WO2012126275A1 - Spiro-containing dihydropyrazole compounds - Google Patents

Abstract

Provided are compounds of formula (I), pharmaceutically acceptable salts, esters, or solvates, or prodrugs or isomers thereof. Thereinto, Cy¹, L, X, Y¹, Y², n¹, n², n³, n⁴, R^1a, R^1b, R^3a, R^3b, R⁴, R⁵ and m are defined as in the description.

Description

 The present invention claims the priority of the Chinese Patent Application No. 201110065760.7, the entire disclosure of which is hereby incorporated by reference. The contents of all of the documents cited in this application are also incorporated by reference in their entirety. Technical field

 The invention belongs to the technical field of medicine, and particularly relates to a dihydropyrazole compound containing a spiro ring, a pharmaceutically acceptable salt, an ester thereof, a solvate thereof or a prodrug or an isomer thereof, and a method for preparing the same, which comprises Pharmaceutical preparations of the compounds, pharmaceutically acceptable salts, esters, solvates thereof or prodrugs or isomers thereof, and the compounds, pharmaceutically acceptable salts, esters, solvates or prodrugs thereof The use of a construct for the preparation of a medicament for the treatment and/or prevention of kidney damage, hypertension or endocrine diseases. Background technique

 Primary nephropathy, secondary nephropathy such as diabetic nephropathy, renal insufficiency and other kidney injury diseases, clinical manifestations of large amounts of proteinuria, if not treated in time will lead to kidney failure. There are many causes of kidney damage, such as diabetes, high blood pressure and other common diseases can cause kidney damage. For example, 15% to 25% of type 1 diabetes and 30% to 40% of patients with type 2 diabetes have diabetic nephropathy, which has become the leading cause of end-stage renal disease (40%). There is currently no effective treatment for the treatment of kidney damage.

 Aldosterone is a mineralocorticoid synthesized in the adrenal cortex. It is distributed in the kidney, colon, epithelial cells of the sweat gland, blood vessels, brain, heart muscle and other tissues. It promotes its receptor by binding to the mineralocorticoid receptor. The retention of sodium and the excretion of potassium play an important role in electrolyte balance and in altering the structure and function of endothelial cells, vascular smooth muscle cells, fibroblasts and adventitia of the arterial wall, and the matrix on the shield.

Excessive levels of aldosterone cause abnormal activation of the mineralocorticoid receptor, which leads to electrolysis Quality imbalance and renal vascular injury and fibrosis, causing kidney damage and high blood pressure.

 Drugs compete with the mineralocorticoid receptor to block the binding of aldosterone to the mineralocorticoid receptor to inhibit aldosterone-mediated toxicity and thereby reduce kidney damage. There are currently two drugs on the market: Spironolactone and Eplerenone. The indications are for the treatment of hypertension, heart failure and kidney syndrome. Both of them are body compounds, which have poor selectivity to other steroid hormone receptors, are prone to cause hyperkalemia, and have large side effects; and the structure is complicated and difficult to synthesize, and the physical and chemical properties are poor, which affects clinical application.

 The non-steroidal compounds mentioned in the patent CN200780043333.0 (as shown in Formula V) have entered the first phase of clinical trials, and their preclinical efficacy and safety are better than those of marketed drugs, reducing proteinuria and reducing

 However, in vitro cell-level activity tests showed poor activity and poor physical and chemical properties. In order to improve clinical treatment and facilitate clinical safety, it is necessary to develop new non-steroidal compounds with good activity, easy synthesis, and good physicochemical properties. Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to provide novel non-steroidal compounds which are active and easy to synthesize and a process for their preparation.

 Another object of the present invention is to provide novel alternatives to existing compounds for the prevention and/or treatment of kidney damage, and their use in the treatment and/or prevention of drugs for kidney damage, hypertension or endocrine diseases.

 Specifically, the present invention provides:

(1) a compound of the formula (I), a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof,

Wherein Cy ¹ is C _3-8 cycloalkyl, 5-10 membered heteroaryl or 6-14 aryl;

L is C(0), C(0)0, C(O), NHC(0), CH ₂ C(0), NHC(0)NH, NHS(0), NHS(0) ₂ , S( O) or S(0) ₂ ;

 X represents C, CH, O or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

11 ¹ , n ² , n ³ and n ⁴ are each independently an integer of 0-4, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is a hydrogen atom, a 13⁄4 atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a carboxyl group, a methanesulfonyl group, a decyloxycarbonyl group;

R ^lb is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a decyl group, a sulfonic acid group, an amino decanoyl group, a d- ₆ alkyl group, a C _1-6 alkoxy group, a C _3-8 ring. alkyl, C _{2. 6} alkenyl group, C _5-8 cycloalkenyl, C _2-6 alkynyl, C _3-8 cycloalkoxy, d. ₆ alkylamino, di (d_ ₆ alkyl) amine , d. ₆ alkylthio, d- ₆ alkylcarbonyl, ^ ₆ alkylaminoformyl, alkylamido, C ₆ alkylsulfonyl, alkylaminosulfonyl, .6 alkylsulfonamide a bis(d.6 alkyl)aminodecanoyl group, a di(C _1-6 alkyl)aminosulfonyl group, a d. ₆ alkoxycarbonyl group or a d- ₆ alkylcarbonyloxy group, said C _{1 -6} alkyl, C _{3 8} cycloalkyl, C ₂ -. ₆ alkenyl group, C _5-8 cycloalkenyl, C _2-6 alkynyl group, an alkoxy group, cycloalkoxy group, d_ ₆ alkylamino , di (d. ₆ alkyl) amino, .6 alkylthio, CL ₆ alkylcarbonyl, d_ ₆ alkyl carbamoyl, d- ₆ alkylamido, d. ₆ alkylsulfonyl group, C _1-6 alkylaminosulfonyl, d- ₆ alkylsulfonylamino, bis(d. ₆ alkyl)aminoformyl, bis(^ ₆ alkyl)aminosulfonyl, d- ₆ alkoxycarbonyl and C _w alkylcarbonyloxy Optionally substituted with 1-6 substituents selected from halogen atoms, cyano, hydroxy, carboxy or amino identical or different substituents, m is an integer of 0 to 4, wherein m is 2, 3 or 4, R ^lb The groups represented may be the same or different; R ^2a is a hydrogen atom, C _1-6 alkyl, C _{3. 8} cycloalkyl, C _5-8 cycloalkenyl, phenyl or a 3-8 membered heterocyclic group, the C _1-6 alkyl, The C _3-8 cycloalkyl group, the C _5-8 cycloalkenyl group, the phenyl group and the 3- to 8-membered heterocyclic group may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, and d. Substituted with the same or different substituents in ₆ alkyl or substituted d- ₆ alkyl;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom, an alkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, a C _{2 -6} alkenyl group, . C _{5 8} cycloalkenyl, C _2-6 alkynyl or C ₃ - ₈ cycloalkyl group, said d ₆ alkyl, (¾_ ₈ cycloalkyl, C _{2 6} alkenyl group, ₍₅ _. ₈ cycloalkenyl, C _2-6 alkynyl, d- ₆ alkoxy and C _3-8 cycloalkoxy may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted with the same or different substituents;

R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or a 3-8 membered heterocyclic group, and R ⁴ and R ⁵ may form a C _{3 .8} cycloalkyl group, C ₅ _ with the X to which they are attached. ₈ cycloalkenyl, phenyl, 3-8 membered heterocyclic, 5-10 membered fused ring, 5-12 membered spiro group and 6-10 membered bridged ring group, said d- ₆ alkyl group, C _3-8 cycloalkyl, C ₅ - ₈ cycloalkenyl, phenyl, 3-8 membered heterocyclyl, 5-10 membered fused ring group, a 5-12 membered cycloalkyl group or 6-10 membered spiro ring group may be bridged Optionally substituted with 0-4 R ^4a or R ^5a ;

R ^4a is a hydrogen atom, a nitro group, a cyano group, a pertin atom, a hydroxyl group, a carboxyl group, an amino group, a d. ₆ alkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _5-8 cycloalkyl alkenyl, C _2-6 alkynyl, or C ₃ _ ₈ cycloalkyl group, said d_ ₆ alkyl, C _{3 8} cycloalkyl, C ₂ -. ₆ alkenyl, C ₅ The _8- cycloalkenyl group, the C _{2 -6} alkynyl group, the d ₆ alkoxy group, and the C _{3 -8} cycloalkoxy group may be optionally 1 to 6 selected from a 13-tetralole atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted by the same or different substituents;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)R ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , C(0)NR ⁸ R ⁹ , NR ⁸ C(0)R ⁷ , NR ⁸ R ⁹ , S(0)qR ⁷ , NHCOOR ⁷ , NHCONR ⁸ R ⁹ , S(0)qNR ⁸ R ⁹ , NR ⁸ S(0) _q R ⁷ or C (0) NHS(0)qR ⁷ ;

R ^7, R ⁸ and R ⁹ are each independently a hydrogen atom, d- ₆ alkyl or C _{3. 8} cycloalkyl, R ⁸ and R ⁹ may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, the d_ ₆ alkyl, C ₃ _ ₈ cycloalkyl, and 3-8 membered heterocyclyl may optionally be selected from 1-6 halogen atoms, cyano, ^{pyrrolidinyl, OR 10, C (O)} R ¹⁰ , C(O)OR ¹⁰ , OC(O)R ¹⁰ , C(0)NR ⁿ R ¹² > NR ^U R ¹² , NR ⁿ C(0)R ¹⁰ , S(O)qR ¹⁰ , SC^qNRUR ¹² Or the same or different substituents in NRHs C qR ¹⁰ ; R ¹⁰ R ¹¹ and R ¹² each independently represent a hydrogen atom, d. ₆ alkyl, C _{3. 8} cycloalkyl or phenyl, R ¹¹ and R ¹² may form a 3-8 membered heterocyclic ring with the nitrogen to which they are attached The d- ₆ alkyl group, the _C3-8 cycloalkyl group, the phenyl group and the 3-8 membered heterocyclic group may be optionally the same as 1 to 6 selected from a genio, a cyano group, a hydroxy group or a carboxy group. Or substituted with a different substituent;

 p is an integer from 0 to 6;

 q is an integer from 0-2.

 (2) A compound represented by the above formula (I), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, wherein preferably:

Cy ¹ is a 5-8 membered heteroaryl or 6-14 aryl;

L is C(0), C(0)0, CH ₂ C(0), NHC(0)NH, C(0)NH, NHC(0), NHS(0) ₂ or S(0) ₂ ;

 X represents C, CH, O or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

Nn\ n ³ and n ⁴ are independently 0, 1, or 2, respectively, and n ¹ and n ⁴ cannot be simultaneously

0, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, sulfonyl, methoxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a d. ₆ alkyl group, an alkoxy group , C ₂ _ ₆ alkenyl, C _{2. 6} alkynyl group, d. ₆ alkylamino, di (d_ ₆ alkyl) amino, d. ₆ Yue alkylamino group, d_ ₆ alkylamide group, D ₆ alkylsulfonyl, d. ₆ alkylaminosulfonyl, alkylsulfonylamino, d- ₆ alkoxycarbonyl or d. ₆ alkylcarbonyloxy, said d. ₆ alkyl, C _{1- 6} alkoxy, C ₂ .6 alkenyl, C _{2. 6} alkynyl, alkylamino, di (D- ₆ alkyl) amino, C _1-6 alkyl carbamoyl, d. ₆ alkoxy An amide group, a d. ₆ alkyl acyl group, a Ci. ₆ alkyl amino sulfonyl group, a C _1-6 alkyl sulfonyl amide group, a ^ ₆ alkoxycarbonyl group and a d ₆ alkyl carbonyloxy group may optionally be 1 Substituted to 4 identical or different substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group, m is 0, 1, 2 or 3, wherein when m is 2 or 3, the group represented by R ^lb Can be the same or different;

R ^2a is a hydrogen atom, C ₃ -. ₈ cycloalkyl, C _{5 8} cycloalkenyl, phenyl or 3-8-membered heterocyclic group, The C _3-8 cycloalkyl group, C _5-8 cycloalkenyl group, phenyl group and 3-8 membered heterocyclic group may be optionally selected from 1 to 6 selected from a sulfonium atom, a cyano group, a hydroxy group, a carboxyl group and an amino group. , d_ ₆ alkyl or 1¾ same or different (^ ₆ alkyl substituents;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom, a d. ₆ alkyl group, an alkoxy group, a C _{3 -8} cycloalkyl group or a C _{2 -6} alkynyl group, said d - ₆ alkyl, d- ₆ alkoxy,

. C ₃ - ₈ cycloalkyl or C _{2 6} alkynyl group and may optionally be selected from a 1-6 atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group in the same or different substituents;

R ⁴ and R ⁵ are each independently hydrogen, alkyl or a 3-8 membered heterocyclic group, and R ⁴ and R ⁵ may form a C _{3 -8} cycloalkyl group, a C _5-8 cycloalkenyl group with the X to which they are attached. a 3-8 membered heterocyclic group, a 6-10 membered fused ring group, a 7-10 membered spirocyclic group or a 6-10 membered bridged ring group, said d- ₆ alkyl group, C _{3 -8} cycloalkyl group , C _5-8 cycloalkenyl 3-8 membered heterocyclic group, 6-10 membered fused ring group, 7-10 membered spiro ring group or

A 6-10 membered bridged ring group may be optionally substituted with 0-3 R ^4a or;

R ^4a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, an alkyl group,

CL ₆ alkoxy, C _{3 -8} cycloalkyl, C _{2 6} alkenyl or C ₂ -. ₆ alkynyl group, a C _1-6 alkyl group, C _{1 -6} alkoxy, C ₃ _ ₈ a cycloalkyl group, a C _2-6 alkenyl group and a C _2-6 alkynyl group may be optionally substituted by 1 to 6 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ ,

C(0)NR ⁸ R ⁹ , NR ⁸ C(0)R ⁷ , NR ⁸ R ⁹ , S(0) _q R ⁷ , NHCONR ⁸ R ⁹ , S(0) _q NR ⁸ R ⁹ ,

NR ⁸ S(0)qR ⁷ or C(0)NHS(0) _q R ⁷ ;

R ^7, R ⁸ and R ⁹ are each independently a hydrogen atom, d- ₆ alkyl or C ₃ - ₈ cycloalkyl, R ^8, and

R ⁹ may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, and the C _1-6 alkyl group, the C _{3 -8} cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 to 6 Selected from a halogen atom, a cyano group, a pyrrolidin group,

OR ¹⁰ , C(O)OR ¹⁰ , OC(O) R ¹⁰ , C(0)NR ⁿ R ¹² , NR ⁿ R ¹² , NR ⁿ C(0)R ¹⁰ ,

Substituting the same or different substituents in S(O) _Q R ¹⁰ , S(O) _Q NR ^N R ¹² or NRHS O^R; R ^1Q , R ¹¹ and R ¹² are each independently a hydrogen atom, C _{1- 6} alkyl or C _{3. 8} cycloalkyl, R ¹¹ and R ¹² may form with the nitrogen to which they are attached a 3-8 membered heterocyclyl group, the C _1-6 alkyl, C _3-8 cycloalkyl and The 3-8 membered heterocyclic group may be optionally substituted by 1 to 6 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group; p is 0, 1, 2, 3 or 4;

 q is 0, 1, or 2.

