Antagonists of the gpr39 protein

Abstract

Disclosed are novel compounds that are antagonists of the human GPR39 protein. Disclosed are pharmaceutical compositions of antagonists of the human GPR39 protein and methods of use. In particular, disclosed herein are methods of using the antagonists to treat diseases or conditions, including cardiovascular conditions, endocrine system and hormone disorders, cancer disorders, metabolic diseases, gastrointestinal and liver diseases, blood disorders, neurological disorders, and respiratory diseases.

Description

[0001] Related applications

[0002] 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. Technical Field

[0003] This disclosure relates to novel compounds as antagonists of the human GPR39 protein. Furthermore, this disclosure relates to pharmaceutical compositions of human GPR39 protein antagonists and methods of treating diseases or conditions using human GPR39 protein antagonists, said diseases or conditions including cardiovascular conditions, endocrine and hormonal disorders, cancerous conditions, metabolic diseases, gastrointestinal and liver diseases, hematological disorders, neurological disorders, and respiratory diseases. Background Technology

[0004] The use of GPR39 antagonists in the treatment of pain sensitivity, including hyperalgesia, and in methods of suppressing appetite has been described (US Patent Publication No. 2009 / 0298756 - Jin et al.).

[0005] The use of GPR39 agonists and / or antagonists in enhancing glucose regulation and treating impaired glucose metabolism, including in conditions such as diabetes and metabolic syndrome, is discussed in WO 2007 / 141322 - Moreaux et al. - Janssen Pharmaceutica NV.

[0006] The article "Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor-Knockout Mouse" (Gastroenterology, Moechars et al., October 2006, Vol. 131, No. 4, pp. 1131-1141) concludes that GPR39 receptor antagonists can be used for conditions affecting gastric motility, including functional dyspepsia and diabetic gastroparesis, and / or conditions affecting colorectal motility, such as irritable bowel syndrome, diarrhea, or chronic constipation.

[0007] The role of the obestatin / GPR39 system in human gastric adenocarcinomas, Alén et al., Oncotarget 2016, 7:5957-5971, proposed the role of the obestatin / GPR39 system in regulating the motility, EMT and invasion of gastric adenocarcinoma cells.

[0008] GPR39 antagonists are also discussed in the article "Enhanced ZnR / GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth" by Ventura-Bixenshpaner et al., Scientific Reports (2018) 8:8119, particularly their use in the treatment of breast cancer, including ER-negative breast cancer.

[0009] The use of GPR39 antagonists in the treatment of various cancers is discussed in US2004 / 0071708 (Claassen et al.).

[0010] In her article GI functions of GPR39: novel biology, Current Opinion in Pharmacology, 2012, 12: 647-652, Inge Depoortere disclosed the use of GPR39 antagonists in the treatment of motility disorders, such as functional dyspepsia, hemiparesis, and chronic constipation.

[0011] The article "The zinc sensing receptor, ZnR / GPR39, controls proliferation and differentiation of colonocytes and thereby tight junction formation in the colon" (Cohen et al., Cell Death and Disease (2014) 5, e1307) discusses the potential use of GPR antagonists in promoting or enhancing colonic epithelial function and the integrity of the tight junction barrier, including in the treatment of ulcerative colitis and diarrheal diseases. Summary of the Invention

[0012] Provide a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0013]

[0014] in:

[0015] X1 is selected from:

[0016]

[0017] n a It is an integer selected from 0, 1, and 2;

[0018] n b It is an integer selected from 0, 1, 2, 3, and 4;

[0019] The condition is n a +n b The sum of the numbers is not less than 2 and not greater than 4;

[0020] Alternatively, X1 and Z1 together form a fused ring system of type (Ia):

[0021]

[0022] R a Selected from hydrogen and C1-C3 alkyl groups;

[0023] X2 is selected from:

[0024]

[0025] In each case, the wavy line The key represents the bond through which each X1 and X2 portion is joined;

[0026] Y1 is selected from C and N;

[0027] Y2 is selected from C, N, S and O, with the condition that when Y2 is O, R4 does not exist, and with the condition that when Y2 is S, R4 either does not exist or exists once or twice.

[0028] The condition is that at most one of Y1 and Y2 is C;

[0029] Z1, Z2, and Z3 are each independently selected from C and N, provided that no more than two of Z1, Z2, and Z3 can be N, and further provided that Z1, Z2, and Z3 are C when combined with R2;

[0030] R1 is selected from C1-C6 alkyl groups, -(CH2) n1 -C3-C6 cycloalkyl, -NR x R y phenyl and benzyl, wherein the C1-C6 alkyl group and the -(CH2) group are present. n1 The -C3-C6 cycloalkyl, phenyl, and benzyl rings are substituted with 0, 1, 2, or 3 substituents selected from halogens, OH, CF3, and -O-C1-C3 alkyl groups, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0031] n1 is an integer selected from 0, 1, 2, and 3;

[0032] R2 is selected from phenyl and monocyclic, bicyclic, or spirocyclic heterocyclic systems, wherein the heterocyclic system is bonded by a nitrogen heteroatom and contains 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from N and O, wherein the monocyclic, bicyclic, or spirocyclic system of R2 is connected by 0, 1, 2, or 3 alkyl groups selected from C1-C6 alkyl, -O-C1-C6 alkyl, or -(CH2). n1 -C3-C6 cycloalkyl, -CF3, halogen and phenyl substituents;

[0033] R3 exists once or more, and is independently selected from:

[0034] a) Hydrogen;

[0035] b) -CO2H or -CO2- (C1-C6 alkyl);

[0036] c) C1-C6 alkyl groups, which are substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogens, CF3 and OH;

[0037] d) Phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl, wherein the ring of each of the phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogen, -CF3 and OH;

[0038] e) A 5- or 6-membered heterocycle containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heterocycle is substituted with 0, 1, 2, or 3 substituents selected from OH, halogens, benzyl, and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4, or 5 substituents selected from halogens and OH;

[0039] R4 may be present once or twice, and is independently selected from H, oxo, C1-C6 alkyl, and -(CH2). n2 -C3-C6 cycloalkyl groups, -O-(CH2) n2 -C3-C6 cycloalkyl, -C(=O)-O-C1-C6 alkyl, -S(=O)2-C1-C6 alkyl, -C(=O)-NR x R y phenyl, benzyl, or a heterocycle having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0040] Furthermore, when Y2 is carbon, R4 can also be an -O-C1-C6 alkyl group, or two R4 groups can form a carbide ring or a heterocycle;

[0041] The R4 C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, and -O-C1-C6 alkyl, as well as the -(CH2) n2 -C3-C6 cycloalkyl groups and -O-(CH2) n2The rings of the -C3-C6 cycloalkyl, phenyl, and benzyl groups are each independently substituted by 0, 1, 2, or 3 substituents selected from the following: halogen, CF3, OH, heterocycles having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, substituted or unsubstituted phenyl, and -O-C1-C3 alkyl, provided that R4 is not an unsubstituted benzyl when Y1 is nitrogen and Y2 is carbon, and provided that R4 is not an unsubstituted pyridyl or a substituted or unsubstituted phenyl when Y1 is nitrogen and Y2 is nitrogen;

[0042] R5 is selected from H and C1-C6 alkyl groups, wherein the R5 C1-C6 alkyl group is further substituted with 0, 1, 2, 3, 4 or 5 derivatives selected from halogen, -CF3, -NR. x R y Substitution with OH and substituents, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0043] R6 is selected from H, C1-C6 alkyl, heterocycles having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, phenyl, and benzyl, wherein the R6 C1-C6 alkyl group is further characterized by 0, 1, 2, 3, 4, or 5 ring atoms selected from halogens, -CF3, -NR x R y The R6 phenyl and benzyl groups, as well as the heterocycle ring, are substituted with 0, 1, 2, 3, 4, or 5 substituents selected from C1-C6 alkyl, -O-C1-C6 alkyl, halogen, -CF3, and OH, wherein R... x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups; and

[0044] In each case, n2 is an integer selected from 0, 1, 2, and 3;

[0045] The condition is that when R2 is an unsubstituted heptyl ring adjacent to X2, X1 is Partial, R a It is H, R1 is an unsubstituted cyclopropyl group, and X2 is... If Y1 is N, and a) Y2 is O, b) Y2 is N and R4 is H or alkyl, or c) Y2 is C and R4 is H, alkyl, or -C(=O)-O-C1-C6 alkyl, then R3 is not H. Brief description of the attached diagram

[0047] Figure 1 Blood pressure (BP) records were depicted in wild-type (WT) (n=5; circles) and GPR39 KO (n=10; squares) mice under normal salt (0.4%), low salt (0.1%), and high salt (4.0%) diets. BP was recorded continuously using an implanted pressure-sensing telemetry technique. For each experimental condition, data were collected every 5 minutes for 10 seconds each time, for at least 96 hours. BP was reported as 24-hour, daytime, and nighttime mean arterial pressure (MAP).

[0048] Figure 2 The data presented demonstrate the dose-dependent effect of the GPR39 antagonist Example 34 on blood pressure in spontaneously hypertensive rats (SHR). The decrease in BP is expressed as a percentage of baseline BP (*p<0.05).

[0049] Figure 3A The timeline of the experimental design is depicted. Example 34 was administered as a single dose 15 minutes after left coronary artery occlusion, during a 45-minute occlusion period, followed by perfusion for 2 hours.

[0050] Figure 3B The coronary capillary beds in the intermediate-risk area (AAR) and normal perfusion area of ​​WT and GPR39 KO mice were depicted. Endothelial cells were immunolabeled for CD31, and pericytes were immunolabeled for NG2. Within the AAR, capillary constriction was less pronounced in KO animals.

[0051] Figure 3C Infarct size (TTC staining) of WT (n=6) and GPR39 KO (n=6) was depicted, and the infarct size of the latter was significantly reduced.

[0052] Figure 3D Data from WT animals (n=6) treated in Example 34 were depicted, showing a significant reduction in infarct size compared to animals treated with the medium (n=5). Figure 3C and Figure 3D Infarct size is expressed as a percentage of AAR defined by Evans Blue. Summary data are plotted to the right of actual images from individual representative animals.

[0053] Figures 4A to 4D No-reflow data were depicted in WT, GPR39 KO, and Example 34 mice. Thioflavin-S and Evans blue were injected pre-mortemly, and no-reflow measurements were performed (areas without Evans blue in the upper right figure). Figure 4A Examples of WT animals were depicted, showing extensive no-reflow, while examples of GPR39 KO mice showed almost no no-reflow.

[0054] Figure 4B The summary data depicted showed that the no-reflow / AAR ratio was significantly reduced in GPR39 mice (n=4) compared with WT (N=4).

[0055] Figure 4C Examples of mediator-treated WT animals are depicted, showing extensive no-reflow, while mice treated in Example 34 show almost no no-reflow.

[0056] Figure 4D The summarized data showed that the no-reflow / AAR ratio was significantly reduced in mice treated with Example 34 (n=4) compared to mice treated with the medium (n=5). Example 34 was administered 15 minutes after coronary artery occlusion, which lasted for a total of 45 minutes, followed by reperfusion for 2 hours. Detailed Implementation

[0057] Within the scope of compound (I) or a pharmaceutically acceptable salt thereof, there are two other embodiments, which respectively comprise compound (IA) or a pharmaceutically acceptable salt thereof and compound (IB) or a pharmaceutically acceptable salt thereof:

[0058]

[0059] In each case, when present, X1, X2, R2, Z1, Z2, Z3, and all other variables and conditions are as defined above for equation (I).

[0060] It should also be understood that, within the scope of formula (I) and based on the definitions of X1 and X2 above, there are individual and independent embodiments that respectively comprise compounds of formulas (I-1), (I-2), (I-3), (I-4), and (I-5) or their pharmaceutically acceptable salts:

[0061]

[0062] In each case where they exist, all variables, including X1 and R, are considered. a , R1, R2, R3, R4, Y1, Y2, Z1, Z2, Z3, n a n b n1, n2 and the conditions are as defined above for equation (I).

[0063] It should also be understood that, within the scope of formula (I) and based on the definitions of X1 and X2 above, there are individual and independent embodiments that respectively comprise compounds of formulas (Ia) to (I-hh) below or their pharmaceutically acceptable salts:

[0064]

[0065]

[0066]

[0067]

[0068] In each case where they exist, all variables, including R a , R1, R2, R3, R4, R5, R6, Y1, Y2, Z1, Z2, Z3, n a n b n1, n2 and the conditions are as defined above for equation (I).

[0069] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1, Z2, and Z3 are each C, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0070] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1, Z2, and Z3 are each N, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0071] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1 and Z2 are each C, Z3 is N, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0072] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1 and Z3 are each C, Z2 is N, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0073] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1 and Z3 are each N, Z2 is C, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0074] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z1 and Z2 are each N, Z3 is C, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0075] Other individual embodiments provide compounds of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) above, or pharmaceutically acceptable salts thereof, wherein in each embodiment, Z2 and Z3 are each N, Z1 is C, and R a , R1, R2, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I) to (I-hh).

[0076] In each of the embodiments described herein, there exists another embodiment, wherein R2 is selected from:

[0077]

[0078] R7 and R8 are independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -CF3, and phenyl in each case, provided that only one of R7 and R8 can be phenyl. It should be understood that in the embodiments herein, when the R2 group is bicyclic or spirocyclic, R7 and R8 can be bonded to any available cyclic carbon or nitrogen atom in either ring, and R7 and R8 can be bonded to cyclic atoms in the same or different rings.

[0079] In each of the embodiments described herein, there exists another embodiment, wherein R2 is selected from:

[0080]

[0081]

[0082] R7 and R8 are independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -CF3 and phenyl in each case, provided that only one of R7 and R8 can be phenyl.

[0083] Individual embodiments are also provided, each comprising a compound of formula (I), formulas (I-1) through (I-5), and formulas (Ia) through (I-hh), or a pharmaceutically acceptable salt thereof, wherein the individual embodiments comprise a compound of each formula, wherein R2 is defined as each of the groups a) through r) above. For example, a compound of formula (1) or a pharmaceutically acceptable salt thereof is provided, wherein R2 is an aziridine ring of group a) substituted with variable groups R7 and R8. Another embodiment comprises a compound of formula (I), wherein R2 is an aziridine ring of group b) substituted with variable groups R7 and R8. This pattern continues to define the remaining embodiments, each having an R2 group separately referenced from the list above.

[0084] In each embodiment of the compound or its pharmaceutically acceptable salt of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) described above, there are further embodiments in which each variable, including Z1, Z2, Z3, R a , R1, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I), (I-1) to (I-5) and (Ia) to (I-hh), and R2 is selected from:

[0085]

[0086] R7 and R8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, halogen and -CF3.

[0087] In each embodiment of the compound or its pharmaceutically acceptable salt of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) described above, there are further embodiments in which each variable, including Z1, Z2, Z3, R a , R1, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I), (I-1) to (I-5) and (Ia) to (I-hh), and R2 is selected from:

[0088]

[0089] R7 and R8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

[0090] In each embodiment of the compound or its pharmaceutically acceptable salt of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) described above, there are further embodiments in which each variable, including Z1, Z2, Z3, R a , R1, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I), (I-1) to (I-5) and (Ia) to (I-hh), and R2 is selected from:

[0091]

[0092] R7 and R8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

[0093] In each embodiment of the compound or its pharmaceutically acceptable salt of each of formulas (I), (I-1) to (I-5), and (Ia) to (I-hh) described above, there are further embodiments in which each variable, including Z1, Z2, Z3, R a , R1, R3, R4, R5, R6, Y1, Y2, n a n b n1, n2 and the conditions are as defined above for the corresponding equations (I), (I-1) to (I-5) and (Ia) to (I-hh), and R2 is selected from:

[0094]

[0095] R7 and R8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

[0096] In some embodiments herein, R7 and R8 are selected from hydrogen, halogen, -CF3, C1-C4 alkyl, and C1-C4 alkoxy. In other embodiments, R7 and R8 are selected from hydrogen, halogen, -CF3, C1-C3 alkyl, and C1-C3 alkoxy. In other embodiments, hydrogen, F, Cl, -CF3, C1-C3 alkyl, and C1-C3 alkoxy.

[0097] In each embodiment of the compounds and salts comprising the R3 moiety herein, there are additional embodiments of the same range, except that R3 is present one to three times. In each embodiment of the compounds and salts comprising the R3 moiety herein, there are additional embodiments of the same range, except that R3 is present one to two times. In each embodiment of the compounds and salts comprising the R3 moiety herein, there are additional embodiments of the same range, except that R3 is present only once. In each embodiment of the compounds and salts comprising the R3 moiety herein, there are additional embodiments of the same range, except that R3 is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, -CF3, -C1-C4 alkyl-OH, phenyl, pyrazolyl, and thiophenyl, wherein the phenyl, pyrazolyl, and thiophenyl rings are substituted with 0, 1, 2, or 3 substituents selected from halogen, OH, -CF3, C1-C4 alkyl, and C1-C4 alkoxy.

[0098] In each embodiment of the compounds and salts comprising the R3 moiety herein, there are other embodiments of the same range, except that R3 is selected from phenyl, pyrazolyl, and thiophene, and is substituted with 0, 1, 2, or 3 substituents selected from halogen, OH, -CF3, C1-C4 alkyl, and C1-C4 alkoxy.

[0099] For each compound of formula (I) and all other formulas, as well as compounds specifically named herein, pharmaceutically acceptable salts, pharmaceutically acceptable cocrystals, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, hydrates, isomers (including optical isomers, racemates, or other mixtures thereof), tautomers, isotopes, polymorphs, and pharmaceutically acceptable prodrugs are also included.

[0100] The compounds disclosed herein may have asymmetric centers and may be produced as racemic mixtures or as individual enantiomers. Individual enantiomers may be obtained by asymmetric synthesis or by resolving racemic or non-racemic mixtures of intermediates at a suitable stage of synthesis. Individual enantiomers may also be obtained by resolving the compounds using conventional methods, such as crystallization in the presence of a resolving agent or chromatographic analysis using, for example, a chiral high-performance liquid chromatography (HPLC) column. Individual enantiomers, as well as racemic and non-racemic mixtures of enantiomers, are all within the scope of this disclosure, and all are intended to be included in the structures depicted in this specification unless otherwise specifically stated.

[0101] How to use

[0102] Hypertension is the most common chronic disease, affecting 1.13 billion people worldwide and causing 10 million deaths annually. Despite the existence of antihypertensive drugs that have successfully lowered blood pressure (BP) in millions of patients, some significant needs remain unmet. Only half of people with hypertension have their blood pressure controlled, and in a large proportion, current antihypertensive drugs do not restore normal blood pressure. Treatment-resistant hypertension (TRH), also known as refractory hypertension, is on the rise due to the increasing prevalence of diabetes and obesity (which account for up to 75% of hypertension risk and the majority of TRH cases). Identifying new targets and developing new strategies to prevent and treat hypertension and its complications remains a high priority in public health and healthcare.

[0103] A method for inhibiting the activity of GPR39 protein in a subject is provided, the method comprising administering to a subject in need an effective amount of a compound of formula (I') or a pharmaceutically acceptable salt thereof.

[0104] Formula I':

[0105]

[0106] in:

[0107] X1 is selected from:

[0108]

[0109] n a It is an integer selected from 0, 1, and 2;

[0110] n b It is an integer selected from 0, 1, 2, 3, and 4;

[0111] The condition is n a +n b The sum of the numbers is not less than 2 and not greater than 4;

[0112] Alternatively, X1 and Z1 together form a fused ring system of type (Ia):

[0113]

[0114] R a Selected from hydrogen and C1-C3 alkyl groups;

[0115] X2 is selected from:

[0116]

[0117] In each case, the wavy line The key represents the bond through which each X1 and X2 portion is joined;

[0118] Y1 is selected from C and N;

[0119] Y2 is selected from C, N, S and O, with the condition that when Y2 is O, R4 does not exist, and with the condition that when Y2 is S, R4 either does not exist or exists once or twice.

[0120] The condition is that at most one of Y1 and Y2 is C;

[0121] Z1, Z2, and Z3 are each independently selected from C and N, provided that no more than two of Z1, Z2, and Z3 can be N, and further provided that Z1, Z2, and Z3 are C when combined with R2;

[0122] R1 is selected from one of the following: C1-C6 alkyl, -(CH2) n1 -C3-C6 cycloalkyl, -NR x R y phenyl and benzyl, wherein the C1-C6 alkyl group and the -(CH2) group are present. n1 The -C3-C6 cycloalkyl, phenyl, and benzyl rings are substituted by 0, 1, 2, or 3 independent substituents selected from halogens, OH, CF3, and -O-C1-C3 alkyl groups, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0123] n1 is an integer selected from 0, 1, 2, and 3;

[0124] R2 is selected from phenyl and monocyclic, bicyclic, or spirocyclic heterocyclic systems, wherein the heterocyclic system is bonded by a nitrogen heteroatom and contains 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from N and O, wherein the monocyclic, bicyclic, or spirocyclic system of R2 is connected by 0, 1, 2, or 3 alkyl groups selected from C1-C6 alkyl, -O-C1-C6 alkyl, or -(CH2).n1 -C3-C6 cycloalkyl, -CF3, halogen and phenyl substituents;

[0125] R3 exists once or more, and is selected from:

[0126] a) Hydrogen;

[0127] b) -CO2H or -CO2- (C1-C6 alkyl);

[0128] c) C1-C6 alkyl groups, which are substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogens, CF3 and OH;

[0129] d) Phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl, wherein the ring of each of the phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogen, -CF3 and OH;

[0130] e) A 5- or 6-membered heterocycle containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heterocycle is substituted with 0, 1, 2, or 3 substituents selected from OH, halogens, benzyl, and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4, or 5 substituents selected from halogens and OH;

[0131] R4 may be present once or twice, and is independently selected from H, oxo, C1-C6 alkyl, and -(CH2). n2 -C3-C6 cycloalkyl groups, -O-(CH2) n2 -C3-C6 cycloalkyl, -C(=O)-O-C1-C6 alkyl, -S(=O)2-C1-C6 alkyl, -C(=O)-NR x R y phenyl, benzyl, or a heterocycle having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0132] Furthermore, when Y2 is carbon, R4 can also be an -O-C1-C6 alkyl group, or two R4 groups can form a carbide ring or a heterocycle;

[0133] The R4 C1-C6 alkyl, -C(=O)-O-C1-C6 alkyl, and -O-C1-C6 alkyl, as well as the -(CH2) n2 -C3-C6 cycloalkyl groups and -O-(CH2) n2 The -C3-C6 cycloalkyl, phenyl, and benzyl rings are each independently substituted by 0, 1, 2, or 3 substituents selected from the following: halogens, CF3, OH, heterocycles having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, substituted or unsubstituted phenyl and -O-C1-C3 alkyl groups.

[0134] R5 is selected from H and C1-C6 alkyl groups, wherein the R5 C1-C6 alkyl group is further substituted with 0, 1, 2, 3, 4 or 5 derivatives selected from halogen, -CF3, -NR. x R y Substitution with OH and substituents, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups, which are substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups;

[0135] R6 is selected from H, C1-C6 alkyl, heterocycles having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, and S, phenyl, and benzyl, wherein the R6 C1-C6 alkyl group is further characterized by 0, 1, 2, 3, 4, or 5 ring atoms selected from halogens, -CF3, -NR x R y The R6 phenyl and benzyl rings, as well as the heterocycle, are substituted with 0, 1, 2, 3, 4, or 5 substituents selected from C1-C6 alkyl, -O-C1-C6 alkyl, halogen, -CF3, and OH, wherein R... x and R y Each is independently selected from H and C1-C6 alkyl groups, which are substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups; and

[0136] In each case, n2 is an integer selected from 0, 1, 2, and 3.

[0137] In other words, in some embodiments, the method includes administering to a subject in need an effective amount of a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0138] A method for treating hypertension in a person in need is provided, the method comprising administering to the person a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. In one embodiment, the hypertension to be treated is essential hypertension, which may also be referred to as idiopathic hypertension.

[0139] In another embodiment, the hypertension to be treated is secondary hypertension, including but not limited to hypertension caused by: sleep apnea, renal artery occlusion, abnormal levels of hormones, enzymes, growth factors, or other agents that control systemic or local blood pressure (including but not limited to renin, angiotensin I and II, and aldosterone, angiotensin-converting enzyme, catecholamines, thrombin, prostaglandins, natriuretic peptides, vasopressin, adreomedulin, substance P, calcitonin gene-related peptide, kallikrein, kininogen, kinin, kallikrein-degrading enzyme, phosducin, adipokines, and leptin), adrenal disease, thyroid abnormalities (including hyperthyroidism, hypothyroidism, Cushing's disease, pheochromocytoma, and excessive growth hormone), and aortic constriction, including coarctation.

[0140] In one implementation scheme, the hypertension to be treated is treatment-resistant or refractory hypertension.

[0141] In another implementation, the hypertension to be treated is a hypertensive urgency.

[0142] In another implementation, the hypertension to be treated is malignant hypertension, which may also be referred to as a hypertensive emergency or hypertensive crisis.

[0143] In another implementation, the hypertension to be treated is isolated systolic hypertension.

[0144] In another implementation, the hypertension to be treated is salt-sensitive hypertension.

[0145] In another implementation, the hypertension to be treated is pulmonary hypertension.

[0146] Current stroke treatment involves dissolving or removing the clots that cause the blockage. However, despite opening the large vessels, a significant proportion of patients (ranging from 30-50%) still have damaged small vessels, which can lead to ineffective treatment. The compounds described in this article can be combined with current stroke therapies to improve outcomes for most patients.

[0147] Therefore, a method for treating stroke in a person in need is provided, the method comprising administering to the person a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0148] Vascular dementia is a disease of small blood vessels in the brain that impairs blood flow and oxygen delivery to brain cells, leading to neuronal dysfunction. Small vessel disease-related dementia is the second leading cause of dementia after Alzheimer's disease and a leading cause of dementia in people aged 70 and over in developing countries. A method for treating small vessel disease-related dementia in persons of need is provided, the method comprising administering to the person a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0149] In view of their effects on dilating and protecting microvessels, the compounds and compositions described herein can also be used in methods for treating symptoms associated with microvascular dysfunction and microvascular disease, each method comprising administering to a subject in need a pharmaceutically effective amount of a compound of formula (I'), or a compound of formula (I), any subform of formula (I), any specifically named compound herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. This includes methods for treating microvascular complications associated with or caused by diabetes. In one embodiment, the diabetes discussed is type 1 diabetes. In another embodiment, the diabetes discussed is type 2 diabetes. This also includes methods for treating microvascular complications associated with or caused by prediabetes symptoms (also known as prediabetes).

[0150] A method for treating heart failure in a person is also provided, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0151] This includes methods for treating microvascular angina, cerebral small vessel disease (cSVD), vascular cognitive impairment (VCI), systemic microvascular endothelial dysfunction (alone or with infective endocarditis), and chronic kidney disease.

[0152] Peripheral artery disease, primarily small vessel disease, is usually not relieved by surgical and stent implantation techniques that target large vessels but do not treat small vessel disease.

[0153] This article provides a method for treating peripheral artery disease in humans, the method comprising administering to a mammal in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0154] The compounds described 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 commonly the liver and kidneys. This document provides a method for treating preeclampsia in humans, comprising administering to a mammal in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0155] The compounds described in this article can also be used to treat myocardial infarction, particularly in the presence of no-reflow. No-reflow occurs when, despite the restoration of coronary artery blood flow to the myocardium, rupture or blockage of the coronary microvessels significantly reduces blood flow to the infarcted area. In this situation, one-third of myocardial infarction patients will experience blood flow to the microcirculation.

[0156] Therefore, a method for treating myocardial infarction in humans is provided, the method comprising administering to the desired mammal a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0157] A method for treating myocardial infarction in the presence of no-reflow phenomenon is also provided, the method comprising administering to the desired mammal a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0158] The compounds of the present invention can also be used in cases of chronic coronary artery disease in which the large arteries are bypassed or stented; however, about one-third of patients continue to suffer from angina due to microvascular dysfunction.

[0159] Therefore, a method for treating chronic coronary artery disease in humans is provided, the method comprising administering to a mammal in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0160] It also provides a method for treating microvascular dysfunction associated with chronic coronary artery disease in humans, the method comprising administering to a mammal in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0161] The compounds of the present invention can also be used for a condition known as Syndrome X, in which a subject experiences cardiac microvascular dysfunction or constriction causing angina despite normal epicardial coronary artery activity, as diagnosed by angiography. Therefore, a method for treating Syndrome X in humans is provided, the method comprising administering to the desired mammal a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0162] A method for treating breast cancer in a person of need is provided, the method comprising administering to the person a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. In some embodiments, the breast cancer treated in this method is ER-negative breast cancer.

[0163] A method for treating gastric adenocarcinoma in humans is also provided, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0164] It also provides a method for promoting or enhancing colonic epithelial function and tight junction barrier integrity in humans, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0165] Similarly, a method for treating ulcerative colitis in a person is provided, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds. In one embodiment, the ulcerative colitis to be treated is ulcerative colitis. In another embodiment, the ulcerative colitis to be treated is Crohn's disease. In yet another embodiment, the ulcerative colitis to be treated is irritable bowel syndrome (IBS), which may also be referred to as colitis, enteritis, ileitis, or proctitis.

[0166] A method for treating inflammatory bowel disease (IBD) in humans is also provided, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0167] A method for treating diarrhea in humans is also provided, the method comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds.

[0168] Because microvascular complications can inhibit the uniform delivery of anesthetics, in some embodiments, the compounds described herein can be used in methods for the local, regional, or systemic delivery of anesthetics and to improve their effectiveness. Therefore, methods for enhancing the delivery of anesthetics to a person experiencing microvascular complications are also provided, the methods comprising administering to the person in need a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds, and a pharmaceutically effective amount of the anesthetic. In some embodiments, the person is given a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt of any of the foregoing compounds prior to the administration of the anesthetic.

[0169] Pharmaceutical Composition

[0170] This document also provides pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of formula (I'), a compound of formula (I), a compound of any subform of formula (I), any compound specifically named herein, or a pharmaceutically acceptable salt or cocrystal of any of the foregoing compounds, and a pharmaceutically acceptable carrier or excipient. Additional pharmaceutical compositions comprise, respectively, a pharmaceutically effective amount of a compound selected from formulas (I-1), (I-2), (I-3), (I-4), (I-5) and each of formulas (Ia)-(I-hh), as well as a compound specifically named herein, and a pharmaceutically acceptable carrier or excipient.

[0171] This document also provides for the use of compounds of formula (I'), compounds of formula (I), compounds of any subform of formula (I), any compounds specifically named herein, or pharmaceutically acceptable salts or cocrystals of any of the foregoing compounds in the preparation of medicaments. Additional uses include the use of compounds in the preparation of medicaments comprising, respectively, pharmaceutically effective amounts of compounds selected from formulas (I-1), (I-2), (I-3), (I-4), (I-5) and each of formulas (Ia)-(I-hh), as well as compounds specifically named herein.

