obtained.
Yield: 122mg

1H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, 1H), 8.39 (d, 1H), 8.06 (dd, 1H), 7.74 (d, 1H), 7.09 (d, 1H), 3.88 (d, 1H), 3.48 - 3.41 (m, 1H), 3.35 (d, 2H), 2.17 - 1.84 (m, 4H); LC-MS: m/z 385.2 (MH+).

Preparation: 3-(3-cyclopropylpyrazol-1-yl)-4-(4,4-difluoropiperidine-1-carbonyl)benzonitrile

The title compound was synthesized using 3-cyclopropyl-1H-pyrazole in place of 3-(trifluoromethyl)pyrazole, 4-(4,4-difluoropiperidine-1-carbonyl)-3-[3-( The synthesis of trifluoromethyl)pyrazol-1-yl]benzonitrile was carried out analogously. The title compound was obtained in a yield of 44% (96 mg).

1H NMR (400 MHz, DMSO) δ 8.21 (dd, J = 5.3, 2.0 Hz, 2H), 7.85 (dd, J = 7.9, 1.5 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.30 (d, J = 2.5 Hz, 1H), 3.73 (dt, J = 12.3, 5.7 Hz, 1H), 3.63 (ddd, J = 13.1, 7.8, 4.5 Hz, 1H), 3.29 - 3.22 (m, 1H), 3.19 - 3.08 (m, 1H), 2.21 - 1.68 (m, 5H), 0.98 - 0.86 (m, 2H), 0.70 (ddd, J = 9.5, 5.0, 3.2 Hz, 1H), 0.62 (ddd, J = 9.3 , 6.3, 3.2 Hz, 1H); LC-MS: m/z 357.3 (MH+).

Preparation: 4-(4,4-difluoropiperidine-1-carbonyl)-3-(3-propan-2-ylpyrazol-1-yl)benzonitrile

The title compound was synthesized using 3-propan-2-yl-1H-pyrazole in place of 3-(trifluoromethyl)pyrazole, 4-(4,4-difluoropiperidine-1-carbonyl)-3-[ The synthesis was carried out analogously to the synthesis of 3-(trifluoromethyl)pyrazol-1-yl]benzonitrile. The title compound was obtained in a yield of 28% (62 mg).

1H NMR (400 MHz, DMSO) δ 8.22 (dd, J = 7.7, 2.0 Hz, 2H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 3.77 - 3.58 (m, 2H), 3.28 - 3.23 (m, 1H), 3.11 (ddd, J = 13.4, 7.7, 4.4 Hz, 1H), 2.89 (p, J = 7.0 Hz, 1H), 2.18 - 1.65 (m, 4H), 1.26 - 1.13 (m, 6H); LC-MS: m/z 359.2 (MH+).

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

4-(4,4-difluoropiperidine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (123.19 mg, 0.320 mmo
l), dicesium carbonate (313.32 mg, 0.960 mmol), ethanimidoamide hydrochloride (45.46 mg, 0.480 mmol) and copper bromide (5.0 mg, 0.030 mmol) in DMSO (3.429 mL) The mixture was stirred at 120°C for 3 hours. After this time, the reaction was cooled to RT and H2O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by FC on a NH column (DCM to DCM/MeOH 9:1) and again by FC on RPe using acidic conditions (5:95 CH3CN/H2O + 0.1% FA to 30:1). 70 CH3CN/H2O + 1% FA), formula (4,4-difluoropiperidin-1-yl)-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2 A product of -[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanone was obtained.
Yield: 42mg

1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H), 8.57 (dd, 1H), 8.21 (s, 1H), 8.16 - 8.12 (m, 1H), 7.60 (s, 1H), 7.04 ( d, 1H), 3.94 (d, 1H), 3.38 (d, 3H), 2.44 (s,
3H), 2.09 (s, 1H), 1.96 (dd, 3H); LC-MS: m/z 441.2 (MH+).

Preparation: [2-(3-cyclopropylpyrazol-1-yl)-4-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-(4,4-difluoropiperidine-1 -il) methanone

The synthesis of the title compound was modified by substituting 3-(3-cyclopropylpyrazole for 4-(4,4-difluoropiperidine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile). The compound of Example 208 ((4,4-difluoropiperidin-1-yl)-[4-(5 -methyl-4H-1,2,4-triazol-3-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanone). The title compound was obtained with a yield of 28% (30 mg).

1H NMR (400 MHz, DMSO) δ 13.88 (s, 1H), 8.11 (d, J = 1.5 Hz, 1H), 8.08 (d, J = 2.5 Hz, 1H), 7.97 (dd, J = 7.9, 1.6 Hz , 1H), 7.49 (d, J = 7.9 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 3.93 - 3.78 (m, 1H), 3.52 (t, J = 9.2 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.42 (s, 3H), 1.90 (tt, J = 8.4, 5.0 Hz, 4H), 1.76 - 1.52 (m, 1H), 0.92 (ddd, J = 8.3, 3.2, 0.9 Hz , 2H), 0.75 - 0.68 (m, 1H), 0.67 - 0.57 (m, 1H); LC-MS:
m/z 413.3 (MH+).

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

The synthesis of the title compound was carried out using 4-(4,4-difluoropiperidine-1-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile instead of 4-(4,4-difluoropiperidine-1-carbonyl) The compound of Example 208 ((4,4-difluoropiperidin-1-yl)-[4 -(5-Methyl-4H-1,2,4-triazol-3-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanone). The title compound was obtained with a yield of 57% (40 mg).

1H NMR (400 MHz, DMSO) δ 13.88 (s, 1H), 8.12 (d, J = 1.5 Hz, 1H), 8.07 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 7.9, 1.5 Hz , 1H), 7.50 (d, J = 7.9 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 3.86 - 3.78 (m, 1H), 3.53 (ddd, J = 13.3, 8.5, 4.1 Hz, 1H), 3.24 (dt, J = 8.2, 4.7 Hz, 1H), 3.20 - 3.07 (m, 1H), 2.93 (hept, J = 6.9 Hz, 1H),
2.42 (s, 3H), 2.06 (s, 1H), 1.87 (s, 2H), 1.64 - 1.43 (m, 1H), 1.22 (d, J = 6.9
Hz, 6H); 415.3 (MH+).