(3) A compound represented by the formula (I), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, as described in the above (1) or (2), wherein preferably : Cy ¹ is a phenyl or pyridyl group;

L is C(0), C(0)0, CH ₂ C(0) NHC(0)NH, C(0)NH or NHC(O);

X represents C, CH, O or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

II ¹ , n ² , n ³ and n ⁴ are each independently 0, 1 or 2, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, sulfonyl, oxime oxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a d ₆ alkyl group, a d. ₆ alkane Oxyl, C _1-6 alkylamino, di(C _1-6 alkyl)amino, C _1-6 alkylaminoformyl, C _1-6 alkylamido, d ₆ alkylamino a sulfonyl group, a d ₆ alkyl alkanoamide group, a d ₆ alkyloxycarbonyl group or a C _1-6 alkylcarbonyloxy group, said d- ₆ alkyl group, C ₆ alkoxy group, d. ₆ alkylamino group , bis(( _{6- 6} alkyl)amino, C ₆ alkylaminoformyl, C _1-6 alkylamido, d ₆ alkylaminosulfonyl, d. ₆ alkylsulfonylamino, d_ ₆ alkoxycarbonyl and d_ ₆ alkylcarbonyloxy groups may be optionally substituted

1 to 4 substituents selected from the same or different substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group, m is 1, 2 or 3, wherein when m is 2 or 3, the group represented by R ^lb may Same or different;

R ^2a is a hydrogen atom, a cycloalkyl group, a phenyl group or a 4-7 membered heterocyclic group, and the cyclo ₈ alkyl group, the phenyl group and the 4-7 membered heterocyclic group may be optionally selected from 1 to 4 Substituted with the same or different substituents in a aryl group, a cyano group, a hydroxy group, a carboxy group, an amino group, an alkyl group or a substituted d- ₆ alkyl group;

R ^2b, R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom, d_ ₆ alkyl group, an alkoxy group or a C ₂ -.. ₆ alkynyl group, the alkyl group d _6, d ₆ alkoxy alkoxy and C _{2. 6} alkynyl group may be optionally substituted with 1 to 4 substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group are the same or Substituted with the same substituent;

R ⁴ and R ⁵ are each independently hydrogen, d_ ₆ alkyl, or 3-8 membered heterocyclyl group, R ⁴ and R ⁵ may form C _{3. 8} cycloalkyl, or 3-8 membered heteroaryl to which they are attached, X a cycloalkyl group, the C _1-6 alkyl group, the C _{3 -8} cycloalkyl group and the 3-8 membered heterocyclic group may be optionally substituted by 0-2 R ^4a or R ^5a ;

R ^4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, a C _1-6 alkyl group, a d- ₆ alkoxy group or a group. _3.8 cycloalkyl, said d. ₆ alkyl group, d. ₆ alkoxy and C _3-8 cycloalkyl may be optionally substituted by 1 to 4 substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, or Substituting the same or different substituents in the amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , C(0)NR ⁸ R ⁹ , S(0) _q R ⁷ , NR ⁸ S(0) _q R ⁷ NR ⁸ C(0)R ⁷ , NR ⁸ R ⁹ or NHCONR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, d. ₆ alkyl or (: ₄ _ ₇ cycloalkyl, and R ⁸ and R ⁹ may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached. The C _1-6 alkyl group, the C ₄ _ ₇ cycloalkyl group and the 4-7 membered heterocyclic group may be optionally 1 to 4 selected from a halogen atom, a cyano group, an OR ^1Q , a C(0)OR ¹⁰ , OC(0)R ¹⁰ , C(0)NR ⁿ R ¹² , NR ⁿ R ¹² , NRHC CR ¹ or S(0) _q R ¹⁰ substituted with the same or different substituents;

R ^1Q, R ¹¹ and R ¹² each independently represent a hydrogen atom, d_ ₆ alkyl or ₍₄ _ ₇ cycloalkyl, said alkyl and d- _{6 7} cycloalkyl group can be optionally selected from 1-6 | Substituted by the same or different substituents in the atomic, cyano, hydroxy or carboxyl group;

 p is 0, 1, 2, 3 or 4;

 q is 0, 1, or 2.

 (4) The compound of the formula (I), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to any one of the above (1) to (3), Among them, preferably:

Cy ¹ is a phenyl group;

L is C(0), CH ₂ C(0), NHC(0), NHC(0)NH or C(0)0;

 X stands for (, CH, 0 or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH; Nnn ³ and n ⁴ are independently 0, 1, or 2, respectively, and n ¹ and n ⁴ cannot be simultaneously

0, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl or methoxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, an alkyl group, an alkylamino group , d ₆ alkylamido, d- ₆ alkylaminosulfonyl, d. ₆ alkylsulfonylamino, alkoxycarbonyl or d. ₆ alkylcarbonyloxy, said d- ₆ alkyl, d_ ₆ alkylamino decanoyl, C ₆ alkylamido, C ₆ alkylaminosulfonyl, C ₆ alkylsulfonylamino, C _1-6 alkoxycarbonyl and d ₆ alkylcarbonyloxy Substituted by 1 to 4 substituents selected from the same or different substituents in a sulfonium atom, a cyano group, a hydroxy group, a carboxyl group or an amino group, m is an integer of 1-2, wherein when m is 2, the group represented by R ^lb may Same or different;

R ^2a is a hydrogen atom or a C _{4 6} cycloalkyl group, and the Ο ₆ cycloalkyl group may be optionally selected from 1 to 4 selected from a genio atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, an alkyl group or a substituted d- Substituting the same or different substituents in the ₆ alkyl group;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a |3⁄4 atom or a CM alkyl group, and the d.4 alkyl group may be optionally one to four selected from a sulfonyl group and a cyano group. Substituting the same or different substituents in a hydroxyl group, a carboxyl group or an amino group;

R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or 4-6 membered heterocyclic group, and R ⁴ and R ⁵ may form a C ₆ cycloalkyl group or a 4-6 membered hetero atom with the X to which they are attached. a cycloalkyl group, the d. ₆ alkyl group, a C ₄ cycloalkyl group and a 4-6 membered heterocyclic group may be optionally substituted by 0-2 R ^4a or R ^5a ;

R ^4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, a C _1-6 alkyl group or a d. ₆ alkoxy group, and the C _1-6 alkyl group and the C _{1 -6} alkoxy group may be optionally selected. Substituted by 1 to 4 substituents selected from the same or different substituents of a gen atom, a cyano group, a hydroxy group, a carboxyl group or an amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , S(0)qR ⁷ , NR ⁸ S(0)qR ⁷ NR ⁸ C(0)R ⁷ or NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, a C ₆ alkyl group or a Ο ₇ cycloalkyl group, and the alkyl group and the C ₇ cycloalkyl group may be optionally 1 to 4 selected from a halogen atom and a cyanogen group. Substituting the same or different substituents in the OR, OR ¹⁽⁾ , C(0)OR ¹⁰ , OC(0)R ¹⁰ , CC NRUR ¹² or NRHR ¹² ; R ^1G , R ¹¹ and R ¹² are each independently a hydrogen atom or a d ₆ alkyl group, and the alkyl group may be optionally substituted by 1 to 4 of the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group. Base substitution

 p is 0, 1, 2 or 3;

 q is 1 or 2.

(5) A compound represented by the above formula (I), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, wherein preferably : Cy ¹ is a phenyl group;

 L is C(0), NHC(O) or C(0)0;

 X is N, O or CH;

Y ² is N or CH;

Y ¹ is Ν;

II ¹ , η ² , η ³ and η ⁴ are each independently 0, 1 or 2, and η ¹ and η ⁴ cannot be 0 at the same time, and η ² and η ³ cannot be 0 at the same time;

R ^LA is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, methoxycarbonyl;

R ^LB is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group or a C _{1 -6} alkyl group, and the C _1-6 alkyl group may be optionally one to four selected from a genio atom, a cyano group, a hydroxyl group, a carboxyl group or Substituting the same or different substituents in the amino group, m is 1;

R ^2A is a hydrogen atom, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and the cyclobutyl group, the cyclopentyl group and the cyclohexyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, Substituting the same or different substituents in the amino group, d. ₃ alkyl or substituted d. ₃ alkyl;

The alkyl group wherein R ^2B , R ^3A and R ^3B are each independently a hydrogen atom, a cyano group, a sulfonium atom or an alkyl group may be optionally one to four selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted by the same or different substituents;

R ⁴ and R ⁵ are each independently hydrogen, d- ₄ alkyl, 4-6 membered heterocyclic group, and R ⁴ and R ⁵ may form a 4-6 membered heterocyclic group with the X to which they are attached, said CM The alkyl group and the 4-6 membered heterocyclic group may be optionally substituted by R ^5A ;

R ^5A is a hydrogen atom, d. ₄ alkyl or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , S(0) _Q R ⁷ , NR ⁸ S(0)qR ⁷ or NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom or a C _1-4 alkyl group, and the CM alkyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, OR ^1Q , C(0). Substituting the same or different substituents in OR ^1Q or NRUR ¹² ;

R ^1Q , R ¹¹ and R ¹² are each independently a hydrogen atom or a d ₄ alkyl group, and the CM alkyl group may be optionally the same or different from 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group. Substituent substitution;

 p is 0 or 1;

 q is 2.

 (6) The compound of the formula (I), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to any one of the above (1) to (5), Among them, preferably:

Cy ¹ is a phenyl group;

 L is C(O) or NHC(O);

 X is N, 0 or CH;

Y ² is N or CH;

Y ¹ is N;

II ¹ , n ² , n ³ and n ⁴ are each independently 0, 1 or 2, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is a cyano group;

R ^lb is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a hydroxy group, and m is 1;

R ^2a is a cyclopentyl group, and the cyclopentyl group may be optionally 1 to 3 atomic atoms, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a d- ₃ alkyl group or a ? _3⁄4 generation. _1-3 alkyl substituted;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom, a fluorenyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an amino group;

R ⁴ and R ⁵ are each independently hydrogen, decyl, ethyl, tetrahydropyrrolidinyl or tetrahydrofuranyl, and R ⁴ and R ⁵ form a piperidinyl group, a morpholinyl group, a piperazinyl group with the X to which they are attached, Pyrrole Alkyl, ⁰ ^ο or tetrahydropyrrolidinyl, tetrahydrofuranyl, the piperidinyl, morpholinyl,

Piperazinyl, pyrrolidinyl,

R ^5a substitution;

R ^5a is a hydrogen atom, a methyl group or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , S(0) _q R ⁷ , NR ⁸ S(0) _q R ⁷ or NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom or an alkyl group, and the d ₃ alkyl group may be optionally substituted by 1 to 3 halogen atoms, a cyano group, a hydroxyl group or NR"R ¹² ;

R ¹¹ R ¹² are each independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group;

 p is 0;

 q is 2.

 (7) a compound of the formula (A) or a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug thereof,

Wherein Cy ¹ , L, X, , Υ ² , η ¹ , η ² ,

η ⁴ , R ^la , R ^lb , R ^3a , R ^3b , R ⁴ , R ⁵ , and m are as defined in claim 1, and the group represented by R ^2a is as defined in any one of the above (1) to (6). But not hydrogen, R ^2b is hydrogen.

 (8) A pharmaceutical composition comprising the compound according to any one of the above (1) to (7), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug thereof or an isomer thereof.

 (9) The pharmaceutical composition according to the above (8), which further contains one or more pharmaceutically acceptable carriers.

(10) The pharmaceutical composition according to the above (9), which further comprises one or more therapeutic active agents selected from the group consisting of an angiotensin II antagonist (ARB) or a pharmaceutically acceptable salt thereof, calcium Channel blocker (CCB) or a pharmaceutically acceptable salt thereof, angiotensin Invertase (ACE) inhibitor or its pharmaceutically acceptable salt, neutral endopeptidase (ANEP) dual inhibitor, angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) Hanzhong inhibitor or Pharmaceutically acceptable salts, renin inhibitors, diuretics, furosemide, chlorothiazide, biguanides, ct-glucosidase inhibitors, dipeptidyl peptidase (VI) inhibitors, 11 beta-hydroxysteroids Dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) inhibitor, HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, Na-K-ATP enzyme membrane pump Inhibitors, beta-adrenergic receptor inhibitors or alpha-adrenergic receptor blockers, neutral endopeptidase (ΝΕΡ) inhibitors and inotropic agents.

 (11) The compound according to any one of the above (1) to (8), a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug thereof or an isomer thereof, for the preparation of a therapeutic and/or prophylactic kidney Application in drugs for injury, hypertension or endocrine diseases.

 (12) The use according to the above (11), wherein the cardiovascular disease is hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids or Arrhythmia.

 (13) The use according to the above (11), wherein the endocrine disease is primary/secondary aldosteronism, Addison's disease, Cushing's syndrome or Barth Syndrome.

 (14) A method of treating and/or preventing kidney damage, hypertension or endocrine diseases, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of any one of the above (1) to (8) a compound, a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof.

(15) The method for treating and/or preventing kidney damage, cardiovascular disease and endocrine disease according to the above (14), wherein one or more therapeutic active agents selected from the group consisting of: angiotensin II antagonist Agent (ARB) or a pharmaceutically acceptable salt thereof, a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, Double inhibitor of endopeptidase (ANEP), dual inhibitor of angiotensin converting enzyme/neutral endopeptidase (ACENEP) or a pharmaceutically acceptable salt thereof, renin inhibitor, diuretic, furosemide, chlorine Thiazide, biguanide, oc-glucosidase inhibitor, dipeptidyl peptidase (VI) inhibitor, 11 beta-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) ) inhibitor, HMG-Co-A also Pro-enzyme inhibitor or a pharmaceutically acceptable salt thereof; Na-K-ATPase membrane pump inhibitor, β-adrenergic receptor inhibitor or α-adrenergic receptor blocker, neutral endopeptidase (ΝΕΡ) Inhibitors and inotropic agents.