[0172] The term "carrier" refers to an excipient or medium with which a compound is applied, including but not limited to diluents, disintegrants, precipitation inhibitors, surfactants, flow aids, binders, lubricants, etc. Pharmaceutically acceptable carriers are generally described in this article and in EWMartin's "Remington's Pharmaceutical Sciences". Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctadecyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silica, colloidal silica, silicone, silicone binder 4102, and silicone emulsions. However, it should be understood that the carriers selected for the pharmaceutical composition and the amounts of these carriers in the composition can vary depending on the formulation method (e.g., dry granulation formulation, solid dispersion formulation).

[0173] Some examples of suitable excipients for oral formulations include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may also contain: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents.

[0174] As used herein, "pharmaceuticalally acceptable excipients" are pharmaceutically acceptable media, including but not limited to any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, and absorption delay agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except for those incompatible with the active ingredient, any conventional media or agent is intended for use in therapeutic compositions. Complementary active ingredients may also be incorporated into the composition.

[0175] The pharmaceutical composition may be administered in single or multiple doses via any acceptable mode of administration of an agent having similar efficacy, such as as described in those patents and patent applications incorporated herein by reference, including rectal, buccal, intranasal and transdermal routes, via intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, local administration, as an inhalant, or via an impregnated or coated device, such as, for example, a stent or arterial insertion cylindrical polymer.

[0176] One mode of administration is parenteral administration, particularly injection. Compounds of Formula I or their pharmaceutically acceptable salts or cocrystals can be incorporated for injection in the form of aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar drug carriers. Saline solutions are also routinely used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils can also be used. For example, by using coatings such as lecithin, in the case of dispersions, appropriate flowability can be maintained by maintaining the desired particle size, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0177] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to this disclosure, along with various other ingredients listed above, into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating various sterile active ingredients into a sterile medium containing a basic dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying techniques, which produce powders of the active ingredient plus any additional desired ingredients (from their previous sterile filtered solution). In some embodiments, for parenteral administration, sterile injectable solutions are prepared containing a therapeutically effective amount, such as 0.1 mg to 1000 mg of a compound of formula I or a pharmaceutically acceptable salt or cocrystal thereof. However, it should be understood that the amount of compound actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered and its relative activity, the age, weight and response of the individual subject, the severity of the subject's symptoms, etc.

[0178] Oral administration is another route of administration for a compound of formula I or a pharmaceutically acceptable salt or cocrystal thereof. It can be administered via capsules or enteric-coated tablets, etc. In preparing pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt or cocrystal thereof, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier, which may be in the form of capsules, pouches, paper, or other containers. When the excipient is used as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as described above), serving as a medium, carrier, or medium for the active ingredient. Therefore, compositions can be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft gelatin capsules and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0179] In some embodiments, for parenteral administration, each dose 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 salt or cocrystal thereof. In some embodiments, a therapeutically effective amount or pharmacologically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof comprises about 0.1 mg to about 500 mg per dose, administered once or twice daily. In some embodiments, the individual dose is 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.

[0180] However, for any dosage unit described herein, it should be understood that the actual amount of compound administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered and its relative activity, the individual subject's age, weight and response, and the severity of the subject's symptoms.

[0181] Products and reagent kits

[0182] Compositions comprising, for example, formulations and unit doses, of compounds of formula I' or formula I, or pharmaceutically acceptable salts or cocrystals thereof, can be prepared and placed in suitable containers and labeled for the treatment of specified symptoms. Thus, an article, such as a container, is also provided containing a unit dosage form of a compound of formula I' or formula I, or a pharmaceutically acceptable salt or cocrystal thereof, and a label containing instructions for use of these compounds. In some embodiments, the article is a container containing a unit dosage form of a compound of formula I' or formula I, or a pharmaceutically acceptable salt or cocrystal thereof, and at least one pharmaceutically acceptable medium. The article may be a bottle, vial, ampoule, disposable applicator, etc., containing the pharmaceutical compositions provided in this disclosure. The container may be formed of a variety of materials, such as glass or plastic, and in one aspect also includes a label on or associated with the container indicating instructions for the treatment of cancer or inflammatory symptoms. It should be understood that the active ingredient may be packaged in any material capable of improving chemical and physical stability, such as an aluminum foil pouch. In some implementations, the disease or symptom indicated on the label may include, for example, treatment for cancer.

[0183] definition

[0184] Terms such as “microvascular tone,” “microcirculatory tone,” “microcirculatory vascular tone,” and “arteriolar tone” refer to the degree of contraction experienced by microcirculatory vessels relative to their maximum dilated state. Anatomically, the microcirculation can be defined as vessels with a diameter between approximately 250 μm and approximately 100 μm, particularly including vessels with a diameter between approximately 200 μm and approximately 150 μm, which include arterioles, capillaries, and venules (postcapillary venules). These vessels can be collectively referred to as “microvessels,” “microcirculatory vessels,” etc. In the embodiments described herein, the objective is to provide compounds, compositions, and methods for relaxing microvessels in a subject, reducing vascular resistance and protecting the microvessels themselves, and reducing or eliminating end-organ damage associated with microvascular resistance, particularly end-organ damage seen in the eyes, kidneys, and heart, as well as damage to nerve sheaths associated with microvessels. In some embodiments, the microcirculation is defined as vessels with a diameter <200 μm. In the human body, approximately 90% of blood volume is contained in these blood vessels, including arterioles, capillaries, and venules. Arterioles range in diameter from approximately 50 to 200 μm. Some venules contain vascular smooth muscle, while some capillaries are surrounded by pericytes, both of which are contractile cells that allow these vessels to constrict and relax, thereby delivering more or less blood and oxygen to the cells and removing cellular waste. The size of these arterioles is strictly regulated to meet the oxygen demands of the cells they supply.

[0185] Coronary microvascular disease is a heart condition that affects the walls and lining of the tiny blood vessels branching off from the larger coronary arteries. It is also known as "cardiac syndrome X" or "non-obstructive coronary heart disease." In the heart or other parts of the body, it can also be called "small artery disease," "small vessel disease," or "arteriosclerosis of the small arteries."

[0186] Such small vessel diseases are common in essential hypertension, stroke, and hypertensive nephropathy. Kidney damage typically involves afferent arterioles and interlobular arteries and may involve intimal thickening, vascular smooth muscle cell proliferation, and extracellular matrix deposition, thereby increasing the media-to-lumen ratio. The areas of vascular smooth muscle cells are subsequently replaced by fibrosis and cell death.

[0187] "Microvascular angina" refers to a form of chest pain caused by abnormalities in the heart's microvessels (including but not limited to malrelaxation or spasm).

[0188] In this article, "heterocyclic" or "heterocyclic group" refers to a chemical ring containing a carbon atom and at least one cyclic heteroatom selected from O, S, and N, including saturated, unsaturated, partially saturated, and aromatic rings.

[0189] Examples of 3-membered heterocycles in this article, such as those seen in the definitions of R3 and R4, include, for example, but not limited to, azadirynyl, azirinyl, ethylene oxide, and thiohexacyclopropane.

[0190] Examples of 4-membered heterocycles in this article, such as those seen in the definitions of R3 and R4, include, for example, but not limited to, azetidinyl, dihydro-1λ 4 -Azetyl, azetyl, 1,3-diazacyclobutane, and oxobutane.

[0191] Examples of 5-membered heterocycles in this article, such as those seen in the definitions of R3 and R4, include, for example, but not limited to, thiazolyl, tetrahydrothiophene, sulfur-oxidized tetrahydrothiophene, furanyl, thiophene, pyrrole, dihydropyrrole, pyrazolyl, imidazolyl, tetrazolyl, pyrrolidinyl, 2-pyrrolidone, dihydropyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, triazine, thiophene, 2H-pyrrole, isothiazolyl, isoxazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, and oxazolyl.

[0192] Examples of 6-membered heterocycles in this article, such as those seen in the definitions of R3 and R4, include, for example, but not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), pyrimidyl, piperidinyl, thiadiazinyl, thiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, pyrazinyl, pyridazinyl, piperazinyl, thiophenyl, thiaran, dithanyl, morpholinyl, and thiomorpholinyl.

[0193] Examples of 7-membered heterocycles in this article include, but are not limited to, boron-heptatrienyl, azirheptatrienyl, azirheptatrienyl, oxoheptatrienyl, oxoheptatrienyl, thioheptatrienyl, thiepanyl, diazaheptatrienyl, diazaheptatrienyl, and thiazepinyl.

[0194] Examples of 8-membered heterocycles in this article include, but are not limited to, azocinyl, oxocanyl, oxocinyl, thiocanyl, and thiocinyl.

[0195] Examples of 9-membered heterocycles in this article include, but are not limited to, monocyclic heterocycles such as aza-nonyl, aza-nonatetraenyl, oxonyl, thionyl, and thionyl, as well as fused heterocycles such as indolyl, indolinyl, isoindolyl, inazinyl, indazolyl, indazole, aza-indolyl, benzimidazolyl, aza-indazolyl, pyrazolopyrimidinyl, purine, benzofuranyl, isobenzofuranyl, benzothiophene, benzo[d]isooxazolyl, benzo[d]isothiazolyl, benzo[d]oxazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[d]thiazolyl, benzo[isothiazolyl, adenine, and guanine.

[0196] Examples of 10-membered heterocycles in this article include, but are not limited to, decahydroisoquinolinyl, decahydroquinolinyl, tetrahydroquinolinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinoxalinyl, quinazinyl, phthalazinyl, quinazolinyl, cinnolinyl, isocinnolinyl, naphthidyl, 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, quinolinoneyl, thieno[pyrimidinyl (including thieno[3,2-d]pyrimidinyl), and isoquinolinoneyl.

[0197] It should be understood that the general term for heterocycles as used herein includes every isomer of the heterocycle, for example, the term “dithiaalkyl” includes 1,2-dithiaalkyl, 1,3-dithiaalkyl and 1,4-dithiaalkyl, the term “thiadiazinyl” includes 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl, the term “azaindolyl” includes 4-azaindolyl, 5-azaindolyl, 6-azaindolyl and 7-azaindolyl, and “benzothiophenyl” includes benzo[b]thiophenyl and benzo[c]thiophenyl.

[0198] Similarly, general heterocyclic names include each variation of one or more unsaturation points. For example, the term "dihydropyrrole" refers to both "2,3-dihydro-1H-pyrrole" and "2,5-dihydro-1H-pyrrole".

[0199] The term "alkyl" refers to a straight-chain or branched hydrocarbon. For example, an alkyl group can have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C6 alkyl). 1-6Alkyl groups). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, ... --CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, --C(CH3)3), 1-pentyl (n-pentyl, --CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-Methyl-1-butyl (--CH2CH2CH(CH3)2), 2-Methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (--CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-Methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-Methyl-2- pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (--C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (--C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0200] The term "alkoxy" refers to a group having the formula "-O-alkyl", wherein the alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group may have a specific number of carbon atoms, for example, 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C...). 1-6 Alkoxy groups. Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or --OMe), ethoxy (-OCH2CH3 or --OEt), t-butoxy (-O--C(CH3)3 or --OtBu), etc.

[0201] The term "cycloalkyl" refers to a saturated ring having 3 to 6 carbon atoms as a monocyclic ring, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0202] The term "halogen" refers to an atom selected from the elements chlorine, fluorine, bromine, and iodine.

[0203] The term "oxo" refers to the double bond oxygen "=O".

[0204] The terms "therapeutic effective amount" and "pharmacologically effective amount" refer to the amount sufficient to achieve the treatment as defined below when administered to a subject requiring such treatment (e.g., a mammal, such as a human). Therapeutic effective amounts or pharmacologically effective amounts will vary depending on the subject being treated and the disease condition, 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. For example, a "therapeutic effective amount" or "pharmacologically effective amount" of a compound of formula I or a pharmaceutically acceptable salt or cocrystal thereof is an amount sufficient to antagonize GPR39 expression or activity, thereby treating a subject (e.g., a human) with the indication or improving or alleviating existing symptoms of the indication. For example, a therapeutic effective amount or pharmacologically effective amount may be an amount sufficient to alleviate symptoms of a disease or symptom that responds to inhibition of GPR39 activity.

[0205] "Treatment / treating" is a method of achieving a beneficial or desired outcome (including clinical outcomes). A beneficial or desired clinical outcome may include one or more of the following: (i) suppressing a disease or symptom (e.g., reducing one or more symptoms caused by the disease or symptom, and / or alleviating the severity of the disease or symptom); (ii) slowing or preventing the development of one or more clinical symptoms associated with the disease or symptom (e.g., stabilizing the disease or symptom, preventing or delaying the worsening or progression of the disease or symptom, and / or preventing or delaying the spread of the disease or symptom (e.g., metastasis)); and / or (iii) alleviating the disease, i.e., causing the remission of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or symptom, enhancing the effect of another medication, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0206] The term "inhibiting / inhibition" refers to a reduction in the baseline activity of a biological activity or process, such as a significant reduction. "Inhibition of GPR39 activity" refers to a reduction in GPR39 activity as a direct or indirect response to the presence of such a compound or its pharmaceutically acceptable salt or cocrystal, relative to the activity of GPR39 in the absence of a compound of Formula I or its pharmaceutically acceptable salt or cocrystal. The reduction in activity may be due to a direct interaction between the compound and GPR39, or due to the interaction of the compound described herein with one or more other factors that in turn affect the expression and / or activity of GPR39. For example, the presence of a compound can reduce GPR39 activity by directly binding to GPR39, by inducing (direct or indirect) a reduction in the expression or activity of GPR39 by another factor, or by (direct or indirect) reducing the amount of GPR39 protein present in a cell or organism. In some embodiments, the inhibition of GPR39 activity can be compared in the same subject or in other untreated subjects prior to treatment. The term “inhibitor” should be understood as a compound or agent that provides the desired inhibitory activity when administered to a person in need at a pharmaceutically or therapeutically effective dose.

[0207] "Delaying" the development of a disease or condition refers to postponing, hindering, slowing, delaying, stabilizing, and / or postponing its progression. The duration of this delay varies depending on the history of the disease or condition and / or the subject being treated. Methods of "delaying" the development of a disease or condition involve reducing the probability of its development and / or the severity of its development within a given timeframe compared to not using such methods. These comparisons are typically based on clinical studies using statistically significant numbers of subjects. The development of a disease or condition can be detected using standard methods such as routine physical examination, mammography, imaging, or biopsy. Development can also refer to the progression of a disease or condition that may initially be undetectable, including occurrence, recurrence, and onset.

[0208] As used herein, unless the context clearly indicates otherwise, the singular terms “a” and “the” include the plural referent. Similarly, unless the context clearly indicates otherwise, the word “or” is intended to include “and”. Furthermore, as used herein, the term “comprising” means “including”. Therefore, “comprising A or B” means including A, B, or A and B.

[0209] The numerical values ​​in the specification and claims of this application should be understood to include the same numerical values ​​when reduced to the same number of significant figures and numerical values ​​whose difference from the stated values ​​is less than the experimental error of conventional measurement techniques of the type described in this application that determined the value.

[0210] All scopes disclosed and / or claimed herein include the stated endpoints and may be combined independently (e.g., the scopes “2 to 10” and “2-10” include endpoints 2 and 10 as well as all intermediate values ​​3, 4, 5, 6, 7, 8 and 9).

[0211] “Significant” means any detectable change that is statistically significant in a standard parametric test (such as Student’s T test) where p < 0.05.

[0212] "Pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Examples of salts can include hydrochlorides, phosphates, bisphosphonates, hydrobroms, sulfates, sulfinates, nitrates, malates, maleates, fumarates, tartrates, succinates, citrates, acetates, lactates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, and alkylates (e.g., acetates, HOOC-(CH2)). n --COOH, where n is 0-4). Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing the solution of the acid salt. Conversely, if the product is a free base, the addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with acid, following conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable addition salts.

[0213] The term "crystal form" and related terms used herein refer to various crystallization variants of a given substance, including but not limited to polymorphs, solvates, hydrates, eutectics, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and their polymorphs. The crystal form of a substance can be obtained by a variety of methods known in the art. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives such as anti-molecules of eutectics, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent drop grinding.

[0214] As used herein, the term "co-crystal" or "co-crystal salt" refers to a crystalline material composed of two or more distinct solids at room temperature, each solid possessing unique physical properties such as structure, melting point and heat of fusion, hygroscopicity, solubility, and stability. Co-crystals or co-crystal salts can be prepared using co-crystallization methods known per se. The term co-crystal or co-crystal salt also refers to a multi-component system in which one or more host API (active pharmaceutical ingredient) molecules (e.g., Formula I compound) and one or more guest (or co-formed) molecules are present. In a particular embodiment, a pharmaceutically acceptable co-crystal of Formula I or Formula II compound and co-formed molecule is a crystalline form selected from malonic acid co-crystal, succinic acid co-crystal, decanoic acid co-crystal, salicylic acid co-crystal, vanillic acid co-crystal, maltol co-crystal, or glycolic acid co-crystal. Co-crystals may have improved properties compared to the parent form (i.e., free molecules, zwitterions, etc.) or salts of the parent compound. Improved properties may include increased solubility, increased dissolution, increased bioavailability, increased dose-response, reduced hygroscopicity, crystalline form of normally amorphous compounds, crystalline form of compounds that are difficult or impossible to salt, reduced form diversity, and more desirable forms.

[0215] As used herein, the terms “isotope” and “isotopic” with respect to compounds disclosed herein refer to the substitution of one or more atoms of a compound by an isotope of those atoms. An “isotope” is any of two or more forms of a chemical element having the same number of protons in its nucleus but different numbers of neutrons. For example, an isotopic compound includes a compound in which one or more hydrogen atoms (H) have been substituted by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and substituting hydrogen atoms (at one or more positions) with deuterium makes the resulting compound an isotopic compound. For example, and referring to formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with a fully deuterated methyl group (-CH(CD3)2) would result in an isotopic compound of formula (I). Besides replacing hydrogen with deuterium, other stable (non-radioactive) isotopic substitutions include replacing carbon-12 with carbon-13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon-12 with carbon-14, and replacing iodine-127 with iodine-123 or iodine-125, etc. Therefore, all references herein to isotopic compounds of formula (I), and all references to their various embodiments, refer to compounds having one or more isotopic substitutions, including (but not limited to) one or more hydrogen atoms being replaced by one or more deuterium atoms, and any occurrence in the compound. For this reason, the isotopic compounds disclosed herein offer improved advantages relative to their non-isotopic forms. Isotopic modification thus provides a means to improve existing drugs and / or serves as a tool for designing new drugs. For example, isotopic drug design has proven successful in terms of the kinetic isotopic effects of deuterium (D). Because D has twice the mass of H, the CD bond is more resistant to oxidation processes (e.g., its ability to be catalyzed by CYP450 or other enzymes involved in metabolism), while maintaining very similar spatial properties. Therefore, electronic substitutions such as HD often preserve the pharmacodynamics of compounds while improving their pharmacokinetics, affecting half-life and / or area under the curve, and ultimately dose and / or dosing regimens. For example, drug exposure can be increased through isotopic modification and / or reduced clearance. Such benefits are provided to the compounds disclosed herein through their isotopic derivatization.

[0216] Terms such as “subject” and “patient” refer to animals, such as mammals, that are already or will be the subjects of treatment, observation, or experimentation. The methods described herein are applicable to human treatment and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. “Subject in need thereof” or “person in need” refers to a subject who may have or is suspected of having a disease or condition that would benefit from certain treatments, such as a human; for example, treated with a compound of formula I described herein or a pharmaceutically acceptable salt or cocrystal thereof. This includes subjects who can be identified as being at risk or susceptible to such a disease or condition, such that treatment could prevent the development of the disease or condition.

[0217] The term "prediabetes" or "prediabetic condition" refers to a condition in which a subject's blood glucose levels are not high enough to be considered diabetes, but may be a precursor to type 2 diabetes. A prediabetic condition can be defined in a subject as a fasting blood glucose level of 100 mg / dL or higher, but below 126 mg / dL (the diagnostic level for diabetes). Hemoglobin A1c (HbA1c) levels are another laboratory test for diabetes. An HbA1c level of 6.5% or higher is characteristic of diabetes, while a level of 5.7% to 6.4% suggests prediabetes.

[0218] Example

[0219] Measurement of intracellular calcium response in PC3 cells expressing endogenous human GPR39 receptor

[0220] Human prostate adenocarcinoma (PC3) cells endogenously expressing the human GPR39 receptor were seeded at a density of 7,500 cells / well in 384-well plates with a black-walled clear substrate in DMEM (low glucose) supplemented with 10% heat-inactivated fetal bovine serum and 1% Pen / Strep, and grown overnight at 37°C and 5% CO2. After washing with assay buffer (20 mM HEPES, 137 mM NaCl, 5.4 mM KCl, 10 mM glucose, 0.8 mM MgSO4, 1.3 mM CaCl2, 0.3 mM Na2HPO4, 0.4 mM KH2PO4, 4.2 mM NaHCO3, pH 7.4), the cells were incubated with a calcium-6 probe (Molecular Devices) at 37°C for 2 hours, and then equilibrated at room temperature for 30 minutes on a metal block. Fluorescence was measured in real time using a fluorescence imaging plate reader (FLIPR TETRA, Molecular Devices) (excitation wavelength 470-495nm, emission wavelength 515-575nm).

[0221] The compound of the present invention was serially diluted 1000 times in pure DMSO and plated in 384-well plates, and then diluted 200 times in assay buffer containing 150 μM ZnCl2 (30 μM final concentration) and 1.1% DMSO (0.32% final concentration).

[0222] The double-addition FLIPR protocol was used, consisting of a first addition of a compound diluted 200-fold in assay buffer containing 150 μM ZnCl2 and 1.1% DMSO, followed by a second addition of a submaximal concentration of hGPR39 receptor agonist C3 (Tocris, TC-G 1008) at 1.5 μM EC90 (the concentration that produces 90% of the maximum response) 10 minutes later.

[0223] Fluorescence was monitored throughout the entire measurement run. Ca 2+ The peak value of the stimulus (minus the baseline) was expressed as the percentage of maximum inhibition of the EC90C3 response, and plotted against the concentration of the test compound. Curve fitting and IC50 estimation were performed using a four-parameter logistic model with XLfit software.

[0224] The potency of the compound is reported as the functional pKi(-Log10Ki) obtained using the modified Cheng-Prusoff relation (Cheng, Y., Prusoff, WH 1973.).

[0225] fKi = IC50 / (1 + [L] / EC50), where IC50 is the antagonist concentration required to inhibit the maximum response by 50%, [L] is the concentration of the agonist used (EC90), and EC50 is the agonist concentration required to induce 50% of the maximum response (obtained on each experimental plate).

[0226] fpKi data is shown in Table 1 below. fpKi values ​​less than 5.2 are reported as "+ / -". fpKi values ​​between 5.2 and 5.9 are reported as "+". fpKi values ​​between 6.0 and 6.5 are reported as "++". fpKi values ​​between 6.6 and 7.2 are reported as "+++". fpKi values ​​equal to or greater than 7.3 are reported as "++++".

[0227] Table 1

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235] synthesis

[0236] The compounds described herein can be prepared by methods known in the art, as illustrated by the following non-limiting description.

[0237] The variation of the R2 position can be prepared using the following synthetic route 1.

[0238] Synthesis Route 1

[0239]

[0240] Synthetic route 1 - Reagents and conditions: a) N-propylpiperazine, HATU, DIPEA, DMF, rt, 2h; b) Zn, AcOH, rt, 1h; c) Cyclopropylformyl chloride, TEA, DCM, rt, overnight, y = 62%; d) Buckwald, Suzuki or Stille conditions.

[0241] Preparation: 1-(2-bromo-4-nitrobenzoyl)-4-propylpiperazine

[0242]

[0243] N,N-diisopropylethylamine (5.31 mL, 30.49 mmol) was added to a solution of 2-bromo-4-nitrobenzoic acid (5.0 g, 20.32 mmol) and HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium;hexafluorophosphate (8.5 g, 22.36 mmol) in DMF (50 mL), and the mixture was stirred at room temperature for 30 min. Subsequently, 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) was added, and the resulting solution was stirred at room temperature for 2 h. The mixture was diluted with saturated NaHCO3 solution (ss) 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 give the product of formula (1-(2-bromo-4-nitrobenzoyl)-4-propylpiperazine).

[0244] Yield: 7g

[0245] 1 H NMR (400MHz, chloroform-d) δ8.48(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 / z356.11,358.14(MH+).

[0246] Preparation of 3-bromo-4-(4-propylpiperazine-1-carbonyl)aniline

[0247]

[0248] (2-Bromo-4-nitrophenyl)-(4-propylpiperazin-1-yl) methyl ketone (6.63 g, 18.61 mmol) was dissolved in acetic acid (51.13 mL), and zinc (6.08 g, 93.06 mmol) was added to the solution. The resulting suspension was stirred at room temperature for 60 min. The suspension was then filtered and the solution was concentrated under vacuum. The residue was absorbed with saturated NaHCO3 solution and extracted three times with AcOEt. The organic layer was collected, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The resulting substance was purified by FC on an NH column (DCM to DCM / AcOEt 7:) to give the product of formula (4-amino-2-bromophenyl)-(4-propylpiperazin-1-yl) methyl ketone.

[0249] Yield: 3.2g

[0250] 1 H NMR(400MHz,DMSO-d6)δ6.91(d,1H),6.78(d,1H),6.56(dd,1H),5.58(s,2H),3.57(s,2H),3.1 5(s,2H),2.44-2.21(m,6H),1.49-1.39(m,2H),0.85(t,3H); LC-MS: m / z326.44,328.44(MH+).

[0251] Preparation: N-[3-bromo-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0252]

[0253] Triethylamine (2.82 mL, 20.23 mmol) was added to a solution of (4-amino-2-bromophenyl)-(4-propylpiperazin-1-yl) methyl ketone (2.2 g, 6.74 mmol) in DCM (30 mL), and the resulting mixture was cooled to 0 °C. Cyclopropylformyl chloride (1.53 mL, 16.86 mmol) was then added dropwise to a solution of DCM (5 mL), and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution and brine. The organic phase was dried using a phase separator, and the solvent was removed under vacuum. The resulting product was purified by FC on silica gel (eluting with DCM to DCM / MeOH 95:5) to give the product of N-[3-bromo-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide.

[0254] Yield: 2.15g

[0255] 1 ¹H NMR (400MHz, 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), 3.37–3.16 (m, 2H), 2.61–2.26 (m, 6H), 1.62–1.46 (m, 3H), 1.13–1.04 (m, 2H), 0.99–0.82 (m, 5H); LC-MS: m / z 394.09, 396.11 (MH+).

[0256] Preparation: N-(4-(4-propylpiperazin-1-carbonyl)-3-(6-azaspiro[3.4]oct-6-yl)phenyl)cyclopropaneformamide

[0257]

[0258] In a vial, N-[3-bromo-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (100.0 mg, 0.250 mmol), sodium tert-butoxide (48.74 mg, 0.510 mmol), and anhydrous toluene (1.5 mL) were added sequentially. The suspension was degassed using a Schlenk line technique, and 6-aza-spiro[3,4]octane (42.29 mg, 0.380 mmol) was added. Then, (1E,4E)-1,5-diphenyl-3-pentan-1,4-dienone; palladium (11.61 mg, 0.010 mmol) and [1-(2-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenylphosphine (15.79 mg, 0.030 mmol) were added, and the suspension was degassed again using a Schlenk line technique for 10 min. The resulting mixture was heated to 120 °C and kept overnight (ON). The following 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 product was purified by FC on RP under alkaline conditions (eluting with 100% aqueous solution of ammonium bicarbonate adjusted to pH 10 with ammonia to 100% CH3CN) to give the product of N-(4-(4-propylpiperazin-1-carbonyl)-3-(6-azaspiro[3.4]oct-6-yl)phenyl)cyclopropaneformamide.

[0259] Yield: 11mg

[0260] 1 H NMR (500MHz, methanol-d4) δppm 7.14(d,1H),7.01(d,1H),6.87(dd,1H),3.98-3.86(m,1H),3.69-3.57(m,1H),3.38-3.30(m,2H),3.29-3.11(m,4H),2.66-2.58(m ,1H),2.53-2.42(m,2H),2.40-2.26(m,3H),2.11-1.86(m,8H),1.79-1.71(m,1H),1.61-1.50(m,2H),0.98-0.81(m,7H); LC-MS: m / z 425.3(MH) + .

[0261] Preparation: (S)-N-(3-(3-isopropylpyrrolidone-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0262]

[0263] The title compound was synthesized in a manner similar to that of the compound in Example 1 (N-(4-(4-propylpiperazin-1-carbonyl)-3-(6-azaspiro[3.4]oct-6-yl)phenyl)cyclopropaneformamide), wherein (3S)-3-prop-2-ylpyrrolidine-1-onium chloride was used instead of 6-azaspiro[3.4]octane. The title compound was obtained in a yield of 6.5% (7.3 mg).

[0264] 1H NMR (500MHz, methanol-d4) δppm 7.18-7.11(m,1H),7.06-6.94(m,1H),6.92-6.85(m,1H),4.07-3.29(m,4 H),3.37-3.26(m,2H),3.38-2.90(m,2H),2.38-2.32(m,2H),2.71-2.18(m ,4H),2.17-2.07(m,1H),1.98-1.83(m,1H),1.79-1.72(m,1H),1.64-1.4 7(m,4H),0.94-0.82(m,4H),1.05-0.80(m,9H); LC-MS: (m / z)427.6(MH+).

[0265] Preparation: N-(3-(1,4-oxazacycloheptane-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0266]

[0267] N-[3-bromo-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (50.0 mg, 0.130 mmol), [1-(2-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenylphosphine (15.79 mg, 0.030 mmol), and Cs₂CO₃ (123.95 mg, 0.380 mmol) were suspended in anhydrous toluene (1.5 mL), and the mixture was purged with N₂ for 10 min. Then, [1,4]oxazacycloheptane (64.13 mg, 0.630 mmol) and (1E,4E)-1,5-diphenyl-3-pent-1,4-dienone were added; palladium (11.61 mg, 0.010 mmol), and the mixture was heated to 120 °C and maintained for 48 h. The reaction mixture was cooled to room temperature, 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 product was purified by FC on RP under alkaline conditions (eluting with 100% aqueous solution of ammonium bicarbonate adjusted to pH 10 with ammonia to 100% CH3CN) to give the product as a white solid of N-[3-(1,4-oxazacycloheptane-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide.