Synthesis scheme 21

Preparation: tert-butyl 3-(2-chlorophenyl)-4-(2-fluoro-4-nitrobenzoyl)piperazine-1-carboxylate

A mixture of 2-fluoro-4-nitrobenzoic acid (300.0 mg, 1.62 mmol) and thionyl dichloride (1.18 mL, 16.21 mmol) was heated to reflux for 1.30 hours. After this time, the reaction was cooled to RT and concentrated under vacuum. The residue was dissolved in DCM (0.500 mL) and cooled to 0°C. After 10 minutes, N,N-diisopropylethylamine (1.13 mL, 6.48 mmol) and tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate (481.0 mg, 1.62 mmol) in DCM (3 mL). ) solution was added. The reaction was stirred at RT overnight. After this time, the reaction was diluted with DCM and s.c. of _NaHCO3 . s. Washed 3 times with The organic phase was washed with brine, dried on a phase separator and concentrated under vacuum to give formula 3-(2-chlorophenyl)-4-(2-fluoro-4-nitrobenzoyl)piperazine-1-carboxylic acid. A tert-butyl product was obtained. This product was used in the next step without further purification.
Yield: 0.74g

LC-MS: m/z 408.17 (MH+).

Preparation: tert-butyl 3-(3-chlorophenyl)-4-(2-fluoro-4-nitrobenzoyl)piperazine-1-carboxylate

The synthesis of the title compound was carried out using tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate in place of tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate. The synthesis was carried out analogously to the synthesis of tert-butyl (chlorophenyl)-4-(2-fluoro-4-nitrobenzoyl)piperazine-1-carboxylate. The title compound was obtained in a yield of 80% (0.6 g).

LC-MS: m/z 408.17 (MH+).

Preparation: tert-butyl 3-(2-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate

tert-butyl 3-(2-chlorophenyl)-4-(2-fluoro-4-nitrobenzoyl)piperazine-1-carboxylate (739.0 mg, 1.59 mmol), 2-oxa-6-azaspiro [3.4 ] A mixture of octane (270.4 mg, 2.39 mmol) and triethylamine (0.44 mL, 3.19 mmol) in DMSO (13.2 mL) was stirred at 80° C. for 5 hours. After this time, the reaction was cooled to RT and diluted with _H2O . The mixed reaction was 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 formula 3-(2-chlorophenyl)-4-[4-nitro-2-(2 A product of tert-butyl -oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate was obtained. This product was used in the next step without further purification.
Yield: 0.9g

LC-MS: m/z 557.22 (MH+).

Preparation: tert-butyl 3-(3-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate

The synthesis of the title compound was modified by substituting 3-(3-chlorophenyl)-4-(2-fluoro- 3-(2-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl using 4-nitrobenzoyl)piperazine-1-carboxylate ) The synthesis was carried out analogously to the synthesis of tert-butyl]benzoyl]piperazine-1-carboxylate. The title compound was obtained in a yield of 90% (0.6 g).

LC-MS: m/z 557.22 (MH+).

Preparation: tert-butyl 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(2-chlorophenyl)piperazine-1-carboxylate

3-(2-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylic acid in acetic acid (40 mL) To a solution of tert-butyl (1.0 g, 1.788 mmol) was added zinc (1.62 g, 24.74 mmol). The reaction mixture was stirred at room temperature. After 2 hours, the reaction was filtered through a Hirsch funnel, washed with EtOAc, and concentrated under vacuum. 2.5 ml of crude product
of MeOH and applied to an SCX cartridge (20 g, washed with MeOH then eluted with NH3 1N in MeOH). The solvent was evaporated under reduced pressure and the product was purified by FC on silica gel (eluted from 100% cHex to cHex/AcOEt 20:80) and had the formula (3-(3-chlorophenyl)-4-[4-nitro- A product of tert-butyl 2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate was obtained.
Yield: 802mg

LC-MS: m/z 527.22 (MH+).

Preparation: tert-butyl 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(3-chlorophenyl)piperazine-1-carboxylate

The synthesis of the title compound was performed using 3-(2-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylic acid. 3-(3-chlorophenyl)-4-[4-nitro-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylic acid instead of tert-butyl Example compound 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(2-chlorophenyl)piperazine using tert-butyl The synthesis was carried out analogously to the synthesis of tert-butyl-1-carboxylate. The title compound was obtained in a yield of 98% (0.6 g).

Preparation: 3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carvone tert-butyl acid

tert-butyl 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(2-chlorophenyl)piperazine-1-carboxylate (0. To a stirred solution of 85 g, 1.522 mmol) and N,N-diisopropylethylamine (0.53 mL, 3.04 mmol) in DCM (20 mL) was added dropwise cyclopropanecarbonyl chloride (0.2 mL, 1.98 mmol). and the reaction mixture was stirred at room temperature overnight. After this time, the mixture was diluted with NaHCO3 s. s. and extracted with DCM (x3). The organic phase was washed with brine, dried on a phase separator and concentrated under vacuum. The crude product was purified by FC on a NH column (elution from cHex/AcOEt 80:20 to cHex/AcOEt 10:90) and was purified with formula 3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2 tert-butyl -(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate was obtained.
Yield: 0.5g

LC-MS: m/z 595.30 (MH+).

Preparation: 3-(3-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)
tert-butyl -2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine-1-carboxylate

The synthesis of the title compound was carried out using 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(2-chlorophenyl)piperazine-1-carboxylic acid. 4-[4-amino-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]-3-(3-chlorophenyl)piperazine-1-carboxylic acid instead of tert-butyl 3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl] using tert-butyl The synthesis was carried out analogously to the synthesis of tert-butyl piperazine-1-carboxylate. The title compound was obtained in a yield of 42% (0.3 g).

Preparation: N-[4-[2-(2-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide

3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine in DCM (8 mL) Trifluoroacetic acid (2 mL, 27.4 mmol) was added to a solution of tert-butyl-1-carboxylate (0.54 g, 0.914 mmol). The reaction was stirred at RT for 1 hour. After this time, the reaction was concentrated under vacuum. The residue was purified by SCX, first washing with MeOH and then eluting with 1M NH3 solution. The basic fractions were collected and concentrated under vacuum. The product was purified by FC on RP using basic conditions (eluted from 100% aqueous ammonium bicarbonate to 100% CH ₃ CN adjusted to pH 10 with ammonia) and had the formula N-[4-[2- A product of (2-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide was obtained.
Yield: 145mg

LC-MS: m/z 495.31 (MH+).