 More preferably, the present invention or a pharmaceutically acceptable salt, ester or solvate thereof







The present invention further preferably comprises the following compounds or pharmaceutically acceptable salts, esters or solvates thereof or prodrugs or isomers thereof:

Detailed description of the invention

The "tin atom" as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As used herein, "alkyl" refers to a straight or branched alkyl group derived from alkane having from 1 to 6 carbon atoms removed by a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, or Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1,2 - dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1, 1-di Methyl butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-di Mercaptobutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1- Methyl propyl and 1-ethyl-2-methyl propyl. Preferably d- ₄ alkyl group, more preferably an alkyl group, the term "CM alkyl", "Cw of alkyl" refers to the specific examples 1 to 4, 1 to 3 carbon atoms contained in the above examples. The "C _2-6 alkenyl group" as used in the present invention means a linear or branched alkenyl group having 2 to 6 carbon atoms containing a double bond, such as a vinyl group, a 1-propenyl group, a 2-propenyl group, and 1 - Methylvinyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-fluorenyl-2- Propenyl, 2-mercapto-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,

1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-indolyl-2-butenyl, 2-indenyl-2 -butenyl, 3-mercapto-2-butenyl, 1-indolyl-3-butenyl, 2-mercapto-3-butenyl, 3-mercapto-3-butenyl, 1 , 1-dimercapto-2-propenyl, 1,2-dimethyl-1-propenyl,

1.2-dimercapto-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl,

2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-nonyl-1-pentenyl, 2-mercapto-1-pentenyl, 3-methyl 1-pentenyl, 4-decyl-1-pentenyl, 1-decyl-2-pentenyl, 2-mercapto-2-pentenyl, 3-decyl-2-pentenyl , 4-decyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-mercapto-3-pentenyl, 4-methyl- 3-pentenyl, 1-methyl-4-pentenyl, 2-mercapto-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1, 1-dimercapto-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-didecyl- 2-butenyl, 1,2-dimercapto-3-butenyl, 1, 3-diindenylbutenyl, 1, 3-dimercapto-2-butenyl, 1,3- Dimercapto-2-butenyl, 2,2-dimercapto-3-butenyl, 2,3-dimercapto-1-butenyl, 2,3-dimethyl-2-butene Base, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl,

3.3-dimethyl-2-butenyl, 1-ethyl-1-butanyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl- 1-butanyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1- Mercapto-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2-mercapto-2-propenyl, 1.3-butadienyl, 1,3-pentane Dienyl, 1, 4-pentadienyl,

2.4-pentadienyl, 1,3-hexadienyl, 1, 4-hexadienyl, 1,5-hexadienyl and 2,4-hexadienyl and the like. The double bond can optionally be cis and trans.

The "C _{2 -6} alkynyl group" as used in the present invention means a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 2-butynyl group, or the like. 3-butynyl, 1-fluorenyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-fluorenyl 3-butynyl, 2-methyl-3-butynyl, 1,1-didecyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentyne 1, 1-mercapto-3-pentynyl, 2-mercapto-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl 4-pentynyl, 1 , 1 -dimethyl-2-butynyl, 1,1 -dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2 ,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl - 1-Mercapto-2-propynyl and the like.

The "^ ₆ alkoxy group" of the present invention means a group in which the term "C alkyl group" is bonded to another structure through an oxygen atom, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group. Base, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.

The "(^ _-6 alkylamino group)" of the present invention is a group in which the term "alkyl group" is bonded to another structure through an amine group, such as methylamino group, ethylamino group, propylamino group, and isopropyl group. Amino group, butylamino group, isobutylamino group, tert-butylamino group, sec-butylamino group, pentyloxyamino group, neopentylamino group, hexyloxyamino group, etc. "Di(Cw alkyl)amino" is a group of two identical or different "d. ₆ alkyl" groups attached to the other structure via an amine group.

 The term "alkylthio" as used in the present invention means a group in which the term "alkyl" is bonded to another structure through a sulfur atom, such as thiol, ethylthio, propylthio, isopropylthio, butylthio, iso Butylthio, tert-butylthio, sec-butylthio, pentylthio, neopentylthio, hexylthio, and the like.

The "(^ _-6 alkylcarbonyl)" according to the present invention means a group in which the term "CW alkyl group" is bonded to another structure through a carbonyl group, such as a mercaptocarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, Butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, neopentylcarbonyl, hexylcarbonyl and the like.

The "d. ₆ alkylaminoformyl" described in the winter invention is a group in which the term "d- ₆ alkyl" is bonded to other structures via a carbamoyl group, such as methylamino decanoyl, ethylamino hydrazine. Acyl, propylaminodecanoyl, isopropylaminodecanoyl, butylaminoformyl, isobutylaminodecanoyl, tert-butylaminoformyl, sec-butylaminodecanoyl, pentyl Aminoformyl, neopentylaminodecanoyl, hexylaminoformyl and the like. The "bis(d- ₆ alkyl)carbamoyl group" of the present invention is a group in which two identical or different "d- ₆ alkyl groups" are bonded to other structures via an aminoformyl group.

The "C ₆ alkoxycarbonyl group" of the present invention is a group in which the term "d- ₆ alkoxy group" is bonded to another structure through a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxycarbonyl group, Butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl and the like.

The "alkylaminosulfonyl group" of the present invention is a group in which the term ".6 alkyl group" is bonded to another structure through an aminosulfonyl group, such as methylaminosulfonyl group, ethylaminosulfonyl group, propylamino group. Sulfonyl, isopropylaminosulfonyl, butylaminosulfonyl, isobutylaminosulfonyl, tert-butylaminosulfonyl, sec-butylaminosulfonyl, pentylaminosulfonyl, neopentylaminosulfonyl, Hexylaminosulfonyl group and the like. The present invention, "di (〇μ ₆ alkyl) aminosulfonyl group" is the same or different, two "^ ₆ alkyl" group by aminosulfonyl connected with other structures.

The "d- ₆ alkyl amido group", "d.6 alkylsulfonyl group", "Cw alkylsulfonylamino group", "d- ₆ alkylcarbonyloxy group" of the present invention are respectively the term "d- ₆ alkyl group". A group attached to the other structure by an amide group, a sulfonyl group, a sulfonylamino group, or a carbonyloxy group.

The "C 8 cycloalkyl group" as used in the present invention means an alkane moiety of 3 to 8 carbon atoms which is removed by a hydrogen atom-derived cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group or a 1-methylcyclobutyl group. Base, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Preference is given to C ₄ _ ₇ cycloalkyl, C _{4 6} cycloalkyl and C ₅ - ₆ cycloalkyl. The term "Ο ₇ cycloalkyl", "C cycloalkyl" are specific examples of the above examples containing 4 to 7, 4 to 6 carbon atoms.

The "C _{3 .8} cycloalkoxy group" as used in the present invention means a group in which the term "^ ₈ cycloalkyl group" is bonded to another structure through an oxygen atom, such as a cyclopropoxy group, a cyclobutoxy group, or a 1- Indenylcyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.

The "C ₈ cycloalkenyl group" as used in the present invention means a cyclic alkyl group derived by removing a hydrogen atom from an olefin moiety of 5 to 8 carbon atoms, a cyclopent-1-enyl group, a cyclopent-2-enyl group. , cyclopent-3-enyl, cyclohexan-1-yl, cyclohex-2-enyl, cyclohex-3-yl, cycloheptan-1-enyl, cyclohept-2-enyl, ring Hept-3-enyl, cyclohept-4-enyl, cyclooct-1-enyl, cyclooct-2-enyl, cyclooct-3-enyl, cyclooctyl-4-enyl, 2,4 -cyclopentadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 2,4-cyclohexadienyl, 2,5-cyclohexadienyl, 1 ,3 - cycloheptadienyl, 1, 4-cycloheptadienyl, 2,4-cycloheptadienyl, 1,5-cyclooctadienyl and the like.

The "heteroaryl" of the present invention includes one or more ring atoms in addition to carbon atoms. A hetero atom, including but not limited to an oxygen atom, a nitrogen atom, and a sulfur atom. The heteroaryl group may be bonded through a carbon or a hetero atom. It includes a 5-8 membered monocyclic heteroaryl group and a 8-14 membered fused heterocyclic aryl group. 5-8 membered monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, furyl, thiophene Base, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-. Oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazinyl, 1,2,4-triazinyl, tetrazolyl ,. Oxytriazole, 2/7- 1,2-oxazinyl, 4/-1,2-. Oxazinyl, 6 /- 1 , 2-3⁄43⁄4 azine, 2/-1,3 azine, 4 /-1 ,3-azine, 6 -1,3-azinyl, 2 ί-1,4- , azinyl, pyrazinyl, isoxazinyl, pyridazinyl, pyrimidinyl and pyrazinyl; etc.; 8-14 membered fused heterocyclic aryl including but not limited to benzofuranyl, isobenzofuranyl, benzothiophene , fluorenyl, isodecyl, quinolyl, isoquinolinyl, pyridazinyl, oxazolyl, pyridazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzo Isozolyl, benzoxazinyl, benzimidazolyl, pyridopyridinyl, pyrazolo[3,4-b]pyridinyl, indolyl, acridinyl and xanthenyl, and the like.

 The term "5-10 membered heteroaryl" refers to a specific example of a ring atom number of 5 to 10 in the above "heteroaryl group". The term "5-6 membered heteroaryl group" means a ring atom of the above "heteroaryl group". The specific examples are 5-6.

 The "aryl group" of the present invention may be a single ring or 2 or 3 fused rings, preferably a monocyclic aryl group, and specific examples include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like, and a phenyl group is preferable.

The "6-14 membered aryl group" as used in the present invention means a monovalent moiety obtained by removing a hydrogen atom from a cyclic aromatic compound having a ring atom of 6 to 14 members. The "6-14 membered aryl group" has a ring atom all of which is a carbon atom, and includes a 6-8 membered monocyclic carbonaryl group and an 8-14 membered fused ring carbonaryl group. The 6-8 membered monocyclic carboaryl group means an all unsaturated aryl group such as a phenyl group, a cyclooctyltetraenyl group or the like. 8- 14-membered fused ring carboaryl refers to a cyclic group in which two or more ring structures share two adjacent carbon atoms, and at least one ring is an all-unsaturated aromatic ring. Including 8-14 members of all unsaturated fused ring carbon aryl groups, such as naphthyl, anthracenyl and phenanthryl, etc., and also include 8-14 membered partially saturated fused ring carbon aryl groups, such as benzo 3-8 saturated single rings. a cycloalkyl, benzo 3-8 member partially saturated monocyclic cycloalkyl group, specific examples are 2,3-dihydroindenyl, fluorenyl, 1,2,3,4-tetrahydronaphthyl, 1,4- Dihydronaphthyl and the like. The "3-8 membered heterocyclic group" in the present invention means a 3-8 membered cyclic group containing one or more hetero atoms, and the "hetero atom" means a nitrogen atom, an oxygen atom, a sulfur atom or the like. The "heterocyclic group" includes a saturated or unsaturated monoheterocyclic group and a saturated or unsaturated fused heterocyclic group.

Examples of the "saturated or unsaturated monoheterocyclic group" are: an oxiranyl group, a dioxanyl group, a thietyl group, an aziridine group, a 2/-azacyclopropane group. , diaziridine, 3 /-diazapropenyl, oxazepine, oxetanyl, 1,2-dioxetyl, thietane 1,2-dithiabutenyl, azetidinyl, 1,2-diazetanyl, azetidinyl, 1,2-diazacyclobutene , furyl, tetrahydrofuranyl, thienyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolyl, 1 ,3-dioxol-2-one, 1,2-dithiolane, 1,3-dithiolanyl, imidazolyl, 4,5-dihydroimidazolyl , imidazolidinyl, pyrazolyl, 4,5-dihydropyrazolyl, pyrazolidinyl, oxazolyl, 4,5-dihydrooxazolyl, isoxazolyl, 4,5-dihydroiso Oxazolyl, 2,3-dihydroisoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiazolyl, 4,5-dihydrothiazide , isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1 , 2,4-triazolyl, tetrazolyl, 2/--pyranyl, 2/7-pyran-2-one, 3,4-dihydro-2 /-pyranyl, 4 /- Pyranyl, tetrahydropyranyl, 4//-pyran-4-one, pyridyl, 2-pyridinone, 4-pyridinone, piperidinyl, 1,4-dioxane Dienyl, 1,4-dithiahexadienyl, 1,4-oxethiohexadienyl, 1,4-dioxanyl, 1,3-dioxole Hexyl, 1,3-oxathianyl, 2-U-oxazinyl, 4/-1,2-oxazinyl, 6/7-1,2-oxazinyl, 2/7 -1,3-oxazinyl, 4 /-1,3-oxazinyl, 6/-1,3-oxazinyl, 2//-1,4-oxazinyl, 4-1,4- Zinyl, 5,6-dihydro-4/-1,3-oxazinyl, morpholinyl, 2/-1,3-1,3-thiazinyl, 4/-1,3-thiazinyl, 5, 6-Dihydro-4/-1,3-thiazinyl, 6#-1,3-thiazinyl, 2/-1,4-thiazinyl, 4/-1,4-thiazinyl, anthracene Azinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4, 5-tetrazinyl, oxygen Heterocyclic heptadienyl, thiethenyl, 1,4-dioxoldinyl, azacycloheptenyl, 1,2-diazaheptatrienyl, 1 , 3-diazepanetrienyl, 1,4-diazepine, azacyclotetradecenyl, 1,4-dihydro-1,4-diazepine Alkenyl and the like. The "4-7 membered heterocyclic group" and "4-6 membered heterocyclic group" as used in the present invention mean a 4-7 membered, 4-6 membered saturated or unsaturated cyclic group in the above examples, respectively. Specific examples.