[0268] Yield: 2.2 mg

[0269] 1 H NMR(400MHz,DMSO-d6)δppm 10.18(s,1H),7.37(d,1H),7.09(dd,1H),6.96(d,1H),3.78-3.58(m,4H),3.61-3.02(m,8H),2.27-2.20(m,2H),2. 46-2.06(m,4H),1.85(quin,2H),1.80-1.71(m,1H),1.51-1.36(m,2H),0.84(t,3H),0.81-0.75(m,4H); LC-MS: m / z 415.3(MH+).

[0270] Preparation: N-(4-(4-propylpiperazin-1-carbonyl)-3-(7-oxa-2-azaspiro[3.5]non-2-yl)phenyl)cyclopropaneformamide

[0271]

[0272] The title compound was synthesized in a manner similar to that of the compound in Example 1 (N-(4-(4-propylpiperazin-1-carbonyl)-3-(6-azaspiro[3.4]oct-6-yl)phenyl)cyclopropaneformamide), wherein 7-oxa-2-azaspiro[3.5]nonane hydrochloride was used instead of 6-azaspiro[3.4]octane. The title compound was obtained in a yield of 6.5% (7.3 mg).

[0273] 1 H NMR(500MHz,DMSO-d6)δppm 10.22-10.06(m,1H),7.00-6.79(m,3H),3.66-3.47(m,10H),3.24-3.10(m,2H),2.46-2.18(m,6H ),1.76(t,1H),1.72-1.67(m,4H),1.48-1.38(m,2H),0.85(t,3H),0.80-0.75(m,4H); LC-MS:m / z 441.4(MH+).

[0274] Preparation: N-(3-(3-phenylpyrrolidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0275]

[0276] The title compound was synthesized in a manner similar to that of the compound in Example 3 (N-(3-(1,4-oxazacycloheptane-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 3-phenyl-pyrrolidine was used instead of [1,4]oxazacycloheptane. The title compound was obtained in a yield of 7.7% (9 mg).

[0277] 1 H NMR(400MHz,DMSO-d6)δ10.12(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+).

[0278] Preparation: N-(4-(4-propylpiperazin-1-carbonyl)-3-(2-oxa-6-azaspiro[3.5]non-6-yl)phenyl)cyclopropane formamide

[0279]

[0280] The title compound was synthesized in a manner similar to that of the compound in Example 3 (N-(3-(1,4-oxazacycloheptane-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 2-oxa-6-azaspiro[3.5]nonane was used instead of [1,4]oxazacycloheptane. The title compound was obtained in a yield of 6% (4.8 mg).

[0281] 1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),7.48(d,1H),7.27(dd,1H),7.03(d,1 H),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+).

[0282] Preparation: N-(3-(4,4-difluoropiperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0283]

[0284] The title compound was synthesized in a manner similar to that of the compound in Example 3 (N-(3-(1,4-oxazacycloheptane-4-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 4,4-difluoropiperidine was used instead of [1,4]oxazacycloheptane. The title compound was obtained in a yield of 22% (12.3 mg).

[0285] 1H NMR(500MHz,DMSO-d6)δppm 10.28(s,1H),7.46(d,1H),7.25(dd,1H),7.06(d,1H),3.75-2.99(m,4H),3.21-2.85(m,4H),2.26-2.19(m,2H),2.45-2. 12(m,4H),2.11-1.95(m,4H),1.84-1.71(m,1H),1.42(sxt,2H),0.84(t,3H),0.81-0.76(m,4H); LC-MS: m / z435.3(MH+).

[0286] Preparation: N-(3-(3-methyl-1H-pyrazol-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide

[0287]

[0288] In a vial, N-[3-bromo-4-(4-propylpiperazin-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 anhydrous toluene (0.254 mL) were added sequentially. The resulting suspension was degassed by bubbling with N2 for 15 minutes, and then cuprous iodide (I) (2.43 mg, 0.010 mmol) and N,N'-dimethylcyclohexane-1,2-diamine (0.0 mL, 0.030 mmol) were added under nitrogen purging, followed by further degassed using a Schlenk line technique. The vial was sealed and stirred overnight at 120 °C. The next day, the reaction mixture was diluted with AcOEt and filtered through a diatomaceous earth mat. The organic layer was evaporated under reduced pressure and purified by FC on RP under alkaline conditions (eluent: 100% ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia to 100% CH3CN), followed by further purification by semi-preparative chiral HPLC.

[0289]

[0290] Preparation: N-[3-(3-methylpyrrolo-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0291]

[0292] The title compound was synthesized in a manner similar to that of the compound in Example 8 (N-(3-(3-methyl-1H-pyrazole-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), except that 3-methyl-1H-pyrrole was used instead of 3-methyl-1H-pyrazole. The title compound was obtained in a yield of 4% (3.6 mg).

[0293] 1H NMR(500MHz,DMSO-d6)δppm 10.50(s,1H),7.75(d,1H),7.48(dd,1H),7.26(d,1H),6.80(t,1H),6.69(s,1H),6.12-6.02(m,1H),3.87-2.66(m,4H),2.11-2. 06(m,2H),2.05(s,3H),1.79(quin,1H),2.41-1.37(m,4H),1.36-1.30(m,2H),0.82(d,4H),0.79(t,3H); LC-MS: m / z395.3(MH+).

[0294] Preparation: N-(6-(4-propylpiperazin-1-carbonyl)-[1,1'-biphenyl]-3-yl)cyclopropaneformamide

[0295]

[0296] N-[3-bromo-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (100.25 mg, 0.250 mmol), phenylboronic acid (31.0 mg, 0.250 mmol), and sodium carbonate (188.63 mg, 1.78 mmol) were suspended in a mixture of toluene (1.112 mL), ethanol (1.112 mL), and water (0.318 mL). The resulting suspension was degassed using a Schlenk line technique, and then tetrakis(triphenylphosphine)palladium (5.89 mg, 0.010 mmol) was added under nitrogen purging. The mixture was degassed again and heated to 140 °C in a microwave oven for 60 minutes. The reaction mixture was cooled to room temperature, diluted with H₂O, 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 crude material was purified by FC on an NH column (eluting with cHex / AcOEt 95:5 to 100% AcOEt) to give the product of formula (N-(6-(4-propylpiperazin-1-carbonyl)-[1,1'-biphenyl]-3-yl)cyclopropaneformamide).

[0297] Yield: 34mg

[0298] 1H NMR(400MHz,DMSO-d6)δppm 10.40(s,1H),7.74(d,1H),7.61(dd,1H),7.51-7.33(m,5H),7.25(d,1H),3.63-2.61(m,4H),2.0 2-1.97(m,2H),1.81(s,1H),1.35-1.24(m,2H),2.40-1.11(m,4H),0.92-0.64(m,7H); LC-MS:m / z 392.7(MH+).

[0299] Preparation: N-(4-(4-propylpiperazin-1-carbonyl)-3-(pyridin-2-yl)phenyl)cyclopropane formamide

[0300]

[0301] N-[3-bromo-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (100.0 mg, 0.250 mmol) was dissolved in anhydrous DMF (1.569 mL), and tributyl(2-pyridyl)stanane (0.1 mL, 0.300 mmol) was added. The solution was then degassed using a Schlenk line technique for 15 min. Tetra(triphenylphosphine)palladium (14.51 mg, 0.010 mmol) was then added under nitrogen purging, and the reaction was stirred overnight at 120 °C. The next day, the reaction mixture was cooled to room temperature, diluted with 10% KF aqueous solution, and extracted three times with AcOEt. The combined organic fractions were then washed with water and brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting substance was purified by FC on an NH column (eluting with cHex / AcOEt 95:5 to 100% AcOEt), and then further purified by FC on RP under alkaline conditions (eluting with 100% ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia to 100% CH3CN) to give a compound of formula (N-[4-(4-propylpiperazin-1-carbonyl)-3-pyridin-2-ylphenyl]cyclopropanecarboxamide).

[0302] Yield: 10.5 mg

[0303] 1H NMR(400MHz,DMSO-d6)δppm 10.44(s,1H),8.62(dd,1H),8.00(d,1H),7.87(td,1H),7.69(dd,1H),7.54(d,1H),7.41-7.36(m,1H),7.25(d,1H),3. 62-2.75(m,4H),2.18-2.05(m,2H),1.88-1.74(m,1H),2.41-1.58(m,4H),1.35(sxt,2H),0.87-0.73(m,7H); LC-MS:m / z 265.3(MH+).

[0304] Synthesis Route 2

[0305]

[0306] Synthetic Route 2 - Reagents and Conditions: a) Cyclopropylformyl chloride, TEA, DCM, 0℃ to room temperature; b) LiOH H2O, THF / MeOH / H2O 40℃, 5h; c) 1-Propylpiperazine, HATU, DIPEA, DMF, RT, overnight; d) Appropriate amine, Δ.

[0307] Preparation: N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0308]

[0309] At 0 °C, a solution of cyclopropanediol chloride (2.82 mL, 31.04 mmol) in 22 mL of DCM was slowly added 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). The mixture was heated to room temperature and stirred overnight. The next day, the reaction mixture was diluted with DCM, washed with NaHCO3 and brine, dried over 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).

[0310] Yield: 1.8g

[0311] 1¹H NMR (400 MHz, chloroform-d) δ 7.92 (t, ¹H), 7.69–7.60 (m, ¹H), 7.23–7.19 (m, ¹H), 1.60 (s, ³H), 1.54 (tt, ¹H), 1.17–1.11 (m, ²H), 0.93 (dt, ²H); LC-MS: 238.0 (MH+).

[0312] Preparation: 4-Cyclopropamido-2-fluorobenzoic acid

[0313]

[0314] A solution of lithium hydroxide (0.37 g, 15.44 mmol) in water (6.432 mL) was added to a solution of methyl 4-(cyclopropanecarbonylamino)-2-fluorobenzoate (1.8 g, 7.72 mmol) in a mixture of THF (6.432 mL) and methanol (3.216 mL), and the reaction was stirred at 40 °C for 5 h. The reaction was then cooled to room temperature and concentrated under vacuum. The residue was absorbed with 1 N HCl, and the suspension was filtered. The obtained solid was washed with H₂O and dried under vacuum to give the product of formula (4-(cyclopropanecarbonylamino)-2-fluorobenzoic acid).

[0315] Yield: 6.9g

[0316] 1 H NMR (400MHz, DMSO-d6) δ13.2(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+).

[0317] Preparation: N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0318]

[0319] To a solution of 4-(cyclopropanecarbonylamino)-2-fluorobenzoic acid (1.5 g, 6.95 mmol) in DCM (35 mL), 1-hydroxybenzotriazole hydrate (2.2 g, 14.36 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-1-propylamine hydrochloride (2.2 g, 11.49 mmol), and N,N-diisopropylethylamine (2.0 mL, 11.49 mmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. Then, a solution of 1-propylpiperazine (1.5 g, 11.49 mmol) in DCM (7 mL) was added, and the reaction mixture was stirred at room temperature overnight. The next day, the mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine, dried using a phase separator, and the solvent was removed under reduced pressure. The residue was purified by FC on an NH column (eluting with 100% DCM to DCM / MeOH 95:5) to give the product of formula (N-[3-fluoro-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide).

[0320] Yield: 1.95g

[0321] 1 H NMR (400MHz, chloroform-d) δ7.62(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+).

[0322] Preparation: N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide

[0323]

[0324] 3-azabicyclo[3.1.0]hexane hydrochloride (358.7 mg, 3 mmol), potassium carbonate (207.27 mg, 1.5 mmol), and N-[3-fluoro-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (100 mg, 0.3 mmol) were mixed in DMF (0.500 mL), and the reaction was heated to 120 °C and maintained for 1 week. The reaction was then cooled to room temperature and purified by FC on RP under alkaline conditions (eluting with 100% aqueous solution of ammonium bicarbonate adjusted to pH 10 with ammonia to 100% CH3CN) to give the product of formula (N-[3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide).

[0325] Yield: 5mg

[0326] 1 H NMR(400MHz,DMSO-d6)δ10.11(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 / z397.6(MH) + .

[0327] Preparation: N-(3-(3-methylpyrrolidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0328]

[0329] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), except that 3-methylpyrrolidine hydrochloride was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 15% (18 mg).

[0330] 1H NMR (500MHz, methanol-d4) δppm 7.19-7.10(m,1H),7.07-6.98(m,1H),6.93-6.87(m,1H),4.10-3.12(m,7H),2.95-2.80(m,1H),2.51-2.42(m,2H),2.79-2.29(m, 4H),2.40-2.28(m,1H),2.15-2.04(m,1H),1.80-1.71(m,1H),1.65-1.51(m,3H),1.18-1.06(m,3H),1.00-0.80(m,7H); LC-MS: m / z 399.6(MH) + .

[0331] The racemic mixture was then separated into individual enantiomers by preparative HPLC.

[0332]

[0333]

[0334] Preparation: cis / trans N-(3-((-3,5-dimethylpiperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropane formamide

[0335]

[0336] The title compound was synthesized in a manner similar to that of the compound of Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 3,5-dimethylpiperidine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in 99% (100 mg) yield as a mixture of cis / trans diastereomers.

[0337] The mixture of cis / trans isomers was then separated into individual isomers by preparative chiral HPLC.

[0338]

[0339]

[0340] Preparation: N-(3-(4-methylpiperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0341]

[0342] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide), wherein 4-methylpiperidine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 26% (32 mg).

[0343] 1H NMR(400MHz,DMSO-d6)δppm 10.21(s,1H),7.37(d,1H),7.18(dd,1H),7.01(d,1H),3.71-3.03(m,4H),3.40-2.31(m,4H),2.28-2.20(m,2H),2.46-2.05(m, 4H),1.80-1.69(m,1H),1.43(sxt,3H),1.89-1.13(m,4H),0.93(d,3H),0.84(t,3H),0.81-0.75(m,4H); LC-MS: m / z413.3(MH+).

[0344] Preparation: N-[4-(4-propylpiperazin-1-carbonyl)-3-(pyrrolidine-1-yl)phenyl]cyclopropaneformamide

[0345]

[0346] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein pyrrolidine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 30% (28 mg).

[0347] 1 H NMR (400MHz, chloroform-d) δ7.39(s,1H),7.18(s,1H),7.06(d,1H),6.66(dd,1H),4.01(d,1H),3.60(t,1H),3.47-3.1 4(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+).

[0348] Preparation: N-(3-(4,4-dimethylpiperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0349]

[0350] N-(3-(4-methylpiperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0351] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide), wherein 4,4-dimethylpiperidine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 24% (37 mg).

[0352] 1 H NMR(400MHz,DMSO-d6)δppm 10.22(s,1H),7.44(d,1H),7.17(dd,1H),7.01(d,1H),3.70-3.47(m,2H),3.20-2.68(m,6H),2.47-2.1 4(m,6H),1.82-1.70(m,1H),1.51-1.34(m,6H),0.95(s,6H),0.84(t,3H),0.81-0.76(m,4H); LC-MS:m / z 427.3(MH+).

[0353] Preparation: N-(3-(3,4-dihydroisoquinoline-2(1H)-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0354]

[0355] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 1,2,3,4-tetrahydroisoquinoline was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 12% (8 mg).

[0356] 1H NMR(400MHz,DMSO-d6)δppm 10.28(s,1H),7.49(d,1H),7.24(dd,1H),7.20-7.03(m,5H),4.25(d,1H),4.01(d,1H),3.36(br d,2H),3.66-3.04(m,4H),2.94-2.78(m,2H),2.36-2.06(m,4H),2.02(t,2H),1 .84-1.72(m,1H),1.35-1.19(m,2H),0.89-0.62(m,7H); LC-MS: m / z447.3(MH+).

[0357] Preparation: N-(3-(piperidin-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0358]

[0359] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide), wherein piperidine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 41% (50 mg).

[0360] 1H NMR(400MHz,DMSO-d6)δppm,10.22(s,1H),7.37(d,1H),7.19(dd,1H),7.02(d,1H),3.82-2.93(m,4H),3.07-2.68(m,4H),2.28-2.20(m, 2H),2.47-2.03(m,4H),1.81-1.71(m,1H),1.69-1.46(m,6H),1.46-1.37(m,2H),0.84(t,3H),0.81-0.74(m,4H); LC-MS: m / z399.3(MH+).

[0361] Preparation: N-[3-(cyclopentylamino)-4-(4-propylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0362]

[0363] The title compound was synthesized in a manner similar to that of the compound in Example 12 (N-(3-(3-azabicyclo[3.1.0]hex-3-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclopropane formamide), wherein cyclopentanamine was used instead of 3-azabicyclo[3.1.0]hexane hydrochloride. The title compound was obtained in a yield of 26% (23 mg).

[0364] 1 H NMR(400MHz,DMSO-d6)δ10.12(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(m,4H),1.50 -1.34(m,4H),0.86(t,3H),0.81-0.74(m,4H); LC-MS: m / z399.50(MH+).

[0365] The X2 group or part thereof, which is bridged by a carbonyl linker, can be prepared using synthesis scheme 3.

[0366] Synthesis Scheme 3

[0367]

[0368]

[0369] Synthetic Scheme 3 - Reagents and Conditions: a) Azacycloheptanine, CH3CN, 100℃, 2 days; b) Pd-C 10%, EtOH, rt, 2h; c) Cyclopropylformyl chloride, TEA, DCM, rt, overnight; d) LiOH, THF / H2O 4:1, 50℃, overnight; e) Suitable amine, HATU, DIPEA, DMF, RT, overnight; f) TFA, DCM, RT, 2h; g) Suitable aldehyde, STAB, DCM, RT, overnight.

[0370] Preparation: Methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzene

[0371]

[0372] A mixture of methyl 2-fluoro-4-nitrobenzene (3.0 g, 15.06 mmol) and 3,5-dimethylpiperidine (6.0 mL, 45.19 mmol) in MeCN (25.11 mL) was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was absorbed with AcOEt and washed with water and brine. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by FC on silica gel (eluting with 100% CHEX to CHEX / AcOEt 7:3) to give the product of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzene as a mixture of cis / trans isomers. The product was used as is in the next step.

[0373] Yield: 4g

[0374] LC-MS: m / z 293.1 (MH+)

[0375] Preparation: Methyl 2-(azacycloheptan-1-yl)-4-nitrobenzoate

[0376]

[0377] The title compound was synthesized in a manner similar to that of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate, except that a high-piperidine was used instead of 3,5-dimethylpiperidine. The title compound was obtained in 93% (2.6 g) yield.

[0378] 1 H NMR (400MHz, chloroform-d) δ7.78(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+).

[0379] Preparation: Methyl 4-nitro-2-pyrrolidine-1-ylbenzoate

[0380]

[0381] The title compound was synthesized in a manner similar to that of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate, except that pyrrolidine was used instead of 3,5-dimethylpiperidin. The title compound was obtained in 94% (5.9 g) yield.

[0382] 1H NMR (400MHz, DMSO-d6) δ7.64(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+).

[0383] Preparation: Methyl 2-(6-azaspiro[3.4]oct-6-yl)-4-nitrobenzoate

[0384]

[0385] To a solution of methyl 2-fluoro-4-nitrobenzoate (600.0 mg, 3.01 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.03 mmol) in DMF (8 mL), 6-azaspiro[3.4]octane (502.47 mg, 4.52 mmol) was added, and the reaction was stirred overnight at 80 °C. The reaction was cooled to room temperature and water was added by UPLC. The mixture was extracted three times with AcOEt. The combined organic matter was washed with brine, dried over a phase separator, and concentrated under vacuum. The crude product was purified by FC on silica gel (eluting with 100% CHEX to CHEX / AcOEt 9:1) to give the product of formula 2-(6-azaspiro[3.4]oct-6-yl)-4-nitrobenzoate.

[0386] Yield: 792mg

[0387] 1H NMR (400MHz, DMSO-d6) δ7.64(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 / z291.1(MH+).

[0388] Preparation: Methyl 2-(3-methylpyrrolidone-1-yl)-4-nitrobenzene

[0389]

[0390] The title compound was synthesized in a manner similar to that of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate, wherein 3-methylpyrrolidine hydrochloride and trimethylamine were used instead of 6-aza-spiro[3,4]octane and N,N-diisopropylethylamine, respectively. The title compound was obtained in 92% (2.45 g) yield.

[0391] 1H NMR(400MHz,DMSO-d6)δ7.64(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+).

[0392] Preparation: Methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate

[0393]

[0394] Palladium (1456.16 mg, 1.37 mmol) was added to a solution of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzene (4.0 g, 13.68 mmol) in ethanol (54.73 mL), and the reaction was stirred at room temperature under a H2 atmosphere for 2 h. The mixture was then filtered through a diatomaceous earth mat, washed with AcOEt, and the solution was concentrated under vacuum to give the product of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate as a mixture of cis / trans isomers. The crude product was used in the next step without further purification.

[0395] Yield: 3.5g

[0396] LC-MS: m / z 264.1 (MH+)

[0397] Preparation: Methyl 4-amino-2-pyrrolidine-1-ylbenzoate

[0398]

[0399] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 4-nitro-2-pyrrolidine-1-ylbenzoate was used instead of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. The title compound was obtained in 92% (5 g) yield.

[0400] 1H NMR (400MHz, DMSO-d6) δ7.29(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+).

[0401] Preparation: Methyl 4-amino-2-(6-azaspiro[3.4]oct-6-yl)benzoate

[0402]

[0403] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 2-(6-azaspiro[3.4]oct-6-yl)-4-nitrobenzoate was used instead of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. The title compound was obtained in 95% (672 mg) yield.

[0404] 1H NMR (400MHz, DMSO-d6) δ7.28(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+).

[0405] Preparation: Methyl 4-amino-2-(3-methylpyrrolidone-1-yl)benzoate

[0406]

[0407] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 2-(3-methylpyrrolidin-1-yl)-4-nitrobenzoate was used instead of methyl 2-(3,5-dimethylpiperidin-1-yl)-4-nitrobenzoate. The title compound was obtained in 99% (1.5 g) yield.

[0408] 1 H NMR(400MHz,DMSO-d6)δ7.28(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 / z245.72(MH+).

[0409] Preparation: Methyl 4-amino-2-(azacycloheptane-1-yl)benzoate

[0410]

[0411] A mixture of methyl 2-(azacycloheptane-1-yl)-4-nitrobenzoate (6.3 g, 22.18 mmol) and carbon-supported 10% palladium (2.36 g, 2.22 mmol) in ethanol (100 mL) was stirred overnight at room temperature under a H2 atmosphere. The next day, the reaction was filtered through a diatomaceous earth mat and concentrated under vacuum to give the product methyl 4-amino-2-(azacycloheptane-1-yl)benzoate.

[0412] Yield: 5.4g

[0413] 1 H NMR (400MHz, chloroform-d) δ7.53(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+).

[0414] Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate

[0415]

[0416] A solution of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate (3.5 g, 13.34 mmol) and N,N-diisopropylethylamine (5.58 mL, 40.02 mmol) in DCM (66.7 mL) was cooled to 0 °C, and cyclopropanediol chloride (2.42 mL, 26.68 mmol) was added dropwise. The mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the product of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate as a mixture of cis / trans isomers, which was used in the next step without further purification.

[0417] Yield: 4.2g

[0418] LC-MS: m / z 331.15 (MH+).

[0419] Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoate

[0420]

[0421] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 4-amino-2-pyrrolidine-1-ylbenzoate was used instead of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. The title compound was obtained in 99% (6 g) yield.

[0422] 1H NMR(400MHz,DMSO-d6)δ10.22(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+).

[0423] Preparation: Methyl 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoate

[0424]

[0425] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 4-amino-2-(6-azaspiro[3.4]oct-6-yl)benzoate was used instead of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. The title compound was obtained in 88% (742 mg) yield.

[0426] 1 H NMR(400MHz,DMSO-d6)δ10.21(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 / z329.11(MH+).

[0427] Preparation: Methyl 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidine-1-yl)benzoate

[0428]

[0429] The title compound was synthesized in a manner similar to that used in the synthesis of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate, except that methyl 4-amino-2-(3-methylpyrrolidin-1-yl)benzoate was used instead of methyl 4-amino-2-(3,5-dimethylpiperidin-1-yl)benzoate. The title compound was obtained in 99% (1.7 g) yield.

[0430] LC-MS: m / z 303.05 (MH+)

[0431] Preparation: Methyl 2-(azacycloheptan-1-yl)-4-cyclopropaneamidobenzoate

[0432]

[0433] A solution of methyl 4-amino-2-(azacycloheptane-1-yl)benzoate (5.4 g, 21.75 mmol) and N,N-diisopropylethylamine (7.58 mL, 43.49 mmol) in DCM (45 mL) was cooled to 0 °C, and cyclopropanecarboxylic acid chloride (2.96 mL, 32.62 mmol) was added dropwise after 5 minutes. The reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on an NH column (eluting with cHex / AcOEt 95:5 to cHex / AcOEt 50:50) to give the product methyl 2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoate.

[0434] Yield: 6.5g.

[0435] 1 H NMR (400MHz, chloroform-d) δ7.55(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+).

[0436] Preparation: 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid

[0437]

[0438] A solution of lithium hydroxide (974 mg, 40.68 mmol) in water (8 mL) was added to a solution of methyl 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoate (742.0 mg, 2.26 mmol) in a mixture of THF (16 mL) and methanol (19 mL). The reaction was stirred at 80 °C for 24 h. Thereafter, the reaction was cooled to room temperature, and the formation of a precipitate was observed. The suspension was filtered and the mother liquor was concentrated under vacuum. The residue was absorbed with H2O and washed three times with DCM. The aqueous phase was acidified with 3N HCl until pH = 1 and extracted three times with AcOEt. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product of formula 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid.

[0439] Yield: 330mg

[0440] 1H NMR(400MHz,DMSO-d6)δ12.68(s,1H),10.23(s,1H),7.49(d,1H),7.30(d,1H),6.92(dd ,1H),3.23-3.13(m,2H),3.11(s,2H),2.05-1.67(m,9H),0.88-0.68(m,4H); LC-MS:m / z 315.16(MH+).

[0441] Preparation: 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidone-1-yl)benzoic acid

[0442]

[0443] A solution of lithium hydroxide (1.5 g, 62.63 mmol) in water (4 mL) was added to a solution of methyl 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidone-1-yl)benzoate (2.46 g, 5.86 mmol) in a mixture of THF (11 mL) and methanol (4 mL), and the reaction mixture was stirred at 50 °C for 60 h. The reaction was cooled to room temperature, acidified with 3N HCl until pH = 1, and concentrated under vacuum. The residue was directly purified by FC on RP under acidic conditions (eluting from CH3CN / H2O 5:95 + 0.1% formic acid to CH3CN / H2O 7:3 + 0.1% formic acid) to give the product of formula 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidone-1-yl)benzoic acid.

[0444] Yield: 1.06g

[0445] 1H NMR(400MHz,DMSO-d6)δ12.82(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,1 H),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+).

[0446] Preparation: 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid

[0447]

[0448] The title compound was synthesized in a manner similar to that used in the synthesis of 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidine-1-yl)benzoic acid, except that methyl 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoate was used instead of methyl 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidine-1-yl)benzoate. The title compound was obtained in 49% (3 g) yield.

[0449] 1H NMR(400MHz,DMSO-d6)δ13.10(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+).

[0450] Preparation: cis / trans-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid

[0451]

[0452] A solution of lithium hydroxide (392.81 mg, 15.74 mmol) in water (3.14 mL) was added to a solution of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (2.6 g, 7.87 mmol) in a mixture of THF (9.44 mL) and methanol (3.14 mL). The resulting mixture was heated to 50 °C and kept overnight. The next day, the reaction was cooled to room temperature, adjusted to pH 2 with 3N HCl, and concentrated under reduced pressure. The obtained solid was absorbed with H2O, filtered, washed with H2O, and dried under vacuum to give the product of 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid as a mixture of cis / trans isomers.

[0453] Yield: 2.37g

[0454] LC-MS: m / z 317.19 (MH+).

[0455] Preparation: cis-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid and trans-4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid

[0456]

[0457] A solution of lithium hydroxide (392.81 mg, 15.74 mmol) in water (3.14 mL) was added to a solution of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (2.6 g, 7.87 mmol) in a mixture of THF (9.44 mL) and methanol (3.14 mL). The resulting mixture was heated to 50 °C and kept overnight. The next day, the reaction was cooled to room temperature, adjusted to pH 2 with 3N HCl, and concentrated under reduced pressure. The obtained solid was absorbed with H2O, filtered, washed with H2O, and dried under vacuum to give the product of formula 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid as a mixture of cis / trans isomers [2.37 g, LC-MS: m / z 317.19 (MH+)].

[0458] The mixture of isomers was then separated into individual isomers using a semi-preparative MDAP method.

[0459]

[0460] Preparation: 2-(azacycloheptan-1-yl)-4-cyclopropaneamidobenzoate

[0461]

[0462] A solution of lithium hydroxide (0.98 g, 41.09 mmol) in water (8 mL) was added to a solution of methyl 2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)benzoate (6.5 g, 20.54 mmol) in THF (24 mL) and methanol (8 mL). The reaction was stirred overnight at 50 °C. The next day, the reaction was cooled to room temperature and concentrated under vacuum. The residue was absorbed with 1 N HCl and stirred at 0 °C for 10 min. A solid was then observed, so the mixture was filtered, and the solid was washed with H₂O and dried under vacuum to give the product of formula 2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)benzoate.

[0463] Yield: 6.45g

[0464] 1 H NMR (400MHz, chloroform-d) δ10.04(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 / z303.2(MH+).

[0465] Preparation: 4-[2-(azacycloheptane-1-yl)-4-cyclopropaneamidobenzoyl]piperazine-1-carboxylic acid tert-butyl ester

[0466]

[0467] N,N-diisopropylethylamine (1.03 mL, 5.9 mmol) was added to a mixture of 2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)benzoate (1.0 g, 2.95 mmol), 1-hydroxybenzotriazole hydrate (0.93 g, 6.09 mmol), and 3-(ethyliminomethyleneamino)-N,N-dimethyl-1-propylamine hydrochloride (0.93 g, 4.87 mmol) in DCM (20 mL), and the reaction was stirred at room temperature for 30 min. Subsequently, tert-butyl 1-piperazincarnate (0.91 g, 4.87 mmol) was added, and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on silica gel (eluting with cHex / AcOEt 9:1 to cHex / AcOEt 1:1) to give the product of formula 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]piperazine-1-carboxylic acid tert-butyl ester.

[0468] Yield: 1.18g

[0469] 1 H NMR (400MHz, chloroform-d) δ7.53-7.49(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+).

[0470] Preparation: N-[3-(azacycloheptane-1-yl)-4-(piperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0471]

[0472] Trifluoroacetic acid (0.96 mL, 12.54 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (1.18 g, 2.51 mmol) in DCM (12.54 mL). The reaction was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum, and the residue was purified by SCX, first by washing with MeOH and then with 1 M NH3 in MeOH, to give the product of formula (N-[3-(azacycloheptane-1-yl)-4-(piperazine-1-carbonyl)phenyl]cyclopropanecarboxamide).