Preparation: N-[4-[2-(3-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed using 3-(2-chlorophenyl)-4-[4-(cyclopropanecarbonylamino)-2-(2-oxa-7-azaspiro[3.4]octan-7-yl)benzoyl]piperazine. -3-(3-chlorophenyl)-4-[4-(chloropetanecarbonylamino)-2-(2-oxa-7-azaspiro[3.4]octane-7- instead of tert-butyl-1-carboxylate) N-[4-[2-(2-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3. The synthesis of 4]octan-7-yl)phenyl]cyclopropanecarboxamide was performed analogously. The title compound was obtained in a yield of 20% (50 mg).

LC-MS: m/z 495.31 (MH+).

Preparation: N-[4-[2-(2-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclo propane carboxamide

N-[4-[2-(2-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclo in methanol (5 mL) To a solution of propanecarboxamide (163 mg, 0.290 mmol) were added formaldehyde (235.78 mg, 2.9 mmol) and sodium triacetoxyborohydride (369 mg, 1.74 mmol). The reaction was stirred at room temperature overnight. The next day, the reaction was concentrated to dryness under reduced pressure and purified by SCX, washing first with MeOH and then eluting with 1N NH3 in MeOH. The basic fractions were evaporated and the residue was purified by FC on a NH column (eluted from 100% cHex to cHex/AcOEt 1:1), giving the formula N-[4-[2-(2-chlorophenyl)-4-methyl The product piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropanecarboxamide was obtained as a racemic mixture.
Yield: 99mg

1H NMR (400 MHz, DMSO-d6) δ 10.13 (d, 1H), 8.13 - 7.65 (m, 1H), 7.56 - 7.23 (m, 3H), 7.21 - 6.81 (m, 3H), 4.71 - 4.16 (m , 4H), 3.47 (dt, 3H), 3.25 - 2.65 (m,
5H), 2.45 - 2.10 (m, 6H), 2.03 - 1.71 (m, 3H), 0.79 (s, 4H); LC-MS: m/z 509.23 (MH+).

Preparation: N-[4-[2-(3-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclo propane carboxamide

The synthesis of the title compound was carried out using N-[4-[2-(3-chlorophenyl)piperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octan-7-yl)phenyl]cyclopropane instead of propanecarboxamide Example compound N-[4-[2-(2-chlorophenyl)-4-methylpiperazine-1-carbonyl]-3-(2-oxa-7-azaspiro[3.4]octane- The synthesis of 7-yl)phenyl]cyclopropanecarboxamide was carried out analogously. The title compound was obtained in a yield of 64% (33 mg).

1H NMR (400 MHz, DMSO-d6) δ 10.15 (d, 1H), 7.92 - 7.50 (m, 1H), 7.48 - 7.13 (m, 3H), 7.11 - 6.82 (m, 2H), 5.86 - 4.14 (m , 4H), 3.31 (s, 5H), 3.19 - 2.63 (m,
4H), 2.40 - 2.12 (m, 6H), 2.06 - 1.64 (m, 3H), 0.85 - 0.72 (m, 4H); LC-MS: m/z 509.23 (MH+).

Synthesis scheme 22

Preparation: (2-fluoro-4-nitrophenyl)-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone

2-fluoro-4-nitrobenzoic acid (391.0 mg, 2.11 mmol), N,N-diisopropylethylamine (2.16 mL, 12.67 mmol) and HATU ([dimethylamino(3-triazolo[4,5-b ]Pyridinyloxy)methylidene]-dimethylammonium hexafluorophosphate (1.2 g, 3.17 mmol)) in DMF (9.11 mL) was stirred at RT for 15 min. Then 2-oxa-7-azaspiro[3.5]nonanesoxalic acid (436.48 mg, 1.27 mmol) was added and the reaction mixture was stirred at RT overnight. The next day, a saturated solution of NaHCO3 was added to the reaction mixture and the aqueous phase was extracted with AcOEt (x3). The organic portion was collected and washed with brine, residual water was removed with Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by FC on silica gel (elution from cHex:AcOEt from 80:20 to 20:80) to give the formula (2-fluoro-4-nitrophenyl)-(2-oxa-7-azaspiro[3.5 ] nonan-7-yl) methanone product was obtained.
Yield: 545 mg.

1H NMR (400 MHz, DMSO-d6) δ 8.23 (dd, J = 9.2, 2.2 Hz, 1H), 8.15 (dd, J = 8.4, 2.2 Hz, 1H), 7.71 (dd, J = 8.4, 6.7 Hz, 1H), 4.43 - 4.21 (m, 4H), 3.59 (t, J =
LC-MS: m/ z 295.1 (MH+).

Preparation: [4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone

In a suitable vial, (2-fluoro-4-nitrophenyl)-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (273.0 mg, 0.930 mmol), N,N- Diisopropylethylamine (0.63 mL, 3.71 mmol) and 3-(trifluoromethyl)pyrrolidine hydrochloride (325.77 mg, 1.86 mmol) were dissolved in DMSO (3.981 mL) and stirred at 120° C. for 48 hours. After this time, the reaction was cooled to RT and _H2O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by FC on RP using acidic conditions (eluted from 90:10 to 50:50 from H2O + 0.1% HCOOH/ _CH3CN ) to give the formula [4-nitro-2-[3-(tri- The product fluoromethyl)pyrrolidin-1-yl]phenyl]-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone was obtained.
Yield: 138 mg.

1H NMR (400 MHz, DMSO-d6) δ7.54 (ddd, J = 10.2, 8.3, 2.2 Hz, 1H), 7.45 (dd, J
= 4.2, 2.2 Hz, 1H), 7.29 (dd, J = 8.3, 0.8 Hz, 1H), 4.39 - 4.27 (m, 4H), 3.74 -
3.28 (m, 7H), 3.30 - 3.02 (m, 2H), 2.31 - 2.18 (m, 1H), 2.11 - 2.00 (m, 1H), 1.88 - 1.66 (m, 4H); LC-MS: m/z 414.2 (MH+)

Preparation: [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl)-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone

[4-nitro-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (138.0 mg, 0 A mixture of Pd-C10% (35.53 mg, 0.030 mmol) was stirred under H ₂ atmosphere (1 atm) overnight. After this time, the reaction was filtered and concentrated in vacuo with the formula [4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(2-oxa-7- The product of azaspiro[3.5]nonan-7-yl)methanone was obtained. This product was used in the next step without further purification.
Yield: 130 mg.

1H NMR (400 MHz, DMSO-d6) δ 6.68 (d, J = 8.1 Hz, 1H), 6.03 - 5.95 (m, 2H), 5.13 (d, J = 7.8 Hz, 2H), 4.34 - 4.28 (m, 4H), 3.45 (d, J = 22.0 Hz, 2H), 3.25 (d,
LC-MS: m /z 384.2 (MH+).