 The "5-10 membered fused ring group" as used in the present invention means a fused ring structure having 5 to 10 carbon atoms formed by two or more ring structures sharing two adjacent atoms with each other. . Including "5-10 yuan saturated fused ring" and "5-10 yuan unsaturated fused ring". Such as bicyclo [3.1.0] hexane, bicyclo [4.1.0] heptane, bicyclo [3.2.0] heptane, bicyclo [4.2.0] octane, octahydropentaene, bicyclo [3.3.0] octane Diene, 1,2,3,4-tetrahydropentadecene, octahydroindene, decahydronaphthalene, benzofuranyl, isobenzofuranyl, dibenzofuranyl, benzo[b]thienyl, Benzo[c]thienyl, fluorenyl, isodecyl, oxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, sulfhydryl, benzotriazolyl, 2-color Ordinyl, 2-chromogen-2-one, 4H-chromenyl, 4//-chromen-4-one, chromanyl, quinolinyl, isoquinolinyl, 2-quinoline Keto, 4-quinolinone, 1-isoquinolinone, acridinyl, phenanthryl, 4 /-1 ,3-benzoxazinyl, phenazinyl, phenothiazine, pyridazine , porphyrin, 2,3-dihydronaphthalene, quinazolinyl, 3,4-dihydroquinazolinyl, fluorenyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl, 1,6-naphthyridinyl, 1,5-naphthyridinyl, 2,7-naphthyridinyl, 2,6-naphthyridinyl, pteridinyl, quinoxalinyl, 1,2-dihydroquinoxaline Base, phenazinyl, tetrahydromethane And [4,5-c]pyridyl, 3-oxo-1,3-dihydroisobenzofuranyl, 4,6-dihydro-furo[3,4-d]imidazolyl, 3 α, 4,6,6α-tetrahydro-1 -furo[3,4-d]imidazolyl, 4,6-dihydrothieno[3,4-]imidazolyl, 4,6-dihydropyrrolo[3 , 4-] imidazolyl, 4,5,6,7-tetrahydrobenzo[ ]imidazolyl, pyrazolo[3,4-b]pyridinyl and the like.

The "6-10 membered fused ring group" of the present invention means a 6-10 membered fused ring structure in the above examples. The "5-12 membered spirocyclic group" of the present invention means a structure having 5 to 12 carbon atoms formed by a class of at least two rings sharing one atom. Including "5-12 yuan saturated spiral ring" and "5-12 yuan unsaturated screw ring". A 5-12-membered saturated spirocyclic group means that all of the rings of the spirocyclic group are saturated cyclic groups, and specific examples include, but are not limited to:

The cyclic group structure replaces a group formed by any substitutable hydrogen atom. The 5-12 membered partially saturated spiro group refers to a cyclic group in which at least one ring of the spiro group is unsaturated, and specific examples include but are not limited thereto.

The cyclic group structure replaces a group formed by any substitutable hydrogen atom. A 7- to 10-membered spiro group is preferred, including "7-10 membered saturated spiro group" and "7-10 member unsaturated spiro group".

 The "7- to 10-membered spirocyclic group" of the present invention means a 7- to 10-membered spiro ring structure in the above examples. The "6-10 membered bridged ring group" as used in the present invention means a structure containing 6 to 10 carbon atoms formed by any two rings which are not directly connected to each other. Including "6-10 yuan saturated bridge ring" and "6-10 yuan unsaturated bridge ring". Such as bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [3.2.0] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.1] octane, bicyclo [3.3. 0] octane, bicyclo [3.3.1 ] decane, bicyclo (4.3.0) decane, 4-aza-helium ring [5.3.0] decane, bicyclo [2.2.1] hept-5-ene, bicyclo [3.2.1] Oct-6-ene, bicyclo (4.3.0) indol-5-ene, dicyclopentadiene, and the like.

 The "integer of 0-4" in the present invention means 0, 1, 2, 3, 4; the "integer of 0-6" means 0, 1, 2, 3, 4, 5, 6; "Integer of 0-2" means 0, 1, and 2.

 The above compounds of the present invention can be synthesized by the methods described in the following schemes and/or other techniques known to those skilled in the art, but are not limited to the following methods.

 Reaction equation:

Reaction steps:

 Preparation of the compound of formula (I)

Raw material 1 (1.3-2 equivalents) is dissolved in a polar aprotic solvent (eg dimethylacetamide), feed 2 (1 equivalent) is added, and finally 3 equivalents of tertiary amine (including not limited to diisopropylethyl) Amine), at 90. C-120. After the reaction of C for 3-6 hours, the reaction is terminated, cooled, poured into water, extracted, and the organic phase is dried, dried, and purified by preparative liquid chromatography to give the compound of formula (I). In the reaction equation, Cy L, X, ΥΚ Υ ² , η ¹ , η ² , η ³ , η ⁴ , R ^la , R ^lb , R ^2a , R ^2b , R ^3a , R ^3b , R ⁴ , R ⁵ , and m as defined above.

 The pharmaceutical composition of the present invention containing the compound of the above formula (I), a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof may comprise one or more pharmaceutically acceptable carriers.

 The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, coating material or any type of formulation auxiliary. Some examples of materials useful as pharmaceutically acceptable carriers are sugars, but are not limited to lactose, glucose, and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, carboxy hydrazine Cellulose sodium, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository wax; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, Sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffers such as, but not limited to, magnesium hydroxide and hydroxide Aluminum; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethanol and phosphate buffer, other non-toxic compatible lubricants, such as, but not limited to, lauryl sulfate, according to the formulator's judgment Sodium and magnesium stearate as well as coloring agents, release agents, coating agents, sweeteners, fragrances and fragrances, preservatives and antioxidants may also be present in the pharmaceutical preparations. .

 The present invention also provides a compound of the present invention, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug thereof or an isomer thereof, in the preparation of a medicament for treating and/or preventing kidney damage, cardiovascular disease or endocrine disease Applications. Among them, cardiovascular diseases include, but are not limited to, hypertension, heart failure, myocardial infarction, angina pectoris, heart uterus, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids or arrhythmia; endocrine diseases including but not Limited to primary/secondary aldosteronism, Addison's disease, Cushing's syndrome or Bart's syndrome.

 The invention further provides a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt thereof, an ester or a prodrug thereof, or an isomer thereof, and optionally one or more pharmaceutically acceptable carriers.

The pharmaceutical compositions of the present invention may also contain one or more additional therapeutically active substances including, but not limited to, angiotensin II antagonists (ARBs) or a pharmaceutically acceptable salt thereof, a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, or a neutral endopeptidase ( ANEP) dual inhibitor, angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) dual inhibitor or pharmaceutically acceptable salt thereof, renin inhibitor, diuretic, furosemide, chlorothiazide, Biguanide, α-glucosidase inhibitor, dipeptidyl peptidase (VI) inhibitor, 11 p-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) inhibitor , HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, Na-K-ATPase membrane pump inhibitor, β-adrenergic receptor inhibitor or α-adrenergic receptor blocker , Neutral endopeptidase (ΝΕΡ) inhibitors and inotropic agents.

 The invention also provides a method of treating and/or preventing 'injury, hypertension or endocrine disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, Esters or solvates or their prodrugs or isomers, wherein one or more other therapeutically active substances may also be administered in combination, examples of other active therapeutic agents are listed above.

 The compounds of the present invention can be formulated into any pharmaceutical preparation by methods known in the art, and administered to patients in need of such treatment in the form of oral, parenteral, rectal or pulmonary administration. For oral administration, it can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; or can be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. . When an oral preparation is prepared, a suitable filler, a binder, a disintegrant, a lubricant or the like may be added. For parenteral administration, it can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection. When the injection is prepared, it can be produced by a conventional method in the prior art of pharmacy. When the injection is formulated, the additive may be added, or a suitable additive may be added depending on the nature of the drug. When used for rectal administration, it can be made into a suppository or the like. For pulmonary administration, it can be formulated as an inhalant or a spray.

The amount of administration and frequency of administration of the compounds of the present invention can be adjusted according to the judgment of the clinician or the pharmacist, for example, by factors such as age, health and size of the patient, and the severity of the condition to be treated. In general, the total daily dose of the compounds of the invention will range from about 0.1 to about 2000 mg per day, although variations may occur, depending on the purpose of the treatment, the patient, and the route of administration. In one embodiment, the dosage is from about 1 to about 200 mg/ Days, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in two to four divided doses. When the compound of the present invention, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, is used in combination with other therapeutically active substances, they are administered simultaneously, separately or sequentially to form a single administration. A pharmaceutical composition in a manner. The amount of the other therapeutically active substance to be used in combination may be based on the amount used clinically, and may be appropriately selected depending on the subject to be administered, the route of administration, the disease, the combination, and the like. The form of administration of the other therapeutic active agent shield is not particularly limited as long as the compound of the present invention and other therapeutically active substance are combined at the time of administration.

 The compound of the formula (I) of the present invention can be prepared into a pharmaceutically acceptable salt by a known method, and the salt is a salt obtained by mixing a compound of the formula (I) with an acid or a base.

 Suitable acid addition salts are formed from acids which form non-toxic salts. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, carbonic acid Hydrogen salt, butyrate, camphorate, camphorsulfonate, carbonate, citrate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, citrate, Fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, Malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, palmitate, fruit Gluconate, persulfate, 3-phenylpropionate, picrate, trimethylacetate, propionate, sucrose, stearate, succinate, sulfate, tartrate, sulfur Cyanate, phosphate, hydrogen phosphate, dihydrogen phosphate, p-toluenesulfonate, trifluoroacetate and undecanoate.

The base addition salt can be used during the final isolation and purification of the compound by passing the carboxylic acid containing moiety with a suitable base such as, but not limited to, a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation. Or prepared in situ by reaction with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cations, such as Not limited to lithium, sodium, potassium, calcium, magnesium and aluminum salts, etc., as well as non-toxic quaternary ammonium and amine cations, including ammonium, tetramethylammonium, tetraethylammonium, decylamine, diamine, tridecylamine, three Ethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

 "Stereoisomers" of any of the above compounds of the invention include all epimeric, diastereomeric and tautomeric forms. When a key is represented by a wedge, this indicates that the key will come out of the paper in three dimensions, and when a key is shaded, this indicates that the key will return to the paper in three dimensions.

 The present invention claims a "stereoisomer" of a compound of the formula (I) which contains one or more asymmetric centers and thus acts as a racemate and a racemic mixture, a single enantiomeric A conformation, a mixture of diastereomers and a single diastereomer. The compounds of the invention have asymmetric centers, each of which will independently produce two optical isomers, and the scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound. The invention includes all stereoisomeric forms of these compounds.

 The spirocyclic dihydropyrazole compound of the present invention has more than one chiral center. The synthesized is a racemate, and the desired enantiomerically pure compound can be obtained by chiral resolution: by chromatography with a chiral stationary phase (such as high pressure liquid phase preparation, supercritical fluid chromatography). Chiral fillers include, but are not limited to, Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H. The enantiomerically pure dihydropyrazole compound containing a spiro ring can be further derivatized like a racemic dihydropyrazole compound containing a spiro ring.

 Compared with the prior art, the compound of the present invention has the following advantages:

 (1) The compound of the present invention, a pharmaceutically acceptable salt thereof or an isomer thereof has a good antagonistic effect on an aldosterone receptor (i.e., a mineralocorticoid receptor) for treating and/or preventing various mammals (including humans). Good for kidney damage, cardiovascular disease such as hypertension, and/or endocrine diseases;

(2) The compounds of the invention have low toxicity and side effects; (3) The compound of the invention has simple preparation process, good physical and chemical properties, stable quality and easy large-scale industrial production. The beneficial effects of the compounds of the present invention are further illustrated by in vitro pharmacological experiments, but it should not be understood that the compounds of the present invention have only the following beneficial effects.

Pharmacological activity of the compound of the present invention

 Test sample: Part of the compound of the present invention (see Table 1), self-made, and its chemical name, structural formula and preparation method are as described in the examples.

 Mineralocorticoid receptor (MR) antagonistic test

 Risk method:

 Accurately weigh the test compound (see Table 1), add it to DMSO, mix well, and mix it into 1000 μΜ. The mother liquor was then diluted with DMSO to 200 μΜ, 40 μΜ, 8 μΜ, 1.6 μΜ, 0.3 μΜ, 0·06 μΜ, Ο.ΟΙμΜ, 0 μΜ.

Double luciferase assay: pBind-N (100 ng^L), lμL pG51uc (100 ng/ul), 2.5 μί DMEM and 0.5 L Fugene were mixed and incubated for 15 min at room temperature to prepare a transfection solution. A cell suspension was prepared according to 3xl0 ⁵ cells/mL, and 100 L per well was added, and mixed with the above transfection solution. Incubate for 24 hours at 37 ° C in a 5% CO ₂ incubator.

1 L of each of the above concentrations was added to each well, and after 30 minutes, 1 L of agonist (Aldosterone in 10% DMSO) was added, and incubated at 37 ° C in a 5% CO ₂ incubator for 24 hours.

 Firefly sea kidney luciferase signaling pathway by dual luciferase reporter gene test system

(Promega's Dual Luciferase Reporter Assay System, supplied by Promega).

This test measures the mineralocorticoid receptor IC ₅ Q value (ie, the resistance) of the test compound (test sample).

 Experimental results and conclusions:

Table 1 Inhibition of mineralocorticoid (MR) receptor agonists by the compounds of the invention Sample IC ₅₀ (nM) Compound 1 82.2

 Compound 2 14. 1

 Compound 4 45.90

 Compound 5 43.78

 Compound 6 176.30

 Compound 7 234.80

 Compound 8 27.45

 Compound 10 15.43

 Compound 13 19. 12

 Compound 14 14.03

 Compound 15 30.65

 Compound 23 6.10

 Compound 24 8.64

As can be seen from Table 1, the compounds of the present invention have a good antagonistic effect on the salt Shield Hormone receptor. Detailed ways

 The above-mentioned contents of the present invention are further described in detail by way of the embodiments of the present invention, but the scope of the present invention is not limited to the following embodiments.

 In the examples, the raw material compounds used are commercially available, obtained from Shanghai Haiyan Yan Chemical, Shanghai Titan Chemical, Shanghai Darui, Beijing Coupling Technology Co., Ltd., Zhengzhou Taiji Hongnuo Pharmaceutical Technology Co., Ltd., Sichuan Guangsheng Bio, Suiyuan (Shanghai) Chemical Technology, Alfa Aesar (China), Shanghai TCI, Beijing Belling, Shanghai Bi De Pharmaceutical and other companies.

Example 1 2-Chloro-4-(5-cyclopentyl-3-(2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro[3.51 decane-7-yl-4,5 -Dihydropyrazol-1-yl)benzonitrile (Compound 2) Preparation

 (1) Preparation of tert-butyl 2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro[3.5]decane-7-carboxylate

 In a dry round bottom flask, add 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid (1.2 g, 4.46 mmol), 4-hydroxypiperidine (0.50 g). , 4.94 mmol ) , DMF 30 mL, hydrazine, hydrazine-diisopropylethylamine (DIEA) (0.6 g, 4.64 mmol), and finally 2-(7-azobenzotriazole)-Ν, Ν, Ν', Ν'-tetramethylurea hexafluorophosphate (HATU) (1.86 g, 4.89 mmol), reacted at room temperature overnight. The reaction solution was poured into 150 mL of ice water, extracted with dichloromethane (100 mL×3), and the organic phase was washed with saturated sodium hydrogen carbonate solution, dried and purified by column chromatography ( petroleum ether: ethyl acetate = 1:1) Light yellow viscous liquid 1.40 g, yield 89.0%.