[0473] Yield: 0.8g

[0474] 1 H NMR (400MHz, chloroform-d) δ7.59-7.44(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+).

[0475] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazo-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropane formamide

[0476]

[0477] N-[3-(azacycloheptane-1-yl)-4-(piperazin-1-carbonyl)phenyl]cyclopropaneformamide (50.0 mg, 0.130 mmol) was suspended in MeCN (3 mL), and N,N-diisopropylethylamine (0.05 mL, 0.270 mmol) was added, followed by 1,2-oxazol-3-carboxaldehyde (14.41 mg, 0.150 mmol). The reaction mixture was stirred for 15 min, and then sodium triacetoxyborohydride (57.21 mg, 0.270 mmol) was added. The resulting mixture was stirred overnight at room temperature, then diluted with EtOAc and H2O, and the organic phase was separated. The aqueous phase was back-extracted twice with AcOEt, and the combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum.

[0478] The residue was purified by FC on an NH column (eluting with 100% cHex to 100% EtOAc) to give the product N-[3-(azacycloheptane-1-yl)-4-[4-(1,2-oxazol-3-ylmethyl)piperazine-1-carbonyl]phenyl]cyclopropaneformamide.

[0479] Yield: 20mg.

[0480] 1 H NMR(400MHz,DMSO-d6)δ10.13(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+).

[0481] Preparation: N-[3-(azacycloheptane-1-yl)-4-{4-[(1H-pyrazol-3-yl)methyl]piperazine-1-carbonyl}phenyl]cyclopropaneformamide

[0482]

[0483] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein pyrazole-3-carboxaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 21% (13 mg).

[0484] 1 H NMR(400MHz,DMSO-d6)δ12.62(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+).

[0485] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(oxazol-2-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0486]

[0487] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isooxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 2-oxazolaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 37% (22.5 mg).

[0488] 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.08(d,1H),7.34(d,1H),7.18(d,1H),7.01(dd,1H),6.91(d,1H),3.7 2(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+).

[0489] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0490]

[0491] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 3-methoxybenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 46% (30.5 mg).

[0492] 1H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),7.32(d,1H),7.23(t,1H),7.06-6.97(m,1H),6.94-6.77(m,4H),3.73(s,3H),3.4 7(d,4H),3.25-3.08(m,6H),2.45-2.17(m,4H),1.80-1.43(m,9H)0.82-0.71(m,4H); LC-MS:m / z 491.3(MH+).

[0493] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0494]

[0495] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 3-fluorobenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 40% (25 mg).

[0496] 1H NMR(400MHz,DMSO-d6)δppm 10.13(s,1H),7.33(d,2H),7.18-6.98(m,4H),6.91(d,1H),3.53(d,4H),3.27- 3.10(m,6H),2.46-2.19(m,4H),1.80-1.45(m,9H),0.84-0.72(m,4H); LCMS:m / z 479.3(MH+).

[0497] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(2-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0498]

[0499] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazo-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 2-methoxybenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 59% (58 mg).

[0500] 1H NMR(400MHz,DMSO-d6)δppm 10.19-10.05(m,1H),7.37-7.19(m,3H),6.90(d,4H),3.75(s,3H),3.62-3.49(m,4H), 3.25-3.09(m,6H),2.46-2.20(m,4H),1.75-1.49(m,9H),0.83-0.71(m,4H); LC-MS:m / z 491.3(MH+).

[0501] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0502]

[0503] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 2-fluorobenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 42% (41 mg).

[0504] 1H NMR(400MHz,DMSO-d6)δppm 10.16-10.04(m,1H),7.43-7.36(m,1H),7.32(d,2H),7.20-7.13(m,2H),7.03-6.97(m,1H),6.90(d,1H ),3.57(s,4H),3.23-3.05(m,6H),2.45-2.21(m,4H),1.78-1.43(m,9H),0.82-0.73(m,4H); LC-MS:m / z 479.3(MH+).

[0505] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0506]

[0507] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazo-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-fluorobenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in 65% (56 mg) yield.

[0508] 1H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),7.39-7.27(m,3H),7.19-7.08(m,2H),7.00(dd,1H),6.90(d,1H),3.52-3.43(m,2H),3.25-3.06(m,4H), 3.70-3.06(m,4H),2.46-2.16(m,4H),1.81-1.71(m,1H),1.70-1.43(m,8H),0.85-0.69(m,4H); LC-MS: m / z479.5(MH+).

[0509] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0510]

[0511] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazo-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-methoxybenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in 56% (50 mg) yield.

[0512] 1H NMR(400MHz,DMSO-d6)δppm,10.12(br s,1H),7.32(d,1H),7.19(d,2H),7.00(dd,1H),6.88(dd,3H),3.73(s,3H),3.67-3.47(m,2H),3.42(d,2H),3.24- 3.06(m,6H),2.43-2.16(m,4H),1.82-1.71(m,1H),1.69-1.40(m,8H),0.88-0.70(m,4H); LC-MS: m / z491.5(MH+).

[0513] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(2-chlorobenzyl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0514]

[0515] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 2-chlorobenzaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in 66% (52 mg) yield.

[0516] 1H NMR(400MHz,DMSO-d6)δppm 10.13(s,1H),7.49(dd,1H),7.43(dd,1H),7.43(dd,1H),7.37-7.24(m,3H),7.04-6.97(m,1H),6.92(d,1H) ,3.26-3.09(m,4H),3.74-3.07(m,4H),2.49-2.25(m,4H),1.83-1.45(m,9H),0.85-0.71(m,4H); LC-MS:m / z 495.4(MH+).

[0517] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-(pyridin-3-ylmethyl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0518]

[0519] The title compound was synthesized in a manner similar to that of the compound of Example 22 (N-(3-(azacycloheptane-1-yl)-4-(4-(isoxazol-3-ylmethyl)piperazin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 3-pyridinecarboxaldehyde was used instead of 1,2-oxazol-3-carboxaldehyde. The title compound was obtained in a yield of 34% (25 mg).

[0520] 1H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),8.49(d,1H),8.47(dd,1H),7.71(dt,1H),7.35(dd,1H),7.32(d,1H),7.00(dd,1H),6.91(d,1H),3.53(br d,2H),3.27-3.06(m,4H),3.72-3.06(m,4H),2.46-2.16(m,4H),1.80-1.71(m,1H),1.73-1.41(m,8H),0.85-0.69(m,4H); LC-MS: m / z 462.4(MH+).

[0521] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0522]

[0523] To a solution of N-[3-(azacycloheptane-1-yl)-4-(piperazin-1-carbonyl)phenyl]cyclopropaneformamide (75.0 mg, 0.200 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.300 mmol) in DMSO (2 mL), 7-chlorothiophene[2,3-C]pyridine (41.21 mg, 0.240 mmol) was added, and the reaction was stirred overnight at 120 °C, then heated to 150 °C under microwave conditions and maintained for 2 h. The reaction was concentrated to dryness, and the residue was absorbed with AcOEt. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on silica gel (eluting with 100% AcOEt to AcOEt / MeOH 8:2) to give the product N-[3-(azacycloheptane-1-yl)-4-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide.

[0524] Yield: 9mg

[0525] 1H NMR(400MHz,DMSO-d6)δppm 10.11-10.19(m,1H)8.09(d,1H)8.01(d,1H)7.49(d,1H)7.39(d,2H)7.01(s,2H)3.82-3 .90(m,1H)3.34-3.80(m,7H)3.21-3.27(m,4H)1.45-1.81(m,9H)0.80(d,4H); LC-MS:m / z 504.4(MH+).

[0526] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-thieno[3,2-d]pyrimidin-4-ylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0527]

[0528] The title compound was synthesized in a manner similar to that of the compound in Example 33 (N-[3-(azacycloheptane-1-yl)-4-(4-thieno[2,3-c]pyridin-7-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide), wherein 4-chlorothieno[2,3-D]pyrimidine was used instead of 7-chlorothieno[2,3-C]pyrimidine. The title compound was obtained in 85% (86 mg) yield.

[0529] 1H NMR(400MHz,DMSO-d6)δppm 10.13-10.19(m,1H)8.51(s,1H)8.23(d,1H)7.41-7.48(m,1H)7.33-7.40(m,1H)6.96-7.07(m,2H)3 .65-4.14(m,6H)3.32-3.45(m,2H)3.16-3.26(m,4H)1.43-1.82(m,9H)0.74-0.85(m,4H); LC-MS:m / z 505.4(MH+).

[0530] Preparation: N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropaneformamide

[0531]

[0532] 2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)benzoate (50.0 mg, 0.150 mmol), HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-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 min, followed by the addition of piperidine (14.45 mg, 0.170 mmol). The reaction mixture was stirred at room temperature for 2 minutes. The reaction mixture was then concentrated under vacuum, and the residue was purified using an SCX box, first by washing with MeOH and then eluting with 1 M NH3 in MeOH. The alkaline fraction was evaporated, and the residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 70:30) to give the product N-[3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl]cyclopropaneformamide.

[0533] Yield: 46mg

[0534] 1 H NMR(400MHz,DMSO-d6)δ10.11(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 / z370.3(MH+).

[0535] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0536]

[0537] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), except that azacycloheptane was used instead of piperidine. The title compound was obtained in a yield of 77.2% (470 mg).

[0538] NMR: 1 H NMR(400MHz,DMSO-d6)δ10.13(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+).

[0539] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0540]

[0541] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1,2-dimethylpiperazine was used instead of piperidine. The title compound was obtained in 48% (42 mg) yield.

[0542] 1H NMR(400MHz,DMSO-d6)δ10.13(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+).

[0543] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(trifluoromethyl)piperidin-1-carbonyl)phenyl)cyclopropaneformamide

[0544]

[0545] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), except that 4-(trifluoromethyl)piperidine hydrochloride was used instead of piperidine. The title compound was obtained in 54% (35 mg) yield.

[0546] 1H NMR(400MHz,DMSO-d6)dppm 10.19-10.06(m,1H),7.41-7.30(m,1H),6.98-6.88(m,2H),6.90(s,1H),4.69-4.54(m,1H),3.51-3.37(m, 1H),3.25-3.12(m,4H),3.08-2.89(m,1H),2.76-2.53(m,2H),1.96-1.09(m,12H),0.79(m,4H); LC-MS: m / z 438.3(MH+).

[0547] Preparation: N-(3-(azacycloheptan-1-yl)-4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)cyclopropaneformamide

[0548]

[0549] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1,2,3,4-tetrahydroisoquinoline was used instead of piperidine. The title compound was obtained in 68% (42 mg) yield.

[0550] 1H NMR(400MHz,DMSO-d6)dppm 10.16(s,1H),7.37(dd,1H),7.28-6.92(m,6H),4.90-4.25(m,2H),4.05-3.93(m,1H),3.40(d ,1H),3.25-3.01(m,4H),2.93-2.69(m,2H),1.82-1.24(m,9H),0.87-0.71(m,4H); LC-MS:m / z 418.4(MH+).

[0551] Preparation: N-(3-(azacycloheptan-1-yl)-4-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-2-carbonyl)phenyl)cyclopropaneformamide

[0552]

[0553] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine was used instead of piperidine. The title compound was obtained in 70% (42 mg) yield.

[0554] 1H NMR(400MHz,DMSO-d6)dppm 10.16(s,1H),7.38(dd,1H),7.08-6.94(m,2H),6.66(d,1H),6.07-5.94(m,1H),5.92-5.63(m,1H),4.96-4 .22(m,2H),4.07-3.76(m,3H),3.51(s,1H),3.20(t,4H),1.81-1.26(m,9H),0.88-0.69(m,4H); LC-MS:m / z 407.4(MH+).

[0555] Preparation: N-[3-(azacycloheptane-1-yl)-4-{octahydropyrrolo[1,2-a]pyrazine-2-carbonyl}phenyl]cyclopropaneformamide

[0556]

[0557] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine was used instead of piperidine. The title compound was obtained in 65% (65 mg) yield.

[0558] 1 ¹H NMR (400MHz, 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+).

[0559] Preparation: N-(3-(azacycloheptane-1-yl)-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)cyclopropaneformamide

[0560]

[0561] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 5,6,7,8-tetrahydro-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyrazine was used instead of piperidine. The title compound was obtained in 72% (51 mg) yield.

[0562] 1H NMR(400MHz,DMSO-d6)δppm 10.30-10.12(m,1H),7.53-7.36(m,1H),7.18-6.97(m,2H),5.31-4.46(m,2H),4.35-3.61( m,4H),3.26-3.02(m,4H),1.77(quin,1H),1.69-1.30(m,8H),0.87-0.73(m,4H); LC-MS:m / z 477.4(MH+).

[0563] Preparation: 2-(azacycloheptan-1-yl)-4-cyclopropaneamido-N-[(pyridin-2-yl)methyl]benzamide

[0564]

[0565] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), except that 2-pyridylmethylamine was used instead of piperidine. The title compound was obtained in a yield of 43% (50 mg).

[0566] 1 H NMR(400MHz,DMSO-d6)δ10.31(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 / z393.4(MH+).

[0567] Preparation: 2-(azacycloheptane-1-yl)-N-benzyl-4-cyclopropaneamidobenzamide

[0568]

[0569] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropaneformamide), except that benzylamine was used instead of piperidine. The title compound was obtained in 69% (66 mg) yield.

[0570] 1 H NMR (400MHz, chloroform-d) δ10.86(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+).

[0571] Preparation of 2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)-N-(pyridin-3-ylmethyl)benzamide

[0572]

[0573] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 3-pyridylmethylamine was used instead of piperidine. The title compound was obtained in a yield of 72% (69 mg).

[0574] 1 H NMR (400MHz, chloroform-d) δ11.13(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+).

[0575] Preparation: N-(3-(azacycloheptan-1-yl)-4-(morpholin-4-carbonyl)phenyl)cyclopropaneformamide

[0576]

[0577] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropaneformamide), except that morpholine was used instead of piperidine. The title compound was obtained in 60% (66 mg) yield.

[0578] 1 H NMR(400MHz,DMSO-d6)δ10.14(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 / z372.4(MH+).

[0579] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(pyridin-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0580]

[0581] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), except that 1-(2-pyridyl)piperazine was used instead of piperidine. The title compound was obtained in 60% (77 mg) yield.

[0582] 1 H NMR(400MHz,DMSO-d6)δ10.16(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+).

[0583] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-propylpiperidin-1-carbonyl)phenyl)cyclopropaneformamide

[0584]

[0585] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 3-ethyl-N-methylhexyl-1-amine was used instead of piperidine. The title compound was obtained in a yield of 45% (55 mg).

[0586] 1H NMR(400MHz,DMSO-d6)δppm 10.11(s,1H),7.31(dd,1H),7.03-6.97(m,1H),6.95-6.81(m,1H),3.27-3.09(m,4H),4.61-2.54(m,4H),1 .79-1.39(m,12H),1.36-1.23(m,2H),1.22-0.82(m,4H),0.90-0.82(m,3H),0.81-0.72(m,4H); LC-MS:m / z 412.5(MH+).

[0587] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-ethoxypiperidine-1-carbonyl)phenyl)cyclopropaneformamide

[0588]

[0589] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), except that 4-ethoxypiperidine-1-onium chloride was used instead of piperidine. The title compound was obtained in 61% (75 mg) yield.

[0590] 1H NMR(400MHz,DMSO-d6)δppm 10.12(s,1H),7.32(d,1H),7.04-6.96(m,1H),6.91(dd,1H),4.17-3.39(m,5H),3.31-2.87(m ,6H),1.80-1.7(m,1H),2.11-1.16(m,12H),1.17-1.02(m,3H),0.83-0.72(m,4H); LC-MS:m / z 414.4(MH+).

[0591] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-methylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0592]

[0593] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1-methylpiperazine was used instead of piperidine. The title compound was obtained in 76% (86 mg) yield.

[0594] 1H NMR(400MHz,DMSO-d6)δppm 10.13(s,1H),7.33(d,1H),7.01(dd,1H),6.91(d,1H),3.88-2.96(m,8H),2.4 2-2.07(m,7H),1.83-1.42(m,9H),0.85-0.72(m,4H); LC-MS: m / z385.4(MH+).

[0595] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-benzylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0596]

[0597] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), except that 1-benzylpiperazine was used instead of piperidine. The title compound was obtained in a yield of 23% (31 mg).

[0598] 1H NMR(500MHz,DMSO-d6)δppm 10.13(s,1H),7.37-7.27(m,5H),7.27-7.22(m,1H),7.00(dd,1H),6.90(d,1H ),3.49(d,2H),3.69-3.08(m,4H),3.26-3.08(m,4H),2.46-2.02(m,4H),1.79 -1.71(m,1H),1.71-1.44(m,8H),0.86-0.70(m,4H); LC-MS: m / z 461.4(MH+).

[0599] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-(pyridin-3-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0600]

[0601] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 1-pyridin-3-yl-piperazine was used instead of piperidine. The title compound was obtained in a yield of 20% (26 mg).

[0602] 1H NMR(500MHz,DMSO-d6)δppm 10.16(s,1H),8.31(d,1H),8.02(dd,1H),7.37(d,1H),7.33(ddd,1H),7.22(dd,1H),7.08-7.01(m,1H),7.00-6.94(m,1H),3 .24-3.19(m,4H),3.89-3.00(m,8H),1.81-1.73(m,1H),1.73-1.60(m,4H),1.60-1.43(m,4H),0.83-0.75(m,4H); LC-MS: m / z 448.4(MH+).

[0603] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-phenylpiperazine-1-carbonyl)phenyl)cyclopropaneformamide

[0604]

[0605] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1-phenylpiperazine was used instead of piperidine. The title compound was obtained in a yield of 28% (21 mg).

[0606] 1H NMR(400MHz,DMSO-d6)δppm 10.15(s,1H),7.36(d,1H),7.28-7.16(m,2H),7.08-7.01(m,1H),6.97(d,1H),6.94( d,2H),6.80(t,1H),3.91-3.26(m,4H),3.26-2.91(m,8H),1.84-1.72(m,1H),1.67(br s,4H),1.60-1.39(m,4H),0.91-0.64(m,4H); LC-MS: m / z447.4(MH+).

[0607] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-cyclopentylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0608]

[0609] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1-cyclopentylpiperazine was used instead of piperidine. The title compound was obtained in 68% (73 mg) yield.

[0610] 1 H NMR (400MHz, chloroform-d) δ7.46(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+).

[0611] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(1-benzyltetrazole-5-yl)piperidin-1-carbonyl]phenyl]cyclopropane formamide

[0612]

[0613] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropaneformamide), wherein 2-(1-benzyltetrazole-5-yl)piperidine was used instead of piperidine. The title compound was obtained in 60% (64 mg) yield.

[0614] 1 H NMR (400MHz, chloroform-d) δ7.51-7.34(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 / z528.3(MH+).

[0615] Preparation: N-[3-(azacycloheptane-1-yl)-4-(3,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0616]

[0617] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1,2-dimethylpiperazine was used instead of piperidine. The title compound was obtained in 48% (42 mg) yield.

[0618] 1 H NMR(400MHz,DMSO-d6)δ10.13(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+).

[0619] Preparation: 2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)-N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]benzamide

[0620]

[0621] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropaneformamide), wherein [4-(4-methylpiperazin-1-yl)phenyl]methylamine was used instead of piperidine. The title compound was obtained in 59% (64 mg) yield.

[0622] 1H NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),9.83-9.70(m,1H),7.66-7.50(m,2H),7.18(d,3H),6.89(d,2H),4.35(d,2H),3.15-2.97(m,8H),2.47- 2.38(m,4H),2.21(s,3H),1.81-1.70(m,1H),1.63-1.50(m,4H),1.44(d,4H),0.85-0.72(m,4H); LC-MS: 490.4(MH+).

[0623] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-pyridin-4-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0624]

[0625] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 1-pyridin-4-ylpiperazine was used instead of piperidine. The title compound was obtained in a yield of 24% (32 mg).

[0626] 1 H NMR(400MHz,DMSO-d6)δ10.16(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(td,6H),1.81-1.73(m,1H),1.67(s,4H),1.59-1.45(m,4H),0.87-0.70(m,4H); LC-MS: m / z 448.4(MH+).

[0627] Preparation: N-[4-(3-phenylthiomorpholine-4-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0628]

[0629] N,N-diisopropylethylamine (324.4 mg, 2.51 mmol) and 3-phenylthiomorpholine (150.0 mg, 0.840 mmol) were sequentially added to a solution of 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid (229.52 mg, 0.840 mmol) and HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium; hexafluorophosphate (477.2 mg, 1.26 mmol) in MeCN (2.4 mL). The reaction mixture was heated to 70 °C and stirred overnight. After the reaction was complete, the mixture was cooled to room temperature and then poured into a saturated NaHCO3 solution (30 mL) and AcOEt (45 mL). The phases were separated, and the organic layer was washed with a saturated NH4Cl solution, dried over Na2SO4, and concentrated under vacuum to dryness. The residue was purified by FC on silica gel (eluting with cHex / AcOEt 8:2 to cHex / AcOEt 2:8) to give the product of N-[4-(3-phenylthiomorpholine-4-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide.

[0630] Yield: 180mg

[0631] 1H NMR (400MHz, DMSO-d6) δ10.18-10.01(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+).

[0632] Preparation: N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0633]

[0634] A solution of 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid (100.0 mg, 0.360 mmol), N,N-diisopropylethylamine (0.19 mL, 1.09 mmol), and HATU:([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (207.91 mg, 0.550 mmol)) in DMF (1.823 mL) was stirred at room temperature for 15 minutes. Then, 4,4-difluoropiperidine (53.43 mg, 0.440 mmol) was added, and the reaction mixture was stirred at 80 °C for 2 hours. Subsequently, a saturated NaHCO3 solution was added, and the reaction mixture was extracted three times with AcOEt. The organic fraction was collected, washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by FC on RP under acidic conditions (eluting with CH3CN / H2O5:95+0.1% formic acid to CH3CN / H2O95:5+0.1% formic acid) to give the product of N-[4-(4,4-difluoropiperidin-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide.

[0635] Yield: 58mg

[0636] 1H NMR(400MHz,DMSO-d6)δ10.11(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+).

[0637] Preparation: N-[4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropane formamide

[0638]

[0639] The title compound was synthesized in a manner similar to that of the compound in Example 59 (N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 1,4-thiazine 1,1-dioxide hydrochloride was used instead of 4,4-difluoropiperidine. The title compound was obtained in 46% (66 mg) yield.

[0640] 1 H NMR(400MHz,DMSO-d6)δ10.12(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+).

[0641] Preparation: N-[3-pyrrolidone-1-yl-4-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl]cyclopropaneformamide

[0642]

[0643] The title compound was synthesized in a manner similar to that of the compound of Example 59 (N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-(trifluoromethyl)piperidine was used; hydrochloride was used instead of 4,4-difluoropiperidine. The title compound was obtained in 70% (52 mg) yield.

[0644] 1H NMR(400MHz,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+).

[0645] Preparation: N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0646]

[0647] The title compound was synthesized in a manner similar to that of the compound in Example 59 (N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 1-methyl-3-phenylpiperazine was used instead of 4,4-difluoropiperidine. The title compound was obtained as a racemic mixture in 49% (38.7 mg) yield.

[0648] 1H NMR(400MHz,DMSO-d6)δppm 1H NMR(400MHz,DMSO-d6)δppm 10.16-10.06(m,1H),7.78-7.16(m,5H),7.16-6.75(m,3H),5.85-4.63(m,1H),4.51-3.11(m,4H),4.51-3.11(m,4H),3.0 8-2.57(m,4H),2.28-2.16(m,3H),2.40-1.95(m,2H),1.79-1.71(m,1H),1.94-1.56(m,4H),0.83-0.69(m,4H); LC-MS: m / z 433.27(MH+).

[0649] The racemic mixture (Example 62c) was then separated into individual enantiomers by chiral semi-preparative HPLC.

[0650]

[0651]

[0652] Preparation: 2R or 2S N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide hydrochloride

[0653]

[0654] (2R or 2S)N-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide (enantiomer 1, Example 62a, 10 mg) was dissolved in MeOH (1 mL) and treated with HCl in 1 equivalent of dioxane. After evaporation, the product of formula 2R or 2SN-[4-(4-methyl-2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide hydrochloride was obtained.

[0655] Yield: 10mg

[0656] LC-MS: m / z 433.32 (MH+)

[0657] Preparation: N-[3-(3-methylpyrrolidin-1-yl)-4-[4-(trifluoromethyl)piperidine-1-carbonyl]phenyl]cyclopropaneformamide

[0658]

[0659] Examples 63a, 63b, and 63c

[0660] The title compound was synthesized in a manner similar to that of the compound of Example 59 (N-[4-(4,4-difluoropiperidine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-(trifluoromethyl)piperidine hydrochloride and 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidine-1-yl)benzoic acid were used instead of 4,4-difluoropiperidine and 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid, respectively. The title compound was obtained as a racemic mixture in 67% (98 mg) yield.

[0661] 1 H NMR(400MHz,DMSO-d6)δ10.14-10.05(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+).

[0662] The racemic mixture (Example 63c) was then separated into individual enantiomers by chiral semi-preparative HPLC.

[0663]

[0664] Preparation: N-[4-(4-methyl-2-phenylpiperazin-1-carbonyl)-3-(3-methylpyrrolidone-1-yl)phenyl]cyclopropaneformamide

[0665]

[0666] A stirred solution of 4-(cyclopropanecarbonylamino)-2-(3-methylpyrrolidone-1-yl)benzoic acid (200.0 mg, 0.690 mmol), N,N-diisopropylethylamine (0.36 mL, 2.08 mmol), and HATU ([dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (395.61 mg, 1.04 mmol)) in DMF (7.291 mL) was stirred at room temperature for 15 minutes. Then, 1-methyl-3-phenylpiperazine (146.71 mg, 0.830 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The next day, a saturated NaHCO3 solution was added to the reaction mixture, and the aqueous phase was extracted three times with AcOEt. The organic fraction was collected, washed with brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by FC on an NH column (eluting with 100% CHEX to 100% AcOEt) to give the product of N-[4-(4-methyl-2-phenylpiperazin-1-carbonyl)-3-(3-methylpyrrolidine-1-yl)phenyl]cyclopropaneformamide as a mixture of diastereomers.

[0667] Yield: 150mg

[0668] LC-MS: m / z 447.23 (MH+)

[0669] The mixture of diastereomers was then separated into individual enantiomers by chiral semi-preparative HPLC.

[0670]

[0671]

[0672]

[0673] Preparation: N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)phenyl]cyclopropaneformamide

[0674]

[0675] 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid (112.0 mg, 0.360 mmol), HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (162.55 mg, 0.430 mmol), and N,N-diisopropylethylamine (0.25 mL, 1.43 mmol) were mixed in DMF (3 mL) and stirred for 5 min. Then, thiomorpholine 1,1-dioxide (48.16 mg, 0.360 mmol) was added. The reaction mixture was stirred overnight at room temperature. The next day, water was added, and the mixture was extracted three times with AcOEt. The combined organic matter was washed with brine, dried using a phase separator, and then concentrated under vacuum. The residue was purified by FC on RP under alkaline conditions (eluting from 100% water + 0.1% NH4OH to water + 0.2% NH4OH / CH3CN 6:4) to give the product of formula (N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)phenyl]cyclopropaneformamide).

[0676] Yield: 26.8 mg

[0677] 1H NMR(600MHz,DMSO-d6)δppm 10.12(s,1H),7.16-7.03(m,2H),6.90(dd,1H),4.33-4.45(m,1H),3.71-3.83(m,1H),3.70-3.60(m,1H), 3.59-3.48(m,1H),3.36-2.97(m,8H),2.04-1.80(m,8H),1.79-1.72(m,1H),0.90-0.65(m,4H); LC-MS:m / z 432.2(MH+).

[0678] Preparation: N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(4-methyl-2-phenylpiperazine-1-carbonyl)phenyl]cyclopropane formamide

[0679]

[0680] The title compound was synthesized in a manner similar to that of the compound in Example 65 (N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(1,1-dioxo-1,4-thiazinane-4-carbonyl)phenyl]cyclopropaneformamide), wherein 1-methyl-3-phenylpiperazine was used instead of thiomorpholine 1,1-dioxide. The title compound was obtained as a racemic mixture in a yield of 20% (30 mg).

[0681] 1H NMR(400MHz,DMSO-d6)δppm 10.18-10.00(m,1H),7.16-6.99(m,1H),6.99-6.92(m,1H),6.92-6.84(m,1H),7.84-6.66(m,5H),5.87-4.60(m,1H),3.28-3.20(m ,2H),3.06-2.61(m,2H),4.48-2.29(m,6H),2.27-2.10(m,3H),1.80-1.69(m,1H),2.09-1.53(m,8H),0.84-0.67(m,4H); LC-MS: m / z 473.2(MH+).

[0682] The racemic mixture (Example 66c) was then separated into individual enantiomers by chiral semi-preparative HPLC.

[0683]

[0684] Preparation: cis-N-[3-[-3,5-dimethylpiperidin-1-yl]-4-(1,1-dioxo-1,4-thiazin-4-carbonyl)phenyl]cyclopropane formamide

[0685]

[0686] The title compound was synthesized in a manner similar to that of the compound of Example 65 (N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(1,1-dioxo-1,4-thiazinyl-4-carbonyl)phenyl]cyclopropanecarboxamide), wherein cis-4-(cyclopropanecarbonylamino)-2-[(3,5-dimethylpiperidin-1-yl]benzoic acid was used instead of 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid. The title compound was obtained in a yield of 20% (21 mg).

[0687] 1 H NMR(400MHz,DMSO-d6)δppm 10.27(s,1H),7.42(d,1H),7.26(dd,1H),7.15(d,1H),4.29-3.39(m,4H),3.30-3.00(m,2H),-3.61-2.97(m,4H),2. 38-1.88(m,2H),1.84-1.72(m,2H),1.71-1.48(m,2H),0.82-0.74(m,4H),0.99-0.71(m,6H),0.62(q,1H); LC-MS: m / z 434.2(MH+).

[0688] Preparation: cis-N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0689]

[0690] The title compound was synthesized in a manner similar to that of the compound of Example 66 (N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide), wherein cis-4-(cyclopropanecarbonylamino)-2-[(3,5-dimethylpiperidin-1-yl]benzoic acid was used instead of 2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoic acid. The title compound was obtained as a racemic mixture in 62% (92 mg) yield.

[0691] 1H NMR(400MHz,DMSO-d6)δppm 10.31-10.06(m,1H),7.81-6.94(m,8H),5.74(brs,1H),2.94-2.22(m,4H),2.17(s,2H),1.82-1.76(m,1H),4.43-1.69(m,6 H), 2.01-1.53(m,3H), 2.07-1.03(m,1H), 0.82-0.74(m,4H), 0.71-0.41(m,1H), 0.99-0.38(m,6H); LC-MS: m / z475.3(MH+).

