Novel compounds as dual inhibitors of androgen receptor and phosphodiesterase

Abstract

The present disclosure provides androgen receptor (AR) and phosphodiesterase 5 (PDE-5) inhibitor compounds and compositions comprising the same. The compounds can provide a dual function for inhibiting AR and inhibiting PDE-5. The present disclosure also provides methods of using the compounds and compositions to inhibit AR and PDE-5 in a biological system or sample. Methods of making the compounds and compositions and synthetic precursors of the compounds are also provided.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 124,615, filed December 11, 2020, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Androgen receptors (ARs) are members of the steroid-hormone family involved in regulating normal growth and development in various target organs. AR inhibitors and antagonists are used for a variety of therapeutic applications. Enzalutamide and apalutamide are AR antagonist compounds that can be used to treat cancer.

[0004] Phosphodiesterases (PDEs) encompass a large family of metallophospholipids that participate in regulating cellular cAMP and / or cyclic GMP (cGMP) levels through numerous stimuli. Compounds that selectively inhibit the catalytic activity of PDEs (e.g., PDE5) have been developed for the treatment of various diseases. PDE5 is a cGMP-binding enzyme that specifically hydrolyzes cGMP to 5'-GMP. PDE5 inhibitors increase cGMP levels.

[0005] Compounds with dual activity as AR inhibitors or antagonists and PDE5 inhibitors will be used for overlapping therapeutic indications where there is interest in inhibiting both targets. Summary of the Invention

[0006] This disclosure provides androgen receptor (AR) inhibitors and phosphodiesterase 5 (PDE-5) inhibitor compounds and compositions comprising said compounds. The compounds provide dual functionality for inhibiting or antagonizing androgen receptors and for inhibiting PDE-5. This disclosure also provides methods for inhibiting AR and PDE-5 in biological systems or samples using said compounds and compositions. Methods for preparing said compounds and compositions and synthetic precursors of said compounds are also provided.

[0007] In a first aspect, the present invention provides compounds of formula (I):

[0008]

[0009] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0010] L represents the connecting part;

[0011] R 1 and R 2It is independently selected from -H, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted (C1-C6) alkoxy and optionally substituted (C2-C4) alkenyl;

[0012] Each R 13 Selected from -H, optionally substituted (C1-C6) alkyl and optionally substituted (C1-C6) alkoxy;

[0013] Each R 14 Selected from -H, -CN, -OH, -NH2, -NO2, halogen, optionally substituted (C1-C5) alkyl, optionally substituted (C1-C5) haloalkyl, optionally substituted (C1-C5) alkoxy, optionally substituted (C3-C6) cycloalkyl and optionally substituted (C2-C4) alkenyl;

[0014] X 1 For N or CR 14 ;

[0015] X 2 and X 3 Independently selected from N and CR 13 ;

[0016] Y 1 and Y 2 Independently selected from N and C, where Y 1 and Y 2 One of them is N;

[0017] m is between 0 and 2; and

[0018] n is between 1 and 4.

[0019] In a second aspect, the present invention provides a pharmaceutical composition comprising: a compound of formula (I), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient.

[0020] In a third aspect, the present invention provides a method for modulating androgen receptor and / or inhibiting PDE-5 activity, the method comprising contacting a biological system or sample containing the androgen receptor and / or PDE-5 with an effective amount of a compound of formula (I) or its solvates, hydrates, prodrugs, and / or stereoisomers thereof or pharmaceutically acceptable salts thereof. In some embodiments of the modulation method, the method comprises inhibiting or antagonizing the androgen receptor. In another embodiment, the method comprises inhibiting PDE-5 activity. In some embodiments of the modulation method, the method comprises inhibiting the androgen receptor and inhibiting PDE-5 in the biological system or sample. Detailed Implementation

[0021] 4.1AR and PDE-5 inhibitor compounds

[0022] As summarized above, this disclosure provides compounds having dual activity, for example, as androgen receptor (AR) and PDE-5 inhibitory compounds.

[0023] Generally, it contains substituted 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one Or substituted imidazo[5,1-f][1,2,4]triazine-4(3H)-one Compounds with a bicyclic core structure are obtained by i) 1,3-phenylene, 2,4-pyridyl or 2,6-pyridyl and ii) such as substituted 2-thioimidazolidine-4-one. Multiple linking moieties of methyl, urea, or thiourea groups are covalently attached to multiple cyano-substituted aryl groups.

[0024] More specifically, in a first aspect, the present invention provides compounds of formula (I):

[0025]

[0026] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0027] L represents the connecting part;

[0028] R 1 and R 2 Independently selected from -H, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C6)cycloalkyl, optionally substituted (C1-C6)alkoxy and optionally substituted (C2-C4)alkenyl;

[0029] Each R 13 Selected from -H, optionally substituted (C1-C6) alkyl and optionally substituted (C1-C6) alkoxy;

[0030] Each R 14 Selected from -H, -CN, -OH, -NH2, -NO2, halogen, optionally substituted (C1-C5) alkyl, optionally substituted (C1-C5) haloalkyl, optionally substituted (C1-C5) alkoxy, optionally substituted (C3-C6) cycloalkyl and optionally substituted (C2-C4) alkenyl;

[0031] X 1 For N or CR 14 ;

[0032] X2 and X 3 Independently selected from N and CR 13 ;

[0033] Y 1 and Y 2 Independently selected from N and C, where Y 1 and Y 2 One of them is N;

[0034] m is between 0 and 2; and

[0035] n is between 1 and 4.

[0036] In some embodiments of formula (I), the compound is a compound of formula (Ia):

[0037]

[0038] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0039] in:

[0040] Each R 13 Selected from -H, halogens, and optionally substituted (C1-C6)alkoxy groups; and

[0041] R 4 and each R 14 Independently selected from -H, -CN, -OH, -NH2, -NO2, halogen, optionally substituted (C1-C5) alkyl and optionally substituted (C1-C5) haloalkyl.

[0042] In some implementations of equations (I)-(Ia), -L- is -AB-, where:

[0043] -A- is selected from covalently bonded, optionally substituted (C6-C) 12 ) aryl or (C3-C 12 Heteroaryl, optionally substituted -(C3-C) 12 Heteroaryl-(C1-C5)alkylene-, optionally substituted 3- to 6-membered heterocycles, -NHC(O)R 5 -、 and

[0044] -B- is selected from covalently bonded, optionally substituted 3- to 6-membered heterocycles, -NHC(O)R 5 -、-O-、-S-、-NR 11 -、

[0045] in:

[0046] R11 H or optionally substituted (C1-C3) alkyl;

[0047] R 5 Selected from -OH, -(C1-C5)alkyl, -(C1-C5)haloalkyl and optionally substituted (C1-C5)alkylene;

[0048] R 6 and R 7 Each is independently -H or optionally substituted (C1-C3) alkyl; or R 6 and R 7 It is cyclically linked with the nitrogen atom to which it is attached to, to provide optionally substituted 3- to 6-membered heterocycles;

[0049] Z 1 Selected from O and S; and

[0050] At least one of -A- and -B- is not a covalent bond.

[0051] In some implementations of equation (Ia), -A- is

[0052] In some embodiments of formulas (I)-(Ia), the compound is a compound of formula (IIa) or a compound of formula (IIb):

[0053]

[0054] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0055] R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups; and

[0056] -B- is selected from covalent bonds and optionally substituted 3- to 6-membered heterocycles.

[0057] In some implementations of formula (IIa) or (IIb), each R 14 Independently -H or halogen. In some embodiments of formula (IIa) or (IIb), each R 14 Independently -H or -F. In some embodiments of formula (IIa) or (IIb), each R 14 For -H. In some embodiments of formula (IIa) or (IIb), each R 14 For -F. In some embodiments of formula (IIa) or (IIb), at least one R 14 It is -F.

[0058] In some embodiments of formula (IIa) or (IIb), Z1 For S. In some embodiments of formula (IIa) or (IIb), Z 1 It is O.

[0059] In some embodiments of formula (IIa) or (IIb), R 6 and R 7 It is cyclically linked with the nitrogen atom to which it is attached to, to provide optionally substituted 3- to 6-membered heterocycles.

[0060] In some embodiments of formula (IIa) or (IIb), the compound is a compound of formula (IIIa) or a compound of formula (IIIb):

[0061]

[0062] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0063] R 8 and R 9 Independently selected from -H and optionally substituted (C1-C3) alkyl groups, or R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles; and

[0064] Z 1 It can be O or S.

[0065] In some implementations of formula (IIIa) or (IIIb), each R 14 Independently -H or halogen. In some embodiments of formula (IIIa) or (IIIb), each R 14 Independently -H or -F. In some embodiments of formula (IIIa) or (IIIb), each R 14 For -H. In some embodiments of formula (IIIa) or (IIIb), each R 14 For -F. In some embodiments of formula (IIIa) or (IIIb), at least one R 14 It is -F.

[0066] In some embodiments of formula (IIIa) or (IIIb), Z 1 For S. In some embodiments of formula (IIIa) or (IIIb), Z 1 It is O.

[0067] In some embodiments of formula (IIIa) or (IIIb), -B- is covalently bonded and the compound is a compound of formula (IVa) or a compound of formula (IVb):

[0068]

[0069] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0070] In some implementations of formula (IVa) or (IVb), each R 14 Independently -H or halogen. In some embodiments of formula (IVa) or (IVb), each R 14 Independently -H or -F. In some implementations of formula (IVa) or (IVb), each R 14 For -H. In some implementations of formula (IVa) or (IVb), each R 14 -F. In some embodiments of formula (IVa) or (IVb), at least one R 14 It is -F.

[0071] In some implementations of formula (IVa) or (IVb), Z 1 For S. In some embodiments of formula (IVa) or (IVb), Z 1 It is O.

[0072] In some embodiments of formula (IIIa) or (IIIb), -B- is an optionally substituted 4- to 6-membered heterocycle.

[0073] In some embodiments of formula (IIIa) or (IIIb), the compound is a compound of formula (Va) or a compound of formula (Vb):

[0074]

[0075] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein p and q are independently 1 or 2.

[0076] In some implementations of formula (Va) or (Vb), -B- is selected from...

[0077]

[0078] In some implementations of formula (Va) or (Vb), R 8 For -H. In another embodiment of formula (Va) or (Vb), R 9 It is -H.