Preparation: N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide

[4-amino-2-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]-(2-oxa-7-azaspiro[3.5]nonan-7-yl)methanone (130.0 mg, 0 .340 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.850 mmol) in DCM (3.72 mL) at 0 °C was added dropwise cyclopropanecarbonyl chloride (0.04 mL, 0.410 mmol). added. The reaction was stopped after 1 h at RT and concentrated under vacuum. The residue was purified by FC on RP using basic conditions (eluting from 90:10 to 65:35 with _H2O +0.1% _NH3 / _CH3CN ) and evaporation of the appropriate fractions yielded the formula Racemic N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-[3-(trifluoromethyl)pyrrolidin-1-yl]phenyl]cyclopropanecarboxamide Obtained as a mixture.
Yield: 100mg

1H NMR (400 MHz, DMSO-d6) δ 10.16 (d, J = 4.9 Hz, 1H), 7.13 (dd, J = 10.1, 1.8 Hz, 1H), 7.00 (td, J = 9.5, 8.8, 1.7 Hz, 1H), 6.92 (dd, J = 8.2, 4.4 Hz, 1H), 4.37 - 4.25 (m, 4H), 3.63 - 3.53(m, 1H), 3.51 - 3.41 (m, 1H), 3.33 (s, 6H) , 3.09
(t, J = 5.7 Hz, 1H), 2.18 (dt, J = 12.3, 6.3 Hz, 1H), 2.04 - 1.90 (m, 1H), 1.84
- 1.60 (m, 5H), 0.81 - 0.73 (m, 4H); LC-MS: m/z 452.2 (MH+).

The racemic mixture (Example 213c) was then separated into single enantiomers by chiral semipreparative HPLC.

Synthesis scheme 23

Preparation: 4-(6-Azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile

[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]-dimethylammonium; hexafluorophosphate (841.11 mg, 2.21 mmol), 2-bromo-4-cyanobenzoic acid (0.) and To a solution of 6-azaspiro[2.5]octane hydrochloride (326.62 mg, 2.21 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (857.67 mg, 6.64 mmol). The reaction was stirred at RT for 5 hours. After this time, the reaction was diluted with _H2O . This mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on silica gel (elution from cHex to AcOEt/cHex 1:1). The pure fractions were collected and concentrated under vacuum to yield a product of formula 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile.
Yield: 760mg

1H NMR (400 MHz, DMSO-d6) δ 8.28 (d, 1H), 7.94 (dd, 1H), 7.57 (d, 1H), 3.67 (t, 2H), 3.14 - 3.06 (m, 2H), 1.47 - 1.13 (m, 4H), 0.39 - 0.24 (m, 4H); LC-MS: 319.14, 321.10 m/z (MH+).

Preparation: 4-(6-Azaspiro[2.5]octane-6-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile

4-(6-Azaspiro[2.5]octane-6-carbonyl)-3-bromobenzonitrile (150.0 mg, 0.470 mmol), tripotassium phosphate (212.46 mg, 0.990 mmol), 3 -(trifluoromethyl)pyrazole (76.74 mg, 0.560 mmol), N,N'-dimethylcyclohexane-1,2-diamine (6.68 mg, 0.050 mmol) and copper(I) iodide (4.5 mg , 0.020 mmol) were added sequentially. This mixture was suspended in dry 1,4-dioxane (2.492 mL) and the resulting suspension was degassed with bubbling N ₂ for 5 minutes and 3 cycles of vacuum/N ₂ . The reaction was stirred at 120°C overnight. The next day, the reaction mixture was cooled to RT and diluted with _H2O . The reaction was extracted three times with AcOEt. The combined organic fractions were dried over _Na2SO4 , filtered and concentrated under _vacuum . The residue was purified by FC on silica gel (elution from cHex to cHex/AcOEt 4:6), giving the formula 4-(6-azaspiro[2.5]octane-6-carbonyl)-3-[3-(trifluoromethyl) A product of pyrazol-1-yl]benzonitrile was obtained.
Yield: 146mg

1H NMR (400 MHz, DMSO-d6) δ 8.51 (dt, 1H), 8.33 (d, 1H), 8.02 (dd, 1H), 7.68 (d, 1H), 7.06 (d, 1H), 3.71 - 3.60 ( LC-MS: m/z 375.1 (MH+) .

Preparation: 6-Azaspiro[2.5]octan-6-yl-[4-(5-methyl-4H-1,2,4-triazol-3-yl)-2-[3-(trifluoromethyl)pyrazole -1-yl]phenyl]methanone

4-(6-Azaspiro[2.5]octane-6-carbonyl)-3-[3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (187.0 mg, 0.500 mmol), dicesium carbonate (488 .26 mg, 1.5 mmol), ethanimidoamide hydrochloride (70.84 mg, 0.750 mmol) and copper bromide (3.58 mg, 0.020 mmol) in DMSO (5 mL) at 120 °C. Stir for hours. After this time, the reaction was cooled to RT and _H2O was added. The mixture was then extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over _Na2SO4 , filtered and concentrated under vacuum _. The residue was purified by FC on a NH column (eluted from 100% DCM to DCM/MOH 9:1) and was purified with formula 6-azaspiro[2.5]octan-6-yl[4-(5-methyl-4H-1, A product of 2,4-triazol-3-yl)-2-[3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanone was obtained.
Yield: 38mg

1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.42 (m, 1H), 8.19 (d, 1H), 8.11 (dd, 1H),
7.55 (d, 1H), 7.03 (d, 1H), 3.69 (s, 1H), 3.43 (s, 1H), 3.18 (d, 2H), 2.42 (s, 3H), 1.48 - 1.00 (m, 4H) , 0.41 - 0.14 (m, 4H); LC-MS: m/z 431.5 (MH+).

Synthesis scheme 24

Preparation: N-[4-(4-methylsulfonyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

To a solution of N-[4-(2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (25.0 mg, 0.060 mmol) in DCM (0.500 mL) was added triethylamine. (0.02mL, 0.120mmo
l) followed by methanesulfonyl chloride (0.01 mL, 0.070 mmol). The reaction was stirred at room temperature overnight. The next day, the reaction was diluted with water and extracted with DCM (x2). The organic phase was dried using a phase separator and concentrated under reduced pressure. The crude product was purified by FC on silica gel (eluting from cHex/AcOEt 50:50 to cHex/AcOEt 20:80) to give the formula N-[4-(4-methylsulfonyl-2-phenylpiperazine-1-carbonyl)- A product of 3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained.
Yield: 21.1mg

1H NMR (500 MHz, DMSO-d6) δ ppm 10.24 - 10.04 (m, 1 H), 7.63 - 7.23 (m, 5 H),
7.22 - 6.81 (m, 3 H), 6.04 - 4.79 (m, 1 H), 4.33 - 3.87 (m, 1 H), 2.97 - 2.86 (m, 3 H), 4.67 - 2.73 (m, 5 H), 3.08 - 2.71 (m, 4 H), 1.83 - 1.74 (m, 1 H), 2.05 - 1.60 (m, 4 H), 0.86 - 0.74 (m, 4 H); LC-MS: m/z 497.25 (MH+ ).

Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-N,N-dimethyl-3-phenylpiperazine-1-carboxamide

The compound of Example 215 (N-[4-(4-methylsulfonyl-2-phenylpiperazine)-3-pyrrolidin-1-ylphenyl]cyclo The synthesis of the title compound was carried out analogously to the synthesis of propanecarboxamide). The title compound was obtained in a yield of 77% (0.018 g).

1H NMR (500 MHz, DMSO-d6) δ ppm 10.21 - 9.96 (m, 1 H), 7.55 - 6.61 (m, 8 H), 5.90 - 4.70 (m, 1 H), 4.59 - 2.70 (m, 10 H) ), 2.73 - 2.56 (m, 6 H), 2.05 - 1.47 (m, 5 H), 0.90 - 0.63 (m, 4 H); LC-MS: m/z 490.29 (MH+).

Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoyl]-N-methyl-3-phenylpiperazine-1-carboxamide

A solution of N-[4-(2-phenylpiperazine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide (20.0 mg, 0.050 mmol) in DMF (0.500 mL) was added with carbonyldi Imidazole (7.75 mg, 0.050 mmol) was added and stirred at room temperature for 2 hours. Next, N,N-diisopropylethylamine (0.050 mL, 0.288 mmol) and methanamine hydrochloride (19.45 mg, 0.288 mmol) were added and reacted at 50° C. overnight. The next day, the reaction was cooled to RT, diluted with _H2O , and extracted with EtOAc (x3). The organic phase was dried over _Na2SO4 , filtered, concentrated and subjected to semi-preparative HPLC: column CSH C18 ( _30x100mm , 3μm) (conditions: [A1: water + 0.1% HCOOH]; [B1: MeCN ]. Gradient: 33.0% B1 to 34.0% B1 in 10 minutes (flow: 40.00 mL/min). Detection: UV/Vis detection range 210 nm to 350 nm MS (ES+/ES-) scan range 100 to 1000 AMU) A crude product was obtained which was purified by
Yield: 6.5mg

1H NMR (400 MHz, DMSO-d6) δ ppm 10.20 - 10.02 (m, 1 H), 7.51 - 6.69 (m, 8 H),
6.55 - 6.40 (m, 1 H), 5.74 - 5.56 (m, 1 H), 4.89 - 4.13 (m, 2 H), 3.77 - 3.34 (m, 3 H), 3.26 - 2.81 (m, 5 H), 2.64 - 2.53 (m, 3 H), 1.98 - 1.61 (m, 5 H), 0.79 (br s, 4 H); LC-MS: m/z 476.27 (MH+).

Synthesis scheme 25

Preparation: N-[4-(4-methylsulfonylpiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

To a stirred solution of 4-(cyclopropanecarbonylamino)-2-pyrrolidin-1-ylbenzoic acid (50.0 mg, 0.180 mmol) in DMF (1.165 mL) was added N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) and HATU ([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylidene]dimethylammonium hexafluorophosphate (103.96 mg, 0.270 mmol)) and the reaction was stirred at room temperature for 15 min. Stir for a minute. Then, 4-methylsulfonylpiperidine hydrochloride (43.68 mg, 0.220 mmol) was added and the reaction mixture was stirred at room temperature overnight. A saturated solution of _NaHCO3 was added to the reaction mixture and the aqueous phase was extracted with EtOAc (x3). The organic portion was collected and washed with brine, residual water _was removed with _Na2SO4 , filtered and the solvent was evaporated under reduced pressure. The crude product was purified by FC on RP using basic conditions (eluting with _H2O from 95:5 to 70:30 + 0.1% NH3 _{/ CH3CN} ) to give formula N-[4 A product of -(4-methylsulfonylpiperidine-1-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide was obtained.
Yield: 14mg

1H NMR (400 MHz, DMSO-d6) δ 10.10 (d, J = 8.5 Hz, 1H), 7.13 - 7.04 (m, 1H), 7.00 - 6.86 (m, 2H), 4.64 (d, J = 12.1 Hz, 1H), 3.63 (s, 1H), 3.44 - 3.31 (m, 1H), 3.20 - 3.10 (m, 3H), 2.94 (d, J = 1.6 Hz, 5H), 2.75 (q, J = 14.2, 13.3 Hz , 1H), 2.12 (d, J = 12.9 Hz, 1H), 1.97 (d, J = 16.1 Hz, 1H), 1.90 - 1.82 (m, 4H), 1.76 (tt, J = 7.3, 5.1 Hz, 1H) , 1.61 - 1.41 (m, 2H), 0.82 - 0.73 (m, 4H); LC-MS: m/z 420.5 (MH+).

Preparation: N-[4-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was performed using the compound of Example 218 (N-[4-(4- The synthesis of methylsulfonylpiperidine-1-carbonyl-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide) was performed analogously. The title compound was obtained in a yield of 50% (0.035 g).

1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.03 (s, 1H), 6.89 (q, J = 8.5 Hz,
2H), 4.32 (td, J = 15.9, 14.9, 5.8 Hz, 4H), 3.73 - 3.66 (m, 1H), 3.29 - 2.95 (m, 7H), 1.94 - 1.57 (m, 9H), 0.77 (dd, J = 6.3, 3.9 Hz, 4H); LC-MS: m/z 384.3 (MH+).

Preparation: N-[4-(6-Azaspiro[2.5]octane-6-carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was carried out using 6-azaspiro[2.5]octane hydrochloride in place of 4-methylsulfonylpiperidine hydrochloride to synthesize the compound of Example 218 (N-[4-(4-methylsulfonylpiperidine-1 -carbonyl)-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide). The title compound was obtained in a yield of 51% (0.034 g).