 (2) Preparation of 1-(7-azaspiro3.5]nonane-2-ylcarbonyl)piperidine-4-ol hydrochloride

 Dissolving 2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (1.40 g, 3.97 mmol) in 20 mL of dichloromethane The dry HCl gas was passed through a water bath system. After completion of the reaction, the solvent was evaporated to give a white solid, which was washed three times with diethyl ether to give 1.1 g (yield).

(3) 2-Chloro-4-(5-cyclopentyl-3-(2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro[3.5]壬 Preparation of alk-7-yl)-4,5-dihydropyrazol-1-yl)benzonitrile

 2-Chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (266 mg, 0.86 mmol), 1-(7-aza snail [3.5] decane-2-ylcarbonyl)piperidin-4-ol hydrochloride (500 mg, 1.73 mmol), 2-(7-azobenzotriazole)-Ν, Ν, Ν', Ν '-Tetramethylurea hexafluorophosphate ( DIEA ) ( 446 mg, 3.45 mmol ) was dissolved in 25 mL of dimethylamine (DMA). The system was reacted at 100 ° C for 3 h, protected with nitrogen, and poured into the reaction. The mixture was extracted with EtOAc (3 mL).

Molecular formula: C ₂₉ H ₃₈ C1N ₅ 0 ₂ Molecular weight: 523.27 Mass (M+H): 524.3.

 ^-NMR-DMSO, 400 MHz): δ 7.43 (d, IH), 6.87 (s, 1H), 6.70 (d, IH), 4.71 (d, 1H), 4.58-4.47 (m, IH), 3.94- 3.83 (m, IH), 3.70-3.60 (m, 1H), 3.57-3.47 (m, IH), 3.31-3.22 (m, 3H), 3.21-2.89 (m, 5H), 2.76 (d, IH), 2.34-2.17 (m, IH), 2.01-1.82 (m, 4H), 1.72-0.98 (m, 16H).

 Example 2 4-(5-Cyclopentyl-3-(6-ί4-hydroxypiperidine-1-carbonyl 2,6-diazaspiro)

Preparation of [3.31 heptane-2-yl)-4,5-dihydro-1/-pyrazol-1-yl)-2-mercaptobenzonitrile (Compound 4)

(1) Preparation of tert-butyl 6-(4-hydroxypiperidin-1-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

 In a dry reactor, 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester oxalate ( 1.153 g, 4.0 mmol), triphosgene ( 1.187 g, 4.0 mmol), DIEA (2.77 mL, 15.9 mmol), add 20 mL of 1,2-dichloroethane, stir for 5 min in ice water bath, warm to room temperature for 1 h, add 4-hydroxypiperidine ( 1.618 g, 16.0 mmol), reaction 15 h, LC-MS monitored the disappearance of the starting material and stopped the reaction. The reaction mixture was added with water, and extracted with dichloromethane, and the organic extracts were combined. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated. The rate is 64.5 %.

(2) Preparation of 1-(2,6-diazaspiro[3.3]heptan-2-ylcarbonyl)piperidin-4-ol hydrochloride trifluoroacetate

 In a dry reactor, 6-(4-hydroxypiperidin-1-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 0.400 g (1.23 mmol) dissolved in To 2.5 mL of dichloromethane, 1.9 mL of trifluoroacetic acid was added, and the mixture was stirred for two hours in a water bath. After the completion of the reaction, the solvent was evaporated to give a pale white solid, 0.408 g, yield 17.6%.

 (3) 4-(5-Cyclopentyl-3-(6-(4-hydroxypiperidin-1-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)-4, Preparation of 5-dihydro-pyridyl)-2-methylbenzonitrile

In a dry reactor, 4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazole-1- 2-methylbenzonitrile (230 mg, 0.80 mmol), 1-(2,6-diazaspiro[3.3]heptan-2-ylcarbonyl)piperidin-4-ol trifluoroacetate (408 mg, 1.20 mmol), DIEA ( 1.38 mL, 7.9 mmol), 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 ° C for 3.5 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, and 100 mL of water was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, and the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by reversed phase preparative chromatography. 40 mg of a yellow solid were obtained in a yield of 10.5%.

Molecular formula: C ₂₇ H ₃₆ N ₆ 0 ₂ Molecular weight: 476.29 Mass (M+H): 477.1 ^-NMR^-DMSO, 400 MHz): δ 7.32 (IH, d), 6.80-6.52 (2H, m), 4.80 -4.55 (IH, m), 4.52-4.35 (IH, m), 4.01 (8H, s), 3.65-3.55 (IH, m),

3.54-3.44 (2H, m), 3.08-2.93 (IH, m), 2.91-2.79 (2H, m), 2.36-2.22 (4H, m), 1.73-1.33 (8H, m), 1.28-1.05 (5H , m).

 Example 3 2-Chloro-4-(5-cyclopentyl-3-(6-(4-hydroxypiperidin-1-carbonyl)-2,6-diazaspiroline benzonitrile (Compound 5) Preparation

 In a dry reactor, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (253 mg, 0.82 mmol), 1 -(2,6-diazaspiro[3.3]heptan-2-ylcarbonyl)piperidin-4-ol hydrochloride trifluoroacetate (417 mg, 1.23 mmol), DIEA (1.42 mL, 8.2 mmol), 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 °C for 3.5 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, 100 mL of water was added, ethyl acetate was added, and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, dried and evaporated. Powdered solid 250 mg, yield 61.0%.

Molecular formula: C ₂₆ H ₃₃ C1N ₆ 0 ₂ Molecular weight: 496.24 Shield spectrum (M+H) : 497.0 'H-NMR^-DMSO, 400 MHz): δ 7.47 (IH, d), 6.89 (IH, d), 6.73 (IH, d), 4.71 (IH, d), 4.59-4.51 (IH, m), 4.08 (4H, s), 4.04 (4H, s), 3.67-3.57 (IH, m), 3.56-3.46 (2H, m), 3.11-2.99 (IH, m), 2.93-2.82 (2H, m), 2.33-2.20 (IH, m), 1.74-1.35 (8H, m), 1.31-1.03 (5H, m).

 Example 4 4-(5-Cyclopentyl-3-(7-(4-hydroxypiperidin-1-carbonyl)-2,7-diazaspiro"3.51 decan-2-yl)-4,5 -dihydropyrazol-1-yl)-2-methylbenzonitrile (Compound 6)

 (1) Preparation of tert-butyl 7-(4-hydroxypiperidin-1-carbonyl)-2,7-diazaspiro[3.5]decane-2-carboxylate

 In a dry reactor, tert-butyl 2,7-diazaspiro[3.5]decane-2-carboxylate (1.13 g, 5.0 mmol), triphosgene (1.70 g, 6.0 mmol), DIEA (3.46 mL, 20 mmol ), add 30 mL of 1,2-dichloroethane, stir in water bath for 5 min, transfer to room temperature for 1 h, add 4-hydroxypiperidine (2.023 g, 20 mmol), react for 15 h, LC - MS monitors the disappearance of the raw materials and stops the reaction. The reaction solution was added with water, extracted with dichloromethane, and the organic extracts were combined. The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The yield was 49.8%.

(2) Preparation of 1-(2,7-diazaspiro[3.5]decane-7-ylcarbonyl)piperidin-4-ol hydrochloride

 In a dry reactor, 7-(4-hydroxypiperidin-1-carbonyl)-2,7-diazaspiro[3.5]decane-2-carboxylic acid tert-butyl ester 0.880 g (2.49 mmol) was dissolved. In a mixed solution of 20 mL of dichloromethane and 5 mL of methanol, the dried HC1 gas was passed through a water bath system for two hours. After completion of the reaction, the solvent was evaporated to give a pale yellow solid (0.676 g, yield: 93.

 (3) 4-(5-Cyclopentyl-3-(7-(4-hydroxypiperidines small carbonyl)-2,7-diazaspiro[3.5]decane-2-yl)-4,5- Preparation of dihydro-1 - 1 -yl)-2-methylbenzonitrile

In a dry reactor, 4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)-2-methylbenzonitrile (198 mg, 0.69 mmol) was added. 1-(2,7-diazaspiro[3.5]decane· ⁷ ·ylcarbonyl)piperidin-4-ol hydrochloride (300 mg, 1.04 mmol), DIEA ( 1.19 mL, 6.8 mmol), 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 ° C for 3.5 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, added with 100 mL of water, extracted with ethyl acetate, and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by reverse phase preparative chromatography to obtain 63 mg. Yellow solid, yield 17.4 Molecular formula: C ₂₉ H ₄₀ N ₆ O ₂ Molecular weight: 504.32 Mass spectrometry (M+H) : 505.6

400 MHz) δ 7.33 (IH, d), 6.73-6.69 (IH, m),

6.63 (IH, dd), 4.67 (IH, d), 4.50-4.40 (IH, m), 3.67 (4H, s), 3.64-3.54 (IH m), 3.44-3.34 (2H, m) ₅ 3.12-3.01 (4H, m), 2.89-2.77 (2H, m), 2.59-2.58

(IH, m), 2.31 (3H, s), 2.36-2.23 (IH, m), 1.75-1.12 (17H, m).

Example 5 2-Chloro-4-[5-cyclopentyl-3-(7-[4-hydroxypiperidin-1-carbonyl)-2,7-diazaspiroline 3.51 decan-2-yl Preparation of -4,5-dihydropyrazol-1-yl)benzonitrile (Compound 7)

 In a dry reactor, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (176 mg, 0.57 mmol), 1- (2,7-Diazaspiro[3.5]decane-7-ylcarbonyl)piperidin-4-ol hydrochloride (330 mg, 1.14 mmol), DIEA (0.98 mL, 5.6 mmol), 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 ° C for 3.5 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, added with 100 mL of water, extracted with ethyl acetate, and the organic phase was combined. The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by reverse phase preparative column to obtain 193 mg. Yellow solid, yield 64.9%. '

Molecular formula: C ₂₈ H ₃₇ C1N ₆ 0 ₂ Molecular weight: 524.27 Mass spectrum (M+H): 525.3^-NMR-DMSO, 400 MHz): δ 7.45 (IH, d), 6.88 (IH, d), 6.71

(IH, dd), 4.67 (IH, d), 4.59-4..51 (IH, m), 3.70 (4H, s), 3.65-3.54 (1H, m), 3.45-3.35 (2H, m), 3.12-3.01 (4H, m), 2.83 (2H, t), 2.57 (IH, dd), 2.35-2.20 (IH, m), 1.77-1.05 (17H, m).

 Example 6 2-Chloro-4-(5-cyclopentyl-3-(2-((7Q-3-hydroxypyrrolidin-1-carbonyl)-7-azaspiro"3.51 dec-7-yl) Preparation of -4,5-dihydropyrazole small group) benzoquinone (compound 8) KB -5438

(1) Preparation of 2-((-3-hydroxypyrrolidin-1-carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

 In a dry round bottom flask, add 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid (540 mg, 2.00 mmol), (-pyrrolidin-3-ol) (192 mg, 2.20 mmol), DMF 10 mL, DIEA (0.38 mL, 2.21 mmol), and finally added HATU (840 mg, 2.21 mmol), and reacted overnight at room temperature. After completion of the reaction, the organic solvent was dried and purified by preparative chromatography. Light yellow viscous liquid 610 mg, yield 90.0%.

 (2) Preparation of (3Α)-1-(7-azaspiro[3.5]decane-2-ylcarbonyl)pyrrolidine-3-ol hydrochloride

 2-((-3-Hydroxypyrrolidin-1-carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

(610 mg, 1.80 mmol) was dissolved in 20 mL of methylene chloride. The dried HCl gas was passed through a water bath. After the reaction was completed, the solvent was evaporated to give a white solid. Acid salt), yield 86.7%.

 (3) 2-Chloro-4-(5-cyclopentyl-3-(2-((-3-hydroxypyrrolidin-1-carbonyl)-7-azaspiro[3.5]decane-7-yl)) Preparation of -4,5-dipyrazol-1-yl)benzonitrile

2-Chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (374 mg, 1.21 mmol), (3?)-1-( 7-Azaspiro[3.5]decane-2-ylcarbonyl)pyrrolidin-3-ol hydrochloride (430 mg, 1.56 mmol), DIEA (0.85 mL, 4.87 mmol) dissolved in 25 mL of DMA The system was reacted at 100 ° C for 3 h, nitrogen protection, after the reaction was completed, poured into 100 mL; water was extracted three times with ethyl acetate, and the organic phase was washed with saturated brine and dried. Chromatographic separation and purification gave 200 mg of pale yellow solid, yield: 32.4%.

Molecular formula: C ₂₈ H ₃₆ C1N ₅ 0 ₂ Molecular weight: 509.26 Mass spectrum (M+H): 510.1 匪R (-DMSO, 400ΜΗζ): δ 7.44 (IH, d), 6.89 (IH, d), 6.72 (IH, dd ), 4.91 (IH, dd), 4.57-4.49 (IH, m), 4.31-4.18 (1H, m), 3.45-3.34 (3H, m), 3.31-3.05 (6H, m), 2.78 (IH, dd ), 2.35-2.20 (IH, m), 2.04-1.35 (16H, m), 1.28-1.14 (2H, m), 1.13-1.03 (IH, m).

 Example 7 2-Chloro-4-(5-cyclopentyl-3-(2-(indolyl)-3-(dimethylamino)pyrrolidine-1-carbonyl)-7-azaspiropurine 3.51壬Alkan-7-yl)-4,5-dihydropyrazol-1-yl)benzonitrile (compound

 (1) Preparation of 2-((5 3-(dimethylamino)pyrrolidine small carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

 In a dry round bottom flask, add 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid 540 mg (2.0 mmol), (5 Λ^^-dimethyl Crude alkrolidine-3-amine hydrochloride 750mg, DMF 5mL, DIEA 967 mg (7.5mmol), finally add HATU 836 mg (2.2 mmol), react at room temperature overnight. After the reaction is completed, spin dry the organic solvent, use the preparation color i Purification and purification gave a pale yellow solid, 450 mg, yield 61.6%.