[0079] In some implementations of formula (Va) or (Vb), R 9 It is an optionally substituted (C1-C3) alkyl group. In another embodiment of formula (Va) or (Vb), R 9 It is -CH3.

[0080] In some implementations of formula (Va) or (Vb), R 8 and R 9 Each is independently an optionally substituted (C1-C3) alkyl group. In another embodiment of formula (Va) or (Vb), R 8 and R 9 Each is -CH3.

[0081] In some implementations of formula (Va) or (Vb), Z 1 For S. In some implementations of formula (Va) or (Vb), Z 1 It is O.

[0082] In some implementations of formula (Va) or (Vb), -A- is selected from...

[0083]

[0084] In some implementations of formula (Va) or (Vb), R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles. In some embodiments of formula (Va) or (Vb), R 8 and R 9 It is cyclically linked with the attached carbon atom to provide an optionally substituted 4- or 5-membered carbon ring or a 4- or 5-membered heterocycle. In another embodiment of formula (Va) or (Vb), the optionally substituted 3- to 6-membered carbon ring or the optionally substituted 3- to 6-membered heterocycle is selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0085] In some implementations of formula (Va) or (Vb), -A- is selected from...

[0086]

[0087] In some implementations of formula (Va) or (Vb), each R 14 Independently -H or halogen. In some embodiments of formula (Va) or (Vb), each R 14 Independently -H or -F. In some implementations of formula (Va) or (Vb), each R 14For -H. In some implementations of formula (Va) or (Vb), each R 14 For -F. In some embodiments of formula (Va) or (Vb), at least one R 14 It is -F.

[0088] In some embodiments of formula (IIa) or (IIb), R 6 and R 7 Each is independently -H or optionally substituted (C1-C3) alkyl. In some embodiments of formula (IIa) or (IIb), R 6 and R 7 Each is -H.

[0089] In some embodiments of formula (IIa) or (IIb), the compound is a compound of formula (VIa) or a compound of formula (VIb):

[0090]

[0091] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0092] In some embodiments of formula (VIa) or (VIb), Z 1 For S. In some embodiments of formula (VIa) or (VIb), Z 1 It is O.

[0093] In some implementations of formula (VIa) or (VIb), -B- is a covalent bond.

[0094] In some implementations of formula (VIa) or (VIb), each R 14 Independently -H or halogen. In some embodiments of formula (VIa) or (VIb), each R 14 Independently -H or -F. In some implementations of formula (VIa) or (VIb), each R 14 For -H. In some implementations of formula (VIa) or (VIb), each R 14 For -F. In some embodiments of formula (VIa) or (VIb), at least one R 14 It is -F.

[0095] In some embodiments of formula (VIa) or (VIb), the compound is a compound of formula (VIIa) or a compound of formula (VIIb):

[0096]

[0097] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0098] In some implementations of equation (Ia), -B- is Where R 11 It is -H or optionally substituted (C1-C3) alkyl.

[0099] In some embodiments of formula (Ia), the compound is a compound of formula (VIIIa) or a compound of formula (VIIIb):

[0100]

[0101] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 3 Selected from -H and optionally substituted (C1-C5) alkoxy groups.

[0102] In some embodiments of formula (VIIIa) or (VIIIb), -A- is an optionally substituted 3- to 6-membered heterocycle. In some embodiments of formula (VIIIa) or (VIIIb), -A- is an optionally substituted azacyclic butane, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperidin-2-one, or optionally substituted pyrrolidine-2-one. In some embodiments, the -A- ring is linked to an adjacent 4-cyanophenyl or 2-cyanopyridinyl-5-yl ring via the N atom of an optionally substituted 3- to 6-membered heterocycle (e.g., optionally substituted azacyclic butane, optionally substituted pyrrolidine, optionally substituted piperidine, optionally substituted piperidin-2-one, or optionally substituted pyrrolidine-2-one).

[0103] In some embodiments of formula (VIIIa) or (VIIIb), -A- is

[0104]

[0105] in:

[0106] R 12 Selected from -H, -OH, optionally substituted (C1-C3) alkyl groups and optionally substituted (C1-C5) haloalkyl groups; and

[0107] r, s, and t are independently 0 or 1.

[0108] In some embodiments of formula (VIIIa) or (VIIIb), -A- is selected from:

[0109]

[0110] In some embodiments of formula (VIIIa) or (VIIIb), -A- is a covalent bond.

[0111] In some implementations of formula (VIIIa) or (VIIIb), each R 14 Independently -H or halogen. In some embodiments of formula (VIIIa) or (VIIIb), each R 14 Independently -H or -F. In some embodiments of formula (VIIIa) or (VIIIb), each R 14 For -H. In some embodiments of formula (VIIIa) or (VIIIb), each R 14 For -F. In some embodiments of formula (VIIIa) or (VIIIb), at least one R 14 It is -F.

[0112] In some embodiments of formula (VIIIa) or (VIIIb), the compound is a compound of formula (IXa) or a compound of formula (IXb):

[0113]

[0114] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0115] In some embodiments of formula (VIIIa) or (VIIIb), -A- is optionally substituted with -(C3-C 12 ) heteroaryl-(C 1- C5) alkylene-(e.g., where -A-of-(C3-C 12 (The heteroaryl- and / or (C1-C5) alkylene- are each optionally substituted).

[0116] In some embodiments of formula (VIIIa) or (VIIIb), -A- is In some embodiments of formulas (I)-(Ia), -L- is -AB-, where -A- is an optionally substituted 3-membered to 6-membered heterocycle. In some embodiments, -A- is an optionally substituted pyrrolidone-2-one.

[0117] In some implementations, -A is selected from

[0118]

[0119] In some embodiments of formula (Ia), the compound is a compound of formula (Xa) or a compound of formula (Xb):

[0120]

[0121] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0122] B is as defined above;

[0123] R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups; and

[0124] R 12 Selected from -H and optionally substituted (C1-C3) alkyl groups.

[0125] In some implementations of formula (Xa) or (Xb), R 12 For -H. In some embodiments of formula (Xa) or (Xb), R 12 It is optionally a substituted (C1-C3) alkyl group. In some embodiments of formula (Xa) or (Xb), R 12 It is an ethyl group.

[0126] In some embodiments of formula (Xa) or (Xb), -B- is selected from -O-, -S-, -NH-, -SO2-, and -NHSO2-. In some embodiments of formula (Xa) or (Xb), -B- is -O-. In some embodiments of formula (Xa) or (Xb), -B- is -S-. In some embodiments of formula (Xa) or (Xb), -B- is -SO2-. In some embodiments of formula (Xa) or (Xb), -B- is -NHSO2-.

[0127] In some implementations of formula (Xa) or (Xb), each R 14 Independently -H or halogen. In some embodiments of formula (Xa) or (Xb), each R 14 Independently -H or -F. In some implementations of formula (Xa) or (Xb), each R 14 For -H. In some implementations of formula (Xa) or (Xb), each R 14 For -F. In some embodiments of formula (Xa) or (Xb), at least one R 14 It is -F.

[0128] In some embodiments of equations (I)-(Ia), -L- is -AB-, where -A- is -NHC(O)R 5 In some implementations of -A-, R 5 for In some embodiments, the compound is a compound of formula (XIa) or a compound of formula (XIb):

[0129]

[0130] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups.

[0131] In some embodiments of formula (XIa) or (XIb), -B- is selected from -O-, -S-, -SO2-, and -NHSO2-. In some embodiments of formula (XIa) or (XIb), -B- is -O-. In some embodiments of formula (XIa) or (XIb), -B- is -S-. In some embodiments of formula (XIa) or (XIb), -B- is SO2-. In some embodiments of formula (XIa) or (XIb), -B- is -NHSO2-.

[0132] In some implementations of formula (XIa) or (XIb), each R 14 Independently -H or halogen. In some embodiments of formula (XIa) or (XIb), each R 14 Independently -H or -F. In some implementations of formula (XIa) or (XIb), each R 14 For -H. In some implementations of formula (XIa) or (XIb), each R 14 For -F. In some embodiments of formula (XIa) or (XIb), at least one R 14 It is -F.

[0133] In any of the embodiments of formulas (I) to (XIb) described herein, R 1 It is an optionally substituted (C1-C6) alkyl group. In any of the embodiments of formulas (I) to (XIb) described herein, R 1 It is an optionally substituted (C1-C3) alkyl group. In any of the embodiments of formulas (I) to (XIb) described herein, R 1 It is -CH3.

[0134] In any of the embodiments of formulas (I) to (XIb) described herein, R 2 It is an optionally substituted (C1-C6) alkyl group. In any of the embodiments of formulas (I) to (XIb) described herein, R 2 It is an optionally substituted (C1-C3) alkyl group. In any of the embodiments of formulas (I) to (XIb) described herein, R 2 It is n-propyl.

[0135] In any of the embodiments of formulas (I) to (XIb) described herein, R 3It is optionally a substituted (C1-C3)alkoxy group. In any of the embodiments of formulas (I) to (XIb) described herein, R 3 It is an ethoxylated compound.

[0136] In several embodiments of the compound, each R 14 and R 4 It is optionally a substituted (C1-C5) haloalkyl or halogen. In another embodiment, R 14 and R 4 Each is -CF3, -F, or -Cl.

[0137] In some embodiments of the compound, X 1 X 2 and X 3 Each is CH.

[0138] In some embodiments of the compound, X 1 For N. In another implementation, X 2 and X 3 Each is CH.

[0139] In some embodiments of the compound, X 2 For N. In another implementation, X 1 and X 3 Each is CH.

[0140] In some embodiments of the compound, X 3 For N. In another implementation, X 1 and X 2 Each is CH.

[0141] In some embodiments, the compound is a compound of formula (IVc) or a compound of formula (IVd):

[0142]

[0143] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 14 It is -H or halogen.

[0144] In some implementations of formula (IVc) or (IVd), R 14 For -H or -F. In some implementations of formula (IVc) or (IVd), R 14 For -H. In some implementations of formula (IVc) or (IVd), R 14 It is -F.

[0145] In some implementations of formula (IVc) or (IVd), X1 For CH and R 14 For -F. In some implementations of formula (IVc) or (IVd), X 1 For N and R 14 For -F. In some implementations of formula (IVc) or (IVd), X 1 For CR 14 And each R 14 For -H. In some embodiments of formula (IVc) or (IVd), X 1 For N and R 14 It is -H.