[0692] The racemic mixture (Example 68c) was then separated into individual enantiomers by chiral semi-preparative HPLC.

[0693]

[0694] Preparation: trans-N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0695]

[0696] HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (60.09 mg, 0.160 mmol) was added to a solution of 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoic acid (50.0 mg, 0.160 mmol) in DMF (1.58 mL) and N,N-diisopropylethylamine (0.07 mL, 0.400 mmol), and the mixture was stirred at room temperature for 30 min. Subsequently, 1-methyl-3-phenylpiperazine (32.03 mg, 0.180 mmol) was added, and the reaction was stirred overnight at room temperature. The next day, H₂O was added, and precipitate formation was observed. The solid was filtered and washed with H₂O. The obtained solid was first purified by FC on RP under acidic conditions (eluting from CH3CN / H2O 5:95 + 0.1% formic acid to CH3CN / H2O 6:4 + 0.1% formic acid), and then further purified by a semi-preparative MDAP method.

[0697]

[0698] Preparation: cis-2R or 2S N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide hydrochloride

[0699]

[0700] Cis-2R or 2S N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (enantiomer 1, Example 68a, 14 mg) was dissolved in MeOH (1 mL) and treated with HCl in 1 equivalent of dioxane. After evaporation, the product of cis-2R or 2S N-[3-[3,5-dimethylpiperidin-1-yl]-4-(4-methyl-2-phenylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide hydrochloride was obtained.

[0701] Yield: 10.1 mg

[0702] LC-MS: 475.33 (MH+)

[0703] Preparation: N-[4-(2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0704]

[0705] Trifluoroacetic acid (1.0 mL, 23.77 mmol) was added to a solution of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-phenylpiperazine-1-carboxylate (156.0 mg, 0.300 mmol) in DCM (3 mL), and the reaction was allowed to stand overnight at room temperature. The solvent was removed under vacuum, and the residue was purified by SCX, washed with MeOH, and eluted with NH3 in 1N in MeOH. The basic fraction was evaporated, and the residue was purified by FC on an NH column (eluted with 100% DCM to DCM / MeOH 95:5) to give the product of N-[4-(2-phenylpiperazine-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide as a racemic mixture.

[0706] Yield: 85mg.

[0707] 1H NMR(500MHz,DMSO-d6)δppm 10.18-9.98(m,1H),7.15-7.02(m,1H),6.99-6.70(m,1H),7.98-6.57(m,6H),5.71-4.57(m,1H),3.31-2.76(m,4H), 2.84-2.54(m,2H),4.49-2.54(m,4H),1.79-1.74(m,1H),2.01-1.54(m,4H),0.84-0.65(m,4H); LC-MS: 419.2(MH+).

[0708] Preparation: N-[4-[2-(2-fluorophenyl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0709]

[0710] Trifluoroacetic acid (0.29 mL, 3.73 mmol) was added to a solution of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate (200.0 mg, 0.370 mmol) in DCM (3 mL), and the reaction was stirred at room temperature for 2 h. The solvent was removed under vacuum, and the residue was purified by SCX, washed with MeOH, and eluted with NH3 in 1N in MeOH. The basic fraction was evaporated to give the product of N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide as a racemic mixture.

[0711] Yield: 95mg

[0712] LC-MS: m / z 437.17 (MH+)

[0713] Preparation: N-[4-[2-(4-fluorophenyl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0714]

[0715] The title compound was synthesized in a manner similar to that of the compound in Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a racemic mixture in 95% (85 mg) yield.

[0716] LC-MS: m / z 437.18 (MH+).

[0717] Preparation: N-[4-[2-(3-fluorophenyl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0718]

[0719] The title compound was synthesized in a manner similar to that of the compound in Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a racemic mixture in 99% (75 mg) yield.

[0720] LC-MS: m / z 437.18 (MH+).

[0721] Preparation: N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(2-thiophene-2-ylpiperazine-1-carbonyl)phenyl]cyclopropane formamide

[0722]

[0723] The title compound was synthesized in a manner similar to that of the compound in Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-[2-(6-azaspiro[3.4]oct-6-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester. The title compound was obtained as a racemic mixture in 60% (14 mg) yield.

[0724] LC-MS: m / z 465.18 (MH+).

[0725] Preparation: N-[3-pyrrolidone-1-yl-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0726]

[0727] The title compound was synthesized in a manner similar to that of the compound in Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylate tert-butyl ester. The title compound was obtained as a racemic mixture in 99% (170 mg) yield.

[0728] LC-MS: m / z 425.12 (MH+).

[0729] Preparation: N-[4-[2-(1-methylpyrazol-4-yl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0730]

[0731] The title compound was synthesized in a manner similar to that of the compound in Example 157 (N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a racemic mixture in 88% (88 mg) yield.

[0732] LC-MS: m / z 425.12 (MH+).

[0733] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(thiophene-2-yl)piperazin-1-carbonyl]phenyl]cyclopropaneformamide

[0734]

[0735] 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylic acid tert-butyl ester (145.0 mg, 0.260 mmol) was dissolved in DCM (4 mL), and trifluoroacetic acid (0.2 mL, 2.62 mmol) was added. The mixture was stirred overnight at room temperature, and then the volatiles were removed under vacuum. The residue was loaded onto an SCX, washed with MeOH, and eluted with NH3 in MeOH at 1N. The basic fraction was evaporated to give a compound of the formula (N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide), which was used in the next step without further purification.

[0736] Yield: 94mg

[0737] LC-MS: 453.2 (MH+).

[0738] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-3-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0739]

[0740] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophene-3-ylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 96% (51 mg) yield.

[0741] LC-MS: m / z 453.2 (MH+).

[0742] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(1-methylpyrazol-4-yl)piperazin-1-carbonyl]phenyl]cyclopropane formamide

[0743]

[0744] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 92% (53 mg) yield.

[0745] LC-MS: m / z 451.3 (MH+).

[0746] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0747]

[0748] The title compound was synthesized in a manner similar to that of the compound of Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylic acid tert-butyl ester. The title compound was obtained in 91% (60 mg) yield.

[0749] LC-MS: m / z 448.3 (MH+).

[0750] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(trifluoromethyl)piperazine-1-carbonyl]phenyl]cyclopropaneformamide

[0751]

[0752] The title compound was synthesized in a manner similar to that of the compound of Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(trifluoromethyl)piperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 90% (33 mg) yield.

[0753] LC-MS: m / z 439.3 (MH+).

[0754] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-benzylpiperazine-1-carbonyl)phenyl]cyclopropane formamide

[0755]

[0756] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-benzylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 80% (65 mg) yield.

[0757] LC-MS: m / z 461.3 (MH+).

[0758] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(hydroxymethyl)piperazine-1-carbonyl]phenyl]cyclopropaneformamide

[0759]

[0760] The title compound was synthesized in a manner similar to that of the compound of Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 86% (72 mg) yield.

[0761] LC-MS: m / z 401.6 (MH+).

[0762] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-methylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0763]

[0764] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-methylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 80% (70 mg) yield.

[0765] LC-MS: m / z 385.3 (MH+).

[0766] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-propyl-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0767]

[0768] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-propyl-2-ylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 83% (80 mg) yield.

[0769] LC-MS: m / z 413.3 (MH+).

[0770] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-phenylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0771]

[0772] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-phenylpiperazine-1-carboxylate tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylate tert-butyl ester. The title compound was obtained in 83% (80 mg) yield.

[0773] LC-MS: m / z 447.3 (MH+).

[0774] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0775]

[0776] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylic acid tert-butyl ester was used instead of 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylic acid tert-butyl ester. The title compound was obtained in 92% (60 mg) yield.

[0777] LC-MS: 448.3 (MH+).

[0778] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophen-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0779]

[0780] At 0 °C, sodium triacetoxyborohydride (264.1 mg, 1.25 mmol) was added to a mixture of N-[3-(azacycloheptan-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (94.0 mg, 0.210 mmol) and 37% formaldehyde in H₂O (0.15 mL, 2.08 mmol) in methanol (5 mL). The reaction was heated to room temperature 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, and 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 100% CHEX to CHEX / AcOEt 10:90) and further purified by FC on RP under alkaline conditions (eluting with 100% water + 0.2% NH4OH to water + 0.2% NH4OH / CH3CN 6:4) to give the product of N-[3-(azacycloheptane-1-yl)-4-(4-methyl-2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide.

[0781] Yield: 36mg

[0782] 1H NMR(400MHz,DMSO-d6)δppm 10.21-10.06(m,1H),7.47-7.24(m,2H),7.23 -6.55(m,4H),6.01-4.27(m,1H),2.27-2.19(m,3H),4.40-1.84(m,10H),1. 81-1.67(m,1H),1.85-1.17(m,8H),0.86-0.69(m,4H); LC-MS: 467.21(MH+).

[0783] The racemic mixture (Example 69c) was then separated into individual enantiomers by preparative HPLC.

[0784]

[0785] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophen-3-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0786]

[0787] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazine-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-3-ylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in a yield of 32% (17 mg).

[0788] 1H NMR(400MHz,DMSO-d6)d ppm 10.06-10.27(m,1H)6.73-7.68(m,6H)4.29-5.77(m,1H)3.35-3.41(m,1H)2.57-3.26( m,5H)2.09-2.38(m,4H)1.05-2.01(m,12H)0.66-0.86(m,4H); LC-MS: m / z467.3(MH+).

[0789] The racemic mixture (Example 70c) was then separated into individual enantiomers by preparative HPLC.

[0790]

[0791] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(1-methyl-1H-pyrazol-3-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0792]

[0793] Examples 71a and 71b

[0794] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophen-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-[2-(1-methylpyrazol-4-yl)piperazin-1-carbonyl]phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophen-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 40% (21 mg) yield.

[0795] 1H NMR(500MHz,DMSO-d6)δppm 10.27-9.96(m,1H),7.78 -7.49(m,1H),7.48-7.20(m,2H),7.05-6.75(m,2H),5.74-4.39(m,1H),3.86-3.67(m,3H) ,2.22-2.16(m,3H),4.37-1.83(m,10H),1.81-1.27(m,9H),0.86-0.68(m,4H); LC-MS:m / z 465.5(MH+).

[0796] The racemic mixture was then separated into individual enantiomers by preparative HPLC.

[0797]

[0798] Preparation: N-(3-(azacycloheptane-1-yl)-4-(2-phenyl-4-propylpiperazin-1-carbonyl)phenyl)cyclopropaneformamide

[0799]

[0800] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-phenylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 70% (80 mg) yield.

[0801] 1H NMR (400MHz, DMSO-d6) δppm 10.27-9.95(m,1H),7.81-6.76(m,8H),5.89-4.49(m,1H),3.39-2.87(m,4H),2.15(br s,3H),4.46-1.86(m,6H),1.83-1.67(m,1H),1.84-1.25(m,8H),0.88-0.67(m,4H); LC-MS: m / z 461.4(MH+).

[0802] The racemic mixture was then separated into individual enantiomers by preparative HPLC.

[0803]

[0804] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-phenyl-4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0805]

[0806] 1-Bromopropane (45.44 mg, 0.370 mmol) was added to a solution of N-[3-(azacycloheptane-1-yl)-4-(2-phenylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide (110.0 mg, 0.250 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.370 mmol) in MeCN (1.5 mL), and the reaction was stirred overnight at 60 °C. The next day, the reaction was concentrated to dryness, and the residue was absorbed in AcOEt. The organic phase was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC NH (eluting with 100% CHEX to CHEX / AcOEt 6:4) and further purified by FC on RP (eluting with water / CH3CN 95:5 to water / CH3CN 5:95) to give the product of formula (N-[3-(azacycloheptane-1-yl)-4-(2-phenyl-4-propylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide).

[0807] Yield: 72mg

[0808] 1H NMR(400MHz,DMSO-d6)δppm 10.36-9.79(m,1H),8.12-6.60(m,8H),5.93-4.45(m,1H),3.62-3.35(m,1H)3.35-2.83(4H),4.44-2.82(m,2H),2.81-2.62(m,1H),2.43- 2.28(m,1H),2.29-2.19(m,2H),2.11-1.87(m,1H),1.80-1.66(m,1H),1.51-1.38(m,2H),1.85-1.23(m,8H),0.94-0.72(m,7H); LC-MS: m / z 489.4 (MH+).

[0809] The racemic mixture (Example 73c) was then separated into individual enantiomers by preparative HPLC.

[0810]

[0811]

[0812] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0813]

[0814] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 70% (21 mg) yield.

[0815] 1H NMR(500MHz,DMSO-d6)δppm 10.28-9.92(m,1H),8.70-8.37(m,1H),7.88-7.65(m,1H),7.55-6.68(m,5H),5.72-4.54( m,1H),2.10(s,3H),4.53-1.86(m,10H),1.85-1.36(m,9H),0.92-0.63(m,4H); LC-MS:m / z 462.3(MH+).

[0816] Preparation: N-[3-(azacycloheptane-1-yl)-4-[4-methyl-2-(trifluoromethyl)piperazin-1-carbonyl]phenyl]cyclopropaneformamide

[0817]

[0818] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-[2-(trifluoromethyl)piperazin-1-carbonyl]phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in a yield of 13% (4.4 mg).

[0819] 1H NMR(500MHz,DMSO-d6)δppm 10.31-10.07(m,1H),7.52-7.33(m,1H),6.98(brs,1H),6.98-6.79(m,1H),5.34-3.86(m,1H),3.32(s,2 H),3.27-3.18(m,4H),2.23-2.14(m,3H),2.50(s,4H),1.77-1.40(m,9H),0.89-0.72(m,4H); LC-MS:m / z 453.4(MH+).

[0820] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2-benzyl-4-methylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0821]

[0822] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-benzylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 40% (27 mg) yield.

[0823] 1H NMR(500MHz,DMSO-d6)δppm 10.23-9.99(m,1H),7.46-6.21(m,8H),4.89-3.40(m,1H),3.25-3.17(m,4H)2.20-2.1 0(m,3H), 4.49-1.79(m,8H), 1.78-1.36(m,9H), 0.97-0.69(m,4H); LC-MS: 475.3(MH+).

[0824] Preparation: N-[3-(azacycloheptane-1-yl)-4-[2-(hydroxymethyl)-4-methylpiperazine-1-carbonyl]phenyl]cyclopropaneformamide

[0825]

[0826] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-[2-(hydroxymethyl)piperazin-1-carbonyl]phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in a yield of 12.3% (9.2 mg).

[0827] 1H NMR(500MHz,DMSO-d6)δppm 10.19-10.05(M,1H),7.39-7.27(m,1H),7.08-6.80(m,2H),4.90-4.56( m,1H),4.90-4.56(m,1H),3.84-3.38(m,2H),4.51-3.32(m,1H)4.33-3.1 8(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,4H); LC-MS: 415.3(MH+).

[0828] Preparation: N-[3-(azacycloheptane-1-yl)-4-(2,4-dimethylpiperazine-1-carbonyl)phenyl]cyclopropaneformamide

[0829]

[0830] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-methylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 60% (24 mg) yield.

[0831] 1H NMR(400MHz,DMSO-d6)δ10.12(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+).

[0832] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-2-prop-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide

[0833]

[0834] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-propyl-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 53% (22 mg) yield.

[0835] 1 H NMR(400MHz,DMSO-d6)δ10.14(d,0H),7.41-7.33(m,1H),7.02(ddd,1H),6.94-6.79(m,1H),4.41-4.07(m,1H),3.2 9-3.16(m,6H),3.16-2.57(m,4H),2.40-2.25(m,1H),1.92-1.43(m,12H),1.00-0.51(m,11H); LC-MS: 427.1(MH+).

[0836] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropane formamide

[0837]

[0838] The title compound was synthesized in a manner similar to that of the compound (N-(3-(azacycloheptane-1-yl)-4-(4-methyl-2-(thiophene-2-yl)piperazin-1-carbonyl)phenyl)cyclopropaneformamide) in Examples 69a-69c, wherein N-[3-(azacycloheptane-1-yl)-4-(2-pyridin-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 70% (21.5 mg) yield.

[0839] 1H NMR(500MHz,DMSO-d6)δppm 10.28-9.92(m,1H),8.70-8.37(m,1H),7.88-7.65(m,1H),7.55-6.68(m,5H),5.72-4.54( m,1H),4.53-1.86(m,10H),2.10(s,3H),1.85-1.36(m,9H),0.92-0.63(m,4H); LC-MS:m / z 462.3(MH+).

[0840] Preparation: N-[3-(azacycloheptane-1-yl)-4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropaneformamide

[0841]

[0842] N,N-diisopropylethylamine (0.04 mL, 0.250 mmol) was added to a solution of N-[3-(azacycloheptane-1-yl)-4-(2-phenylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide (55.0 mg, 0.120 mmol) in MeCN (3.5 mL), followed by 3,5-dimethyl-4-isooxazolaldehyde (23.12 mg, 0.180 mmol). The reaction mixture was stirred for 15 min, and then sodium triacetoxyborohydride (52.2 mg, 0.250 mmol) was added. The resulting mixture was stirred overnight at room temperature. 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 an NH column (eluting with 100% CHEX to CHEX / AcOEt 3:7) to give the product N-[3-(azacycloheptane-1-yl)-4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropaneformamide.

[0843] Yield: 32mg

[0844] 1 H NMR(400MHz,DMSO-d6)δ10.13(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,1 LC-MS:m / z 556.4(MH+).

[0845] Preparation: N-[3-(azacycloheptane-1-yl)-4-[4-(1,2-oxazol-3-ylmethyl)-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropane formamide

[0846]

[0847] The title compound was synthesized in a manner similar to that of the compound in Example 81 (N-[3-(azacycloheptane-1-yl)-4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide), wherein 1,2-oxazol-3-carboxaldehyde was used instead of 3,5-dimethyl-4-isooxazolaldehyde. The title compound was obtained in a yield of 20% (7 mg).

[0848] 1 H NMR(400MHz,DMSO-d6)δ10.13(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+).

[0849] Preparation: N-[3-(azacycloheptane-1-yl)-4-[4-(1,3-oxazol-2-ylmethyl)-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropane formamide

[0850]

[0851] Example 83

[0852] The title compound was synthesized in a manner similar to that of the compound in Example 81 (N-[3-(azacycloheptane-1-yl)-4-[4-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-2-phenylpiperazine-1-carbonyl]phenyl]cyclopropanecarboxamide), except that 2-oxazolaldehyde was used instead of 3,5-dimethyl-4-isooxazolaldehyde. The title compound was obtained in a yield of 42% (15 mg).

[0853] 1 H NMR (400MHz, DMSO-d6) δ10.25-10.06(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+).

[0854] Preparation: N-[4-[2-(2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0855]

[0856] Formaldehyde (176.63 mg, 2.18 mmol) and sodium triacetoxyborohydride (276.75 mg, 1.31 mmol) were added to a solution of N-[4-[2-(2-fluorophenyl)-4-methylpiperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide (95.0 mg, 0.220 mmol) in methanol (5 mL). The reaction was stirred overnight at room temperature. The next day, the reaction was concentrated to dryness under reduced pressure and purified by SCX, washed with MeOH and eluted with NH3 in 1N in MeOH. The basic fraction was evaporated and the residue was purified by FC on an NH column (eluted with 100% CHEX to CHEX / AcOEt 1:1) to give the product of N-[4-[2-(2-fluorophenyl)-4-methylpiperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide as a racemic mixture.

[0857] Yield: 54mg

[0858] 1H NMR(500MHz,DMSO-d6)δppm 10.36-9.83(m,1H),8.06-7.40(m,1H),7.39-7.25(m,1H),7.24-6.41(m,5H),6.07-4.84(m,1H),4.65-2.64(m,8H), 2.42-2.23(m,1H),2.21-2.09(m,3H),1.80-1.71(m,1H),2.06-1.42(m,5H),0.87-0.66(m,4H); LC-MS: 451.19(MH+).

[0859] The racemic mixture (Example 84c) was then separated into individual enantiomers by preparative HPLC.

[0860]

[0861] Preparation: N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(4-methyl-2-thiophene-2-ylpiperazine-1-carbonyl)phenyl]cyclopropane formamide

[0862]

[0863] The title compound was synthesized in a manner similar to that of the compound in Examples 84a-84c (N-[4-[2-(2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein N-[3-(6-azaspiro[3.4]oct-6-yl)-4-(2-thiophene-2-ylpiperazine-1-carbonyl)phenyl]cyclopropanecarboxamide was used instead of N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 17% (2.5 mg).

[0864] ¹H NMR (500MHz, methanol-d⁴) δppm 7.40-7.27 (m, 2H), 7.07-7.03 (m, 1H), 6.90-6.82 (m, 1H), 7.19-6.59 (m, 1H), 7.48-6.56 (m, 1H), 6.17-4.97 (m, 1H), 4.55-3.35 (m, 2H), 3.06-3.02 (m, 1H), 3.00-2.86 (m, 1H), 2.85 -2.73(m,1H),2.67-2.57(m,1H),4.64-2.39(m,2H),2.51-2.38(m,1H),2.35-2.26(m,3H ),2.12-1.94(m,1H),1.81-1.65(m,1H),2.22-1.58(m,8H),1.00-0.81(m,4H); LC-MS:m / z 479.2(MH+).

[0865] Preparation: N-[4-(4-methyl-2-thiophene-2-ylpiperazin-1-carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0866]

[0867] The title compound was synthesized in a manner similar to that of the compound in Examples 84a-84c (N-[4-[2-(2-fluorophenyl)-4-methylpiperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein N-[3-pyrrolidine-1-yl-4-(2-thiophene-2-ylpiperazin-1-carbonyl)phenyl]cyclopropanecarboxamide was used instead of N-[4-[2-(2-fluorophenyl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 5.3% (15.9 mg).

[0868] 1H NMR(500MHz,DMSO-d6)δppm 10.26-10.01(m,1H),7.45-7.32(m,1H),7.27-6.55(m,5H),6.05-4.83(m,1H),4.39-2.61(m,8H),2.4 0-2.16(m,4H),2.06-1.82(m,3H),1.80-1.71(m,1H),1.71-1.52(m,2H),0.83-0.72(m,4H); LC-MS:m / z 437.25(MH+).

[0869] The racemic mixture (Example 86c) was then separated into individual enantiomers by preparative HPLC.

[0870]

[0871]

[0872] Preparation: N-[4-[4-methyl-2-(1-methylpyrazol-4-yl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0873]

[0874] The title compound was synthesized in a manner similar to that of the compound in Examples 84a-84c (N-[4-[2-(2-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein N-[4-[2-(1-methylpyrazol-4-yl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide was used instead of N-[4-[2-(2-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in a yield of 30% (27 mg).

[0875] 1H NMR(400MHz,DMSO-d6)δppm 10.23-9.99(m,1H),7.80-7.50(m,1H),7.48-7.01(m,1H),7.15-6.68(m,3H),5.70-4.50(m,1H),3.89 -3.67(m,3H),4.38-2.57(m,8H),2.29-2.07(m,4H),2.04-1.57(m,6H),0.87-0.68(m,4H); LC-MS:m / z 437.23(MH+).

[0876] Preparation: N-[4-[2-(3-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0877]

[0878] A solution of methyl 4-methylbenzenesulfonate (28.87 mg, 0.160 mmol) in 0.500 mL DMF was added to a mixture of N-[4-[2-(3-fluorophenyl)piperazin-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide (72.0 mg, 0.160 mmol), potassium carbonate (42.86 mg, 0.310 mmol), and DMF (1 mL). The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was poured into a saturated NaHCO3 solution and AcOEt. The two phases were separated, the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness under vacuum. The residue was purified by SCX, washed with MeOH, and eluted with NH3 in 1N MeOH. The alkaline fraction was evaporated, and the residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 1:1) to give the product N-[4-[2-(3-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide.

[0879] Yield: 31mg

[0880] 1H NMR (500MHz, DMSO-d6) δppm 10.20-10.05(m,1H),7.59-6.99(m,2H),7.18-6.79(m,2H),7.61-6.76(m,3H) ,5.83-4.65(m,1H),4.50-3.25(m,1H),3.30-2.94(m,4H),2.82-2.57(m,1H),3 .48-2.54(m,2H),2.39-2.22(m,1H),2.27-2.13(m,3H),2.05-1.85(m,1H),1.8 0-1.71(m,1H),1.98-1.59(m,4H),0.86-0.68(m,4H); LC-MS: m / z451.16(MH+).

[0881] The racemic mixture (Example 88c) was then separated into individual enantiomers by preparative HPLC.

[0882]

[0883]

[0884] Preparation: N-[4-[2-(4-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[0885]

[0886] The title compound was synthesized in a manner similar to that of the compound in Examples 88a-88c (N-[4-[2-(3-fluorophenyl)-4-methylpiperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide), wherein N-[4-[2-(4-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide was used instead of N-[4-[2-(3-fluorophenyl)piperazine-1-carbonyl]-3-pyrrolidine-1-ylphenyl]cyclopropanecarboxamide. The title compound was obtained as a racemic mixture in 48% (42 mg) yield.

[0887] 1H NMR(400MHz,DMSO-d6)δ10.10(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 / z451.24(MH+).

[0888] Examples of compounds with different R1 groups can be prepared using synthesis scheme 4.

[0889] Synthesis Scheme 4

[0890]

[0891] Synthetic Scheme 4 - Reagents and Conditions: a) Azacycloheptanine, CH3CN, 80℃, 3 days; b) 1-propylpiperazine dihydrobromide, HATU, DIPEA, DMF, rt, overnight; c) H2 1 atm, Pd-C10%, EtOH, rt, 2 h; d) Coupling

[0892] Preparation: 2-(azacycloheptan-1-yl)-4-nitrobenzoate

[0893]

[0894] A mixture of 2-fluoro-4-nitrobenzoic acid (4.0 g, 21.61 mmol) and perpiperidine (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 absorbed with 1 N HCl, and the suspension was filtered. The solid was then washed with H₂O and dried under vacuum to give the product of formula 2-(azacycloheptane-1-yl)-4-nitrobenzoate. The product was used in the next step without further purification.

[0895] Yield: 5.14g

[0896] 1 H NMR(400MHz,DMSO-d6)δ14.11(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+).

[0897] Preparation: 1-[5-nitro-2-(4-propylpiperazine-1-carbonyl)phenyl]azacycloheptane

[0898]

[0899] N,N-diisopropylethylamine (0.38 mL, 2.16 mmol) was added to a mixture of 2-(azacycloheptan-1-yl)-4-nitrobenzoate (650 mg, 2.16 mmol) and [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (821.8 mg, 2.16 mmol) in DMF (21.8 mL). The reaction mixture was stirred at room temperature for 30 min, after which a solution of N,N-diisopropylethylamine (0.75 mL, 4.32 mmol) and 1-propylpiperazine dihydrobromide (626.87 mg, 2.16 mmol) in DMF (3 mL) was added. The reaction mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with saturated NaHCO3 solution 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 an NH column (eluting with cHex / AcOEt 95:5 to cHex / AcOEt 1:1) to give the compound of formula ([2-(azacycloheptane-1-yl)-4-nitrophenyl]-(4-propylpiperazin-1-yl)methyl ketone).

[0900] Yield: 870mg

[0901] 1H NMR(400MHz,DMSO-d6)δ7.63(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+).

[0902] Preparation of 3-(azacycloheptan-1-yl)-4-(4-propylpiperazine-1-carbonyl)aniline

[0903]

[0904] Pd-C (341.02 mg, 0.320 mmol) was added to a solution of [2-(azacycloheptane-1-yl)-4-nitrophenyl]-(4-propylpiperazin-1-yl) methyl ketone (1.2 g, 3.2 mmol) in ethanol (20 mL). The reaction was stirred at room temperature under a H2 atmosphere for 2 h. The reaction mixture was then filtered through a diatomaceous earth mat and concentrated under vacuum to give the product of formula [4-amino-2-(azacycloheptane-1-yl)phenyl]-(4-propylpiperazin-1-yl) methyl ketone.

[0905] Yield: 1g

[0906] 1 H NMR(400MHz,DMSO-d6)δ6.68(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+).

[0907] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)cyclobutane formamide

[0908]

[0909] N,N-diisopropylethylamine (56.27 mg, 0.440 mmol) was added to a mixture of [4-amino-2-(azacycloheptane-1-yl)phenyl]-(4-propylpiperazin-1-yl) methyl ketone (100 mg, 0.290 mmol), cyclobutanecarboxylic acid (0.03 mL, 0.350 mmol), and [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium; hexafluorophosphate (132.45 mg, 0.350 mmol) in DMF (2 mL), and the reaction was stirred overnight at room temperature. The next day, a saturated NaHCO3 solution was added to the reaction mixture, and it was extracted three times with AcOEt. The combined organic phases were then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on silica gel (eluting with 100% DCM to DCM / MeOH 9:1), and then further purified by FC on an NH column (eluting with cHex / AcOEt 8:2 to AcOEt 100%) to give a compound of the formula N-[3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]cyclobutane formamide.

[0910] Yield: 75mg

[0911] 1H NMR(500MHz,DMSO-d6)δppm 9.66(s,1H),7.33(d,1H),7.05(dd,1H),6.90(d,1H),3.24-3.17(m,5H),3.73-3.06(m,4H),2.25-2.13(m,5H),2.44-2.13(m,4H), 2.09(dtd,2H),2.01-1.88(m,1H),1.85-1.75(m,1H),1.74-1.61(m,4H),1.60-1.47(m,4H),1.42(sxt,2H),0.84(t,3H); LC-MS: m / z 427.32(MH+).

[0912] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)benzamide

[0913]

[0914] The title compound was synthesized in a manner similar to that of the compound of Example 90 (N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclobutanecarboxamide), wherein benzoic acid was used instead of cyclobutanecarboxylic acid. The title compound was obtained in 66% (85 mg) yield.

[0915] 1H NMR(400MHz,DMSO-d6)δ10.18(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+).

[0916] Preparation: N-(3-(azacycloheptan-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)-2,2-difluorocyclopropane-1-carboxamide

[0917]

[0918] The title compound was synthesized in a manner similar to that of the compound of Example 90 (N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclobutanecarboxamide), wherein 2,2-difluoro-1-cyclopropanecarboxylic acid was used instead of cyclobutanecarboxylic acid. The title compound was obtained in a yield of 45% (30 mg).

[0919] 1 H NMR (400MHz, DMSO-d6) δ10.37(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( LC-MS: m / z 449.6(MH+).

[0920] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)isobutyramide

[0921]

[0922] The title compound was synthesized in a manner similar to that of the compound of Example 90 (N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl)cyclobutanecarboxamide), wherein 2-methylpropionic acid was used instead of cyclobutanecarboxylic acid. The title compound was obtained in 63% (76 mg) yield.

[0923] 1 H NMR(400MHz,DMSO-d6)δ9.77(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+).