(2) Preparation of (35)-(7-azaspiro[3.5]decane-2-ylcarbonyl)-N,7^-dimethylpyrrolidin-3-amine hydrochloride

 Dissolving 450 mg (1.23 mmol) of 2-((5)-3-(dimethylamino)pyrrolidin-1-carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester The dried HCl gas was passed through a water bath system in 20 mL of dichloromethane. After the reaction was completed, the solvent was evaporated to give a white solid.

 (3) 2-Chloro-4-(5-cyclopentyl-3-(2-((5 3-(dimethylamino)pyrrolidin-1-carbonyl)-7-azaspiro[3.5]decane- Preparation of 7-base)

 2-Chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydro-1-pyrazol-1-yl)benzonitrile (200 mg, 0.65 mmol), (3S)-l -(7-Azaspiro[3.5]decane-2-ylcarbonyl)didecylpyrrolidin-3-amine hydrochloride crude 390 mg, DIEA (0.88 mL, 5.05 mmol) dissolved in 10 mL of DMA In the system, the system is reacted at 100 ° C for 3 h, nitrogen is protected. After the reaction is completed, it is poured into 100 mL of water, extracted three times with ethyl acetate. The organic phase is washed with water, washed with saturated brine, dried, and dried. Isolation and purification gave 19 mg of pale yellow solid, yield 5.5%.

Molecular formula: C ₃₀ H ₄₁ ClN ₆ O Molecular weight: 536.30 Mass spectrum (M+H): 537.0^-NMR^-DMSO^OOMHz): δ 7.42 (IH, d), 6.86 (IH, d), 6.70 (IH, d ), 4.55-4.45 (IH, m), 3.59-3.40 (2H, m), 3.27-2.88 (8H, m), 2.80-2.71 (IH, m), 2.31-2.20 (IH, m), 2.12, 2.11 (6H, two singlet), 2.02-1.82 (5H, m), 1.74-1.10 (14H, m) .

Example 8 2-Chloro-4-(5-cyclopentyl-3-(2-(4-methylpiperazin-1-carbonyl)-7-azaspiroline 3.51 decane-7-yl) - Preparation of 4,5-dihydro-1/7-pyrazol-1-yl)benzonitrile (Compound 13)

 (1) Preparation of 2-(4-methylpiperazines small carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

 In a dry round bottom flask, 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid (540 mg, 2.0 mmol), N-mercaptopiperazine (220) Mg, 2.2 mmol), DCM 25 mL, DIEA (300 mg, 2.33 mmol), and finally HATU (874 mg, 2.30 mmol). The reaction mixture was dried to give a white solid (yield: 702 mg).

 (2) Preparation of 2-[(4-methylpiperazin-1-yl)carbonyl]-7-azaspiro[3.5]decane hydrochloride

 2-(4-Mercaptopiperazine carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (702 mg, 2.0 mmol) was dissolved in 20 mL of dichloromethane. The dried HCl gas was passed through a water bath system, and after completion of the reaction, the solvent was evaporated to give a crude white powder (yield 680 mg).

(3) 2-Chloro-4-(5-cyclopentyl-3-(2-(4-methylpiperazine-1-carbonyl)-7-azaspiro[3.5]decane-7-yl) - Preparation of 4,5-dihydro-pyrazole-1-yl)benzonitrile

 2-Chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (175 mg, 0.57 mmol), 2-[(4-methyl) Piperazine-1-yl)carbonyl]-7-azaspiro[3.5]decane hydrochloride crude 350 mg, DIEA (746 mg, 5.78 mmol) dissolved in 25 mL of DMA (refers to Ν, Ν-dimethyl In the reaction solution of acetamide, solvent, the system is reacted at 100 ° C for 3.5 h, and nitrogen is protected. After the reaction is completed, it is poured into 100 mL of water, extracted three times with ethyl acetate, and the organic phase is washed with saturated brine and dried. Purification by preparative chromatography gave 58 mg of pale yellow solid, yield 19.5%.

Molecular formula: C ₂₉ H ₃₉ C1N ₆ 0 Molecular weight: 522.29 Mass spectrum (M+H): 523.2^-NMRC^-DMSO, 400 MHz): δ 7.44 (1Η, d), 6.89 (1H, d), 6.72

(1H, dd), 4.60-4.46 (1H, m), 3.45-3.39 (2H, m), 3.23-3.16 (2H, m), 3.15-3.05 (1H, m), 2.27-2.18 (4H, m) , 2.16 (3H, s), 2.05-1.88 (5H, m), 1.74-1.32 (12H, m), 1.31-1.11 (6H, m).

 Example 9 2-Chlorocyclopentyl-3-(2-(4-(dimethylamino)piperidin-1-carbonyl)-7-azaspiroline 3.51 decane-7-yl)-4,5 -dihydropyrazol-1-yl)benzonitrile (compound 14)

(1) Preparation of 2-(4-(dimethylamino)piperidine carbonyl)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester

In a dry reactor, 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid (538 mg, 2.0 mmol), W-dimethylpiperazine-4 was added separately. -Amine (282 mg, 2.2 mmol), DIEA (0.45 mL, 2.6 mmol), and finally HATU (836 mg, 2.2 mmol), CH ₂ C1 ₂ 20 mL, stirred at room temperature overnight, LC-MS monitoring disappeared, stop reaction. The reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh The separation column was purified to obtain 730 mg of a pale yellow viscous liquid with a yield of 96.0%.

 (2) Preparation of 2-[(4-(diamino)piperidinyl)carbonyl]-7-azaspiro[3.5]decane hydrochloride

 2-(4-(Dimethylamino)piperidine-1-hydroxy)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (730 mg, 1.92 mmol) in dry reactor Dissolve in a mixed solution of 20 mL of dichloromethane and 5 mL of methanol, and pass dry HCl gas for two hours in a water bath system. After completion of the reaction, the solvent is evaporated and washed with anhydrous diethyl ether three times to give a white solid. The yield was 98.9%.

 (3) 2-Chloro-4-(5-cyclopentyl-3-(2-(4-(dimethylamino)piperidin-1-carbonyl)-7-azaspiro[3.5]decane-7- Of 4-(4,5-dihydro-1 /-pyrazol-1-yl)benzonitrile

In a dry reactor, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (308 mg, 10 mmol), 2 -[(4-(Dimethylamino)piperidin-1-yl)carbonyl]-7-azaspiro[3.5]decane hydrochloride (600 mg, 1.90 mmol), DIEA ( 1.73 mL, 10 mmol) 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 ° C for 4 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, 100 mL of water was added, and ethyl acetate was extracted three times. The organic phase was combined, and the organic phase was washed with hydrated saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by preparative chromatography to obtain 65 mg of pale yellow. Solid, yield 11.8%.

Molecular formula: C ₃₁ H ₄₃ C1N ₆ 0 Molecular weight: 550.32 Shield i (M+H): 551.1

^-NMRC^-DMSO, 400 MHz): δ 7.45 (1Η, d), 6.89 (1H, d), 6.72 (1H, dd), 4.57-4.49 (1H, m), 4.38-4.28 (1H, m) , 3.75-3.66 (1H, m), 3.32-3.26 (3H, m), 3.21-3.17 (2H, m), 3.16-3.07 (1H, m), 2.95-2.85 (1H, m), 2.82-2.73 ( 1H, m), 2.35-2.22 (2H, m), 2.16 (6H, s), 2.05-1.86 (4H, m), 1.80-1.04 (17H, m).

 Example 10 W1-(7-n-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4,5-dihydropyrazol-3-yl)-7-azaspiro"3.51 Preparation of decane-2-carbonyl)piperidin-4-yl)indolesulfonamide (Compound 15)

 (1) Preparation of tert-butyl 2-(4-(methylsulfonamido)piperidine carbonyl)-7-azaspiro[3.5]decane-7-carboxylate

In a dry reactor, add 7-(tert-butoxycarbonyl)-7-azaspiro[3.5]decane-2-carboxylic acid (538 mg, 2.0 mmol), Ν-(piperidin-4-yl) Methanesulfonylamine hydrochloride (472 mg, 2.2 mmol), DIEA (1.04 mL, 6.0 mmol), finally HATU (836 mg, 2.2 mmol), CH ₂ C1 ₂ 20 mL, stirred at room temperature overnight, LC- MS monitored the disappearance of the starting material and stopped the reaction. The reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh Column purification gave 772 mg of a pale yellow viscous liquid with a yield of 90.0%.

 (2) Preparation of N-(l-(7-azaspiro[3.5]decane-2-carbonyl)piperidin-4-yl)methanesulfonamide hydrochloride

 In a dry reactor, 2-(4-(sulfonamido)piperidin-1-carboxy)-7-azaspiro[3.5]decane-7-carboxylic acid tert-butyl ester (772 mg, 1.80 mmol) Dissolved in a mixed solution of 20 mL of dichloromethane and 5 mL of decyl alcohol, and passed through a dry HCl gas for two hours in a water bath system. After completion of the reaction, the solvent was dried and washed with anhydrous diethyl ether to give 628 mg of white solid. , the yield was 95.6%.

 (3) N-(l-(7-(l-(3-Chloro-4-cyanophenyl)-5-cyclopentyl-4,5-dihydropyrazol-3-yl)-7-nitrogen Preparation of Heterospo [3.5]decane-2-carbonyl)piperidin-4-yl)indolesulfonamide

In a dry reactor, 2-chloro-4-(3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile (308 mg, 1.0 mmol), N- (1-(7-Azaspiro[3.5]decane-2-carbonyl)piperidin-4-yl)methanesulfonamide hydrochloride (628 mg, 1.72 mmol), DIEA ( 1.73 mL, 10 mmol) 20 mL DMA. The reaction system was protected by nitrogen and protected from light. The reaction was carried out at 100 ° C for 4 h, and the reaction was monitored by LC-MS. After the reaction was stopped, it was cooled to room temperature, 100 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was combined, and the organic phase was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. , the yield was 25.0%.

Molecular formula: C ₃ QH ₄₁ C1N ₆ 0 ₃ S Molecular weight: 600.26 Mass spectrometry (M+H): 601.5

H- should be R(i-DMSO, 400 MHz): δ 7.44 (IH, d), 7.12 (IH, d), 6.89 (IH, d), 6.71 (IH, d), 4.59-4.48 (IH, m ), 4.22-4.11 (IH, m), 3.70-3.57 (IH d), 3.32-3.24 (3H, m), 3.22-3.06 (3H, m), 3.05-2.95 (IH, m), 2.93 (3H, Br s), 2.85-2.68 (2H, m), 2.34-2.21 (1H, m), 2.04-1.88 (4H, m), 1.87-1.76 (2H _: m), 1.75-1.36 (10H, m), 1.32 -1.18 (4H, m), 1.13-1.02 (IH, m).

 Example 11 2-Chloro-4-((5^)-5-cyclopentyl-3-(2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro D.51 decane-7 Basement of 4,5-dihydropyrazol-1-yl)benzonitrile (Compound 23)

 (1) Preparation of chloro-4-(-3-chloro-5-cyclopentyl-4,5-dihydro-1/7-pyrazol-1-yl)benzonitrile

 (-2-Chloro-4-(-3-chloro-5-cyclopentyl-4,5-dihydropyrazol-1-yl)benzonitrile is obtained by chiral resolution of a racemic compound. The specific resolution conditions were (Chiral Pak AS-H, 0.46 cm ID χ 15 cm L, supercritical carbon dioxide / acetonitrile = 80:20, 2.0 mL / min). Retention time t = 3.120 min.

Molecular formula: C ₁₅ H ₁₅ C1 ₂ N ₃ Molecular weight: 307.06 Mass spectrometry (M+H): 308.1 ^-NMRC^-DMSO, 400 MHz): δ 7.46 (IH, d), 7.08 (IH, d), 6.87 (IH, dd), 4.98 (IH, dd), 4.61 (IH, dt), 3.07 (IH , dd), 2.91(1H, dd), 2.47-2.51 (IH, m), 1.77-1.81 (IH, m), 1.52-1.70 (4H, m), 1.20-1.23 (2H, m).

 (2) 2-Chloro-4-((5i?)-5-cyclopentyl-3-(2-(4-hydroxypiperidin-1-carbonyl)-7-azaspiro[3.5]decane-7 Preparation of -4,5-dihydropyrazol-1-yl)benzonitrile

 (4-Hydroxypiperidin-1-yl)-7-azaspiro[3.5]decane-2-yl)methanone hydrochloride ( 18.3 g, 0.064 mol), CR)-2-chloro-4- (-3-Chloro-5-cyclopentyl-4,5-dihydro-1H-pyrazol-1-yl)benzonitrile ( 19.5 g, 0.064 mol) was dissolved in 300 mL of V-dimethylacetamide. Diisopropylethylamine (88 mL, 0.5 mol) was slowly added at room temperature, and protected by nitrogen at 100 ° C for 48 h, and the reaction was terminated by LCMS. The reaction solution was poured into water, and extracted with ethyl acetate. The organic phase was acid washed, washed with water, brine, dried over anhydrous sodium sulfate and evaporated. The ethyl acetate was recrystallized to give 17 g of product. Yield: 51.2%. Specific optical rotation is +380° ~ +460° (temperature 20 degrees, concentration 5mg/ml, DMSO dissolved)

Molecular formula: C ₂₉ H ₃₈ C1N ₅ 0 ₂ Molecular weight: 523.27 Mass spectrum (M+H): 524.3^-NMRC^-DMSO, 400 MHz): δ 7.31 (IH, d), 6.89 (1H, d), 6.65 (IH Dd), 4.31(lH,m), 4.09-4.13 (IH, m), 3.93 (IH, m), 3.62 (IH, m), 3.34(2H, t), 3.02-3.23 (5H, m), 2.38 (lH,m), 2.66(1H, dd), 2.05-2.18 (4H, m), 1.89 (2H, m), 1.47-1.74 (16H, m).

Example 12 2-Chloro-4-(T5iQ-5-cyclopentyl-3-(2-(4-methylpiperazine- 1 -carbonyl)-7-azaspiro"3.51 decane-7-yl M, Preparation of 5-dihydropyrazol-1-yl)benzonitrile (Compound 24)

2-Chloro-4-((5 )-5-cyclopentyl-3-(2-(4-methylpiperazin-1-carbonyl)-7-azaspiro[3.5]decane-7-yl) -4,5-Dihydropyrazol-1-yl)benzonitrile was obtained by chiral resolution of racemic compound 13. The specific resolution conditions were (Chiral Pak AS-H, 0.46 cm ID x 15 cm L-hexane/anhydrous ethanol = 70:30 (0.1% diethylamine), 1.0 mL/min). Retention time t= 16.02 min _c

 Referring to the above method, the following compounds were also prepared.