[0146] In some implementations of formula (IVc) or (IVd), R 8 and R 9 Each is independently -H or optionally substituted (C1-C3) alkyl. In another embodiment, R 8 and R 9 Each is independently -CH3.

[0147] In some embodiments of formula (IVc) or (IVd), the compound is selected from:

[0148]

[0149] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0150] In some implementations of formula (IVc) or (IVd), for

[0151] In some embodiments, the compound is selected from...

[0152]

[0153] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0154] In some implementations of formula (IVc) or (IVd), R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or 4- or 5-membered heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0155] In some implementations of formula (IVc) or (IVd), for

[0156] In some embodiments, the compound is selected from:

[0157]

[0158] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0159] In some embodiments, the compound is a compound of formula (IVa), or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0160] X 1 For CH or N;

[0161] Each R 14 Independently -H or halogen; and

[0162] R 8 and R 9 Each is independently H or (C1-C3) alkyl (e.g., R 8 and R 9 Each is -CH3), or R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 5-membered carbon rings or optionally substituted 4- or 5-membered heterocycles (e.g., cyclopentane, cyclobutane, oxetane, or tetrahydrofuran).

[0163] In some embodiments, the compound is a compound of formula (IVc):

[0164]

[0165] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0166] X 1 For CH or N;

[0167] R 14 It is -H or halogen; and

[0168] R 8 and R 9 Each is independently H or (C1-C3) alkyl (e.g., R 8 and R 9 Each is -CH3), or R 8 and R 9It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 5-membered carbon rings or optionally substituted 4- or 5-membered heterocycles (e.g., cyclopentane, cyclobutane, oxetane, or tetrahydrofuran).

[0169] In some embodiments, the compound is selected from:

[0170]

[0171] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0172] In some embodiments, the compound is

[0173]

[0174] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0175] In some embodiments, the compound is

[0176]

[0177] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0178] In some embodiments, the compound is

[0179]

[0180] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0181] In some embodiments, the compound is

[0182]

[0183] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0184] In some embodiments, the compound is

[0185]

[0186] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0187] In some embodiments, the compound is

[0188]

[0189] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0190] In some implementations of formula (IVc) or (IVd), for

[0191] In some embodiments, the compound is selected from:

[0192]

[0193] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0194] In some implementations of formula (IVc) or (IVd), for

[0195] In some embodiments, the compound is selected from:

[0196]

[0197] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0198] In some implementations of formula (IVc) or (IVd), X 2 For N and X 3 For CH, or X 2 For CH and X 3 For N. In another implementation, R 8 and R 9 Each is an optionally substituted (C1-C3) alkyl group. In another embodiment, R 8 and R 9 Each is independently -CH3.

[0199] In some embodiments, the compound is selected from:

[0200]

[0201] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0202] In some implementations of formula (IVc) or (IVd), R 8 and R 9It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or 4- or 5-membered heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0203] In some embodiments, the compound is selected from...

[0204]

[0205] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0206] In some embodiments, the compound is a compound of formula (Vc):

[0207]

[0208] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0209] In some implementations of formula (Vc), R 8 and R 9 Each is independently a optionally substituted (C1-C3) alkyl group. In another embodiment of formula (Vc), R 8 and R 9 Each is -CH3.

[0210] In some embodiments of formula (Vc), the compound is selected from:

[0211]

[0212] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0213] In some implementations of formula (Vc), R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or 4- or 5-membered heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0214] In some embodiments, the compound is selected from:

[0215]

[0216] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0217] In some embodiments, the compound is a compound of formula (VIIc):

[0218]

[0219] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0220] In some embodiments, the compound is selected from:

[0221]

[0222] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0223] In some embodiments, the compound is a compound of formula (VIIIc):

[0224]

[0225] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0226] In some implementations of formula (VIIIc), -A- is

[0227]

[0228] in:

[0229] R 12 Selected from -H, -OH, optionally substituted (C1-C3) alkyl groups and optionally substituted (C1-C5) haloalkyl groups; and

[0230] r, s, and t are independently 0 or 1.

[0231] In some implementations of formula (VIIIc), R 4 It is -CF3.

[0232] In some embodiments, the compound is selected from:

[0233]

[0234] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0235] In some embodiments, the compound is a compound of formula (IXc) or a compound of formula (IXd):

[0236]

[0237] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0238] In some implementations of formula (IXc) or (IXd), R 4 It is -CF3- or -Cl.

[0239] In some embodiments, the compound is selected from:

[0240]

[0241] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0242] In some embodiments, the compound is a compound of formula (VIIId):

[0243]

[0244] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0245] In some implementations of formula (VIIId), R 4 It is -Cl.

[0246] In some embodiments, the compound is

[0247]

[0248] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0249] In some embodiments, the compound is a compound of formula (XIc):

[0250]

[0251] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0252] In some embodiments, the compound is selected from:

[0253]

[0254] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0255] In some embodiments, the compound is a compound of formula (Xc):

[0256]

[0257] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts.

[0258] In some embodiments of formula (Xc), -B- is selected from -NH-, -O-, -S- and -SO2-.

[0259] In some embodiments, the compound is selected from:

[0260]

[0261] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0262] In some embodiments, the compound is represented by the structure of one of the compounds in Table 1 or its solvates, hydrates, prodrugs and / or stereoisomers or pharmaceutically acceptable salts thereof.

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] It should be understood that all variations of salts, solvates, hydrates, prodrugs and / or stereoisomers of the compounds described herein (e.g., compounds of formula (I)-(XIc), such as those in Table 1) are included within the scope of this invention.

[0274] 4.1.1 Isotope-labeled analogues

[0275] This disclosure also includes isotopically labeled compounds that are identical to those described herein, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those normally found in nature (“isotopes”). The compounds of this disclosure may also contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. Examples of isotopes that may be incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, as follows: 2 H(“D”), 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 C1. For example, the compounds described herein may have one or more H atoms that are replaced by deuterium.

[0276] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or where carbon is enriched. 13 C or 14 Compounds having the structure of this invention, other than carbon substitution of C, are within the scope of this disclosure.

[0277] In some implementations, certain isotopically labeled compounds, such as those labeled with... 3 H and 14 C-labeled compounds can be used for the determination of compound and / or matrix tissue distribution. Tritium ( 3 H) and carbon-14 ( 14 C) Isotopes may be particularly preferred due to their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium can provide certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements, and is therefore preferred in certain cases. Isotopically labeled compounds can generally be prepared by procedures similar to those disclosed herein, for example, in the Examples section, by replacing unlabeled reagents with isotopically labeled reagents.

[0278] In some embodiments, the compounds disclosed in this invention are deuterated analogs of any one of the compounds described herein or of their salts. A deuterated analog of any compound of formulas (I)-(XIc) is a compound in which one or more hydrogen atoms are substituted with deuterium. In some embodiments, the deuterated analog is any compound of formulas (I)-(XIc) comprising deuterated R. 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 Or R 14 Group. In certain embodiments of the deuterated analogues of any of the compounds in formulas (I)-(XIc), R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Independently selected from optionally substituted (C1-C6) alkyl, optionally substituted (C1-C6) alkoxy, optionally substituted (C1-C6) alkylene-heterocyclic alkyl, optionally substituted monocyclic or bicyclic carbocyclic and optionally substituted monocyclic or bicyclic heterocyclic, including at least one deuterium atom.

[0279] Deuterium-substituted compounds are synthesized using a variety of methods described in the following: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Published in: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0280] Deuteration starting materials are readily available and can be synthesized using the methods described herein to provide for the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and structural units are available from chemical suppliers such as Aldrich Chemical Co.

[0281] 4.1.2 Fluorinated analogues

[0282] In some embodiments, the compounds disclosed herein are fluorinated analogs of any one of the compounds described herein or of their salts. A fluorinated analog of any compound of formulas (I)-(XIc) is a compound in which one or more hydrogen atoms or substituents are substituted with fluorine atoms. In some embodiments, the fluorinated analog is any compound of formulas (I)-(XIc) comprising a fluorinated R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 Or R 14 Group. In certain embodiments of the fluorinated analogues of any of the compounds in formulas (I)-(XIc), R 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 and R 14 Independently selected from optionally substituted (C1-C6) alkyl groups, optionally substituted (C1-C6) alkoxy groups, optionally substituted (C1-C6) alkylene-heterocyclic alkyl groups, optionally substituted monocyclic or bicyclic carbocyclic rings, optionally substituted monocyclic or bicyclic heterocyclic rings, optionally substituted aryl groups, and optionally substituted heteroaryl groups. In some embodiments of fluorinated analogs of any of the compounds in formulas (I)-(XIc), the hydrogen atom of the aliphatic or aromatic CH bond is replaced by a fluorine atom. In some embodiments of fluorinated analogs of any of the compounds in formulas (I)-(XIc), at least one hydrogen atom of the optionally substituted aryl or optionally substituted heteroaryl group is replaced by a fluorine atom. In some embodiments of fluorinated analogs of the compound of formula (I), the hydroxyl substituent (-OH) or amino substituent (-NH2) is replaced by a fluorine atom.

[0283] 4.1.3 Salt, solvate, hydrate, prodrug, and / or stereoisomer forms

[0284] In some embodiments, the compounds described herein also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of those compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0285] In some embodiments, the compounds described herein are present in a prodrug form. Any convenient prodrug form of the target compound may be prepared, for example, according to the protocols and methods described by Rautio et al. (“Prodrugs: design and clinical applications”, Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0286] The compounds described herein may exist as solvates, particularly hydrates, and unless otherwise specified, all such solvates and hydrates are intended. Hydrates may form during the manufacture of the compound or a composition comprising the compound, or may form over time due to the hygroscopic nature of the compound. The compounds of this invention may also exist as organic solvates, including DMF, ethers, and alcohol solvates. The identification and preparation of any specific solvate are within the skill of a person skilled in the art of synthetic organic chemistry or medicinal chemistry.

[0287] In some embodiments, the compounds described herein are present as solvates.

[0288] In some implementations, when the solvent component of the solvate is water, the compounds described herein exist as hydrates.

[0289] In some embodiments, the compounds described herein have one or more chiral centers. It should be understood that, unless explicitly indicated by absolute stereochemistry, each chiral center may independently be an R-configuration or an S-configuration or a mixture thereof.