[0924] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)propionamide

[0925]

[0926] A solution of [4-amino-2-(azacycloheptane-1-yl)phenyl]-(4-propylpiperazin-1-yl)methyl ketone (50.0 mg, 0.150 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.290 mmol) in 1,4-dioxane (1 mL) was cooled to 0 °C, and propionyl chloride (0.02 mL, 0.220 mmol) was added after 10 min. The reaction was heated to room temperature and stirred overnight. The next day, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 2:8) to give the product N-[3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]propionamide.

[0927] Yield: 40.7 mg

[0928] 1 H NMR(400MHz,DMSO-d6)δ9.80(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+).

[0929] Preparation: N-(3-(azacycloheptane-1-yl)-4-(4-propylpiperazine-1-carbonyl)phenyl)acetamide

[0930]

[0931] Acetic anhydride (0.02 mL, 0.200 mmol) was added to a mixture of [4-amino-2-(azacycloheptane-1-yl)phenyl]-(4-propylpiperazin-1-yl)methyl ketone (70.0 mg, 0.200 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.410 mmol) in DCM (2 mL), and the reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on NH4OH (eluting with cHex / AcOEt 8:2 to cHex / AcOEt 2:8) to give the product N-[3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]acetamide.

[0932] Yield: 60mg

[0933] 1 H NMR(400MHz,DMSO-d6)δ9.87(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+).

[0934] Preparation of: [3-(azacycloheptan-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]urea

[0935]

[0936] Potassium cyanate (111.95 mg, 1.38 mmol) was dissolved in warm water (0.459 mL) and gradually added to a solution of [4-amino-2-(azacycloheptan-1-yl)phenyl]-(4-propylpiperazin-1-yl) methyl ketone (50.0 mg, 0.140 mmol) in a mixture of water (0.919 mL) and acetic acid (0.100 mL). The reaction was stirred at room temperature for 1 h. 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 (eluting with CH3CN / H2O 5:95 + 0.1% formic acid to CH3CN / H2O 95:5 + 0.1% formic acid). The fractions containing the desired product were collected and concentrated under vacuum. The resulting product was dissolved in DCM, washed with saturated NaHCO3 solution, filtered through a phase separator, and dried. The solvent was removed under vacuum to give the product of formula [3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]urea.

[0937] Yield: 6mg

[0938] 1H NMR(500MHz,DMSO-d6)δppm 8.54(s,1H),7.07(s,1H),6.91-6.77(m,2H),5.81(s,2H),3.18(br t,4H),3.72-3.03(m,4H),2.22(br t,2H),2.45-2.09(m,4H),1.76-1.47(m,8H),1.42(sxt,2H),0.84(t,3H); LC-MS: m / z 388.6(MH+).

[0939] Preparation: (2-(azacycloheptan-1-yl)-4-((5-cyclopropyl-4H-1,2,4-triazol-3-yl)amino)phenyl)(4-propylpiperazin-1-yl)methyl ketone

[0940] Step a:

[0941]

[0942] A mixture of potassium thiocyanate (193.75 mg, 1.99 mmol) and cyclopropionic acid chloride (0.18 mL, 1.99 mmol) in MeCN (8 mL) was stirred at 80 °C for 2 h. Subsequently, a solution of [4-amino-2-(azacycloheptane-1-yl)phenyl]-(4-propylpiperazin-1-yl)methyl ketone (300.0 mg, 0.870 mmol) in MeCN (2 mL) was added, and the reaction was stirred at the same temperature for 1 h. The reaction was then cooled to room temperature, filtered, and the supernatant was concentrated under vacuum. The residue was purified by FC on silica gel (eluting with 100% DCM to DCM / MeOH 9:1) to give the intermediate 1-[3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-1-carbonyl)phenyl]-3-cyclopropanecarbonylthiourea.

[0943] Yield: 316mg

[0944] LC-MS: m / z 472.3 (MH+)

[0945] Step b:

[0946]

[0947] Intermediate 1-[3-(azacycloheptane-1-yl)-4-(4-propylpiperazin-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 room temperature for 24 h. The reaction was then concentrated under vacuum, and the residue was purified by FC on RP under alkaline conditions (eluent: 100% ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia to 100% CH3CN), and further purified by FC on silica gel (eluting with 100% DCM to DCM / MeOH 9:1) to give a compound of formula 2-(azacycloheptane-1-yl)-4-((5-cyclopropyl-4H-1,2,4-triazol-3-yl)amino)phenyl)(4-propylpiperazin-1-yl)methyl ketone.

[0948] Yield: 13mg

[0949] 1H NMR(400MHz,DMSO-d6)δppm 13.25-12.46(m,1H),9.31-8.76(m,1H),7.31(s,1H),6.97-6.73(m,2H),3.24-3.18(m,4H),3.79-3.02(m ,4H),2.25-2.20(m,1H),2.43-2.10(m,4H),1.97-1.86(m,1H),1.80-1.48(m,8H),1.42(sxt,2H),0.98(br d,2H), 0.89-0.78(m,5H); LC-MS: m / z 452.34(MH+).

[0950] Scheme 5 below illustrates the synthesis of a compound in which X2 is an imidazo[1,5-a]pyrazinyl group.

[0951] Option 5

[0952]

[0953]

[0954] Scheme 5 - Reagents and conditions: a) 2-Aminomethylpyrazine, HATU, DIPEA, overnight, RT; b) POCl3, CH3CN; 85℃, 2 days; c) Azacycloheptanane, DIPEA, DMF, 80℃, 4h; d) H2 1atm, Pd-C 10%, EtOH, rt, 2h; e) Cbz-Cl, TEA, DCM, rt, 2h; f) Cyclopropylformyl chloride, TEA, DCM, rt, overnight; g) H2 1atm, Pd-C 10%, EtOH, rt, 3h; h) Appropriate aldehyde, DIPEA, STAB, DCM, rt, overnight.

[0955] Preparation: 2-Fluoro-4-nitro-N-[(pyrazin-2-yl)methyl]benzamide

[0956]

[0957] 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 mixed in DMF (50 mL) and stirred for 30 min. Then, 2-aminomethylpyrazine (1.41 g, 12.97 mmol) was added to DMF (5 mL) at 0 °C. The reaction mixture was heated to room temperature and stirred overnight at the same temperature. The next day, the reaction was concentrated to dryness, and the residue was absorbed with AcOEt. The organic phase was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residue was absorbed with DCM and filtered. The solid was washed with DCM and dried under vacuum to give the product of formula 2-fluoro-4-nitro-N-(pyrazin-2-ylmethyl)benzamide, which was used in the next step without further purification.

[0958] Yield: 1.9g

[0959] 1H NMR (400MHz, DMSO-d6) δ9.33(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+).

[0960] Preparation: 3-(2-fluoro-4-nitrophenyl)imidazo[1,5-a]pyrazine

[0961]

[0962] 1.9 g (6.88 mmol) of 2-fluoro-4-nitro-N-(pyrazin-2-ylmethyl)benzamide was dissolved in 95 mL of CH3CN, followed by dropwise addition of phosphorus oxychloride (V) (6.41 mL, 68.79 mmol), and the reaction mixture was stirred at 85 °C for 48 h. The reaction mixture was cooled to room temperature and evaporated. The residue was absorbed with DCM and filtered. The solid was washed with DCM and dried under vacuum to give the product of formula 3-(2-fluoro-4-nitrophenyl)imidazo[1,5-a]pyrazine.

[0963] Yield: 1g

[0964] 1H NMR (400MHz, DMSO-d6) δ9.29(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+).

[0965] Preparation: 3-[2-(azacycloheptane-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine

[0966]

[0967] 3-(2-fluoro-4-nitrophenyl)imidazo[1,5-a]pyrazine (920.0 mg, 3.56 mmol) was added to a solution of N,N-diisopropylethylamine (0.62 mL, 3.56 mmol) and perpiperidine (1.2 mL, 10.69 mmol) in DMF (9 mL), and the reaction was stirred at 80 °C for 4 h. The reaction was then cooled to room temperature and 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 passing it through an FC NH₄ column (eluting with cHex to cHex / AcOEt 1:1). The fractions containing the desired product were combined and evaporated. The residue was ground with pentane to give the product of formula 3-[2-(azacycloheptane-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine.

[0968] Yield: 800mg

[0969] 1 H NMR (400MHz, chloroform-d) δ9.09(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+).

[0970] Preparation: 3-(4-nitro-2-pyrrolidine-1-ylphenyl)imidazo[1,5-a]pyrazine

[0971]

[0972] The title compound was synthesized in a manner similar to that of 3-[2-(azacycloheptane-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine, except that pyrrolidine was used instead of piperidine. The title compound was obtained in 99% (600 mg) yield.

[0973] 1H NMR (400MHz, 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+).

[0974] Preparation: cis / trans-3-[2-(3,5-dimethylpiperidin-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine

[0975]

[0976] The title compound was synthesized in a manner similar to that of 3-[2-(azacycloheptane-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine, wherein 3,5-dimethylpiperidine was used instead of homopiperidine. The title compound, as a mixture of stereoisomers, was obtained in 87% (475 mg) yield.

[0977] LC-MS: m / z 352.15 (MH+)

[0978] Preparation of 3-(azacycloheptan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

[0979]

[0980] To a mixture of 3-[2-(azacycloheptan-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine (380.0 mg, 1.13 mmol) and acetic acid (67.64 mg, 1.13 mmol) in MeOH (10 mL), 20% palladium hydroxide (2+) (395.43 mg, 0.560 mmol) was added, and the reaction was stirred at room temperature for 2 hours under H2 atmosphere. The reaction mixture was then filtered through diatomaceous earth and the solvent was removed under vacuum. The residue was purified by SCX, first by washing with MeOH and then with 1 M NH3 in MeOH, to give the product of formula 3-(azacycloheptan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)aniline.

[0981] Yield: 300mg

[0982] 1 H NMR (400MHz, chloroform-d) δ7.10(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 / z312.2(MH+).

[0983] Preparation: 3-pyrrolidine-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

[0984]

[0985] A mixture of 3-(4-nitro-2-pyrrolidine-1-ylphenyl)imidazo[1,5-a]pyrazine (597.0 mg, 1.93 mmol), acetic acid (0.33 mL, 5.79 mmol), and 20% palladium hydroxide (2+) (271.04 mg, 0.390 mmol) in methanol (15 mL) was stirred at room temperature for 1 h under H2 atmosphere. The mixture was then filtered through a diatomaceous earth mat, and the solvent was removed under vacuum. The residue was purified by an SCX box, first by washing with MeOH, then by elution with 1 M NH3 in MeOH, to give the product 3-pyrrolidine-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)aniline.

[0986] Yield: 358mg

[0987] 1 H NMR(400MHz,DMSO-d6)δ6.81-6.50(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.

[0988] Preparation: cis / trans-3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline

[0989]

[0990] The title compound was synthesized in a manner similar to that of 3-pyrrolidine-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline, wherein cis / trans-3-[2-(3,5-dimethylpiperidin-1-yl)-4-nitrophenyl]imidazo[1,5-a]pyrazine was used instead of 3-(4-nitro-2-pyrrolidine-1-ylphenyl)imidazo[1,5-a]pyrazine. The title compound, as a mixture of stereoisomers, was obtained in 47% (120 mg) yield.

[0991] LC-MS: m / z 326.1 (MH+)

[0992] Preparation: Benzyl 3-[4-amino-2-(azacycloheptane-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

[0993]

[0994] A solution of 3-(azacycloheptan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline (300.0 mg, 0.960 mmol) and triethylamine (0.27 mL, 1.93 mmol) in 16 mL of DCM was cooled to 0 °C, and Cbz-Cl (0.12 mL, 0.870 mmol) was added dropwise after 5 minutes. The reaction was stirred at the same temperature for 2 hours. 1 N HCl was added, and the organic phase was separated. The aqueous phase was then adjusted to pH 8 with a saturated solution of NaHCO3 and extracted three times with DCM. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by FC on an NH column (eluting with 100% AcOEt to AcOEt / MeOH 9:1) to give the product of formula 3-[4-amino-2-(azacycloheptane-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester.

[0995] Yield: 165mg

[0996] 1 H NMR (400MHz, chloroform-d) δ7.42-7.35(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+).

[0997] Preparation: Benzyl 3-(4-amino-2-pyrrolidine-1-ylphenyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate

[0998]

[0999] The title compound was synthesized in a manner similar to that of 3-[4-amino-2-(azacycloheptane-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester, wherein 3-pyrrolidine-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)aniline was used instead of 3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)aniline. The title compound was obtained in 43% (126 mg) yield.

[1000] 1H NMR(400MHz,DMSO-d6)δ7.43-7.26(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+).

[1001] Preparation: 3-[2-(azacycloheptan-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester

[1002]

[1003] A solution of 3-[4-amino-2-(azacycloheptane-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate (165.0 mg, 0.370 mmol) and N,N-diisopropylethylamine (0.13 mL, 0.740 mmol) in DCM (3 mL) was cooled to 0 °C, and cyclopropionic acid chloride (0.05 mL, 0.560 mmol) was added dropwise after 5 minutes. The reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM and washed with saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by FC on an NH column (eluting with cHex / AcOEt 95:5 to cHex / AcOEt 40:60) to give the product of formula 3-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester.

[1004] Yield: 175mg

[1005] LC-MS: m / z 514.3 (MH+)

[1006] Preparation: 3-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylphenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester

[1007]

[1008] The title compound was synthesized in a manner similar to that of the compound of Example 99 (3-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate), wherein 3-(4-amino-2-pyrrolidine-1-ylphenyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate was used instead of 3-[4-amino-2-(azacycloheptane-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate. The title compound was obtained in 88% (130 mg) yield.

[1009] 1H NMR (400MHz, DMSO-d6) δ10.13(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 / z486.2(MH+).

[1010] Preparation: cis / trans-3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester

[1011]

[1012] A solution of 3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)aniline (119.0 mg, 0.370 mmol) and triethylamine (0.1 mL, 0.730 mmol) in DCM (7 mL) was cooled to 0 °C, and after 10 minutes, carbonochloridic acid (phenylmethyl) ester (0.05 mL, 0.330 mmol) was added dropwise. The reaction was stirred at the same temperature for 2 h. Subsequently, triethylamine (0.1 mL, 0.730 mmol) was added, followed by cyclopropionyl chloride (0.04 mL, 0.400 mmol). The reaction was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM, and the organic phase was washed with saturated NaHCO3 solution and brine, dried using a phase separator, and concentrated under vacuum. The residue was purified by FC on silica gel (eluting with 100% CHEX to 100% AcOEt) to give the product of 3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester as a mixture of cis / trans isomers.

[1013] Yield: 121mg

[1014] LC-MS: 528.23 (MH+)

[1015] Preparation: N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide

[1016]

[1017] A mixture of 3-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylic acid benzyl ester (175.0 mg, 0.340 mmol) and acetic acid (0.35 mL, 6.13 mmol) in ethanol (7 mL) was added to a carbon-supported 10% palladium (36.26 mg, 0.030 mmol), and the reaction mixture was stirred at room temperature for 3 h under a H2 atmosphere. The reaction mixture was then filtered through a diatomaceous earth mat and concentrated under vacuum. The residue was purified by SCX, first washed with MeOH and then with 1 M NH3 in MeOH, to give the product of N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-3-yl)phenyl]cyclopropaneformamide.

[1018] Yield: 95mg

[1019] LC-MS: m / z 380.3 (MH+).

[1020] Preparation: N-[3-pyrrolidone-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide

[1021]

[1022] The title compound was synthesized in a manner similar to that of N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide, wherein 3-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylphenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-carboxylate was used instead of 3-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-carboxylate. The title compound was obtained in 87% (81 mg) yield.

[1023] 1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),7.15(s,1H),6.97(s,2H),6.65(d,1H),3.88(s,2H),3.4 7(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+).

[1024] Preparation: cis / trans N-[3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropane formamide

[1025]

[1026] The title compound was synthesized in a manner similar to that of N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide, wherein cis / trans-3-[4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-carboxylate was used instead of 3-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)phenyl]-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-carboxylate. The title compound was obtained as a mixture of cis / trans isomers in 80% (72 mg) yield.

[1027] LC-MS: m / z 394.26 (MH+)

[1028] Preparation: N-[3-(azacycloheptan-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-3-yl}phenyl]cyclopropaneformamide

[1029]

[1030] At 0 °C, sodium triacetoxyborohydride (150.79 mg, 0.710 mmol) was added to a mixture of N-[3-(azacycloheptan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide (45.0 mg, 0.120 mmol) and 37% formaldehyde in H2O (0.09 mL, 1.19 mmol) in methanol (2 mL). The reaction was heated to room temperature 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, and 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 (eluting with Cy / EtOAc 100:0 to 10:90) to give the product N-[3-(azacycloheptane-1-yl)-4-(7-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide.

[1031] Yield: 21.5 mg

[1032] 1 H NMR(400MHz,DMSO-d6)δ10.17(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+).

[1033] Preparation: N-[4-(7-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[1034]

[1035] The title compound was synthesized in a manner similar to that of the compound of Example 102 (N-[3-(azacycloheptane-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-3-yl}phenyl]cyclopropanecarboxamide), wherein N-[3-pyrrolidine-1-yl-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide. The title compound was obtained in 64% (54 mg) yield.

[1036] 1H NMR(400MHz,DMSO-d6)δppm 10.12(br s,1H),7.22-7.13(m,1H),7.05-6.94(m,2H),6.69(s,1H),3.65-3.56(m,2H),3.53(s,2H),2.79-2.70(m,4H),2.64(br t,2H),2.34(s,3H),1.83-1.76(m,1H),1.75-1.69(m,4H),0.84-0.73(m,4H); LC-MS: m / z 355.2(MH+).

[1037] Preparation: cis / trans N-[3-(3,5-dimethylpiperidin-1-yl)-4-(7-methyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropane formamide

[1038]

[1039] The title compound was synthesized in a manner similar to that of the compound of Example 102 (N-[3-(azacycloheptane-1-yl)-4-{7-methyl-5H,6H,7H,8H-imidazo[1,5-a]pyrazin-3-yl}phenyl]cyclopropanecarboxamide), wherein cis / trans-N-[3-(3,5-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide was used instead of N-[3-(azacycloheptane-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide. The title compound was obtained as a mixture of cis / trans isomers in 99% (75 mg) yield.

[1040] LC-MS: m / z 409.9 (MH+).

[1041] The mixture of isomers was then separated into isomers using a semi-preparative MDAP method.

[1042]

[1043] Preparation: N-[3-(azacycloheptane-1-yl)-4-(7-propyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide

[1044]

[1045] Sodium triacetoxyborohydride (39.09 mg, 0.180 mmol) was added to a mixture of N-[3-(azacycloheptan-1-yl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropanecarboxamide (35.0 mg, 0.090 mmol) and propionaldehyde (6.43 mg, 0.110 mmol) in MeCN (2 mL) at 0 °C. The reaction was heated to room temperature and stirred overnight. The mixture was purified directly by SCX, first by washing with MeOH, then with 1M NH3 in MeOH, and further purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 1:1) to give the product N-[3-(azacycloheptane-1-yl)-4-(7-propyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)phenyl]cyclopropaneformamide.

[1046] Yield: 15mg

[1047] 1 H NMR(400MHz,DMSO-d6)δ10.17(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+).

[1048] Option 6

[1049]

[1050] Synthesis Scheme 6 - Reagents and Conditions: a) 2,4-Dimethoxybenzylamine, CsF, DMSO, 60℃, 2h; b) TFA, DCM, rt, 30min; c) Azacycloheptan, DMF, 80℃, 4h; d) Cyclopropylformyl chloride, pyridine, 80℃, overnight; e) LiOH H2O, MeOH / THF / H2O, 40℃, overnight; f) 1-Propylpiperazine dihydrobromide, DIPEA, DMF, rt, overnight.

[1051] Preparation: Methyl 3-chloro-5-{[(2,4-dimethoxyphenyl)methyl]amino}pyrazine-2-carboxylate

[1052]

[1053] To a solution of methyl 3,5-dichloropyrazine-2-carboxylate (1.0 g, 4.83 mmol) in DMSO (16.1 mL), methylamine (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 h. The reaction was then cooled to room temperature and diluted with H₂O. The reaction mixture 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 an NH₄ column (100% CHEX to CHEX / AcOEt 1:1) to give the product methyl 3-chloro-5-[(2,4-dimethoxyphenyl)methylamino]pyrazine-2-carboxylate.

[1054] Yield: 1.4g

[1055] 1 H NMR(400MHz,DMSO-d6)δ8.47(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+).

[1056] Preparation: Methyl 5-amino-3-chloropyrazine-2-carboxylate

[1057]

[1058] 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) was stirred at room temperature for 30 min. The reaction was then concentrated under vacuum. The residue was purified directly by SCX, first by washing with MeOH, then with 1 M NH3 in MeOH, to give the product of formula methyl 5-amino-3-chloropyrazine-2-carboxylate, which was used in the next step without further purification.

[1059] Yield: 220mg

[1060] 1 H NMR (400MHz, DMSO-d6) δ7.85 (s, 1H), 7.69 (s, 2H), 3.79 (s, 3H); LC-MS: m / z186.11 (MH).

[1061] Preparation: Methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate

[1062]

[1063] Cyclopropylformyl chloride (0.32 mL, 3.52 mmol) was added to a suspension of methyl 5-amino-3-chloropyrazine-2-carboxylate (220.0 mg, 1.17 mmol) in pyridine (6 mL), and the reaction was stirred overnight at 80 °C. The next day, the reaction was concentrated under vacuum. The residue was dissolved in AcOEt, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product of formula methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate. The product was used in the next step without further purification.

[1064] Yield: 220mg

[1065] 1 H NMR (400MHz, DMSO-d6) δ11.75(s,1H),9.32(s,1H),3.90(s,3H),2.04(tt,1H),0.95-0.88(m,4H).

[1066] Preparation: Methyl 3-(azacycloheptan-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate

[1067]

[1068] To a solution of methyl 3-chloro-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate (222.0 mg, 0.870 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.870 mmol) in DMF (2.22 mL), perpiperidine (0.29 mL, 2.61 mmol) was added, and the reaction was stirred at 80 °C for 4 h. The reaction was then cooled to room temperature and 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 NH₄ column (eluting with cHex to cHex / AcOEt 1:1) to give the product methyl 3-(azacycloheptane-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylate.

[1069] Yield: 240mg

[1070] 1 H NMR (400MHz, DMSO-d6) δ10.73(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+).

[1071] Preparation: 3-(azacycloheptane-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid

[1072]

[1073] A solution of lithium hydroxide hydrate (63.26 mg, 1.51 mmol) in water (0.500 mL) was added to a mixture of methyl 3-(azacycloheptane-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid (240 mg, 0.750 mmol) in THF (1 mL) / methanol (1 mL). The reaction was stirred overnight at 40 °C. The next day, the reaction was cooled to room temperature and acidified to pH 1 with 1 N HCl. The mixture was concentrated under vacuum. The residue was absorbed with H₂O and filtered. The solid was dried under vacuum to give the product of formula 3-(azacycloheptane-1-yl)-5-(cyclopropanecarbonylamino)pyrazine-2-carboxylic acid. The product was used in the next step without further purification.

[1074] Yield: 230mg

[1075] LC-MS: m / z 305.33 (MH+)

[1076] Preparation: N-[6-(azacycloheptane-1-yl)-5-(4-propylpiperazin-1-carbonyl)pyrazin-2-yl]cyclopropaneformamide

[1077]

[1078] To a solution of 3-(azacycloheptane-1-yl)-5-(cyclopropanecarbonylamino)pyrazin-2-carboxylic acid (230.0 mg, 0.790 mmol) and [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (299.85 mg, 0.790 mmol) in DMF (3 mL), N,N-diisopropylethylamine (0.14 mL, 0.790 mmol) was added, and the mixture was stirred at room temperature for 10 min. Subsequently, 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, and the reaction was stirred overnight at room temperature. The following day, the reaction mixture was diluted with saturated NaHCO3 solution 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, first by washing with MeOH, then with 1M NH3 in MeOH, and then by FC on C18 (eluting with 5:95 CH3CN / water solution adjusted to pH 10 with ammonia to 95:5 CH3CN / water solution adjusted to pH 10 with ammonia) to give the product of formula N-[6-(azacycloheptane-1-yl)-5-(4-propylpiperazin-1-carbonyl)pyrazin-2-yl]cyclopropaneformamide.

[1079] Yield: 20mg

[1080] 1H NMR(400MHz,DMSO-d6)δppm 10.54(s,1H),8.44(s,1H),3.60(br s,2H),3.53-3.43(m,4H),3.37(br t,2H),2.37(br s,2H),2.34-2.28(m,2H),2.28-2.21(m,2H),2.10-1.97(m,1H),1.73(br s,4H),1.54-1.36(m,6H),0.90-0.79(m,7H); LC-MS: m / z 415.4(MH+).

[1081] Option 7

[1082]

[1083] Preparation: Methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate

[1084]

[1085] A mixture of methyl 2,6-dichloro-3-pyridinecarboxylate (1.2 g, 5.82 mmol), (2,4-dimethoxyphenyl)methylamine (0.88 mL, 5.82 mmol), and cesium fluoride (0.88 g, 5.82 mmol) in DMF (19.41 mL) was stirred at 80 °C for 3 h. The reaction was then cooled to room temperature, 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 NH₄ column (eluting with cHex to cHex / AcOEt 1:1) to give the product methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate.

[1086] Yield: 726mg

[1087] 1H NMR(500MHz,DMSO-d6)δppm 7.93(br s,1H),7.87(br d,1H),7.13(br d,1H),6.57(d,1H),6.54-6.45(m,1H),6.48(dd,1H),4.36(br s, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 3.74 (s, 3H); LC-MS: m / z 337.2 (MH+).

[1088] Preparation: Methyl 2-(azacycloheptan-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate

[1089]

[1090] A mixture of methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (726.0 mg, 2.16 mmol), N,N-diisopropylethylamine (1.12 mL, 4.31 mmol), and perpiperidine (0.5 mL, 3.80 mmol) in DMF (14 mL) was stirred at 120 °C for 5 h. The reaction was then cooled to room temperature 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 an NH₄ column (eluting with 100% CHEX to CHEX / AcOEt 1:1) to give the product methyl 2-(azacycloheptane-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate.

[1091] Yield: 543mg

[1092] 1H NMR(400MHz,DMSO-d6)δ7.54(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+).

[1093] Preparation: Methyl 6-[(2,4-dimethoxyphenyl)methylamino]-2-pyrrolidine-1-ylpyridine-3-carboxylate

[1094]

[1095] A mixture of methyl 2-chloro-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (820.0 mg, 2.43 mmol), N,N-diisopropylethylamine (0.85 mL, 4.87 mmol), and pyrrolidine (0.41 mL, 4.87 mmol) in DMF (16.4 mL) was heated to 80 °C and maintained for 5 h. The reaction was then cooled to room temperature 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 an NH₄ column (eluting with 100% CHEX to CHEX / AcOEt 3:7) to give the compound of formula 6-[(2,4-dimethoxyphenyl)methylamino]-2-pyrrolidine-1-ylpyridine-3-carboxylate.

[1096] Yield: 900mg.

[1097] LC-MS: 372.2 (MH+).

[1098] Preparation: [6-(azacycloheptane-1-yl)-5-methoxycarbonylpyridin-2-yl]ammonium nitrogen; 2,2,2-trifluoroacetate

[1099]

[1100] Trifluoroacetic acid (0.19 mL, 2.5 mmol) was added to a mixture of methyl 2-(azacycloheptane-1-yl)-6-[(2,4-dimethoxyphenyl)methylamino]pyridine-3-carboxylate (200.0 mg, 0.500 mmol) in DCM (2 mL). The reaction was stirred at room temperature for 2 h. The reaction was then concentrated under vacuum to give the product of the formula [6-(azacycloheptane-1-yl)-5-methoxycarbonylpyridin-2-yl]ammonium nitrogen; 2,2,2-trifluoroacetate.

[1101] Yield: 200mg

[1102] LC-MS: m / z 250.10 (MH+).

[1103] Preparation: (5-methoxycarbonyl-6-pyrrolidine-1-ylpyridin-2-yl)ammonium nitrogen; 2,2,2-trifluoroacetate

[1104]

[1105] Trifluoroacetic acid (0.93 mL, 12.12 mmol) was added to a solution of methyl 6-[(2,4-dimethoxyphenyl)methylamino]-2-pyrrolidine-1-ylpyridin-3-carboxylate (900.0 mg, 2.42 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The next day, the reaction was concentrated under vacuum to give the product of (5-methoxycarbonyl-6-pyrrolidine-1-ylpyridin-2-yl)ammonium nitrogen; 2,2,2-trifluoroacetate.

[1106] Yield: 800mg

[1107] LC-MS: m / z 222.0 (MH+)

[1108] Preparation: Methyl 2-(azacycloheptan-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate

[1109]

[1110] A mixture of [6-(azacycloheptane-1-yl)-5-methoxycarbonylpyridin-2-yl]ammonium nitrogen; 2,2,2-trifluoroacetate (200.0 mg, 0.550 mmol) and cyclopropanecarboxylic acid chloride (0.05 mL, 0.550 mmol) in pyridine (2.752 mL) was heated to 80 °C and maintained for 3 h. The reaction was then cooled to room temperature, H₂O was added, and the mixture was filtered. The solid was washed with H₂O and dried under vacuum to give methyl 2-(azacycloheptane-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate, which was used in the next step without further purification.

[1111] Yield: 165mg

[1112] 1 H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.78(d,1H),7.32(d,1H),3.75(s,3 H),3.40(t,4H),2.13-2.00(m,1H),1.76(s,4H),1.45(q,4H),0.80(d,4H).

[1113] Preparation: Methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylpyridine-3-carboxylate

[1114]

[1115] A mixture of (5-methoxycarbonyl-6-pyrrolidine-1-ylpyridin-2-yl)ammonium nitrogen; 2,2,2-trifluoroacetate (800.0 mg, 2.39 mmol) and cyclopropionic acid chloride (0.22 mL, 2.39 mmol) in pyridine (11.01 mL) was heated to 80 °C and maintained for 3 h. The reaction was then cooled to room temperature, H₂O was added, and the resulting suspension was filtered. The solid was washed with H₂O and dried under vacuum to give the product methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylpyridin-3-carboxylate, which was used in the next step without further purification.

[1116] Yield: 275mg

[1117] 1 H NMR(400MHz,DMSO-d6)δ10.44(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+).