 G

 Combined structure

Object

55



Further, the configuration of the compound of the present invention can also be estimated by referring to the prior art. For example, the compounds described in the Journal of Medicinal Chemistry (2010), 53(16), 5979-6002 are consistent with the targets of the compounds of the present invention, and the configuration and compounds of the compounds for analyzing the single chiral centers are also described. A crystal diagram in which the active configuration is R, for example, the compounds R-4b and S-4b and the R-4g are compared with the S-4g, and the R configuration is Very much better than the compound of the s configuration

Clmpd > (nM

CN, ,COGH F

With reference to the above results, it is presumed that the configuration of the compound of the present invention is good for the conformation of the compound: 2-chloro-4-((55 5-cyclopentyl-3-(2-(4-mercaptopiperazine-1) - carbonyl) -7-aza-spiro [3.5] nonan-7-yl) -4,5-dihydro-pyrazol-1-yl) benzonitrile, both the IC ₅₀ are 8.64ηΜ, 1220nM, mechanized As described above, the present application presumes that the compound with IC ₅ o of 8.64 nM is the configuration of compound 24, and the compound with IC ₅ o of 1220 nM is of the S configuration: 2-chloro-4-((55 5-cyclopentyl-3) -(2-(4-Methylpiperazines small carbonyl)-7-azaspiro[3.5]decane-7-yl)-4,5-dihydropyrazol-1-yl)benzonitrile.

 The invention is not limited to the specific embodiments disclosed in the examples, which are exemplary of the invention, and any embodiments that are functionally equivalent are within the scope of the invention. Various modifications of the invention are apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

Claims

Rights request

A compound represented by the formula (I), a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof,

Wherein Cy ¹ is C _{3 -8} cycloalkyl, 5-10 membered heteroaryl or 6-14 membered aryl;

L is C(0), C(0)0, C(0)NH, NHC(0), C(0)N(CH ₃ ), CH ₂ C(0), NHC(0)NH, NHS(0 ), NHS(0) ₂ , S(O) or S(0) ₂ ;

 X stands for C, CH or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

11 ¹ , n ² , n ³ and n ⁴ are each independently an integer of 0-4, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxyl group, an amino group, a carboxyl group, a methanesulfonyl group, an anthraceneoxycarbonyl group;

R ^lb is a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a nitro group, a decyl group, a sulfonic acid group, a carbamoyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, a C ₃ - ₈ group cycloalkyl, C _2-6 alkenyl, C _{5 8} cycloalkenyl, C ₂ -.. ₆ alkynyl, C ₃ _ ₈ cycloalkyl group, d ₆ alkylamino, di (C _1-6 alkyl Amino, CM alkylthio, alkylcarbonyl, d. ₆ alkylaminoformyl, d. ₆ alkylamido, CL ₆ alkylsulfonyl, C ₆ alkylaminosulfonyl, d. ₆ alkylsulfonylamino, bis(C^alkyl)aminoformyl, bis(C alkyl)aminosulfonyl, d. ₆ alkoxycarbonyl or d. ₆ alkylcarbonyloxy, said C ₆ alkyl, C _{3. 8} cycloalkyl, C _C2-6 alkenyl group, C _5-8 cycloalkenyl, C _C2-6 alkynyl, C alkoxy, C ₈ cycloalkoxy, alkyl Amino, bis(d. ₆ alkyl)amino, d- ₆ alkylthio, C _1-6 alkylcarbonyl, d. ₆ alkylaminoformyl, ^ ₆ alkylamido, d ₆ alkyl Sulfonyl, d_ ₆ alkyl aminosulfonyl, d_ ₆ alkylsulfonyl group, di (Cw of alkyl) amino group Yue, di (d. ₆ alkyl) aminosulfonyl, C _1-6 alkoxy The carbonyl group and the alkylcarbonyloxy group may be optionally substituted by 1 to 6 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group, and m is an integer of 0-4, wherein m is 2 At 3 or 4, the groups represented by R ^lb may be the same or different;

R ^2a is a hydrogen atom, d. ₆ alkyl group, C _3-8 cycloalkyl group, C _{5 -8} cycloalkenyl group, phenyl group or 3-8 membered heterocyclic group, said C _1-6 alkyl group, C ₃ - ₈ cycloalkyl, C _5-8 cycloalkenyl, phenyl and 3- to 8-membered heterocyclic groups may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, C _1- Substituted with the same or different substituents in the ₆ alkyl or halo C ₆ alkyl group;

R ^2b, R ^3a and R ^3b are each independently a hydrogen atom, a nitro group, a cyano group, a halogen atom, an alkyl group, alkoxy group, C _{3. 8} cycloalkyl, C _2-6 alkenyl, C _{5. 8} cycloalkenyl, C ₂ - ₆ alkynyl group or C ₃ _ ₈ cycloalkyl group, the C _1-6 alkyl, C _{3 8} cycloalkyl, C _{2 6} alkenyl group, C _5-8 cycloalkyl. alkenyl, C _2-6 alkynyl group, an alkoxy group, and C _{3. 8} cycloalkyl group may optionally be substituted with same or different 1-6 substituents selected from halogen atoms, cyano, hydroxy, carboxy or amino group Base substitution

R ⁴ and R ⁵ are each independently hydrogen, d ₆ alkyl or 3-8 membered heterocyclic, and R ⁴ and R ⁵ may form a C _3-8 cycloalkyl group, C _{5 .8} ring with the X to which they are attached. alkenyl, phenyl, 3-8 membered heterocyclyl, 5-10 membered fused ring group, and a 5-12 membered spiro ring group bridged 6-10 membered cycloalkyl group, said d_ ₆ alkyl, C ₈ cycloalkyl a group, a C _5-8 cycloalkenyl group, a phenyl group, a 3-8 membered heterocyclic group, a 5-10 membered fused ring group, a 5-12 membered spiro ring group or a 6-10 membered bridged ring group may optionally be 0- Four 1 ⁴³ or R ^5a substitutions;

R ^4a is a hydrogen atom, a nitro group, a cyano group, a pertin atom, a hydroxyl group, a carboxyl group, an amino group, a d. ₆ alkyl group, a C _1-6 alkoxy group, a C _3-8 cycloalkyl group, a C _2-6 alkenyl group, a C _5-8 cycloalkyl alkenyl, C _{2. 6} alkynyl group, or a C _3-8 cycloalkoxy group, a C _1-6 alkyl, C _3-8 cycloalkyl, C _2-6 alkenyl, C _{8 8} cycloalkenyl, C ₂ -6 alkynyl, C _1-6 alkoxy and C _{3 -8} cycloalkoxy may be optionally 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or Substituting the same or different substituents in the amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)R ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , C(0)NR ⁸ R ⁹ , NR ⁸ C(0)R ⁷ , NR ⁸ R ⁹ , S(0) _q R ⁷ > NHCOOR ⁷ , NHCONR ⁸ R ⁹ , S(0) _q NR ⁸ R ⁹ , NR ⁸ S(0) _q R ⁷ Or C(0)NHS(0)qR ⁷ ;

R ^7, R ⁸ and R ⁹ are each independently a hydrogen atom, C _1-6 alkyl or (¾_ ₈ cycloalkyl, R ^8, and R ⁹ may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, and the C alkyl group, the C _{3 -8} cycloalkyl group and the 3-8 membered heterocyclic group may be optionally 1 to 6 selected from the group consisting of Atom, cyano, pyrrolidinyl, OR ¹⁰ , C(O)R ¹⁰ , C(O)OR ¹⁰ , OC(O)R ¹⁰ , C(0)NR ^N R ¹² , NR ^N R ¹² , NR ^N C (0) R ¹⁰ , S(O)qR ¹⁰ , SO^NRHR ¹² or NR ^U S(0)qR ^{1 ()} substituted with the same or different substituents;

R ^1G , R ¹¹ and R ¹² are each independently a hydrogen atom, a C _1-6 alkyl group, a C _{3 -8} cycloalkyl group or a phenyl group, and R ¹¹ and R ¹² may form a 3-8 member with the nitrogen to which they are attached. heterocyclyl, said d_ ₆ alkyl, C _{3. 8} cycloalkyl, phenyl, and 3-8-membered heterocyclyl may optionally be selected from 1-6 halogen atoms, a cyano group, a hydroxyl group or a carboxyl group Substituted with the same or different substituents;

 p is an integer from 0 to 6;

 q is an integer from 0-2.

 2. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 1,

Wherein Cy ¹ is a 5-8 membered heteroaryl group or a 6-14 membered aryl group;

L is C(0), C(0)0, C3⁄4C(0), NHC(0)NH, C(0)NH, NHC(0), C(0)N(CH ₃ ), NHS(0) ₂ Or S(0) ₂ ;

 X stands for (:, CH or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

η n ² n ³ and n ⁴ are each independently 0, 1 or 2, but cannot be 0 at the same time, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, methoxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a C ₆ alkyl group, a C _{1- 6} alkoxy, C ₂ . ₆ alkenyl, C _2-6 alkynyl, d- ₆ alkylamino, bis(d. ₆ alkyl)amine, C _1-6 alkylaminoformyl, d_ _{a 6} alkylamide group, a C ₆ alkylsulfonyl group, a d. ₆ alkylaminosulfonyl group, a d. ₆ alkylsulfonylamino group, a d. ₆ alkoxycarbonyl group or a d ₆ alkylcarbonyloxy group, Alkyl, d. ₆ alkoxy, C _2-6 alkenyl, C ₂ alkynyl, C _1-6 alkylamino, bis(Cw alkyl)amino, C ₆ alkylaminoformyl , d_ ₆ alkylamido, d_ ₆ alkylsulfonyl group, d_ ₆ Alkyl aminosulfonyl, C alkylsulfonyl group, C ^ ₆ alkoxycarbonyl group and a C _1-6 alkylcarbonyl group may be optionally substituted with 1 to 4 substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, or Substituting the same or different substituents in the amino group, m is 0, 1, 2 or 3, wherein when m is 2 or 3, the groups represented by R ^lb may be the same or different;

R ^2a is a hydrogen atom, a C _3-8 cycloalkyl group, a C _5-8 cycloalkenyl group, a phenyl group or a 3- to 8-membered heterocyclic group, said C ₈ cycloalkyl group, C _{5 -8} cycloalkenyl group, The phenyl group and the 3-8 membered heterocyclic group may be optionally substituted by 1 to 6 substituents selected from the group consisting of the same or different substituents selected from the group consisting of a 13 atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, an alkyl group or a C alkyl group;

R ^2b, R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom, d. ₆ alkyl, C alkoxy, C ₃ _ ₈ cycloalkyl or C _{2. 6} alkynyl group, the C _{1 -6} alkyl, d. ₆ alkoxy, C _3- 8 cycloalkyl or C _{2. 6} alkynyl group, and may optionally be selected from 1-6 halogen atoms, cyano, hydroxy, carboxyl or amino Substituted with the same or different substituents;

R ⁴ and R ⁵ are each independently hydrogen, alkyl, or 3-8 membered heterocyclyl group, R ⁴ and R ⁵ may form a C _3-8 cycloalkyl group to which they are attached, X, C ₅ _ ₈ cycloalkenyl group a 3-8 membered heterocyclic group, a 6-10 membered fused ring group, a 7-10 membered spirocyclic group or a 6-10 membered bridged ring group, said C _1-6 alkyl group, C _{3 -8} cycloalkane a C _{3 -8} cycloalkenyl 3-8 membered heterocyclic group, a 6-10 membered fused ring group, a 7-10 membered spiro group or a 6-10 membered bridged ring group may optionally be 0-3 1 ^1⁄2 or R ^5a substituted;

R ^4a is a hydrogen atom, a nitro group, a cyano group, a halogen atom, a hydroxyl group, an amino group, d. ₆ alkyl, C _1-6 alkoxy, C _{3. 8} cycloalkyl, C _2-6 alkenyl or C _{2 -6} alkynyl, said C! _-6 alkyl, C _1-6 alkoxy, C _{3 -8} cycloalkyl, C^ ₆ alkenyl and C _{2 -6} alkynyl may optionally be 1 to 6 Substituting the same or different substituents selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , C(0)NR ⁸ R ⁹ , NR ⁸ C(0) R ⁷ , NR ⁸ R ⁹ , S(0) _q R ⁷ , NHCONR ⁸ R ⁹ , S(0) _q NR ⁸ R ⁹ NR ⁸ S(0)qR ⁷ or C(0)NHS(0)qR ⁷ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, a C _1-6 alkyl group or a C _{3 -8} cycloalkyl group, and R ⁸ and R ⁹ may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached. , the C _1-6 alkyl group, the C _3-8 cycloalkyl group, and the 3-8 membered heterocyclic group may be optionally 1 to 6 selected from a sulfonium atom, a cyano group, a pyrrolidinyl group, and an OR ¹⁰ > C ( O) OR ¹⁰ , OC(O) R ¹⁰ , C(0)NR ⁿ R ¹² NR ^U R ¹² , NR ⁿ C(O)R ¹⁰ , Substituting the same or different substituents in S(0)qR ^1D , S(0)qNR"R ¹² or NR ⁿ S(0)qR ^1Q ; R ^1G , R ¹¹ and R ¹² are each independently a hydrogen atom, an alkane group or a C ₃ - ₈ cycloalkyl, R ¹¹ and R ¹² may form a 3-8 membered heterocyclic group with the nitrogen to which they are attached, a C _1-6 alkyl group, C _{3 8} cycloalkyl and 3- The 8-membered heterocyclic group may be optionally substituted by 1 to 6 substituents selected from the same or different substituents of a ? atom atom, a cyano group, a hydroxyl group or a carboxyl group;

 p is 0, 1, 2, 3 or 4;

 q is 0, 1, or 2.