[0290] Unless explicitly specified in the stereochemistry, "all chiral, diastereomeric, and racemic forms of the compound" are intended. Therefore, as is apparent from the description, the compounds described herein include optical isomers enriched or split at any or all asymmetric atoms. Racemic mixtures of R-enantiomers and S-enantiomers, and enantiomer-rich stereoisomer mixtures containing R-enantiomers and S-enantiomers, as well as individual optical isomers, can be isolated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and all such stereoisomers are within the scope of the present invention.

[0291] In some embodiments, the compounds described herein are present in the form of salts.

[0292] In some embodiments, the compound or its prodrug form is provided in the form of a pharmaceutically acceptable salt.

[0293] The term "pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a subject. It should be understood that such salts containing counterions will have acceptable mammalian safety for a given dosage regimen. Such salts can also be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids, and may contain both organic and inorganic counterions. The neutral form of the compounds described herein can be converted to the corresponding salt form by contacting the compound with a base or acid and separating the resulting salt.

[0294] For therapeutic purposes, salts of the compounds disclosed herein may be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds.

[0295] The inherently basic compounds included in the compositions of the present invention are capable of forming a variety of salts with a wide range of inorganic and organic acids. The pharmaceutically acceptable acid addition salts that can be used to prepare such basic compounds are those that form non-toxic acid addition salts, i.e., acids containing pharmaceutically acceptable anions. Compounds containing amine functional groups or nitrogen-containing heteroaryl groups are inherently basic and can react with any number of inorganic and organic acids to form the corresponding pharmaceutically acceptable salts. In some embodiments, the salt is an acid addition salt form of the compound (e.g., as described herein). In some embodiments, the acid addition salt is an inorganic acid salt. In some embodiments, the acid addition salt is an organic acid salt.

[0296] The inherently acidic compounds included in the compositions of the present invention are capable of forming base salts with a variety of pharmaceutically acceptable cations.

[0297] The compounds comprising basic or acidic moieties in the compositions of the present invention can also form pharmaceutically acceptable salts with various amino acids. The compounds disclosed herein may contain both acidic and basic groups; for example, an amino group and a carboxylic acid group. In this case, the compounds may exist as acid addition salts, zwitterions, or basic salts.

[0298] It should be understood that this invention is intended to include all variations of salts, solvates, hydrates, prodrugs, and stereoisomers.

[0299] 4.1.4 Prodrug

[0300] Several aspects of this disclosure include prodrug forms of any of the compounds described herein. Any convenient prodrug form of the host compound may be prepared, for example, according to the strategies and methods described by Rautio et al. (“Prodrugs: design and clinical applications”, Nature Reviews Drug Discovery 7, 255-270 (February 2008)).

[0301] The term "prodrug" refers to an agent that is converted into a biologically active drug substance in vivo through some physiological or chemical process. In some embodiments, the prodrug is converted into the desired drug form when acted upon by a biological system at physiological pH. In some embodiments, the prodrug is converted into the desired drug form by an enzyme when acted upon by a biological system.

[0302] The prodrug form of any of the compounds described herein can be used, for example, to provide specific therapeutic benefits due to an extended half-life of the resulting compound in vivo or a reduction in the required active dose.

[0303] Prodrugs can be useful in some cases because they are easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, while the parent drug may not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug.

[0304] The prodrug forms or derivatives of the compounds disclosed herein typically contain a promoiety substituent at a suitable unstable site in the compound. The promoiety refers to a group that can be removed by enzymatic or chemical reactions during the conversion of the prodrug into a drug in vivo.

[0305] In some embodiments, the first part is a group (e.g., optionally substituted C1-6 alkyl or optionally substituted C1-6 alkyl) attached to the hydroxyl or carboxylic acid group of the compound or drug via an ester bond.

[0306] 4.2 Compound Synthesis

[0307] The compounds disclosed herein can be synthesized according to standard methods known in the art [see, for example, Morrison and Boyd in "Organic Chemistry", 6th edition, Prentice Hall (1992)]. Some of the compounds and / or intermediates disclosed herein are commercially available, known in the literature, or readily available to those skilled in the art using standard procedures. Some of the compounds disclosed herein can be synthesized using the schemes, examples, or intermediates described herein. Without fully describing the synthesis of the compounds, intermediates, or variants thereof, those skilled in the art will recognize that reaction times, reagent equivalences, and / or temperatures can be modified from the reactions described herein to prepare the proposed compounds or intermediates or variants thereof, and that different processing and / or purification techniques may be necessary or required to prepare such compounds, intermediates, or variants.

[0308] The synthesized compound can be verified to have the correct structure by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and / or mass spectrometry.

[0309] In various embodiments, the compounds described herein are represented by the structure of one of the compounds in Table 1. This invention is intended to include any of the compounds in Table 1, or their salts, single stereoisomers, mixtures of stereoisomers, and / or isotopically labeled forms.

[0310] 4.3 Pharmaceutical Composition

[0311] The compounds disclosed herein may be included in compositions comprising one or more such compounds and at least one excipient (e.g., a pharmaceutically acceptable excipient). Such compositions may include PDE-5 and / or androgen receptor inhibitor compounds (e.g., as described herein).

[0312] The compounds described herein can be used in pharmaceutical compositions administered to subjects in need of treatment in a variety of therapeutic applications requiring inhibition of PDE-5 and / or androgen receptors. In some embodiments, the compounds disclosed herein can be formulated as pharmaceutical compositions.

[0313] Therefore, in a second aspect, this disclosure provides pharmaceutical compositions comprising at least one compound described herein, a pharmaceutically acceptable salt thereof or a prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0314] The term "pharmaceutical composition" is intended to include compositions suitable for administration to subjects (e.g., mammals, especially humans). Generally, a "pharmaceutical composition" is sterile and preferably free of contaminants that could cause undesirable reactions in a subject (i.e., the compounds in the pharmaceutical composition are pharmaceutical grade). Pharmaceutical compositions can be designed to be administered to subjects or patients in need via a variety of different routes of administration, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, and subcutaneous administration.

[0315] The terms “pharmaceuticalally acceptable excipient,” “pharmaceuticalally acceptable diluent,” “pharmaceuticalally acceptable carrier,” and “pharmaceuticalally acceptable adjuvant” are used interchangeably and refer to any component other than the compounds of the invention described herein that has substantially non-toxic and non-inflammatory properties to patients (e.g., a vehicle that can suspend or dissolve the active compound or any other convenient pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or additive). The phrase “pharmaceuticalally acceptable excipient” includes one or more such excipients, diluents, carriers, and / or adjuvants. Excipients may include, for example: anti-adhesives, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavoring agents, fragrances, flow enhancers, lubricants, preservatives, printing inks, adsorbents, dispensing or dispersing agents, sweeteners, and water for hydration. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound as described herein, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0316] The pharmaceutical composition can be formulated by any convenient method and can be prepared in a variety of forms for oral administration, such as tablets, pills, powders, capsules, syrups, suspensions, emulsions, and microemulsions, or in forms for non-oral administration, such as eye drops, or for intramuscular, intravenous, or subcutaneous administration. In one example, the pharmaceutical composition can be administered via the eye as eye drops. In one example, the pharmaceutical composition can be an ophthalmic composition, such as an eye drop composition.

[0317] In some embodiments, the pharmaceutical composition is formulated for oral delivery. Examples of additives or carriers that may be used when the pharmaceutical composition is prepared in a form suitable for oral administration include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, magnesium stearate, stearic acid, stearate, talc, surfactants, suspending agents, emulsifiers, and diluents. Examples of additives or carriers that may be used when the pharmaceutical composition of the present invention is prepared as an injectable formulation include water, saline solution, glucose solution, pseudosugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, and emulsifiers.

[0318] In some embodiments, the pharmaceutical composition is formulated for parenteral administration to a subject in need. In some parenteral embodiments, the pharmaceutical composition is formulated for intravenous administration to a subject in need. In some non-enteral embodiments, the pharmaceutical composition is formulated for subcutaneous administration to a subject in need.

[0319] 4.4 Methods for regulating androgen receptor (AR) and phosphodiesterase 5 (PDE-5)

[0320] This disclosure includes methods for modulating androgen receptors and / or PDE-5 in a biological system or sample by contacting a compound that exhibits dual functionality by i) modulating the androgen receptor and ii) modulating PDE-5. In some embodiments, the compound, as described herein, inhibits the androgen receptor in a biological system or sample. In another embodiment, the compound, as described herein, inhibits PDE-5 in a biological system or sample.

[0321] In some implementations, the biological system or sample is in vitro. In some cases, the sample is a cell sample.

[0322] The "androgen receptor," or "nuclear receptor subfamily 3, c group, member 4," or "NR3C4," is a type of nuclear receptor that is activated by binding to either androgen hormones (including testosterone and dihydrotestosterone in the cytoplasm) and subsequently translocating to the nucleus.

[0323] Phosphodiesterase 5 (PDE-5) is a phosphodiesterase. Inhibition of PDE-5 suppresses the breakdown of cGMP, which subsequently leads to increased PKG activity and increased cGMP concentration. Increased PKG activity can subsequently cause phosphorylation of many biologically important targets, smooth muscle relaxation, and increased blood flow.

[0324] This disclosure provides compounds with potent PDE-5 inhibitory activity. These compounds can be evaluated using in vitro enzyme assays. For example, Table 3 of Example 3 in the Experimental Section shows the IC50 values ​​of exemplary compounds in in vitro PDE-5 assays. 50 value.

[0325] This disclosure also provides compounds exhibiting inhibitory and antagonistic activity against androgen receptors (AR). These compounds can be evaluated using cellular analysis. For example, Table 4 of Example 4 in the Experimental Section shows the IC50 values ​​of exemplary compounds in in vitro AR reporter assays. 50 Value. As illustrated in Example 4, the tested compounds exhibited excellent anti-AR antagonistic activity, with an IC50 value that was more effective or comparable to that of enzalutamide and apalutamide. 50 Values. Furthermore, Table 5 of Example 5 in the Experimental Section demonstrates the binding affinity of the exemplary compounds in in vitro radioligand binding analysis. As illustrated in Example 5, the exemplary compounds exhibit better or comparable binding affinity and AR inhibition compared to enzalutamide and apalutamide.

[0326] Aspects of this disclosure include methods for inhibiting both PDE-5 and AR using the PDE-5 and AR inhibitor compounds described herein. Such methods may include methods for inhibiting AR and PDE-5 in a biological system by contacting the biological system with compounds of this disclosure (e.g., AR and PDE-5 inhibitor compounds having the structure of any of those compounds according to Table 1 or their pharmaceutically acceptable salts).