[1118] Preparation: N-[6-pyrrolidone-1-yl-5-[4-(trifluoromethyl)piperidin-1-carbonyl]pyridin-2-yl]cyclopropaneformamide

[1119]

[1120] A solution of 4-(trifluoromethyl)piperidine (0.19 mL, 0.380 mmol) in toluene (2 mL) was cooled to 0 °C, and after 10 min, a solution of 2M trimethylalumane (0.19 mL, 0.380 mmol) in toluene was added under N2. The mixture was stirred at the same temperature for 30 min, and then added to a mixture of methyl 6-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylpyridine-3-carboxylate (100.0 mg, 0.350 mmol) in toluene (2 mL). The reaction was heated to reflux and maintained for 72 h. The reaction was then cooled to room temperature and concentrated under vacuum. The residue was purified by FC on an NH column (100% DCM to DCM / MeOH 95:5) and further purified by RP under alkaline conditions (eluting with 100% water + 0.1% NH4OH to 100% CH3CN) to give the product of N-[6-pyrrolidine-1-yl-5-[4-(trifluoromethyl)piperidin-1-carbonyl]pyridin-2-yl]cyclopropaneformamide.

[1121] Yield: 9.5 mg

[1122] 1H NMR(500MHz,DMSO-d6)δppm 10.37-10.18(m,1H),7.40-7.27(m,2H),4.69-3.54(m,2H),3.51-3.16(m,4H),3.18-2.68(m,2H),2.6 8-2.51(m,1H),2.13-2.01(m,1H),1.94-1.60(m,6H),1.46-1.22(m,2H),0.88-0.70(m,4H); LC-MS:m / z 411.2(MH+).

[1123] Preparation: 6-amino-2-(azacycloheptane-1-yl)pyridine-3-carboxylic acid; formic acid

[1124]

[1125] A solution of lithium hydroxide hydrate (43.63 mg, 1.04 mmol) in water (0.701 mL) was added to a solution of methyl 2-(azacycloheptane-1-yl)-6-(cyclopropanecarbonylamino)pyridine-3-carboxylate (165.0 mg, 0.520 mmol) in THF (1.752 mL) / methanol (0.701 mL). The reaction was stirred overnight at 50 °C. The reaction was cooled to room temperature, acidified to pH 1 with 1 N HCl, and concentrated under vacuum. The residue was purified by FC column chromatography on a C18 column (eluting with H2O / CH3CN 95:5 + 0.1% formic acid to H2O / CH3CN 5:95 + 0.1% FA) to give the product of formula 6-amino-2-(azacycloheptane-1-yl)pyridine-3-carboxylic acid formic acid.

[1126] Yield: 180mg

[1127] LC-MS: m / z 236.10 (MH+).

[1128] Preparation of: [6-amino-2-(azacycloheptane-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl)methyl ketone

[1129]

[1130] N,N-diisopropylethylamine (0.74 mL, 4.27 mmol) was added to a mixture of [dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (270.33 mg, 0.710 mmol), 6-amino-2-(azacycloheptane-1-yl)pyridine-3-carboxylic acid (200.0 mg, 0.710 mmol) and 1-propylpiperazine dihydrobromide (412.41 mg, 1.42 mmol) in DMF (6 mL), and the reaction was stirred overnight at room temperature. The following day, the reaction mixture was purified by FC on RP under acidic conditions (eluting with CH3CN / H2O 5:95 + 0.1% formic acid to CH3CN / H2O 95:5 + 0.1% formic acid), and further purified by FC on RP under alkaline conditions (eluting with an aqueous solution of 5:95 CH3CN / adjusted to pH 10 with ammonia to an aqueous solution of 95:5 CH3CN / adjusted to pH 10 with ammonia) to give the product of formula [6-amino-2-(azacycloheptane-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl) methyl ketone.

[1131] Yield: 33mg

[1132] LC-MS: m / z 346.28 (MH+).

[1133] Preparation: N-[6-(azacycloheptane-1-yl)-5-(4-propylpiperazin-1-carbonyl)pyridin-2-yl]cyclopropaneformamide

[1134]

[1135] Cyclopropylformyl chloride (0.01 mL, 0.100 mmol) was added to a solution of [6-amino-2-(azacycloheptane-1-yl)pyridin-3-yl]-(4-propylpiperazin-1-yl)methyl ketone (33.0 mg, 0.100 mmol) in pyridine (2 mL), and the reaction was stirred at 80 °C for 2 h. The reaction was then cooled to room temperature and concentrated under vacuum. The residue was purified by SCX, first by washing with MeOH, then with 1M NH3 in MeOH, and then by FC on RP under acidic conditions (eluting with 5:95CH3CN / H2O + 0.1% formic acid to 95:5CH3CN / H2O + 1% FA), and further purified by SCX, first by washing with MeOH, then with 1M NH3 in MeOH, to give the product of N-[6-(azacycloheptane-1-yl)-5-(4-propylpiperazin-1-carbonyl)pyridin-2-yl]cyclopropaneformamide.

[1136] Yield: 14mg

[1137] 1H NMR(400MHz,DMSO-d6)δppm 10.22(s,1H),7.37-7.23(m,2H),3.58(br t,2H),3.54-3.35(m,4H),3.26(br t,2H),2.42-2.18(m,6H),2.05(quin,1H),1.82-1.62(m,4H),1.58-1.35(m,6H),0.85(t,3H),0.81-0.75(m,4H); LC-MS: m / z 414.28(MH+).

[1138] Option 8

[1139]

[1140] Synthesis Scheme 8 - Reagents and Conditions: a) Hydrazine hydrate, EtOH, reflux, overnight; b) Methyl isothiocyanate, THF, MW 130℃, 8 min, then saturated NaHCO3 solution, MW 100℃, 3 min; c) CH3I, NaOH, EtOH, 30 min, RT or iodobenzene, CuI, K2CO3, DMF, 120℃, overnight or (2-bromoethyl)dimethylamine hydrobromide, K2CO3, acetone, 65℃, overnight; d) Zn, AcOH, RT, 1 h; e) Cyclopropylformyl chloride, TEA, DCM, RT, overnight.

[1141] Preparation: 2-(azacycloheptan-1-yl)-4-nitrobenzoylhydrazine

[1142]

[1143] Hydrazine hydrate (2.56 mL, 33.96 mmol) was added to a solution of methyl 2-(azacycloheptan-1-yl)-4-nitrobenzoate (1.89 g, 6.79 mmol) in ethanol (15.79 mL), and the reaction was heated to reflux and stirred overnight. The next day, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The result was purified by FC on an NH column (eluting with DCM / AcOEt 95:5 to DCM / ACOEt 6:4) to give the product of formula 2-(azacycloheptan-1-yl)-4-nitrobenzoylhydrazine.

[1144] Yield: 690mg

[1145] 1 H NMR (400MHz, DMSO-d6) δ9.62(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+).

[1146] Preparation: 5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-thiol

[1147]

[1148] Methyl isothiocyanate (0.15 mL, 2.17 mmol) was added to a solution of 2-(azacycloheptan-1-yl)-4-nitrobenzoylhydrazine (550.0 mg, 1.98 mmol) in THF (10 mL), and the mixture was stirred at 130 °C for 8 min under MW conditions. The organic solution was concentrated and 12.5 mL of saturated NaHCO3 solution was added, and the reaction mixture was stirred at 100 °C for 3 min under MW conditions. The aqueous solution was then neutralized with 2 M HCl 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 (eluting with 100% CHEX to CHEX / AcOEt 7:3) to give the product of formula 5-[2-(azacycloheptan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-thiol.

[1149] Yield: 420mg

[1150] 1 H NMR (400MHz, chloroform-d) δ11.14(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+).

[1151] Preparation: 1-[2-(4-methyl-5-methylthioalkyl(sulfanyl)-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane

[1152]

[1153] 5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-thiol (250.0 mg, 0.750 mmol), 1 M sodium hydroxide solution (1.57 mL, 1.57 mmol), and methyl iodoform (0.07 mL, 1.2 mmol) were mixed in ethanol (0.375 mL), and the reaction was stirred at room temperature for 30 min. The reaction mixture was diluted with NaHCO3 and extracted three times with EtOAc. The organic layers were collected, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product of formula 1-[2-(4-methyl-5-methylthioalkyl-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane. The product was used in the next step without further purification.

[1154] Yield: 224mg

[1155] 1 ¹H NMR (400MHz, 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+).

[1156] Preparation: 1-[2-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane

[1157]

[1158] A solution of 5-[2-(azacycloheptan-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-thiol (66 mg, 0.198 mmol) in DMF (0.2 mL) was added to a solution of iodobenzene (0.03 mL, 0.240 mmol), cuprous iodide (I) (1.9 mg, 0.010 mmol), and potassium carbonate (35.57 mg, 0.260 mmol) in anhydrous DMF (2 mL). The resulting mixture was degassed using a Schlenk line technique and stirred overnight at 120 °C. The following day, the reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 solution and extracted with AcOEt, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the product of formula 1-[2-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane, which was used in the next step without further purification.

[1159] Yield: 40mg

[1160] LC-MS: m / z 410.14 (MH+)

[1161] Preparation: 2-[[5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-yl]thioalkyl]-N,N-dimethylethylamine

[1162]

[1163] Potassium carbonate (82.91 mg, 0.600 mmol) was added to a mixture of 5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-thiol (100.0 mg, 0.300 mmol), (2-bromoethyl)dimethylamine hydrobromide, and acetone (3 mL). The reaction mixture was stirred overnight at 65 °C. The reaction mixture was then cooled to room temperature, diluted with saturated NaHCO3 solution, and extracted three times with DCM. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product of formula 2-[[5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-yl]thioalkyl]-N,N-dimethylethylamine, which was used in the next step without further purification.

[1164] Yield: 120mg

[1165] LC-MS: m / z 405.15 (MH+).

[1166] Preparation of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline

[1167]

[1168] Zinc (94.09 mg, 1.44 mmol) was slowly added to a solution of 1-[2-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane (100.0 mg, 0.290 mmol) in anhydrous acetic acid (3 mL). The resulting suspension was stirred at room temperature for 1 h. The reaction mixture was filtered and washed with AcOEt, and the organic phase was concentrated under reduced pressure. The resulting product was absorbed with saturated NaHCO3 solution and extracted three times with AcOEt. The combined organic fractions were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a product of formula 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline, which was used in the next step without further purification.

[1169] Yield: 60mg

[1170] LC-MS: m / z 318.20 (MH+)

[1171] Preparation of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)aniline

[1172]

[1173] The title compound was synthesized in a manner similar to that used in the synthesis of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline, except that 1-[2-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane was used instead of 1-[2-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane. The title compound was obtained in 71% (80 mg) yield.

[1174] LC-MS: m / z 380.18 (MH+)

[1175] Preparation of 3-(azacycloheptane-1-yl)-4-[5-[2-(dimethylamino)ethylthioalkyl]-4-methyl-1,2,4-triazol-3-yl]aniline

[1176]

[1177] The title compound was synthesized in a manner similar to that used in the synthesis of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline, wherein 2-[[5-[2-(azacycloheptane-1-yl)-4-nitrophenyl]-4-methyl-1,2,4-triazol-3-yl]thio]-N,N-dimethylethylamine was used instead of 1-[2-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)-5-nitrophenyl]azacycloheptane. The title compound was obtained in 67% (50 mg) yield.

[1178] LC-MS: m / z 375.27 (MH+).

[1179] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide

[1180]

[1181] A solution of 3-(azacycloheptan-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline (60.0 mg, 0.190 mmol) and triethylamine (0.08 mL, 0.570 mmol) in DCM (0.945 mL) was cooled to 0 °C, and cyclopropionic acid chloride (0.04 mL, 0.470 mmol) was added. The mixture was allowed to reach room temperature and stirred overnight. The next day, the reaction mixture was diluted with DCM, washed with saturated NaHCO3 solution, dried using a phase separator, and concentrated under reduced pressure. The resulting substance was purified by FC on RP under acidic conditions (eluting with CH3CN / H2O 5:95+0.1% formic acid to CH3CN / H2O 95:5+0.1% formic acid) to give the product of N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthioalkyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide.

[1182] Yield: 16.8 mg

[1183] 1 H NMR (400MHz, chloroform-d) δ7.76(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+).

[1184] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropane formamide

[1185]

[1186] The title compound was synthesized in a manner similar to that of the compound of Example 109 (N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide), wherein 3-(azacycloheptane-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)aniline was used instead of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline. The title compound was obtained in a yield of 12% (19 mg).

[1187] 1¹H NMR (400MHz, 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.

[1188] Preparation: N-[3-(azacycloheptane-1-yl)-4-[5-[2-(dimethylamino)ethylthioalkyl]-4-methyl-1,2,4-triazol-3-yl]phenyl]cyclopropaneformamide

[1189]

[1190] The title compound was synthesized in a manner similar to that of the compound of Example 109 (N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide), wherein 3-(azacycloheptane-1-yl)-4-[5-[2-(dimethylamino)ethylthio]-4-methyl-1,2,4-triazol-3-yl]aniline was used instead of 3-(azacycloheptane-1-yl)-4-(4-methyl-5-methylthio-1,2,4-triazol-3-yl)aniline. The title compound was obtained in a yield of 9% (6.3 mg).

[1191] 1H NMR (400MHz, chloroform-d) δppm 7.73 (br s,1H),7.58-7.47(m,1H),7.28(s,1H),6.78(dd,1H),3.45(t,2H),3.32(s,3H),3.19-3.04(m,4H),2.74(s,2H),2.31(s,6H),1.52(br s,9H),1.19-1.05(m,2H),0.96-0.83(m,3H); LC-MS:443.18(MH+).

[1192] Synthesis Scheme 9

[1193]

[1194] Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropane formamide

[1195]

[1196] Hydrazine hydrate (3.43 mL, 45.4 mmol) was added to a solution of methyl 4-(cyclopropanecarbonylamino)-2-(3,5-dimethylpiperidin-1-yl)benzoate (1.5 g, 4.54 mmol) in ethanol (10.56 mL). The resulting solution was stirred at 85 °C for 4 h. The reaction was then cooled to room temperature and concentrated under reduced pressure to give N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazinecarbonyl)phenyl]cyclopropaneformamide as a mixture of cis / trans isomers.

[1197] Yield: 1.5g

[1198] LC-MS: 331.22 (MH+).

[1199] Preparation: N-[3-(azacycloheptane-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropane formamide

[1200]

[1201] To a solution of 2-(azacycloheptan-1-onthiol-1-yl)-4-(cyclopropanecarbonylamino)benzoic acid chloride (250.0 mg, 0.740 mmol) in DMF (7.018 mL), HATU=[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (308.6 mg, 0.810 mmol) and hydrazine hydrochloride (252.74 mg, 3.69 mmol) were added. This solution was stirred at room temperature for 30 min, and N,N-diisopropylethylamine (333.75 mg, 2.58 mmol) was slowly added to a solution of DMF (2 mL), and the mixture was stirred overnight at room temperature. The next day, the reaction mixture was diluted with DCM, washed three times with saturated NaHCO3 solution, washed with brine, dried through a phase separator, and concentrated under vacuum. The residue was purified by FC on RP under acidic conditions (eluting with CH3CN / H2O 5:95+0.1% formic acid to CH3CN / H2O 95:5+0.1% formic acid) to give the product of N-[3-(azacycloheptane-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropane formamide.

[1202] Yield: 60mg

[1203] 1H NMR(400MHz,DMSO-d6)δ10.22(s,1H),9.98(s,1H),7.47(d,1H),7.38(d,1H),7.11(dd,1H),4 .41(s,2H),3.20-3.10(m,4H),1.79-1.71(m,5H),1.59(dt,4H),0.89-0.67(m,4H); LC-MS:m / z 317.23(MH+).

[1204] Preparation: N-[4-(hydrazine carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropane formamide

[1205]

[1206] The title compound was synthesized in a manner similar to that used in the synthesis of N-[3-(azacycloheptane-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropanecarboxamide, wherein 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid was used instead of 2-(azacycloheptane-1-onthiol)-4-(cyclopropanecarbonylamino)benzoyl chloride. The title compound was obtained in 99% (1 g) yield.

[1207] 1H NMR(400MHz,DMSO-d6)δ10.09(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 / z289.16(MH+).

[1208] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4-methyl-5-phenyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide

[1209]

[1210] A solution of N-methylbenzamide (25.63 mg, 0.190 mmol) and 2,6-dimethylpyridine (0.04 mL, 0.380 mmol) in anhydrous DCM (0.948 mL) was cooled to 0 °C. After 10 minutes, oxalyl dichloride (0.02 mL, 0.190 mmol) was carefully added under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 30 minutes. Subsequently, N-[3-(azacycloheptan-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropaneformamide (60.0 mg, 0.190 mmol) was added, and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was then concentrated, the residue was absorbed with 5 mL of saturated NaHCO3 solution, and the mixture was refluxed overnight. The next day, the reaction mixture was acidified to pH 2 with 1 N HCl and concentrated under vacuum. The residue was purified by FC on RP under alkaline conditions (eluting with 100% water + 0.1% NH4OH to 100% CH3CN) to obtain the compound of formula.

[1211] Yield: 5.8 mg

[1212] 1H NMR(400MHz,DMSO-d6)δppm 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+).

[1213] Preparation: N-[3-(azacycloheptane-1-yl)-4-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]cyclopropane formamide

[1214]

[1215] 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, oxaloyl chloride (0.04 mL, 0.510 mmol) was carefully added under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 30 min, and then N-[3-(azacycloheptan-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropaneformamide (160.0 mg, 0.510 mmol) was added. The reaction was heated to room temperature and stirred for 3.5 h. Volatile substances were removed under reduced pressure, and the resulting product was absorbed with 3.5 mL of saturated NaHCO3 solution and stirred at 100 °C for 45 min. Subsequently, the reaction was cooled to room temperature and extracted three times with DCM. The combined organic fractions were dried through a phase separator and concentrated under vacuum. The obtained substance was purified twice by FC on RP under acidic conditions (eluting with CH3CN / H2O 5:95+0.1% formic acid to CH3CN / H2O 95:5+0.1% formic acid) to obtain the product of N-[3-(azacycloheptane-1-yl)-4-(4,5-dimethyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide.

[1216] Yield: 4.8 mg

[1217] H NMR (500MHz, methanol-d4) δppm 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),1.8 3-1.73(m,1H),1.63-1.41(m,8H),0.97(quin,2H),0.92-0.82(m,2H); LC-MS: m / z354.26(MH+).

[1218] Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thioalkyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide

[1219]

[1220] Methylimino(sulfanylidene)methane (0.316 g, 4.33 mmol) was added to a solution of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropaneformamide (1.3 g, 3.93 mmol) in THF (23.36 mL), and the reaction was stirred at 130 °C for 8 min under MW irradiation. The reaction was then cooled to room temperature, and 30 mL of saturated NaHCO3 solution was added. The resulting mixture was heated to reflux overnight. The next day, the reaction was cooled to room temperature and acidified with 2N HCl 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 (eluting with 100% CHEX to CHEX / AcOEt 7:3) to give a compound of the formula N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thioalkyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide.

[1221] Yield: 1.1g

[1222] LC-MS: m / z 386.2 (MH+)

[1223] Preparation: N-[4-(4-methyl-5-thioalkyl-1,2,4-triazol-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide

[1224]

[1225] The title compound was synthesized in a manner similar to that of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thioalkyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide, wherein N-[4-(hydrazine carbonyl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide was used instead of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropaneformamide. The title compound was obtained in 18% (405 mg) yield.

[1226] 1H NMR(400MHz,DMSO-d6)δ13.73(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 / z344.16 (MH+).

[1227] Preparation: N-[4-[4-[2-(dimethylamino)ethyl]-5-thioalkyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl]cyclopropaneformamide

[1228]

[1229] N',N'-dimethylethane-1,2-diamine (0.09 mL, 0.830 mmol) was added to a solution of bis(1-imidazolyl)methanethione (177.98 mg, 1 mmol) in THF (7.566 mL), and the mixture was stirred for 15 min. N-[3-(3,5-dimethylpiperidin-1-yl)-4-(hydrazine carbonyl)phenyl]cyclopropaneformamide (250.0 mg, 0.760 mmol) was added to this solution, and the resulting solution was heated to 130 °C under MW irradiation and held for 10 min. The reaction mixture was then concentrated under vacuum, and 10 mL of saturated NaHCO3 solution was added. The resulting mixture was further stirred at 100 °C for 1 h under MW irradiation. The reaction mixture was adjusted to pH 2 with 2N HCl and concentrated under reduced pressure. The crude material was purified by FC to RP under acidic conditions (eluting with CH3CN / H2O 5:95+0.1% formic acid to CH3CN / H2O 95:5+0.1% formic acid) to obtain the product of N-[4-[4-[2-(dimethylamino)ethyl]-5-thioalkyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl]cyclopropaneformamide.

[1230] Yield: 70mg

[1231] LC-MS: 443.5 (MH+).

[1232] Preparation: N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide

[1233]

[1234] Iodobenzene (0.09 mL, 0.780 mmol) was added to a solution of cuprous iodide (I) (6.21 mg, 0.030 mmol), 1,10-phenanthroline (11.69 mg, 0.060 mmol), and potassium carbonate (116.51 mg, 0.840 mmol) in anhydrous DMF (4.323 mL). To this solution, a solution of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thioalkyl-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide (250.0 mg, 0.650 mmol) in anhydrous DMF (2.162 mL) was added, and the resulting mixture was degassed using a Schlenk line technique. The mixture was heated to 120 °C and maintained 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 Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by FC on RP under alkaline conditions (eluting from 100% water + 0.1% NH4OH to water + 0.1% NH4OH / CH3CN 6:4) to give the product of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide as a mixture of cis / trans isomers.

[1235] Yield: 70mg

[1236] LC-MS: m / z 462.03 (M+Na)

[1237] The mixture of cis / trans isomers (Example 114c) was then separated into individual isomers by semi-preparative chiral HPLC.

[1238]

[1239]

[1240] Preparation: N-[4-[4-[2-(dimethylamino)ethyl]-5-phenylthioalkyl-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl]cyclopropaneformamide

[1241]

[1242] The title compound was synthesized in a manner similar to that of the compound (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide) in Examples 114a and 114b, wherein N-[4-[4-[2-(dimethylamino)ethyl]-5-thio-1,2,4-triazol-3-yl]-3-(3,5-dimethylpiperidin-1-yl)phenyl]cyclopropaneformamide was used instead of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide. The title compound was obtained as a mixture of cis / trans isomers in a yield of 41% (35 mg).

[1243] 1H NMR(500MHz,DMSO-d6)δppm 10.37(s,1H),7.53(d,1H),7.40-7.30(m,6H),7.24(d,1H),3.99(t,2H),3.00-2.7 5(m,2H),2.07(t,2H),2.04-1.86(m,2H),1.82(s,6H),1.80-1.75(m,1H),1.52(br d,1H),1.35-0.95(m,2H),0.84-0.79(m,4H),0.77-0.54(m,6H),0.47(q,1H); LC-MS: m / z 519.3(MH+).

[1244] Preparation: N-[4-(4-methyl-5-pyridin-2-ylthioalkyl-1,2,4-triazol-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropane formamide

[1245]

[1246] The title compound was synthesized in a manner similar to that of the compound (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide) in Examples 114a and 114b, wherein N-[4-(4-methyl-5-thio-1,2,4-triazol-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide and iodopyridine were used instead of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide and iodobenzene, respectively. The title compound was obtained in a yield of 27% (43 mg).

[1247] 1H NMR(400MHz,DMSO-d6)δ10.25(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+).

[1248] Preparation: N-[4-(4-methyl-5-pyridin-3-ylthioalkyl-1,2,4-triazol-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropane formamide

[1249]

[1250] The title compound was synthesized in a manner similar to that of the compound (N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-phenylthio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide) in Examples 114a and 114b, wherein N-[4-(4-methyl-5-thio-1,2,4-triazol-3-yl)-3-pyrrolidine-1-ylphenyl]cyclopropaneformamide and iodopyridine were used instead of N-[3-(3,5-dimethylpiperidin-1-yl)-4-(4-methyl-5-thio-1,2,4-triazol-3-yl)phenyl]cyclopropaneformamide and iodobenzene, respectively. The title compound was obtained in 88% (140 mg) yield.

[1251] 1H NMR (400MHz, DMSO-d6) δ10.25(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+).

[1252] Option 10

[1253]

[1254] Scheme 10 - Reagents and conditions: a) Azacycloheptanine, CH3CN, RT, overnight; b) NH2OH HCl, TEA, tBuOH, 80℃, overnight, then Cs2CO3, Cu(OAc)2, cyclopropaneformonitrile, Na2SO4, DMSO, 120℃, overnight; c) LiOH, MeOH / THF / H2O, 50℃, overnight, then HATU, DIPEA, 1-propylpiperazine, DMF, RT, overnight.

[1255] Preparation: Methyl 2-(azacycloheptan-1-yl)-4-cyanobenzoate

[1256]

[1257] A mixture of methyl 4-cyano-2-fluorobenzoate (1.2 g, 6.7 mmol) and perpiperidine (3.77 mL, 33.49 mmol) in MeCN (11 mL) was stirred overnight at room temperature. The reaction was concentrated under vacuum, and the residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 9:1) to give the product methyl 2-(azacycloheptane-1-yl)-4-cyanobenzoate.

[1258] Yield: 1.3g

[1259] 1 H NMR (400MHz, chloroform-d) δ7.56(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+).

[1260] Preparation: Methyl 2-(azacycloheptan-1-yl)-4-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)benzoate

[1261]

[1262] A mixture of methyl 2-(azacycloheptan-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) in tert-butanol (3.5 mL) was stirred overnight at 80 °C. The reaction was then cooled to room temperature, and cyclopropaneformonitrile (165.0 mg, 2.46 mmol), copper acetate (45.17 mg, 0.250 mmol), cesium carbonate (1.21 g, 3.69 mmol), anhydrous Na₂SO₄ (1.2 g, 8.61 mmol), and DMSO (3 mL) were added. The reaction was then stirred overnight at 120 °C. The reaction was cooled to room temperature and concentrated. The residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 70:30) to give the product methyl benzoate of formula 2-(azacycloheptane-1-yl)-4-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)benzoate.

[1263] Yield: 30mg

[1264] LC-MS: m / z 341.2 (MH+)

[1265] Preparation of: [2-(azacycloheptane-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-propylpiperazin-1-yl)methyl ketone

[1266]

[1267] A solution of lithium hydroxide (4.22 mg, 0.180 mmol) in water (0.037 mL) was added to a solution of methyl 2-(azacycloheptan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)benzoate (30.0 mg, 0.090 mmol) in THF (0.111 mL) and methanol (0.037 mL). The reaction was stirred overnight at 50 °C. The next day, the reaction was cooled to room temperature, acidified to pH 5 with 1 N HCl, and concentrated under vacuum to give an intermediate of 2-(azacycloheptan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)benzoic acid, which was used in the next step without further purification. LC-MS: m / z 327.1 (MH+).

[1268] Intermediate 2-(azacycloheptan-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)benzoic acid (25.0 mg, 0.075 mmol) was dissolved in DMF (0.5 mL), followed by the addition of N,N-diisopropylethylamine (0.05 mL, 0.310 mmol) and HATU:[dimethylamino(3-triazolo[4,5-b]pyridyloxy)methylene]-dimethylammonium hexafluorophosphate (69.9 mg, 0.180 mmol). The mixture was stirred at room temperature for 10 min, and then 1-propylpiperazine (51.1 mg, 0.180 mmol) was added dropwise to the DMF (0.5 mL) solution. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was purified by SCX, first washing with MeOH, then washing with 1 M NH3 in MeOH. The basic fraction was evaporated, and the residue was purified by FC on an NH column (eluting with 100% AcOEt to AcOEt / MeOH 9:1). The product was further purified by FC on RP under acidic conditions (eluting with CH3CN / H2O 95:5 to CH3CN / H2O 95:5 to 0.1% formic acid) to give the product of formula [2-(azacycloheptane-1-yl)-4-(5-cyclopropyl-4H-1,2,4-triazol-3-yl)phenyl]-(4-propylpiperazin-1-yl) methyl ketone.

[1269] Yield: 15mg

[1270] 1H NMR(500MHz,DMSO-d6)δppm 14.26(m,1H)-13.34,7.54(br s,1H),7.38(br d,1H),7.08(br d,7.3Hz,1H),3.26(t,4H),3.55-3.10(m,2H),3.75-3.10(m,2H),2.27-2.21(m,2H),2.48-2.13(m,4H),2.06(br s,1H),1.77-1.48(m,8H),1.42(sxt,2H),1.10-0.87(m,4H),0.84(t,3H); LC-MS: m / z 437.4(MH+).

[1271] Synthesis Scheme 11

[1272]

[1273] Preparation: Methyl 4-bromo-2-pyrrolidine-1-ylbenzoate

[1274]

[1275] Pyrrolidine (1.43 mL, 17.17 mmol) was added to a solution of methyl 4-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol) in DMF (7.122 mL), and the reaction was stirred at 80 °C for 8 h. The reaction was then cooled to room temperature and H₂O was added. The mixture was stirred for 10 min and filtered. The obtained solid was washed with H₂O and dried under vacuum to give the product methyl 4-bromo-2-pyrrolidine-1-ylbenzoate.

[1276] Yield: 1g

[1277] 1H NMR (400MHz, DMSO-d6) δ7.35(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 / z284.03,286.01(MH+).

[1278] Preparation: 4-Bromo-2-pyrrolidine-1-ylbenzoic acid

[1279]

[1280] A solution of lithium hydroxide hydrate (147.67 mg, 3.52 mmol) in water (1 mL) was added to a mixture of methyl 4-bromo-2-pyrrolidine-1-ylbenzoate (0.5 g, 1.76 mmol) in THF (3 mL) / methanol (1 mL), and the reaction was stirred overnight at 50 °C. The next day, 3N HCl was added until pH = 1, and the reaction was extracted with AcOEt. The organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the product of formula 4-bromo-2-pyrrolidine-1-ylbenzoic acid, which was used in the next step without further purification.

[1281] Yield: 387mg

[1282] 1H NMR (400MHz, 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+).

[1283] Preparation of (4-bromo-2-pyrrolidine-1-ylphenyl)-(4-propylpiperazin-1-yl)methyl ketone

[1284]

[1285] 4-Bromo-2-pyrrolidine-1-ylbenzoic acid (389.0 mg, 1.44 mmol), HATU:[dimethylamino(3-triazolo[4,5-b]pyridyloxy)methylene]-dimethylammonium hexafluorophosphate (657.08 mg, 1.73 mmol), and N,N-diisopropylethylamine (0.5 mL, 2.88 mmol) were mixed in DMF (6 mL) and stirred for 5 min. Then, a solution of 1-propylpiperazine dihydrobromide (480.34 mg, 1.66 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.88 mmol) in DMF (2 mL) was added. The reaction mixture was stirred overnight at room temperature. The next day, the solvent was removed under vacuum. The residue was purified using an SCX cartridge, first washed with MeOH and then eluted with 1 M NH3 in MeOH. The alkaline fraction was evaporated, and the residue was purified by FC on an NH column (eluting with 100% CHEX to CHEX / AcOEt 7:3) to give the product of formula (4-bromo-2-pyrrolidine-1-ylphenyl)-(4-propylpiperazin-1-yl) methyl ketone.