1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 7.03 (s, 1H), 6.91 (s, 2H), 3.80 - 3.72 (m, 1H), 3.48 (t, J = 9.4 Hz, 1H), 3.28 (s, 1H), 3.25 - 3.17 (m, 3H), 3.08 (d, J = 6.1 Hz, 2H), 1.91 - 1.83 (m, 4H), 1.76 (qd, J = 7.4, 5.1 Hz , 1H), 1.51 - 1.10 (m, 4H), 0.78 (q, J = 6.8, 5.2 Hz, 4H), 0.38 - 0.30 (m, 4H); LC-MS: m/z 368.5 (MH+).

Synthesis scheme 26

Preparation: tert-butyl 3-pyrimidin-5-ylpiperazine-1-carboxylate

To a solution of SnAP Pip reagent (642.86 mg, 1.39 mmol) in dry DCM (7.05 mL) at room temperature was added 5-pyrimidinecarboxaldehyde (150.0 mg, 1.39 mmol) and MS 3A. The reaction was stirred at room temperature for 5 hours and filtered through a short layer of Celite (DCM rinse). The filtrate was concentrated under reduced pressure to obtain the imine. Separately, 2,6-lutidine (148.68 mg, 1.39 mmol) was suspended in dry HFIP (5.5 mL, 1.39 mmol) and anhydrous copper(II) trifluoromethanesulfonic acid (501.87 mg, 1.39 mmol). was added to the solution all at once and stirred at room temperature for 1 hour, during which time a homogeneous suspension was formed. A solution of the imine in dry DCM (22.5 mL) was added in one portion and the resulting mixture was stirred at room temperature overnight. After 18 hours, the reaction was quenched with 10% aqNH ₄ OH (4 mL) and stirred vigorously for 15 minutes. The layers were separated and the aqueous layer was extracted 3x with DCM. The combined organic layers were washed with 3x H ₂ O and 1x brine, dried using a phase separator, and concentrated. The crude product was purified by column chromatography (Sfar C18 12 g, eluent: H20 + NH4OH 0.1% 100% to H20 + NH4OH 0.1%/AcCN 80:20) to give the formula 3-pyrimidin-5-ylpiperazin-1-carboxylic acid tert. -Butyl product was obtained.
Yield: 0.090g

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.20 (s, 1 H), 9.92 (s, 2 H), 5.11 - 4.73 (m, 3 H), 4.23 - 3.68 - 4.23 (m, 5 H ), 2.50 (s, 9 H); LC-MS: m/z 265.12 (MH+).

Preparation: tert-butyl 3-(3-chloropyridin-4-yl)piperazine-1-carboxylate

The title compound was synthesized using 3-chloro-4-pyridinecarboxaldehyde in place of 5-pyrimidinecarboxaldehyde to synthesize the compound of Example 221 (tert-butyl 3-pyrimidin-5-ylpiperazine-1-carboxylate). The synthesis was carried out analogously to that of The title compound was obtained with a yield of 37% (0.116 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.60 (s, 1 H), 8.57 - 8.50 (m, 1 H), 7.70 - 7.61 (m, 1 H), 3.72 (br t, J=5.83 Hz, 4 H), 3.08 - 2.62 (m, 4 H), 1.53 - 1.36 (m,
9H); LC-MS: m/z 298.11 (MH+).

Preparation: tert-butyl 3-pyridin-3-ylpiperazine-1-carboxylate

The synthesis of the title compound was similar to that of the compound of Example 221 (tert-butyl 3-pyrimidin-5-ylpiperazine-1-carboxylate) using 3-pyridinecarboxaldehyde in place of 5-pyrimidinecarboxaldehyde. So I went. The title compound was obtained in a yield of 32% (0.118 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.65 - 8.58 (m, 1 H), 8.52 - 8.46 (m, 1 H), 7.84 - 7.78 (m, 1 H), 7.42 - 7.31 (m, 1 H), 3.93 - 3.76 (m, 2 H), 3.69 - 3.58 (m,
1 H), 3.28 (s, 1 H), 3.00 - 2.57 (m, 4 H), 1.41 (s, 9 H); LC-MS: m/z 264.36 (MH+).

Preparation: N-[4-[2-(5-chloropyridin-3-yl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidin-1-ylphenyl]cyclopropanecarboxamide

The synthesis of the title compound was similar to that of the compound of Example 221 (tert-butyl 3-pyrimidin-5-ylpiperazine-1-carboxylate) using 5-chloronicotinaldehyde in place of 5-pyrimidinecarboxaldehyde. So I went. The title compound was obtained in a yield of 45% (0.067 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.61 - 8.51 (m, 2 H), 7.97 - 7.91 (m, 1 H), 3.93 - 3.65 (m, 3 H), 3.05 - 2.58 (m, 5 H), 1.41 (s, 9 H); LC-MS: m/z 298.13 (MH+).

Hypertension To investigate whether deletion of the GPR39 gene changes blood pressure (BP), we
BP of knockout mice (Cyagen) and their wild type (WT) littermates was measured using radiotelemetry, allowing continuous monitoring of blood pressure over several weeks in conscious, unrestrained mice. Figure 1 shows the circadian variation (hourly) of MAP, and there was no difference between the two groups when fed a normal diet (0.4% Na) or a sodium-deficient diet (0.1% Na). do not have. However, when placed on a high-salt diet (4.0% NaCl added), GPR39KO mice (n=10) were protected from the high-salt diet-induced increase in blood pressure in WT mice (Combe R, Mudgett J, El Fertak L, Champy MF , Ayme-Dietrich E, Petit-Demouliere B, Sorg T, Herault Y, Madwed JB, Monassier L. How Does Circadian Rhythm Impact Salt Sensitivity of BP in Mice? A Study in Two Close C57Bl/6 Substrains. PLoS One. 2016Apr 18 ;11(4):e0153472) (BP of WT mice transiently increased when switching from a low-salt diet to a high-salt diet). The overall increase in BP in WT mice averaged 12.6 ± 6.0 mmHg (baseline ratio, n = 5) compared to 5.0 ± 1.3 mmHg (n = 10) in GPR39KO mice. (p=0.075). Resistance of GPR39KO mice to salt-induced hypertension provides a rationale for developing GPR39 inhibitors for the treatment of hypertension, particularly salt-sensitive hypertension, where the role of epoxyeicosatrienoic acids (EETs) is well known. It is.

The effect of acute intravenous administration of Example 34 on BP in spontaneously hypertensive rats (SHR) was determined. Figure 2 shows that at concentrations greater than 10 mg/kg, Example 34 significantly reduced BP (measured through the femoral artery catheter under isoflurane anesthesia) in SHR. At 10 mg/kg, BP decreased by 15%, and at 25 mg/kg, the reduction exceeded 20% of pre-dose baseline. Example 34 was administered slowly as a bolus injection via the jugular vein in a vehicle consisting of 100% PEG400, and the change in BP after administration (minimum value over 10 minutes) was normalized to the pre-administration baseline. This is the first demonstration that pharmacological inhibition of GPR39 acutely lowers BP in a well-established animal model of hypertension.