[0327] In some embodiments, methods for inhibiting AR and PDE-5 include contacting a biological system or sample containing AR and PDE-5 with an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof, or any of a pharmaceutical composition as described herein, to inhibit AR and PDE-5. In some embodiments, the biological system or sample is in vitro. The biological system may include, but is not limited to, cells, tissues, organs, body fluids, organisms, non-mammalian subjects, and mammalian subjects (e.g., humans).

[0328] AR and PDE-5 inhibitors can inhibit the activity of AR and PDE-5 in a sample, as assessed, for example, by AR or PDE-5 inhibition assays as described in Examples 3 and 4. AR and PDE-5 inhibitors according to such methods may each have IC50 of less than 5000 nM, for example, 1000 nM or less, 200 nM or less, 100 nM or less, or 20 nM or less for AR and PDE-5 inhibition. 50 Values ​​(e.g., those assessed by the analyses in Examples 3 to 4). Biological systems may include subjects (e.g., human subjects).

[0329] In some embodiments of the method, the AR and PDE-5 inhibitors (e.g., compounds of formula (I)) exhibit dual functionality. In some embodiments, the dual functionality of the compounds described herein is the inhibition of AR and the inhibition of PDE-5.

[0330] In some embodiments, this disclosure provides methods for inhibiting AR and PDE-5 activity in a biological system (e.g., a subject). In some cases, the percentage of AR activity inhibited in the biological system (e.g., a subject) may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%. In some cases, the percentage of PDE-5 activity inhibited in a biological system (e.g., a subject) may be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9%.

[0331] In some cases, this level of inhibition and / or maximal inhibition of AR and PDE-5 activity can be achieved by approximately 1 to approximately 3 hours after application, approximately 2 to approximately 4 hours after application, approximately 3 to approximately 10 hours after application, approximately 5 to approximately 20 hours after application, or approximately 12 to approximately 24 hours after application. Inhibition of AR and / or PDE-5 activity can last for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 8 weeks, at least 3 months, at least 6 months, or at least 1 year. In some cases, this level of inhibition can be achieved by daily application. Such daily application may include application for at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 2 months, at least 4 months, at least 6 months, at least 1 year, or at least 5 years. In some cases, the compounds or compositions disclosed herein may be administered to the subject for life.

[0332] In some embodiments, the compounds of this disclosure can be used in analyses evaluating AR and PDE-5 inhibition. In some cases, the compounds may be included in drug development methods. In some embodiments, the methods of this disclosure include using the AR and PDE-5 inhibitory compounds of this disclosure to evaluate the inhibition of AR and PDE-5 by other compounds. Such methods may include binding the AR and PDE-5 inhibitory compounds to one or more detectable labels (e.g., fluorescent dyes) and measuring the dissociation of both AR and PDE-5 in the presence of other compounds (detected by the detectable labels). The detectable labels may include fluorescent compounds.

[0333] 4.5 Therapeutic indications

[0334] This disclosure includes methods of treating a target therapeutic indication using the compounds and / or compositions disclosed herein. The term "therapeutic indication" means any symptom, condition, ailment, or disease that can be relieved, stabilized, improved, cured, or otherwise resolved by some form of treatment or other therapeutic intervention (e.g., by administration of AR and PDE-5 inhibitors). Therapeutic indications associated with aberrant AR and / or PDE-5 biological activity are referred to herein as "AR and / or PDE-5-related indications." In some embodiments, the methods of this disclosure may include treating an AR and / or PDE-5-related indication by administering the compounds and / or compositions disclosed herein (e.g., AR and PDE-5 inhibitor compounds).

[0335] In one embodiment, the method of the present invention comprises using AR and PDE-5 inhibitors as single active ingredients or in a composition. The AR and PDE-5 inhibitors of the present invention are suitable for: a) benign prostatic hyperplasia, prostate cancer; b) breast cancer, uterine cancer, and ovarian cancer; and / or c) reducing the incidence of prostate cancer, preventing prostate cancer, or causing prostate cancer regression.

[0336] The scope of this invention also includes methods for treating breast cancer, delaying the progression of breast cancer, and preventing and treating recurrence and / or metastasis of breast cancer, comprising administering a selective androgen receptor modulator in combination with one or more therapeutic agents.

[0337] The terms “treat,” “treatment,” and similar terms refer to the relief or alleviation of a pathological process. In the context of this disclosure, whenever any of the other conditions listed below is involved, the terms “treat,” “treatment,” and similar terms refer to the relief or alleviation of at least one symptom associated with such condition, or to slowing or reversing the progression or anticipated progression of such condition.

[0338] The terms "individual" and "subject" are used interchangeably and refer to a subject who requires treatment for a disease. More specifically, it refers to a human or non-human primate, mouse, dog, cat, horse, cow, rabbit, rat, or other mammal.

[0339] In some implementations, after administration of a composition or compound as described herein, the target in a subject is reduced or relieved of one or more symptoms of the therapeutic indication.

[0340] In some embodiments, the method includes oral administration of the compound or composition of the invention. The dosage may be determined according to the purpose, administered orally or non-orally in an amount effective for the prevention or treatment of the individual or patient in question. When administered orally, the compound may be administered such that 0.01 mg to 1000 mg, more specifically, 0.1 mg to 300 mg of the active ingredient per kg body weight, and when administered non-orally, the compound may be administered such that 0.01 mg to 100 mg, more specifically, 0.1 mg to 50 mg of the active ingredient per kg body weight. The dosage may be administered once or multiple times. The dosage for a specific individual or patient should be determined based on a variety of relevant factors, such as weight, age, sex, health status, diet, administration interval, method of administration, and severity of disease, and may be appropriately increased or decreased by an expert. The above dosage is not intended to limit the scope of the invention in any way. A physician or veterinarian with ordinary skills in the relevant art can readily determine and prescribe the effective required dosage of the pharmaceutical composition. For example, a physician or veterinarian may start at a level below that required to achieve the desired therapeutic effect and gradually increase the dosage of the compound of the present invention in the pharmaceutical composition until the desired effect is achieved.

[0341] The compounds and compositions disclosed herein may be administered alone, in combination with compounds according to another example of this disclosure, or concurrently, alone, or sequentially with at least one other therapeutic agent.

[0342] 4.5.1 AR-related indications

[0343] Therapeutic indications associated with AR activity and / or dysfunction are referred to herein as “AR-related indications”. In some embodiments, the methods of this disclosure may include treating AR-related indications by administering compounds and / or compositions disclosed herein (e.g., AR and PDE5 modulator compounds).

[0344] In some embodiments, as illustrated by Examples 4 and 5, application of the compounds disclosed herein can cause significant changes in AR activity.

[0345] 4.5.2 PDE-5 related indications

[0346] This disclosure includes methods for treating a target therapeutic indication using the compounds and / or compositions disclosed herein. Therapeutic indications associated with PDE5 activity and / or dysfunction are referred to herein as “PDE5-related indications.” In some embodiments, the methods of this disclosure may include treating a PDE5-related indication by administering the compounds and / or compositions disclosed herein (e.g., PDE5 and AR inhibitor compounds).

[0347] PDE5 inhibitors are a class of well-defined agents with multiple activities. Human phosphodiesterase 5 (PDE5) inhibition assays in host cells can be used to assess the ability of the compounds of this disclosure to inhibit target PDE5. In some embodiments, as illustrated by Example 3, administration of the compounds of this disclosure can induce significant changes in PDE5 activity.

[0348] 4.6 Definition

[0349] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0350] It should be understood that the definitions provided in this article are not intended to be mutually exclusive. Therefore, some chemical terms may fall under the definition of more than one term.

[0351] As used in this article, symbols It refers to covalent bonds, including single or double bonds.

[0352] Term "C" x -C y "When used in conjunction with chemical moieties such as alkyl, alkenyl, or alkynyl, it is intended to include groups containing x to y carbons in the chain. For example, the term 'C1-C6 alkyl' refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched alkyl groups containing 1 to 6 carbons. In some embodiments, the term '(C1-C6 alkyl)' is used..." x -C y "(C)alkylene" refers to a substituted or unsubstituted alkylene chain having x to y carbons in the chain. For example, "(C) x -C y "alkylene" can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which may be optionally substituted.

[0353] The term "alkyl" refers to an unbranched saturated hydrocarbon chain or a branched saturated hydrocarbon chain. In some embodiments, as used herein, the alkyl group has 1 to 20 carbon atoms (C1-C2). 20 Alkyl groups, 1 to 10 carbon atoms (C1-C1) 10Alkyl groups have 1 to 8 carbon atoms (C1-C8)alkyl, 1 to 6 carbon atoms (C1-C6)alkyl, or 1 to 5 carbon atoms (C1-C5)alkyl. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When naming alkyl residues having a specific number of carbons, all geometric isomers having said number of carbons may be included. For example, "butyl" may include n-butyl, sec-butyl, isobutyl, and tert-butyl, and "propyl" may include n-propyl and isopropyl. Unless otherwise specifically stated in this specification, the alkyl chain may optionally be substituted with one or more substituents (such as those described herein).

[0354] The term "alkylene" refers to a straight divalent hydrocarbon chain in which the remainder of the molecule is attached to a free radical. It consists only of carbon and hydrogen, contains no unsaturation, and preferably has 1 to 20 carbon atoms (C1-C2). 20 Alkylene), 1 to 10 carbon atoms (C1-C1) 10 Alkylene chains are alkylene chains with 1 to 6 carbon atoms ((C1-C6)alkylene chains) or 1 to 5 carbon atoms ((C1-C5)alkylene chains). Examples include, but are not limited to, methylene, ethylene, propylene, butylene, etc. The alkylene chain is attached to the rest of the molecule and to a free radical by a single bond. The attachment points of the alkylene chain to the rest of the molecule and to the free radical are respectively through the terminal carbon. Unless otherwise specifically stated in this specification, the alkylene chain is optionally substituted with one or more substituents (such as those described herein). Examples include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2-CH(CH3)-CH2-), hexylene (-(CH2)6-), etc.

[0355] The term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, including straight-chain, branched, and cyclic alkenyl groups. In some embodiments, the alkenyl group has 2-10 carbon atoms (C2-C2). 2-10 Alkenyl group). In another embodiment, the alkenyl group has 2-4 carbon atoms (C4-C5) in the chain. 2-4 Alkenyl groups are included, but are not limited to, vinyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexyl-butenyl, and decenyl. Alkyl alkenyl groups are alkyl groups as defined herein that are bonded to an alkenyl group as defined herein. Alkenyl groups may be unsubstituted or may be formed by substitution of available carbon atoms with one or more alkyl groups as defined above.