[1286] Yield: 430mg

[1287] 1H NMR(400MHz,DMSO-d6)δ6.94-6.85(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+).

[1288] Preparation of: (4-propylpiperazin-1-yl)-[4-(pyridin-2-ylamino)-2-pyrrolidine-1-ylphenyl] methyl ketone

[1289]

[1290] A mixture of (4-bromo-2-pyrrolidone-1-ylphenyl)-(4-propylpiperazin-1-yl) methyl ketone (0.2 g, 0.530 mmol), (1E,4E)-1,5-diphenyl-3-pent-1,4-dienone; palladium (24.08 mg, 0.030 mmol), cesium carbonate (257.01 mg, 0.790 mmol), 2-pyridinamine (59.39 mg, 0.630 mmol), and [1-(2-diphenylphosphino-1-naphthyl)-2-naphthyl]-diphenylphosphine (32.74 mg, 0.050 mmol) was suspended in toluene (2.815 mL). The reaction mixture was degassed with N2 for 10 min and then stirred overnight at 100 °C. The next day, the reaction mixture was filtered through a diatomaceous earth mat and concentrated under vacuum. The residue was purified by FC on RP under alkaline conditions (eluting with H2O + 0.1% ammonium hydroxide / CH3CN 95:5 to H2O + 0.1% ammonium hydroxide / CH3CN 5:95) to give the product of formula (4-propylpiperazin-1-yl)-[4-(pyridin-2-ylamino)-2-pyrrolidine-1-ylphenyl] ketone.

[1291] Yield: 5.8 mg

[1292] 1 H NMR(400MHz,DMSO-d6)δ8.95(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+).

[1293] Preparation of (4-bromo-2-pyrrolidone-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl)methyl ketone

[1294]

[1295] The title compound was synthesized in a manner similar to that of (4-bromo-2-pyrrolidone-1-ylphenyl)-(4-propylpiperazin-1-yl)methyl ketone, wherein 1-methyl-3-phenylpiperazine was used instead of 1-propylpiperazine dihydrobromide. The title compound was obtained in 66% (1.04 g) yield.

[1296] 1H NMR(400MHz,DMSO-d6)δ7.83-7.15(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+).

[1297] Preparation of: (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidine-1-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl] ketone

[1298]

[1299] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (311.22 mg, 1.23 mmol), (4-bromo-2-pyrrolidine-1-ylphenyl)-(4-methyl-2-phenylpiperazin-1-yl) methyl ketone (500.0 mg, 1.17 mmol), and potassium acetate (347.19 mg, 3.5 mmol) in 1,4-dioxane (22 mL) was degassed by five nitrogen / vacuum cycles. Then, the complex of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride with dichloromethane (19.11 mg, 0.020 mmol) was added, and after degassing again by five nitrogen / vacuum cycles, the reaction mixture was heated at 100 °C for 2 hours. Subsequently, the reaction mixture was cooled to room temperature and filtered through a diatomaceous earth pad, washed with AcOEt. The organic solution was concentrated under reduced pressure to give the product of formula (4-methyl-2-phenylpiperazin-1-yl)-[2-pyrrolidine-1-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl] ketone, which was used in the next step without further purification.

[1300] Yield: 559mg

[1301] LC-MS: m / z 476.22 (MH+).

[1302] Preparation of: [4-(1-methylimidazol-2-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl) methyl ketone

[1303]

[1304] A mixture of tetra(triphenylphosphine)palladium (6.08 mg, 0.010 mmol), 2M sodium carbonate aqueous solution (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-dioxaborhecyclopentan-2-yl)phenyl]methyl ketone (50.0 mg, 0.110 mmol) in 1,2-dimethoxyethane (1 mL) was degassed by five nitrogen / vacuum cycles. Then, 2-bromo-1-methylimidazolium (0.01 mL, 0.120 mmol) was added, and the container was sealed. The reaction mixture was degassed again by five nitrogen / vacuum cycles, and then heated to 95 °C and maintained overnight. The following day, the reaction was cooled to room temperature, and the mixture was directly purified by FC on RP under acidic conditions (eluting with CH3CN / H2O 5:95 + 0.1% formic acid to CH3CN / H2O 5:5 + 0.1% formic acid). Appropriate fractions were collected and concentrated under vacuum. The residue was further purified by FC on RP under basic conditions (eluting with H2O + 0.1% ammonium hydroxide / CH3CN 95:5 to H2O + 0.1% ammonium hydroxide / CH3CN 2:8) to give the product [4-(1-methylimidazol-2-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl) methyl ketone as a racemic mixture.

[1305] Yield: 11.6 mg

[1306] 1H NMR(400MHz,DMSO-d6)δ7.81-7.69(m,1H),7.49(d,1H),7.44-6.89(m,8H),5.90-4.74(m,1H),3.83-3.68(m,3 LC-MS:m / z 430.22(MH+).

[1307] Preparation of: [4-(2-methyl-1H-imidazol-5-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methyl ketone

[1308]

[1309] The title compound was synthesized in a manner similar to that of the compound in Example 121 ([4-(1-methylimidazol-2-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methyl ketone), except that 4-bromo-2-methylimidazolium was used instead of 2-bromo-1-methylimidazolium. The title compound was obtained in a yield of 38.3% (17.3 mg).

[1310] 1H NMR(400MHz,DMSO-d6)δ11.94(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+).

[1311] Preparation of: [4-(5-methyl-1,3,4-oxadiazol-2-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methyl ketone

[1312]

[1313] The title compound was synthesized in a manner similar to that of the compound in Example 121 ([4-(1-methylimidazol-2-yl)-2-pyrrolidine-1-ylphenyl]-(4-methyl-2-phenylpiperazin-1-yl)methyl ketone), except that 2-bromo-5-methyl-1,3,4-oxadiazole was used instead of 2-bromo-1-methylimidazolium. The title compound was obtained as a racemic mixture in a yield of 16.5% (7.5 mg).

[1314] 1H NMR (400MHz, DMSO-d6) δ8.03-6.97(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+).

[1315] Option 12

[1316]

[1317] Synthesis Scheme 12 - Reagents and Conditions: a) tetrakis(triphenylphosphine)palladium, appropriate borate ester, 2M Na2CO3, 1,2-dimethoxyethane, 95°C, 1.5h; or b) PtO2, EtOH, RT, 1atm, 3h; c) Boc2O, TEA, DCM, 0°C to room temperature, overnight.

[1318] Preparation: 2-Thiophene-2-ylpyrazine

[1319]

[1320] A mixture of 2-chloropyrazine (2.6 mL, 29.13 mmol), thiophene-2-ylboronic acid (4.1 g, 32.04 mmol), and 2M sodium carbonate aqueous solution (43.69 mL, 87.38 mmol) in 1,2-dimethoxyethane (100 mL) was degassed by five nitrogen / vacuum cycles. Tetra(triphenylphosphine)palladium (1.7 g, 1.46 mmol) was then added, and the container was sealed. The reaction mixture was degassed again by five nitrogen / vacuum cycles, and then heated to 95 °C and held overnight. The reaction was cooled to room temperature, diluted with H₂O, and extracted with EtOAc (x3). The organic fraction was collected, washed with brine, dried over Na₂SO₄, and the solvent was evaporated under reduced pressure. The residue was purified by FC on an NH₄ column (eluting with 100% CHEX to CHEX / AcOEt 8:2) to give 2-thiophene-2-ylpyrazine.

[1321] Yield: 3.9g

[1322] LC-MS: m / z 162.85 (MH+).

[1323] Preparation: 3-Thiophen-2-ylpyrazine

[1324]

[1325] The title compound was synthesized in a manner similar to that of 2-thiophene-2-ylpyrazine, except that 3-thiopheneboronic acid was used instead of thiophene-2-ylboronic acid. The title compound was obtained in 85% (3 g) yield.

[1326] 1H NMR (400MHz, chloroform-d) δppm 8.94(d,1H)8.57(dd,1H)8.45(d,1H)8.01(dd,1H)7.71(dd,1H)7.46(dd,1H); LC-MS: m / z 162.9(MH+).

[1327] Preparation: 2-(1-methylpyrazol-4-yl)pyrazine

[1328]

[1329] The title compound was synthesized in a manner similar to that of 2-thiophene-2-ylpyrazine, except that 1-methylpyrazol-4-boronic acid pinacol ester was used instead of thiophene-2-ylboronic acid. The title compound was obtained in 96% (0.8 g) yield.

[1330] 1H NMR (400MHz, 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+).

[1331] Preparation: 2-pyridine-2-ylpyrazine

[1332]

[1333] A mixture of 2-chloropyrazine (250.0 mg, 2.18 mmol) and tributyl(2-pyridyl)stanane (0.85 mL, 2.62 mmol) in anhydrous toluene (10 mL) was degassed, and tetrakis(triphenylphosphine)palladium (126.12 mg, 0.110 mmol) was added under nitrogen purging. The suspension was degassed again and stirred overnight at 115 °C. The next day, the reaction mixture was diluted with 10 mol% KF aqueous solution and extracted three times with EtOAc. The organic fraction was washed with water and brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The resulting product was purified by FC on silica gel (eluting with 100% CHEX to CHEX / AcOEt 60:40) to give the product of formula 2-pyridin-2-ylpyrazine.

[1334] Yield: 350mg

[1335] 1 ¹H NMR (400MHz, 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+).

[1336] Preparation: 2-Thiophene-2-ylpiperazine

[1337]

[1338] A mixture of 2-thiophene-2-ylpyrazine (275.0 mg, 1.7 mmol) and platinum oxide (IV) (192.49 mg, 0.850 mmol) in ethanol (5 mL) and AcOH (1 mL) was stirred at room temperature for 3 h under a 1 atm H2 atmosphere. The next day, the reaction was filtered through a diatomaceous earth mat and concentrated under vacuum. The residue was purified by SCX, first washed with MeOH and then with 1 M NH3 in MeOH, to give the product of formula 2-thiophene-2-ylpiperazine.

[1339] Yield: 240mg

[1340] LC-MS: m / z 169.0 (MH+).

[1341] Preparation: 2-(1-methylpyrazol-4-yl)piperazine

[1342]

[1343] The title compound was synthesized in a manner similar to that of 2-thiophene-2-ylpiperazine, except that 2-(1-methylpyrazol-4-yl)pyrazine was used instead of 2-thiophene-2-ylpyrazine. The title compound was obtained in 53% (550 mg) yield.

[1344] LC-MS: m / z 167.0 (MH+)

[1345] Preparation: 2-Thiophene-3-ylpiperazine

[1346]

[1347] A mixture of 2-thiophene-3-ylpyrazine (315.0 mg, 1.94 mmol) and platinum oxide (IV) (220.49 mg, 0.970 mmol) in ethanol (8 mL) and AcOH (1 mL) was stirred overnight at room temperature under a 6 bar H₂ atmosphere. The reaction was filtered through a diatomaceous earth mat and concentrated under vacuum. The residue was purified by SCX, first washed with MeOH and then with 1 M NH₃ in MeOH, to give the product of formula 2-thiophene-3-ylpiperazine.

[1348] Yield: 150mg

[1349] LC-MS: m / z 169.0 (MH+)

[1350] Preparation: 2-pyridine-2-ylpiperazine

[1351]

[1352] The title compound was synthesized in a manner similar to that of 2-thiophene-3-ylpiperazine, except that 2-pyridin-2-ylpyrazine was used instead of 2-thiophene-3-ylpyrazine. The title compound was obtained in 83% (130 mg) yield.

[1353] 1 ¹H NMR (400MHz, 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).

[1354] Preparation: tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate

[1355]

[1356] A mixture of 2-thiophene-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 h. The reaction mixture 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 an NH₄ column (eluting with 100% CHEX to CHEX / AcOEt 90:10) to give the product of tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate.

[1357] Yield: 200mg

[1358] 1H NMR (400MHz, chloroform-d) d ppm 7.21-7.15 (m, 1H), 7.04-6.99 (m, 2H), 4.05-3.92 (m., 2H), 2.90 (dd, 4H), 1.82-1.57 (m, 2H), 1.48 (s, 9H).

[1359] Preparation: tert-butyl 3-thiophene-3-ylpiperazine-1-carboxylate

[1360]

[1361] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate, except that 2-thiophene-3-ylpiperazine was used instead of 2-thiophene-2-ylpiperazine. The title compound was obtained in a yield of 20% (45 mg).

[1362] LC-MS: m / z 269.1 (MH+).

[1363] Preparation: tert-butyl 3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate

[1364]

[1365] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate, except that 2-(1-methylpyrazol-4-yl)piperazine was used instead of 2-thiophene-2-ylpiperazine. The title compound was obtained in 99% (430 mg) yield.

[1366] LC-MS: m / z 267.1 (MH+)

[1367] Preparation: tert-butyl 3-pyridine-2-ylpiperazine-1-carboxylate

[1368]

[1369] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate, except that 2-pyridin-2-ylpiperazine was used instead of 2-thiophene-2-ylpiperazine. The title compound was obtained in 46% (185 mg) yield.

[1370] LC-MS: m / z 264.3 (MH+)

[1371] Preparation: tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate

[1372]

[1373] A solution of di-tert-butyl dicarbonate (242.2 mg, 1.11 mmol) in 1 mL of DCM was slowly added to a solution of 2-(3-fluorophenyl)piperazine (200.0 mg, 1.11 mmol) and triethylamine (0.17 mL, 1.22 mmol) in 2.5 mL of DCM, and the reaction was stirred at room temperature for 1 h. The solution was diluted with another DCM and washed with H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to give the product of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate as a racemic mixture. The product was used in the next step without further purification.

[1374] Yield: 300mg

[1375] 1 ¹H NMR (400MHz, 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+).

[1376] Preparation: tert-butyl 3-(2-fluorophenyl)piperazine-1-carboxylate

[1377]

[1378] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate, except that 2-(3-fluorophenyl)piperazine-1,4-dionium dichloride was used instead of 2-(3-fluorophenyl)piperazine. The title compound was obtained in 99% (220 mg) yield.

[1379] LC-MS: m / z 281.1 (MH+).

[1380] Preparation: tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate

[1381]

[1382] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate, except that 2-(4-fluorophenyl)piperazine was used instead of 2-(3-fluorophenyl)piperazine. The title compound was obtained in 90% (280 mg) yield.

[1383] 1 ¹H NMR (400MHz, methanol-d⁴) 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⁺).

[1384] Preparation: tert-butyl 3-(2-chlorophenyl)piperazine-1-carboxylate

[1385] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate, except that 2-(2-chlorophenyl)piperazine was used instead of 2-(3-fluorophenyl)piperazine. The title compound was obtained in 99% (752 mg) yield.

[1386] 1H NMR (400MHz, DMSO-d6) δppm 7.68 (dd, J=7.59, 1.87Hz, 1H), 7.44 (dd, J=7.81, 1.43Hz, 1H), 7.40-7.28 (m, 2H), 4.03 (br d,J=12.10Hz,1H),3.97-3.81(m,2H),2.98(br d,J=11.00Hz,1H),2.93-2.73(m,2H),2.73-2.63(m,2H),1.41(s,9H); LC-MS: m / z297.132(MH+).

[1387] Preparation: tert-butyl 3-(3-chlorophenyl)piperazine-1-carboxylate

[1388]

[1389] The title compound was synthesized in a manner similar to that used in the synthesis of tert-butyl 3-(3-fluorophenyl)piperazine-1-carboxylate, except that 2-(3-chlorophenyl)piperazine was used instead of 2-(3-fluorophenyl)piperazine. The title compound was obtained in 99% (752 mg) yield.

[1390] 1H NMR(400MHz,DMSO-d6)δppm 7.48(s,1H),7.44-7.31(m,4H),3.81(br d, J=12.32Hz, 2H), 3.60 (dd, J=10.34, 2.86Hz, 1H), 3.03-2.73 (m, 2H), 2.73-2.59 (m, 2H), 1.41 (s, 9H); LC-MS: 297.16 (MH+).

[1391] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-2-thiophene-2-ylpiperazine-1-carboxylic acid tert-butyl ester

[1392]

[1393] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 2-thiophene-2-ylpiperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 89% (145 mg) yield.

[1394] LC-MS: m / z 553.4 (MH+)

[1395] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-thiophene-3-ylpiperazine-1-carboxylic acid tert-butyl ester

[1396]

[1397] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-thiophene-2-ylpiperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 80% (65 mg) yield.

[1398] LC-MS: m / z 553.4 (MH+).

[1399] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(1-methylpyrazol-4-yl)piperazine-1-carboxylic acid tert-butyl ester

[1400]

[1401] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-(1-methylpyrazol-4-yl)piperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 58% (70 mg) yield.

[1402] LC-MS: m / z 551.4 (MH+).

[1403] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylic acid tert-butyl ester

[1404]

[1405] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-pyridin-2-ylpiperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 50% (80 mg) yield.

[1406] LC-MS: m / z 548.52

[1407] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(trifluoromethyl)piperazine-1-carboxylic acid tert-butyl ester

[1408]

[1409] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in a yield of 40% (45 mg).

[1410] LC-MS: m / z 539.4 (MH+)

[1411] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-benzylpiperazine-1-carboxylic acid tert-butyl ester

[1412]

[1413] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-benzylpiperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 88% (100 mg) yield.

[1414] LC-MS: m / z 561.4 (MH+)

[1415] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester

[1416]

[1417]

[1418] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropaneformamide), wherein 1-boc-3-hydroxymethyl-piperazine was used instead of piperidine. The title compound was obtained in 72% (80 mg) yield.

[1419] LC-MS: m / z 501.3 (MH+)

[1420] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester

[1421]

[1422] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-methyl-1-piperazincarnate was used instead of piperidine. The title compound was obtained in 98% (105 mg) yield.

[1423] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-propyl-2-ylpiperazine-1-carboxylic acid tert-butyl ester

[1424]

[1425] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-propyl-2-piperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 99% (120 mg) yield.

[1426] LC-MS: m / z 513.4 (MH+)

[1427] Preparation: tert-butyl 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-phenylpiperazine-1-carboxylate

[1428]

[1429] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidine-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-phenyl-piperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 91% (145 mg) yield.

[1430] LC-MS: m / z 547.5 (MH+)

[1431] Preparation: 4-[2-(azacycloheptane-1-yl)-4-(cyclopropanecarbonylamino)benzoyl]-3-pyridin-2-ylpiperazine-1-carboxylic acid tert-butyl ester

[1432]

[1433] The title compound was synthesized in a manner similar to that of the compound in Example 35 (N-(3-(azacycloheptane-1-yl)-4-(piperidin-1-carbonyl)phenyl)cyclopropanecarboxamide), wherein tert-butyl 3-pyridin-2-ylpiperazine-1-carboxylate was used instead of piperidine. The title compound was obtained in 91% (145 mg) yield.

[1434] LC-MS: m / z 548.5 (MH+)

[1435] Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-phenylpiperazine-1-carboxylic acid tert-butyl ester

[1436]

[1437] 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid (100.0 mg, 0.360 mmol), HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium 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 min. Then, N1 Coc-protected 3-phenylpiperazine (95.64 mg, 0.360 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then at 60 °C overnight. The next day, the reaction mixture was cooled to room temperature, poured into H2O, and extracted three times with AcOEt. The organic fractions were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by FC on an NH column (eluting with 100% CHEX to AcOEt / CHEX 3:7) to give the product as a racemic mixture of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-phenylpiperazine-1-carboxylate.

[1438] Yield: 156 mg.

[1439] 1 H NMR(400MHz,DMSO-d6)δ10.19-10.04(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+).

[1440] Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[1441]

[1442] To a solution of 4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoic acid (136.5 mg, 0.500 mmol) and HATU:[dimethylamino(3-triazolo[4,5-b]pyridinyloxy)methylene]-dimethylammonium hexafluorophosphate (283.81 mg, 0.750 mmol) in DMF (3 mL), N,N-diisopropylethylamine (0.26 mL, 1.49 mmol) and tert-butyl 3-(4-fluorophenyl)piperazine-1-carboxylate (150.0 mg, 0.500 mmol) were added sequentially. The reaction mixture was heated to 80 °C and allowed to react overnight. After the reaction was complete, the mixture was cooled to room temperature and then poured into a saturated NaHCO3 solution and AcOEt. The phases were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to dryness under vacuum to obtain a racemic mixture of tert-butyl 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate. The product was used in the next step without further purification.

[1443] Yield: 110mg.

[1444] 1 H NMR (400MHz, chloroform-d) δ7.63-7.26(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+).

[1445] Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[1446]

[1447] The title compound was synthesized in a manner similar to that of the compound in Example 136 (4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(4-fluorophenyl)piperazine-1-carboxylate tert-butyl ester), wherein 3-(3-fluorophenyl)piperazine-1-carboxylate tert-butyl ester was used instead of 3-(4-fluorophenyl)piperazine-1-carboxylate tert-butyl ester. The title compound was obtained as a racemic mixture in a yield of 52.2% (100 mg).

[1448] LC-MS: m / z 537.24 (MH+).

[1449] Preparation: 4-[4-(cyclopropanecarbonylamino)-2-pyrrolidine-1-ylbenzoyl]-3-(2-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester

[1450]

[1451] The title compound was synthesized in a manner similar to that of the compound in Example 136 (4-[4-(cyclopropanecarbonylam...

Claims

1. A compound of formula (IA) or a pharmaceutically acceptable salt thereof: in: X1 is selected from the following groups: , and ; R a Selected from hydrogen and C1-C3 alkyl groups; X2 is selected from the following groups: In each case, the wavy line The key represents the bond through which each X1 and X2 portion is joined; Y1 is selected from C(H) and N; Y2 is selected from C(H), N and S, and the condition is that when Y2 is S, R4 either does not exist or exists once or twice; The condition is that at most one of Y1 and Y2 is C; Z1, Z2 and Z3 are each independently selected from C(H) and N, provided that no more than two of Z1, Z2 and Z3 can be N; R1 is selected from C1-C6 alkyl groups, -(CH2) n1 -C3-C6 cycloalkyl, -NR x R y phenyl and benzyl, wherein the C1-C6 alkyl group and the -(CH2) group are present. n1 The ring of the -C3-C6 cycloalkyl, phenyl, and benzyl groups is substituted with 0, 1, 2, or 3 substituents selected from halogens, OH, CF3, and -O-C1-C3 alkyl groups, and wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups; n1 is an integer selected from 0, 1, 2, and 3; R2 is selected from pyridyl groups bonded by carbon atoms and monocyclic, bicyclic, or spirocyclic heterocyclic systems, wherein the monocyclic, bicyclic, or spirocyclic heterocyclic systems are bonded by nitrogen heteroatoms and contain 3, 4, 5, 6, 7, or 8 ring carbon atoms and 0, 1, 2, 3, or 4 additional ring heteroatoms selected from N and O, wherein the R2 monocyclic, bicyclic, or spirocyclic system is connected by 0, 1, 2, or 3 alkyl groups selected from C1-C6 alkyl, -O-C1-C6 alkyl, or -(CH2). n1 -C3-C6 cycloalkyl, -CF3, halogen and phenyl substituents; R3 exists once or more and is independently selected from the following groups: a) Hydrogen; b) -CO2H or -CO2- (C1-C6 alkyl); c) C1-C6 alkyl groups, which are substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogens, CF3 and OH; d) Phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl, wherein the ring of each of the phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl is substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogen, -CF3 and OH; e) A 5- or 6-membered heterocycle containing 1, 2, or 3 cyclic heteroatoms independently selected from O, S, and N, wherein the 5- or 6-membered heterocycle is substituted with 0, 1, 2, or 3 substituents selected from OH, halogens, benzyl, and C1-C6 alkyl, wherein the C1-C6 alkyl is further substituted with 0, 1, 2, 3, 4, or 5 substituents selected from halogens and OH; R4 exists once or twice and is independently selected from H, oxo, CHF2, CF3, and -(CH2). n2 -C3-C6 cycloalkyl groups, -O-(CH2) n2 -C3-C6 cycloalkyl, -S(=O)2-C1-C6 alkyl, -C(=O)-NR x R y , benzyl, thiophene-pyrimidinyl, or pyridinyl, wherein R x and R y Each is independently selected from H and C1-C6 alkyl groups substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups; Furthermore, when Y2 is carbon, R4 can also be an -O-C1-C6 alkyl group, or two R4 groups can form a carbide ring; Among them, R4 contains -(CH2) n2 -C3-C6 cycloalkyl groups and -O-(CH2) n2 The rings of the -C3-C6 cycloalkyl and benzyl groups are each independently substituted by 0, 1, 2 or 3 substituents selected from the following: halogen, CF3, OH, heterocycles having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms and wherein 1, 2, 3 or 4 ring atoms are selected from N, O and S, and -O-C1-C3 alkyl, provided that R4 is not an unsubstituted benzyl when Y1 is nitrogen and Y2 is carbon, and provided that R4 is not an unsubstituted pyridyl when Y1 is nitrogen and Y2 is nitrogen; and n2 is an integer selected from 0, 1, 2, and 3 in each case; The condition is that when R2 is an unsubstituted heptyl ring adjacent to X2, X1 is Partial, R a It is H, R1 is an unsubstituted cyclopropyl group, and X2 is... If Y1 is N, and a) Y2 is N and R4 is H, or b) Y2 is C and R4 is H, then R3 is not H.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: in, Z1, Z2, Z3, Y1, Y2, R a R1, R2, R3 and R4 are as defined in claim 1.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the following formula: (Iu); in, Z1, Z2, Z3, Y1, Y2, R1, R2, R3, and R4 are as defined in claim 1.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having the following formula: in, Z1, Z2, Z3, Y1, Y2, R1, R2, R3, and R4 are as defined in claim 1.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z1, Z2 and Z3 are each C(H).

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z1 and Z2 are each C(H).

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z1 and Z3 are each C(H) and Z2 is N.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z1 and Z3 are each N and Z2 is C(H).

9. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z1 and Z2 are each N and Z3 is C(H).

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z2 and Z3 are each N and Z1 is C(H).

11. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: and R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

12. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: and R7 and R8 are independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl, -CF3 and phenyl in each case, provided that only one of R7 and R8 can be phenyl.

13. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: and R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

14. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is a group consisting of: R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

15. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of: and R5 and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, -O-C1-C6 alkyl and -CF3.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently selected from hydrogen, C1-C4 alkyl and C1-C4 alkoxy.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R5 and R6 are each independently selected from hydrogen, C1-C3 alkyl and C1-C3 alkoxy.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R3 is present 3 times, 2 times, or only once; and optionally, or wherein R3 is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, -CF3, -C1-C4 alkyl-OH, phenyl, benzyl, pyrazolyl, and thiophene, wherein the phenyl, pyrazolyl, and thiophene rings are substituted with 0, 1, 2, or 3 substituents selected from halogen, OH, CF3, and C1-C4 alkyl.

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein Y1 and Y2 are each N.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein Y1 is N and Y2 is C(H).

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein Y1 is C(H) and Y2 is N.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is a C1-C6 alkyl group substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R1 is a C1-C4 alkyl group substituted with 0, 1, 2 or 3 substituents selected from halogens, OH, CF3 and -O-C1-C3 alkyl groups.

24. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from -(CH2). n1 -C3-C6 cycloalkyl, phenyl, and benzyl, wherein -(CH2) n1 The -C3-C6 cycloalkyl, phenyl, and benzyl groups are substituted with 0, 1, 2, or 3 substituents selected from halogens, OH, CF3, and -O-C1-C3 alkyl groups.

25. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R a It is H.

26. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R a It is a C1-C3 alkyl group.

27. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R3 is H.

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R3 is a C1-C3 alkyl group.

29. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from CO2H and -CO2-(C1-C6 alkyl).

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R3 is selected from phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl, each of the phenyl, benzyl, C3-C6 cycloalkyl and -CH2-C3-C6 cycloalkyl groups having a ring substituted with 0, 1, 2 or 3 substituents selected from OH, halogen and C1-C6 alkyl, wherein the C1-C6 alkyl group is further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogen, -CF3 and OH.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R3 is selected from a 5- or 6-membered heterocycle containing 1, 2 or 3 cyclic 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, halogens and C1-C6 alkyl groups, wherein said C1-C6 alkyl groups are further substituted with 0, 1, 2, 3, 4 or 5 substituents selected from halogens and OH groups.

32. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R4 is -(CH2). n2 -C3-C6 cycloalkyl, wherein -(CH2) n2 The cycloalkyl ring of the -C3-C6 cycloalkyl group is substituted with 0, 1, 2 or 3 substituents selected from halogens, CF3, OH and -O-C1-C3 alkyl groups; and n2 is an integer selected from 0, 1, 2 and 3.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R4 is benzyl, and the ring of the benzyl group is substituted with 0, 1, 2 or 3 substituents selected from halogens, CF3, OH and -O-C1-C3 alkyl groups.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein the ring of the benzyl group of R4 is independently substituted by 0, 1, 2 or 3 substituents selected from halogens, CF3, OH and -O-C1-C3 alkyl groups.

35. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Y2 is C, and R4 is selected from H and -O-(CH2). n2 -C3-C6 cycloalkyl, wherein -O-(CH2) n2 -C3-C6 cycloalkyl rings are substituted with 0, 1, 2 or 3 substituents selected from halogens, CF3, OH and -O-C1-C3 alkyl groups; or two R4s form a C3-C6 cycloalkyl carbon ring.

36. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein the -C1-C6 alkyl group of R1 and the -O-(CH2) group of R4 are present. n2 -C3-C6 cycloalkyl groups are each independently substituted by 0, 1, 2 or 3 substituents selected from halogens and OH.

37. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 。 38. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 37, and a pharmaceutically acceptable carrier or excipient.

39. Use of the pharmaceutical composition of claim 38 in the preparation of a medicament for treating hypertension in a person in need.

40. The use according to claim 39, wherein the hypertension is essential hypertension.

41. The use according to claim 39, wherein the hypertension is secondary hypertension.

42. The use according to claim 39, wherein the hypertension is refractory or anti-therapeutic hypertension.

43. The use according to claim 39, wherein the hypertension is pulmonary hypertension.

44. Use of the pharmaceutical composition of claim 38 in the preparation of a medicament for treating human heart failure.

45. Use of the pharmaceutical composition of claim 38 in the preparation of a medicament for enhancing the delivery of anesthetics to a person experiencing microvascular complications.

46. ​​The use according to claim 45, wherein the person is experiencing microvascular complications associated with or caused by prediabetes.

47. The use according to claim 45, wherein the person is experiencing microvascular complications related to or caused by diabetes.

48. Use of the pharmaceutical composition of claim 38 in the preparation of a medicament for treating stroke in people in need.

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