 3. A compound according to claim 2, a pharmaceutically acceptable salt, ester or solvate thereof or a prodrug or isomer thereof:

Wherein Cy ¹ is a phenyl group or a pyridyl group;

L is C(0), C(0)0, CH ₂ C(0), NHC(0)NH, C(0)NH or NHC(O);

X stands for C, CH or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

n ¹ , n ² , n ³ and n ⁴ are each independently 0, 1 or 2, but cannot be 0 at the same time, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, decyloxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, an alkyl group, a d. ₆ alkoxy group , d ₆ alkylamino group, bis(d- ₆ alkyl)amino group, C _1-6 alkylamino decanoyl group, d ₆ alkyl amide group, alkylamino sulfonyl group, C ₆ fluorenyl sulfonamide a d- ₆ alkoxycarbonyl group or a C _1-6 alkylcarbonyloxy group, said d- ₆ alkyl group, alkoxy group, _-6 alkylamino group, bis(Cw alkyl)amino group, alkylamine carbamoyl group, d_ ₆ alkyl amide group, an alkyl sulfonyl amino group, d_ ₆ alkylsulfonylamino group, an alkoxycarbonyl group, and the CM d- ₆ alkylcarbonyloxy groups may be optionally substituted one to four substituents selected from halogen Substituting the same or different substituents in the atom, cyano group, hydroxyl group, carboxyl group or amino group, m is 1, 2 or 3, wherein when m is 2 or 3, the groups represented by R ^lb may be the same or different;

R ^2a is a hydrogen atom, a C _{3 -8} cycloalkyl group, a phenyl group or a 4-7 membered heterocyclic group, and the C _{3 -8} cycloalkyl group, a phenyl group and a 4-7 membered heterocyclic group may be optionally 1 to 4 halogen atoms, cyano group, hydroxyl group, A carboxyl group, an amino group, or a group D- embankment ₆ Generation (^ ₆ alkyl identical or different substituents.;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom, a d. ₆ alkyl group, a C _1-6 alkoxy group or a C _{2 -6} alkynyl group, said d. ₆ alkyl group And d. ₆ alkoxy and alkynyl may be optionally substituted by 1 to 4 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group;

R ⁴ and R ⁵ are each independently hydrogen, C _1-6 alkyl or 3-8 membered heterocyclic group, and R ⁴ and R ⁵ may form C _{3 .8} cycloalkyl or 3-8 with the X to which they are attached. a heterocyclic group, the alkyl group, the alkyl group. _{The 3-8} cycloalkyl and 3-8 membered heterocyclyl can be optionally substituted with 0-2 R ^4a or R ^5a ;

R ^4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, d- ₆ alkyl, d ₆ alkoxy or C ₃ -. ₈ cycloalkyl group, the C _1-6 alkyl, C _{1- 6} alkoxy and C _{3 -8} cycloalkyl may be optionally substituted by 1 to 4 substituents selected from the same or different ones selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , C(0)NR ⁸ R ⁹ , S(0) _q R ⁷ , dish ⁸ S (0) qR ⁷ NR ⁸ C (0) R ⁷ , NR ⁸ R ⁹ or NHCONR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, a C _1-6 alkyl group or a C ₄ - ₇ cycloalkyl group, R ⁸ and

R ⁹ may form a 4-7 membered heterocyclic group with the nitrogen to which they are attached, and the d ₆ alkyl group, C ₄ - ₇ cycloalkyl group and 4-7 membered heterocyclic group may be optionally selected from 1 to 4 Halogen atom, cyano group, OR ^1G , C(O)OR ¹⁰ , OC(O)R ^I0 , C(0)NR ⁿ R ¹² , NR ^U R ¹² , NRHC CR ¹⁰ or S(0) _q R ¹⁰ Substituted with the same or different substituents;

R ^1Q , R ¹¹ and R ¹² are each independently a hydrogen atom, a d ₆ alkyl group or a C ₄ _ ₇ cycloalkyl group, and the d ₆ alkyl group and the C ₇ cycloalkyl group may be optionally 1 to 6 selected from the group consisting of Substituted by the same or different substituents in a 13 atom, a cyano group, a hydroxy group or a carboxy group;

 p is 0, 1, 2, 3 or 4;

 q is 0, 1, or 2.

 4. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 3,

Wherein Cy ¹ is a phenyl group;

L is C(0), CH ₂ C(0), NHC(0), NHC(0)NH or C(0)0; X represents C, CH, O or N;

Y ¹ represents CH or N;

Y ² represents CH, CH ₂ , N or NH;

11 ¹ , n ² , n ³ and n ⁴ are each independently 0, 1 or 2, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

R ^la is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, oxime oxycarbonyl; R ^lb is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a sulfonic acid group, a d. ₆ alkyl group, d. ₆ alkyl carbamoyl, d. ₆ alkylamide group, d- ₆ alkyl aminosulfonyl, d_ ₆ alkylsulfonylamino group, an alkoxycarbonyl group or d_ ₆ alkylcarbonyloxy group, the alkyl group , d_ ₆ alkyl carbamoyl, alkylamido, d_ ₆ alkyl aminosulfonyl, d_ ₆ alkylsulfonylamino group, d- ₆ alkoxycarbonyl and d_ ₆ alkylcarbonyloxy groups may be optionally substituted 1 to 4 substituents selected from the same or different substituents selected from the group consisting of a prime atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group, m is an integer of 1-2, wherein when m is 2, the group represented by R ^lb may be the same or different;

R ^2a is a hydrogen atom or a C _{4. 6} cycloalkyl group, the C ₆ cycloalkyl can be optionally substituted with 1 to 4 substituents selected atom, cyano, hydroxy, carboxy, amino, d- ₆ alkyl, or Substituting the same or different substituents in the ^- ₆ alkyl group;

R ^2b , R ^3a and R ^3b are each independently a hydrogen atom, a cyano group, a halogen atom or a d- ₄ alkyl group, and the d. ₄ alkyl group may be optionally 1 to 4 selected from a halogen atom and a cyano group. Substituting the same or different substituents in a hydroxyl group, a carboxyl group or an amino group;

R ⁴ and R ⁵ are each independently hydrogen, d ₆ alkyl or 4-6 membered heterocyclic group, and R ⁴ and R ⁵ may form a Ομ ₆ cycloalkyl group or a 4-6 membered heterocyclic group with the X to which they are attached. ., according to d ₆ alkyl, C _{4 6} cycloalkyl, and 4-6 membered heterocyclyl may optionally be substituted with 0-2 R ^4a or R ^5a;

R ^4a is a hydrogen atom, a cyano group, a halogen atom, a hydroxyl group, an amino group, an alkyl group or a d. ₆ alkoxy group, and the d. ₆ alkyl group and the d. ₆ alkoxy group may be optionally selected from 1 to 4 Substituted from the same or different substituents in the halogen atom, cyano group, hydroxyl group, carboxyl group or amino group;

R ^5a is a hydrogen atom or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , C(0)OR ⁷ , OC(0)R ⁷ , S(0) _q R ⁷ , R ⁸ S(0)qR ⁷ NR ⁸ C(0)R ⁷ or NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently a hydrogen atom, an alkyl group or a hydrogen atom. ₄ _ ₇ cycloalkyl, the The C _1-6 alkyl group and the C ₄ _ ₇ cycloalkyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, OR ^1G , C(0)OR ¹⁰ , OC(0)R ^1G , C(0 Substituting the same or different substituents in NR ^U R ¹² or NR ^U R ¹² ;

R ^1Q , R ^{1 1} and R ¹² are each independently a hydrogen atom or a ( _{6. 6} alkyl group, and the alkyl group may be optionally the same as 1 to 4 selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group; Substituted by different substituents;

 p is 0, 1, 2 or 3;

 q is 1 or 2.

 5. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 4,

Wherein Cy ¹ is a phenyl group;

 L is C(0), NHC(O) or C(0)0;

 X is N or CH;

Y ² is N or CH;

Y ¹ is N;

n ¹ n ² , n ³ and n ⁴ are each independently 0, 1 or 2, and n ¹ and n ⁴ cannot be 0 at the same time, n ² and n ³ cannot be 0 at the same time;

1 ¹³ is cyano, nitro, hydroxy, amino, carboxy, methylsulfonyl, methoxycarbonyl;

R ^LB is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group or a d. ₆ alkyl group, and the d- ₆ alkyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group or an amino group. Substituted by the same or different substituents, m is 1;

R ^2A is a hydrogen atom, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and the cyclobutyl group, the cyclopentyl group and the cyclohexyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, Substituting the same or different substituents in the amino group, Ci-3 alkyl group or alkyl group;

The alkyl group wherein R ^2B , R ^3A and R ^3B are each independently a hydrogen atom, a cyano group, a halogen atom or a CM alkyl group may be optionally one to four selected from a genio atom, a cyano group, a hydroxy group, a carboxyl group or an amino group. Substituted with the same or different substituents;

R ⁴ and R ⁵ are each independently hydrogen, d. ₄ alkyl, 4-6 membered heterocyclic group, and R ⁴ and R ⁵ may be used. Forming a 4-6 membered heterocyclic group with the X to which they are attached, said d- ₄ alkyl group and 4-6 membered heterocyclic group may be optionally substituted by R ^5A ;

R ^5A is a hydrogen atom, CM alkyl or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , S(0) _Q R ⁷ , NR ⁸ S(0)qR ⁷ or NR ⁸ R ⁹ ;

RR ⁸ and R ⁹ are each independently a hydrogen atom or a CM alkyl group, and the d. ₄ alkyl group may be optionally 1 to 4 selected from a halogen atom, a cyano group, OR ^{1 ()} , C(0)OR ^1Q. Or the same or different substituents in NR ^U R ¹² ;

R ¹⁰ R ¹¹ and R ¹² are each independently a hydrogen atom or a d. ₄ alkyl group, and the d ₄ alkyl group may be optionally the same or different from 1 to 6 selected from a halogen atom, a cyano group, a hydroxyl group or a carboxyl group. Replacement of a substituent;

 p is 0 or 1;

 q is 2.

 6. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 5,

Wherein Cy ¹ is a phenyl group;

 L is C(O);

X and Y ² are each independently 1^ or CH;

Y ¹ is N;

II ¹ , n ² , n ³ and n ⁴ are each independently 0, 1 or 2, and n ¹ and n ⁴ cannot be 0 at the same time, and n ² and n ³ cannot be 0 at the same time;

R ^LA is a cyano group;

R ^LB is a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group or a hydroxy group, and m is 1;

R ^2A is a cyclopentyl group, and the cyclopentyl group may be optionally the same or different from 1 to 3 selected from a halogen atom, a cyano group, a hydroxyl group, a carboxyl group, an amino group, a d- ₃ alkyl group or an alkyl group. Substituent substitution;

R ^2B , R ^3A and R ^3B are each independently a hydrogen atom, a cyano group, a halogen atom, a fluorenyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, a methylol group or an aminomethyl group; R ⁴ and R ⁵ are each independently hydrogen, methyl, ethyl, tetrahydropyrrolidinyl or tetrahydrofuranyl, and R ⁴ and R ⁵ form a piperidinyl group, a morpholinyl group, a piperazinyl group with the X to which they are attached. Pyrrole

An alkyl group, a tetrahydrofuranyl group, the piperidinyl group, a morpholinyl group,

Piperazinyl

Pyrrolidinyl, R ^5a substituted;

R ^5a is a hydrogen atom, a fluorenyl group or (CH ₂ ) _P R ⁶ , wherein R ⁶ is OR ⁷ , S(0) _q R ⁷ , NR ⁸ S(0)qR ⁷ or NR ⁸ R ⁹ ;

RR ⁸ and R ⁹ are each independently a hydrogen atom or a C _1-3 alkyl group, and the c _1:3 alkyl group may be optionally the same as 1 to 3 selected from a halogen atom, a cyano group, a hydroxyl group or NRHR ¹² Or substituted with a different substituent;

R ^u and R ¹² are each independently a hydrogen atom, a thiol group, an ethyl group or an isopropyl group;

 p is 0;

 q is 2.

 7. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 1, which is selected from the group consisting of:

^{8. A} compound as claimed in claim 1 or a pharmaceutically acceptable salt, ester or solvate or prodrug thereof which is shown in the general formula ([pi) requirements:

R ⁴

/ r ⁵ ( II ) wherein Cy ^! , L, X, ΎΚ Y ² , nn ² , n ³ , n ⁴ , R ^la , R ^lb , R ^3a , R ^3b R ⁴ , R ⁵ , and m are as defined As claimed in claim 1, the group represented by R ^2a is as described in claim 1 but is not hydrogen, and R ^2b is hydrogen.

 9. A pharmaceutical composition comprising a compound of claim 1, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, and one or more pharmaceutically acceptable carriers.

 The pharmaceutical composition according to claim 9, which further comprises one or more therapeutically active substances selected from the group consisting of angiotensin II antagonist (ARB) or a pharmaceutically acceptable salt thereof, calcium channel block Agent (CCB) or a pharmaceutically acceptable salt thereof, an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, a dual inhibitor of neutral endopeptidase (ANEP), angiotensin converting enzyme/ Neutral endopeptidase (ACE/NEP) dual inhibitor or a pharmaceutically acceptable salt thereof, a renin inhibitor, a diuretic, furosemide, a chlorothiazide, a biguanide, an alpha-glucosidase inhibitor, two Peptidyl peptidase (VI) inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) inhibitor, HMG-Co-A reductase inhibitor or pharmaceutical thereof Acceptable salts, Na-K-ATPase membrane pump inhibitors, beta-adrenergic receptor inhibitors or alpha-adrenergic receptor blockers, neutral endopeptidase (ΝΕΡ) inhibitors and variants Force agent.

 11. A compound, a pharmaceutically acceptable salt, ester or solvate thereof, or a prodrug or isomer thereof, according to claim 1, in the manufacture of a medicament for the treatment and/or prophylaxis of spleen, cardiovascular or endocrine diseases Application, wherein the cardiovascular disease is hypertension, heart failure, myocardial infarction, angina pectoris, cardiac hypertrophy, myocarditis, cardiac vascular fibrosis, baroreceptor dysfunction, excessive body fluids or arrhythmia, said endocrine disease For primary/secondary aldosteronism, Addison's disease, Cushing's syndrome or Bart's.

12. A method of treating and/or preventing kidney damage, cardiovascular disease and endocrine disease, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt, ester or solvate thereof or Their prodrugs or isomers.

 13. A method of treating and/or preventing kidney damage, cardiovascular disease and endocrine disease according to claim 12, wherein one or more therapeutically active substances selected from the group consisting of angiotensin II antagonists (ARB) are also used in combination: Or a pharmaceutically acceptable salt thereof, a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, an angiotensin converting enzyme (ACE) inhibitor or a pharmaceutically acceptable salt thereof, a neutral endopeptide Double inhibitor of enzyme (ANEP), dual inhibitor of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) or its pharmaceutically acceptable salt, renin inhibitor, diuretic, furosemide, chlorothiazide Oxazine, biguanide, α-glucosidase inhibitor, dipeptidyl peptidase (VI) inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor, endothelin receptor blocker, cholesterol ester transferase (CETP) inhibition Agent, HMG-Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, Na-K-ATPase membrane pump inhibitor, β-adrenergic receptor inhibitor or α-adrenergic receptor block And neutral endopeptidase (ΝΕΡ) inhibitors Inotropic agents.