[0356] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and having at least 1, preferably 1 to 2 alkynyl (C≡C-) unsaturated sites. Examples of such alkynyl groups include, but are not limited to, ethynyl (C≡CH) and propynyl (CH2C≡CH).

[0357] The term "aryl" refers to a monocyclic or polycyclic group having at least one aromatic hydrocarbon ring, wherein all ring atoms of the at least one aromatic hydrocarbon ring are carbon atoms. Aryl groups may include groups having a single aromatic ring (e.g., phenyl) and groups having multiple fused aromatic rings (e.g., naphthyl, anthracene). Aryl groups may also include groups having one or more aromatic rings fused to one or more non-aromatic rings (e.g., fluorenyl; 2,3-dihydro-1H-indene; 1,2,3,4-tetrahydronaphthalene). In some embodiments, an aryl group includes a group having an aromatic ring fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one cyclic heteroatom independently selected from the group consisting of N, O, and S. For example, in some embodiments, an aryl group includes a group having a phenyl ring fused to a non-aromatic ring, wherein the non-aromatic ring comprises at least one cyclic heteroatom independently selected from the group consisting of N, O, and S (e.g., chromane; thiochromane; 2,3-dihydrobenzofuran; indoline). In some embodiments, such as those used herein, the aryl group has 6 to 14 carbon atoms (C6-C14). 14 aryl group or 6 to 10 carbon atoms (C6-C) 10 (aryl). In the case where the aryl group includes a fused ring, the aryl group can be connected to one or more substituents or portions of the formula described herein by any atom of the fused ring, provided that the valence permits.

[0358] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated hydrocarbon. In some embodiments, the cycloalkyl group has 3 to 20 carbon atoms (C3-C4). 20 Cycloalkyl groups have 3 to 8 carbon atoms (C3-C8 cycloalkyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl), or 3 to 5 carbon atoms (C3-C5 cycloalkyl). In some embodiments, the cycloalkyl group has 3 to 8 carbon atoms and has one or more cyclic rings, including fused rings, bridged rings, and spirocyclic systems. Examples of suitable cycloalkyl groups include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, octahydropentenyl, octahydro-1H-indene, decahydronaphthalene, cubane, bicyclo[3.1.0]hexane, and bicyclo[1.1.1]pentane, etc.

[0359] The term "carbocyclic ring" refers to a saturated ring, an unsaturated ring, and / or an aromatic ring, wherein each atom of the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocyclic ring may be selected from a saturated ring, an unsaturated ring, and an aromatic ring. In exemplary embodiments, the aromatic ring (e.g., phenyl) may be fused with a saturated ring or an unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Where valence permits, bicyclic carbocyclic rings include any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings. Bicyclic carbocyclic rings include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, dihydroindenyl, and naphthyl.

[0360] The term "heterocycle" refers to a saturated ring, unsaturated ring, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Where valence allows, bicyclic heterocycles include any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings. In exemplary embodiments, an aromatic ring (e.g., pyridyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene). Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems.

[0361] The term "heteroaryl" refers to an aromatic group having 4 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Such heteroaryls may have a single ring (i.e., pyridyl or furanyl) or multiple condensed rings (i.e., indolizinyl or benzothiophene), wherein the condensed rings may or may not be aromatic and / or contain heteroatoms, the limitation being that the attachment point passes through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N oxide (N→O), sulfinyl, or sulfonyl moiety. Preferred heteroaryls include 5- or 6-membered heteroaryls, such as pyridyl, pyrroleyl, indolyl, thiophene, and furanyl.

[0362] The term "heteroalkyl" refers to an alkyl substituent in which one or more carbon atoms and any attached hydrogen atoms are independently replaced by the same or different heteroatom substituents. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom substituents.

[0363] The term "substituted" refers to the portion of a compound in which one or more hydrogen atoms on a carbon atom or a substituted heteroatom (e.g., NH or NH2) are replaced by a substituent. It should be understood that "substituted" or "replaced by" includes the implicit limitation that such substitution conforms to the permissible valences of the substituted atom and the substituent, and that the substitution produces a stable compound. For example, stable compounds include, but are not limited to, compounds that do not spontaneously undergo transformations (such as by rearrangement, cyclization, elimination, etc.). In some embodiments, substituted means the portion in which two hydrogen atoms on the same carbon atom are replaced by a substituent, such as replacing two hydrogen atoms on a single carbon atom with an oxo group, an imino group, or a thio group. As used herein, the term "substituted" is considered to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, permissible substituents may be one or more, and may be the same or different.

[0364] Those skilled in the art will understand that a substituted element itself can be substituted where appropriate. Unless expressly stated as "unsubstituted," references to the chemical part herein should be understood to include substituted variants. For example, unless otherwise specified, references to "heteroaryl" groups or partly implicitly include both substituted and unsubstituted variants.

[0365] The phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on the specified atom, and therefore, this specification includes structures in which non-hydrogen substituents are present and structures in which non-hydrogen substituents are absent.

[0366] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a)2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2). In another exemplary embodiment, the substituents include alkyl, alkenyl, alkynyl, aryl, aralkyl, areneyl, arynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may optionally be substituted by: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, imino, oxime, hydrazine, -R b OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a-R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and each R a R b and R c Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; and wherein each R a R b and R c Where the valence permits, it may optionally be substituted with the following: alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, imino, oxime, hydrazine, -R b OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -Rb -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2).

[0367] The term "isomer" refers to two or more compounds that contain the same number and type of atoms, groups or components but have different atomic arrangements and connections.

[0368] The term "tautomer" refers to one of two or more structural isomers that readily transforms from one isomer form to another and exists in equilibrium.

[0369] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention envisions various stereoisomers and mixtures thereof, including "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0370] Individual enantiomers and diastereomers of the compounds disclosed herein can be prepared synthetically from commercially available starting materials containing asymmetric or stereosymmetric centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. Such resolution methods are exemplified by: (1) attaching a mixture of enantiomers to a chiral auxiliary agent, separating the resulting diastereomer mixture by recrystallization or chromatography, and releasing an optically pure product from the auxiliary agent; (2) forming a salt using an optically active resolving agent; (3) directly separating a mixture of optically enantiomers on a chiral liquid chromatography column; or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their respective enantiomers by well-known methods, such as chiral gas chromatography or crystallization of the compounds in chiral solvents. Stereoselective synthesis, namely chemical or enzymatic reactions in which a single reactant forms an unequal mixture of stereoisomers during the formation of a new stereocenter or the transformation of an existing stereocenter, is well known in the art. Stereoselective synthesis includes both enantioselective and diastereoselective transformations. See, for example, Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH:Weinheim, 2009.

[0371] Geometric isomers arising from the arrangement of substituents around carbon-carbon double bonds or around cycloalkyl or heterocyclic rings may also exist in the compounds disclosed herein. The symbol = indicates a bond that may be a single bond, double bond, or triple bond as described herein. Substituents around carbon-carbon double bonds are designated as “Z” or “E” configurations, wherein the terms “Z” and “E” are used according to IUPAC standards. Unless otherwise specified, the description of the double bond includes both “E” and “Z” isomers.

[0372] Substituents around a carbon-carbon double bond can also be referred to as "cis" or "trans," where "cis" indicates a substituent located on the same side of the double bond and "trans" indicates a substituent located on opposite sides of the double bond. The arrangement of substituents around the carbon ring can also be referred to as "cis" or "trans." The term "cis" indicates a substituent on the same side of the ring plane, and the term "trans" indicates a substituent on opposite sides of the ring plane. A mixture of compounds with substituents located on both sides of the ring plane is called "cis / trans."

[0373] In the context of describing elements, the indefinite articles (“a”, “an”) and definite articles (“the”) and similar indicators in the singular form should be understood to cover both singular and plural, unless otherwise stated herein or obviously contradicted by the context. Unless otherwise indicated herein, the enumeration of numerical ranges herein is intended only as a shorthand method of individually referring to each independent value (including the upper and lower limits of the range) belonging to the range, and each independent value is incorporated into this specification as if it were individually enumerated herein. Unless otherwise indicated herein or obviously contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise stated, the use of any and all instances or exemplary language (i.e., “for example”) provided herein is intended only to better illustrate the embodiments and is not intended to limit the scope of the claims.

[0374] In some embodiments, unless otherwise specifically stated, when the term "about" is used before a numerical value, this disclosure also includes the specific numerical value itself. Unless otherwise indicated or inferred, as used herein, the term "about" means a variation of ±10% of a nominal value. Unless otherwise stated or understood from the context, when a percentage of the amount of a component or substance in a composition is provided, the percentage should be understood as a weight-based percentage.

[0375] Unless otherwise stated or understood from the context, if a molecular weight (e.g., the molecular weight of a polymer) is provided instead of an absolute value, the molecular weight shall be understood as an average molecular weight.

[0376] It should be understood that the order of steps or the sequence of actions is not important, as long as the disclosure remains operable. Furthermore, two or more steps or actions can be performed simultaneously.

[0377] A hyphen ("-") not between two letters or symbols indicates the bonding or attachment point of a substituent. For example, -NH2 is attached via a nitrogen atom.

[0378] The terms “active agent,” “drug,” “pharmacologically active agent,” and “active pharmaceutical ingredient” are used interchangeably to refer to a compound or composition that, when administered to a subject, induces the desired pharmacological or physiological effect through local or systemic action, or both.

[0379] The terms “individual,” “host,” and “subject” are used interchangeably and refer to animals, including but not limited to: human and non-human primates, including apes and humans; rodents, including rats and mice; bovines; equines; sheep; felines; canines; and the like. “Mammal” means one or more members of any mammalian species, including, for example, canines, felines, equines, bovines, sheep, rodents, and primates, i.e., non-human primates and humans. Non-human animal models, i.e., mammals, non-human primates, rodents, rabbits, etc., can be used for experimental research.

[0380] "Patient" refers to a human subject.