Heart attack (acute myocardial infarction)
We investigated the role of pericytes in tissue necrosis after coronary artery occlusion (Fig. 3A). Wild-type NG2-dsRed mice that were reperfused for 2 hours after left coronary artery occlusion for 45 minutes had a markedly reduced number of healthy perfused capillaries, as shown by endothelial CD31 immunolabeling, whereas global GPR39 Capillary perfusion was significantly promoted in knockout mice (Fig. 3B). The infarct size/area at risk (AAR) ratio was also significantly smaller in global GPR39 knockout mice (Figure 3C) and those treated with Example 34 (Figure 3D).

No-reflow This phenomenon represents a lack of microvascular perfusion despite the arteries being open during a heart attack, and is associated with poor prognosis.

Because infarct size and postmortem no-reflow cannot be measured in the same animal, we investigated the role of pericytes in no-reflow after reperfusion in a separate group of animals. After reperfusion, Thioflavin S, a perfusion marker, was injected into the left coronary artery. The left coronary artery was then briefly reoccluded and 0.2 ml of Evans blue (1%) was injected. The heart was then removed, cut into 5-6 pieces transversely, photographed under UV light (under which Thioflavin S fluoresces blue) to identify the no-reflow area, and AAR measured under standard illumination. The no-reflow area was expressed as a percentage of AAR. When Example 34 (1.5 mg/kg i.v.) was administered to global GPR39 knockout mice and wild type mice, the no-reflow range was negligible compared to the control (Figures 4A-D ).

Claims (21)

A compound of formula (I) or a pharma- ceutically acceptable salt thereof:

(Wherein,
_X1 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 of n _a +n _b is 2 or more and 4 or less;
or _X1 and _Z1 together form a fused ring system of formula (Ia):

R _a is selected from the group of hydrogen and C ₁ -C ₃ alkyl;
_X2 is selected from the following group:


Wavy lines in each example
represents the bond where each _X1 and _X2 moiety is attached;
Y ₁ is selected from the group C(H) and N;
_Y2 is selected from the group C(H), N, S and O, with the proviso that when _Y2 is O, _R4 is absent, and when _Y2 is S, _R4 is absent or present once or twice;
With the proviso that only one of _Y1 and _Y2 is C;
Z ₁ , Z ₂ and Z ₃ are each independently selected from the group C(H) and N, with the proviso that only two of Z ₁ , Z ₂ and Z ₃ may be N, and further, when combined with R ₂ , Z ₁ , Z ₂ and Z ₃ are C;
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, where the rings of the C ₁ -C ₆ alkyl and -(CH ₂ ) _n1 -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 -O-C ₁ -C ₃ alkyl, and R ^x and R ^y are each independently selected from the group of H and C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 substituents selected from the group of halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl;
n1 is an integer selected from the group of 0, 1, 2 and 3;
R ₂ is selected from the group of pyridinyl bonded through a carbon atom and monocyclic heterocycles or bicyclic or spirocyclic heterocyclic ring systems bonded through a nitrogen heteroatom and containing 3, 4, 5, 6, 7 or 8 ring carbon atoms and 0, 1, 2, 3 or 4 additional ring heteroatoms selected from the group of N and O, said monocyclic ring or bicyclic or spirocyclic ring system of R ₂ being substituted with 0, 1, 2 or 3 substituents selected from the group of C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -(CH ₂ ) _n1 -C ₃ -C ₆ cycloalkyl, -CF ₃ , halogen and phenyl;
_R3 occurs one or more times and is independently selected from the following group:
a) hydrogen;
b) _-CO2H or _-CO2- ( _C1 - _C6 alkyl);
c) C 1 -C ₆ alkyl substituted with 0 _, 1, 2, 3, 4 or 5 substituents selected from the group halogen, CF ₃ and OH;
d) phenyl, benzyl, C ₃ -C ₆ cycloalkyl and -CH ₂ -C ₃ -C ₆ cycloalkyl, each ring of the phenyl, benzyl, C ₃ -C ₆ cycloalkyl and -CH ₂ -C ₃ -C ₆ cycloalkyl groups is substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl groups being further substituted with 0, 1, 2, _{3 ,} 4 or 5 substituents selected from the group of halogen, _{-CF 3 and OH ;}
e) a 5- or 6-membered heterocycle containing 1, 2 or 3 ring heteroatoms independently selected from O, S and N, said 5- or 6-membered heterocycle being substituted with 0, 1, 2 or 3 substituents selected from OH, halogen, benzyl and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl group being further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen and OH;
R ₄ occurs 1 or 2 times and is independently selected from the group of H, 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)-O-C ₁ -C ₆ alkyl, -S(═O) ₂ -C ₁ -C ₆ alkyl, -C(═O)-NR ^x R ^y , phenyl, benzyl or a heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms of which 1, 2, 3 or 4 ring atoms are selected from the group of N, O and S, R ^x and R ^y are each independently H and C ₁ -C 6 substituted with 0, 1, 2 or 3 substituents selected from halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl. ₆ alkyl;
When Y ₂ is carbon, R ₄ may be -O-C ₁ -C ₆ alkyl, or two R ₄ may form a carbocyclic or heterocyclic ring;
The _rings of the C ₁ -C ₆ alkyl, -C(═O)-O-C ₁ -C ₆ alkyl and -O-C ₁ -C ₆ alkyl groups, -(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl and -O-(CH ₂ ) _n2 -C ₃ -C ₆ cycloalkyl, phenyl and benzyl groups of R 4 are each independently halogen, CF ₃ , OH, a heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are substituted with 0, 1, 2 or 3 substituents selected from the group of heterocycles selected from the group of N, O and S, substituted or unsubstituted phenyl, and -O-C ₁ -C ₃ alkyl, with the proviso that when Y ₁ is nitrogen and Y ₂ is carbon, R ₄ is not unsubstituted benzyl, and when Y ₁ is nitrogen and Y ₂ is nitrogen, R ₄ is not unsubstituted pyridinyl or substituted or unsubstituted phenyl;
R ₅ is selected from the group of H and C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl group of R ₅ is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF ₃ , -NR ^x R ^y and OH, R ^x and R ^y are each independently selected from the group of H and C ₁ -C ₆ alkyl substituted with 0, 1, 2 or 3 substituents selected from the group of halogen, OH, CF ₃ and -O-C ₁ -C ₃ alkyl;
R ₆ is H, C ₁ -C ₆ alkyl, a heterocycle having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are selected from the group of N, O and S, a heterocycle, phenyl and benzyl, the C ₁ -C ₆ alkyl group of R ₆ is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of halogen, -CF ₃ , -NR ^x R ^y and OH, the ring of the phenyl group and the benzyl group of R ₆ and the ring of the heterocycle are substituted with 0, 1, 2, 3, 4 or 5 substituents selected from the group of C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, halogen, -CF ₃ and OH, R ^x and R ^y are each independently H and halogen, OH, CF ₃ and -O-C ₁ -C C _{1 -C 6} alkyl substituted with 0, 1, 2 or 3 substituents selected from C ₁ -C ₆ alkyl;
In each instance, _n2 is an integer selected from the group of 0, 1, 2, and 3;
provided that _R2 is an unsubstituted azepanyl ring ortho to _X2 and _X1 is the moiety
R _a is H, R ₁ is unsubstituted cyclopropyl, and X ₂ is