[0381] The term "treating" or similar terms refers to achieving a desired pharmacological and / or physiological effect, such as reducing one or more symptoms of a disease or condition. Such effect may be preventative in terms of complete or partial prevention of the disease or its symptoms, and / or therapeutic in terms of partial or complete cure of the disease and / or adverse effects attributable to said disease. As used herein, "treating" encompasses any treatment of diseases in mammals, particularly humans, including: (a) preventing the occurrence of the disease or its symptoms in subjects who may be susceptible to the disease but have not yet been diagnosed with it (i.e., including diseases that may be related to or caused by a primary disease); (b) suppressing the disease, i.e., halting its development; and (c) alleviating the disease, even if the disease subsides (i.e., reducing pain or other symptoms).

[0382] The term “improvement” or any grammatical variations thereof (e.g., ameliorate / ameliorating / amelioration, etc.) includes, but is not limited to, delaying the onset of a disease or condition (e.g., diarrhea, bacteremia, and / or endotoxemia) or reducing the severity of a disease or condition. As used herein, improvement does not require the complete disappearance of symptoms.

[0383] The phrase "therapeutic effective amount" refers to the amount of a compound that, when administered to a mammal or other subject to treat a disease, condition, or ailment, would be sufficient to affect the treatment of said disease, condition, or ailment. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0384] Generally, references or descriptions of an element (such as hydrogen or H) are intended to include all isotopes of that element. For example, if the R group is defined to include hydrogen or H, it also includes deuterium and tritium. Therefore, including elements such as tritium, 14 C 32 P and 35 Compounds containing radioactive isotopes of S are within the scope of this invention. Based on the disclosure herein, procedures for inserting such markings into compounds of this invention will be apparent to those skilled in the art.

[0385] 4.7 Exemplary Implementation Scheme

[0386] As described herein, various embodiments of the compounds, compositions, and methods of the present invention are mentioned. The various embodiments described are intended to provide illustrative examples and should not be construed as descriptions of alternatives. Rather, it should be noted that the descriptions of the various embodiments provided herein may have overlapping scope. The embodiments discussed herein are illustrative only and are not intended to limit the scope of the invention.

[0387] Despite the appended claims, aspects of this disclosure are described by the following provisions.

[0388] Clause 1. Compounds of formula (I):

[0389]

[0390] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0391] L represents the connecting part;

[0392] R 1 and R 2 Independently selected from -H, optionally substituted (C1-C6)alkyl, optionally substituted (C3-C6)cycloalkyl, optionally substituted (C1-C6)alkoxy and optionally substituted (C2-C4)alkenyl;

[0393] Each R 13 Selected from -H, optionally substituted (C1-C6) alkyl and optionally substituted (C1-C6) alkoxy;

[0394] Each R 14Independently selected from -H, -CN, -OH, -NH2, -NO2, halogen, optionally substituted (C1-C5) alkyl, optionally substituted (C1-C5) haloalkyl, optionally substituted (C1-C5) alkoxy, optionally substituted (C3-C6) cycloalkyl and optionally substituted (C2-C4) alkenyl;

[0395] X 1 For N or CR 14 ;

[0396] X 2 and X 3 Independently selected from N and CR 13 ;

[0397] Y 1 and Y 2 Independently selected from N and C, where Y 1 and Y 2 One of them is N;

[0398] m is between 0 and 2; and

[0399] n is between 1 and 4.

[0400] Clause 2. The compound as described in Clause 1, wherein the compound is a compound of formula (Ia):

[0401]

[0402] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0403] Each R 13 Selected from -H, halogens, and optionally substituted (C1-C6)alkoxy groups; and

[0404] R 4 and each R 14 Independently selected from -H, -CN, -OH, -NH2, -NO2, halogen, optionally substituted (C1-C5) alkyl and optionally substituted (C1-C5) haloalkyl.

[0405] Clause 3. A compound as described in Clause 1 or 2, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -L- is -AB-, wherein:

[0406] -A- is selected from covalently bonded, optionally substituted (C6-C) 12 ) aryl or (C3-C 12 Heteroaryl, optionally substituted -(C3-C) 12Heteroaryl-(C1-C5)alkylene-, optionally substituted 3-membered to 6-membered heterocycles, -NHC(O)R 5 -、

[0407] and

[0408] -B- is selected from covalently bonded, optionally substituted 3- to 6-membered heterocycles, -NHC(O)R 5 -、-O-、-S-、-NR 11 -、

[0409] in:

[0410] R 11 H or optionally substituted (C1-C3) alkyl;

[0411] R 5 Selected from -OH, -(C1-C5)alkyl, -(C1-C5)haloalkyl and optionally substituted (C1-C5)alkylene;

[0412] R 6 and R 7 Each is independently -H or optionally substituted (C1-C3) alkyl; or R 6 and R 7 It is cyclically linked with the nitrogen atom to which it is attached to, to provide optionally substituted 3- to 6-membered heterocycles;

[0413] Z 1 Selected from O and S; and

[0414] At least one of -A- and -B- is not a covalent bond.

[0415] Clause 4. The compound as described in Clause 3, or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein -A- is

[0416] Clause 5. A compound as described in Clause 4, wherein the compound is a compound of formula (IIa) or a compound of formula (IIb):

[0417]

[0418] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0419] R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups; and

[0420] -B- is selected from covalent bonds and optionally substituted 3- to 6-membered heterocycles.

[0421] Clause 6. A compound as described in Clause 5, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 It is cyclically linked with the nitrogen atom to which it is attached to, to provide optionally substituted 3- to 6-membered heterocycles.

[0422] Clause 7. A compound as described in Clause 6, wherein the compound is a compound of formula (IIIa) or a compound of formula (IIIb):

[0423]

[0424] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0425] R 8 and R 9 Independently selected from -H and optionally substituted (C1-C3) alkyl groups, or R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles; and

[0426] Z 1 It can be O or S.

[0427] Clause 8. A compound as described in Clause 7, wherein B is covalently bonded and the compound is a compound of formula (IVa) or a compound of formula (IVb):

[0428]

[0429] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0430] Clause 9. The compound as described in Clause 7, or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein -B- is optionally a substituted 4- to 6-membered heterocycle.

[0431] Clause 10. A compound as described in Clause 9, wherein the compound is a compound of formula (Va) or a compound of formula (Vb):

[0432]

[0433] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein p and q are independently 1 or 2.

[0434] Clause 11. The compound as described in any one of Clauses 9 to 10, or its solvate, hydrate, prodrug, and / or stereoisomer, or its pharmaceutically acceptable salt, wherein -B- is

[0435]

[0436] Clause 12. The compound of any one of Clauses 7 to 11, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 8 It is -H.

[0437] Clause 13. The compound of any one of Clauses 7 to 12, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 9 It is -H.

[0438] Clause 14. The compound of any one of Clauses 7 to 12, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 9 It is an optionally substituted (C1-C3) alkyl group.

[0439] Clause 15. The compound of any one of Clauses 7 to 11, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is independently a optionally substituted (C1-C3) alkyl group.

[0440] Clause 16. The compound of any one of Clauses 7 to 15, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z 1 Let it be S.

[0441] Clause 17. A compound as described in Clause 16, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is selected from:

[0442]

[0443] Clause 18. The compound of any one of Clauses 7 to 11, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles.

[0444] Clause 19. The compound as described in Clause 18, or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein the optionally substituted 3- to 6-membered carbon ring or optionally substituted 3- to 6-membered heterocycle is selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted tetrahydrofuran.

[0445] Clause 20. A compound as described in Clause 18, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is selected from...

[0446]

[0447] Clause 21. The compound as described in Clause 5, wherein R 6 and R 7 Each of the following compounds is -H and is a compound of formula (VIa) or a compound of formula (VIb):

[0448]

[0449] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0450] Clause 22. A compound as described in Clause 21, wherein -B- is a bond and the compound is a compound of formula (VIIa) or a compound of formula (VIIb):

[0451]

[0452] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0453] Clause 23. A compound as described in Clause 3, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -B- is And R 11 It is -H or optionally substituted (C1-C3) alkyl.

[0454] Clause 24. A compound as described in Clause 23, wherein the compound is a compound of formula (VIIIa) or a compound of formula (VIIIb):

[0455]

[0456] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 3 Selected from -H and optionally substituted (C1-C5) alkoxy groups.

[0457] Clause 25. A compound as described in Clause 23 or 24, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is optionally a substituted 3- to 6-membered heterocycle.

[0458] Clause 26. A compound as described in Clause 25, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is

[0459]

[0460] in:

[0461] R 12 Selected from -H, -OH, optionally substituted (C1-C3) alkyl groups and optionally substituted (C1-C5) haloalkyl groups; and

[0462] r, s, and t are independently 0 or 1.

[0463] Clause 27. A compound as described in Clause 26, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is selected from:

[0464]

[0465] Clause 28. A compound as described in Clause 23 or 24, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is a covalent bond.

[0466] Clause 29. The compound as described in Clause 28, wherein the compound is a compound of formula (IXa) or a compound of formula (IXb):

[0467]

[0468] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0469] Clause 30. A compound as described in Clause 23 or 24, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is optionally substituted -(C3-C 12 ) heteroaryl-(C 1- C5) Alkylene-.

[0470] Clause 31. A compound as described in Clause 30, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is

[0471] Clause 32. The compound as described in Clause 3, or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein -A- is optionally a substituted 3- to 6-membered heterocycle.

[0472] Clause 33. A compound as described in Clause 32, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is

[0473]

[0474] in:

[0475] R 12 Selected from -H, -OH, optionally substituted (C1-C3) alkyl groups and optionally substituted (C1-C5) haloalkyl groups; and

[0476] r, s, and t are independently 0 or 1.

[0477] Clause 34. A compound as described in Clause 33, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is selected from...

[0478]

[0479] Clause 35. A compound as described in Clause 33, wherein the compound is a compound of formula (Xa) or a compound of formula (Xb):

[0480]

[0481] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0482] R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups; and

[0483] R 12 It is -H or optionally substituted (C1-C3) alkyl.

[0484] Clause 36. A compound as described in Clause 35, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 12 It is an ethyl group.

[0485] Clause 37. The compound of any one of Clauses 32 to 36, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein -B- is -O-, -S-, -NH-, -SO2- or -NHSO2-.

[0486] Clause 38. A compound as described in Clause 3, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is -NHC(O)R 5 -

[0487] Clause 39. A compound as described in Clause 38, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 for

[0488] Clause 40. The compound as described in Clause 39, wherein the compound is a compound of formula (XIa) or a compound of formula (XIb):

[0489]

[0490] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof, wherein R 3 Selected from -H and optionally substituted (C1-C6) alkoxy groups.