and Y ₁ is N, and if either a) Y ₂ is O, b) Y 2 is N and R 4 is H or alkyl, c) Y ₂ is C and R 4 is H, alkyl or -C(=O)-C ₁ -C ₆ alkyl, then R ₃ is not H). The formula below:

(wherein X ₁ , Z ₁ , Z ₂ , Z ₃ , Y ₁ , Y ₂ , R ₂ , R ₃ and R ₄ are as defined in claim 1)
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The formula below:
(wherein X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ and R ₃ are as defined in claim 1)
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The formula below:

(wherein X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ and R ₃ are as defined in claim 1)
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof. The formula:
(wherein X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ and R ₄ are as defined in claim 1 ).
2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof. The formula:
(wherein X ₁ , Z ₁ , Z ₂ , Z ₃ , R ₂ , R ₄ , R ₅ and R ₆ are as defined in claim 1 ).
2. The compound of claim 1 having the formula: or a pharma- ceutically acceptable salt thereof. Z ₁ , Z ₂ and Z ₃ are each C ;
Z ₁ , Z ₂ and Z ₃ are each N ;
Z ₁ and Z ₂ are each C ,
Z ₁ and Z ₃ are each C and Z ₂ is N ,
Z ₁ and Z ₃ are each N and Z ₂ is C ,
Z ₁ and Z ₂ are each N and Z ₃ is C, or
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 , wherein Z ₂ and Z ₃ are each N and Z ₁ is C. R ₂ is the following group:

(wherein R ₅ and R ₆ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl and -CF ₃ )
A compound according to any one of claims 1 to 7 , or a pharmaceutically acceptable salt thereof, selected from: R ₂ is the following group:

selected from
where R ₇ and R ₈ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl, -CF ₃ , and phenyl, with the proviso that R ₇ and R ₈ may be phenyl , or a pharmaceutically acceptable salt thereof. R ₂ is the following group:

(wherein R ₅ and R ₆ are each independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl, -O-C ₁ -C ₆ alkyl and -CF ₃ )
A compound according to any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, selected from: R ₃ is present from 1 to 3 times, 2 times, or only once; optionally, R ₃ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, -CF ₃ , selected from the group -C ₁ -C ₄ alkyl-OH, phenyl, benzyl, pyrazolyl and thiophenyl, wherein said phenyl, pyrazolyl and thiophenyl rings are halogen, OH, CF3, C ₁ -C ₄ alkyl and C substituted with 0, 1, 2 or 3 substituents selected from the group of ₁ -C ₄ alkoxy; or R ₃ is halogen, OH, CF3, C ₁ -C ₄ alkyl and C ₁ - Any one of claims 1 to 10 , which is selected from the group of phenyl, benzyl, pyrazolyl and thiophenyl substituted with 0, 1, 2 or 3 substituents selected from the group of C ₄ alkoxy. or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a pharma- ceutical effective amount of a compound selected from any one of claims 1 to 11 , a compound selected from any one of Examples 1 to 220, a compound of formula (I'), or a pharma- ceutically acceptable salt of any of the foregoing, and a pharma- ceutically acceptable carrier or excipient. Use of a compound selected from any of claims 1 to 11 , a compound selected from Examples 1 to 220, a compound of formula (I') or a pharma- ceutically acceptable salt of any of the foregoing in the preparation of a medicament. A compound selected from any of claims 1 to 11 , a compound selected from Examples 1 to 220, a compound of formula (I') or a pharma- ceutically acceptable salt of any of the foregoing for use as a medicament. A compound selected from any of claims 1 to 11 , a compound selected from Examples 1 to 220, a compound of formula (I') for use as a drug for inhibiting the activity of GPR39 protein in a subject. or a pharmaceutically acceptable salt of any of the foregoing. A compound selected from any of claims 1-11 , a compound selected from Examples 1-220, a compound of formula (I ) for use as a medicament for treating hypertension in a subject in need of treatment. ') or a pharmaceutically acceptable salt of any of the foregoing. A compound selected from any of claims 1 to 11 , a compound selected from Examples 1 to 220, a compound of formula (I') or any of the foregoing for use as a medicament for treating heart failure in a subject . Any pharmaceutically acceptable salt. A compound selected from any of claims 1-11, a compound selected from examples 1-220, a compound of formula (I') or a pharma- ceutically acceptable salt of any of the foregoing, for use as a medicament for treating breast cancer in a subject in need of treatment, gastric adenocarcinoma in a subject in need of treatment, ulcerative bowel disease in a subject in need of treatment, inflammatory bowel disease in a subject in need of treatment, diarrhea in a subject in need of treatment, or stroke in a subject in need of treatment. A compound selected from any of claims 1-11, a compound selected from examples 1-220, a compound of formula (I') or a pharma- ceutically acceptable salt of any of the foregoing, for use as an agent for promoting or enhancing colonic epithelial function and tight junction barrier integrity in a subject in need thereof, or for enhancing delivery of an anesthetic agent to a subject experiencing a microvascular complication. a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound selected from any of claims 1-11 , a compound selected from Examples 1-220, formula one or more compositions comprising a compound of (I') or a pharmaceutically acceptable salt of any of the foregoing and a pharmaceutically acceptable carrier or excipient;
b) instructions for administering said one or more compositions to a subject in need thereof. A compound according to any one of Examples 1-34, 37-42, 44, 47, 48, 50, 51 and 53-220, or a pharmaceutically acceptable salt thereof.

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