[0491] Clause 41. The compound of any one of Clauses 38 to 40, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein -B- is selected from -O-, -S-, -SO2- and -NHSO2-.

[0492] Clause 42. The compound of any one of Clauses 1 to 41, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is an optionally substituted (C1-C6) alkyl group.

[0493] Clause 43. A compound as described in Clause 42, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3.

[0494] Clause 44. The compound as described in any one of Clauses 1 to 43, wherein R 2 It is an optionally substituted (C1-C6) alkyl group.

[0495] Clause 45. A compound as described in Clause 44, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 It is n-propyl.

[0496] Clause 46. The compound of any one of Clauses 1 to 45, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3It is optionally substituted (C1-C3)alkoxy group.

[0497] Clause 47. A compound as described in Clause 46, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It is an ethoxylated compound.

[0498] Article 48. The compound of any one of Articles 1 to 47, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein each R 14 and R 4 It is optionally substituted (C1-C5) haloalkyl or halogen.

[0499] Clause 49. A compound as described in Clause 48, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R 14 and R 4 It can be -CF3, F, or -Cl.

[0500] Clause 50. The compound of any one of Clauses 1 to 49, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein X 1 X 2 and X 3 Each is CH.

[0501] Clause 51. The compound of any one of Clauses 1 to 49, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

[0502] Clause 52. A compound as described in Clause 51, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 2 and X 3 Each is CH.

[0503] Clause 53. The compound of any one of Clauses 1 to 49, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein X 2 Let N be the number of elements in the array.

[0504] Clause 54. A compound as described in Clause 53, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 3 Each is CH.

[0505] Clause 55. The compound of any one of Clauses 1 to 49, or its solvate, hydrate, prodrug and / or stereoisomer, or pharmaceutically acceptable salt thereof, wherein X 3 Let N be the number of elements in the array.

[0506] Clause 56. A compound as described in Clause 55, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Each is CH.

[0507] Clause 57. A compound as described in Clause 8, wherein the compound is a compound of formula (IVc) or a compound of formula (IVd):

[0508]

[0509] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof; wherein R 14 It can be -H or a halogen (e.g., -F).

[0510] Clause 58. A compound as described in Clause 57, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is independently H or optionally substituted (C1-C3) alkyl (e.g., -CH3).

[0511] Clause 59. The compound as described in Clause 58, wherein said compound is selected from...

[0512]

[0513] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0514] Article 60. The compound as described in Article 58, wherein

[0515] for

[0516] Clause 61. A compound as described in Clause 60, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from...

[0517]

[0518] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0519] Clause 62. A compound as described in Clause 57, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or 4- or 5-membered heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0520] Clause 63. A compound as described in Clause 62, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein for

[0521] Article 64. The compound as described in Article 63, wherein the compound is selected from:

[0522]

[0523] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0524] Article 65. The compound of any one of Articles 60 to 64, wherein the compound is selected from:

[0525]

[0526] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0527] Clause 66. A compound as described in Clause 62, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0528] for

[0529] Article 67. The compound as described in Article 66, wherein the compound is selected from:

[0530]

[0531] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0532] Clause 68. A compound as described in Clause 62, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0533] for

[0534] Article 69. The compound as described in Article 68, wherein the compound is selected from:

[0535]

[0536] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0537] Article 70. A compound as described in Article 8, wherein the compound is a compound of formula (IVc):

[0538]

[0539] Or its pharmaceutically acceptable salt, wherein:

[0540] X 1 For CH or N;

[0541] R 14 It is -H or halogen; and

[0542] R 8 and R 9 Each is independently H or (C1-C3) alkyl (e.g., R 8 and R 9 Each is -CH3), or R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 5-membered carbon rings or optionally substituted 4- or 5-membered heterocycles (e.g., cyclopentane, cyclobutane, oxetane, or tetrahydrofuran).

[0543] Article 71. The compound as described in Article 70, wherein the compound is selected from:

[0544]

[0545] Or its pharmaceutically acceptable salt.

[0546] Clause 72. A compound as described in Clause 8, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X 2 For N and X 3 For CH, or X 2 For CH and X 3 Let N be the number of elements in the array.

[0547] Clause 73. A compound as described in Clause 72, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is an optionally substituted (C1-C3) alkyl group (e.g., -CH3).

[0548] Article 74. The compound as described in Article 73, wherein the compound is selected from:

[0549]

[0550] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0551] Clause 75. A compound as described in Clause 72, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0552] Clause 76. The compound as described in Clause 75, wherein said compound is

[0553]

[0554] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0555] Clause 77. The compound as described in Clause 10, wherein the compound is a compound of formula (Vc):

[0556]

[0557] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0558] Clause 78. A compound as described in Clause 77, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is an optionally substituted (C1-C3) alkyl group (e.g., -CH3).

[0559] Article 79. The compound as described in Article 78, wherein said compound is selected from:

[0560]

[0561] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0562] Clause 80. A compound as described in Clause 77, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 It is cyclically linked with the attached carbon atom to provide optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles (e.g., 4- or 5-membered carbon rings or 4- or 5-membered heterocycles), said optionally substituted 3- to 6-membered carbon rings or optionally substituted 3- to 6-membered heterocycles selected from optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted tetrahydrofuran.

[0563] Article 81. The compound as described in Article 80, wherein the compound is selected from:

[0564]

[0565] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0566] Article 82. The compound as described in Article 22, wherein the compound is a compound of formula (VIIc):

[0567]

[0568] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0569] Clause 83. The compound as described in Clause 82, wherein the compound is selected from:

[0570]

[0571] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0572] Clause 84. The compound as described in Clause 24, wherein the compound is a compound of formula (VIIIc):

[0573]

[0574] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0575] Clause 85. A compound as described in Clause 84, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -A- is

[0576]

[0577] in:

[0578] R 12 Selected from -H, -OH, optionally substituted (C1-C3) alkyl groups and optionally substituted (C1-C5) haloalkyl groups; and

[0579] r, s, and t are independently 0 or 1.

[0580] Article 86. The compound as described in Article 85, wherein -A- is selected from:

[0581]

[0582] Clause 87. A compound as described in Clause 85 or 86, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3.

[0583] Clause 88. The compound as described in Clause 87, wherein said compound is selected from:

[0584]

[0585] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0586] Clause 89. A compound as described in Clause 29, wherein the compound is a compound of formula (IXc) or a compound of formula (IXd):

[0587]

[0588] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0589] Clause 90. A compound as described in Clause 89, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3- or -Cl.

[0590] Article 91. The compound as described in Article 90, wherein the compound is selected from:

[0591]

[0592] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0593] Clause 92. The compound as described in Clause 24, wherein the compound is a compound of formula (VIIId):

[0594]

[0595] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0596] Clause 93. A compound as described in Clause 92, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl.

[0597] Clause 94. The compound as described in Clause 92 or 93, wherein -A- is optionally substituted -(C3-C) 12 )heteroaryl-(C1-C5)alkylene-.

[0598] Clause 95. The compound as described in Clause 94, wherein said compound is

[0599]

[0600] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0601] Clause 96. The compound as described in Clause 41, wherein the compound is a compound of formula (XIc):

[0602]

[0603] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0604] Clause 97. The compound as described in Clause 96, wherein the compound is selected from:

[0605]

[0606] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0607] Clause 98. The compound as described in Clause 36, wherein the compound is a compound of formula (Xc):

[0608]

[0609] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0610] Clause 99. A compound as described in Clause 98, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein -B- is selected from -NH-, -O-, -S-, and -SO2-.

[0611] Article 100. The compound as described in Article 99, wherein the compound is selected from:

[0612]

[0613] Or its solvates, hydrates, prodrugs and / or stereoisomers, or pharmaceutically acceptable salts thereof.

[0614] Article 101. A compound as described in Article 1, wherein the compound is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0615] Article 102. A pharmaceutical composition comprising:

[0616] The compound as described in any one of paragraphs 1 to 101, or its solvate, hydrate, prodrug and / or stereoisomer, or a pharmaceutically acceptable salt thereof; and

[0617] At least one pharmaceutically acceptable excipient.

[0618] Article 103. A compound for use in regulating androgen receptors and / or inhibiting PDE-5, wherein the compound is a compound as described in any one of Articles 1 to 101, or a solvate, hydrate, prodrug, and / or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0619] Article 104. A pharmaceutical composition for use in regulating androgen receptors and / or inhibiting PDE-5, wherein the pharmaceutical composition is as described in Article 102.

[0620] Article 105. A method for modulating androgen receptors and / or inhibiting PDE-5, the method comprising contacting a biological system comprising the androgen receptor and / or the PDE-5 with an effective amount of a compound as described in any one of Articles 1 to 100, or a solvate, hydrate, prodrug, and / or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0621] Article 106. The method of Article 105, wherein the biological system is contained in an in vitro sample.

[0622] Article 107. The method as described in Article 105 or 106, wherein the method includes inhibiting androgen receptors.

[0623] Article 108. The method of any one of Articles 105 to 107, wherein the method includes suppressing PDE-5.

[0624] 5. Examples

[0625] The following embodiments are provided to illustrate the present invention and are not intended to limit the scope of the invention in any way. Any functionally equivalent methods are within the scope of the present invention. Based on the foregoing description and drawings, various modifications to the present invention, in addition to those described herein, will become apparent to those skilled in the art. Such modifications fall within the scope of the appended claims.

[0626] Unless otherwise stated, all temperatures are in degrees Celsius. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental error and bias should be allowed.

[0627] In the following embodiments, if no abbreviation is defined, it has its generally accepted meaning.

[0628] aq. = containing water

[0629] LC-MS = Liquid Chromatography-Mass Spectrometry

[0630] MS = Mass Spectrometry

[0631] THF = Tetrahydrofuran

[0632] NaHCO3 = Sodium bicarbonate

[0633] Cs₂CO₃ = Cesium carbonate

[0634] NaH = Sodium hydride

[0635] o / n = overnight

[0636] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-Oxyhexafluorophosphate

[0637] rt = room temperature

[0638] LAH = Lithium Aluminum Hydrogen

[0639] DCM = dichloromethane

[0640] DMF = dimethylformamide

[0641] DMSO = dimethyl sulfoxide

[0642] DIEA = diisopropylethylamine

[0643] equiv. = equivalent

[0644] EtOAc or EA = ethyl acetate

[0645] EtOH = ethanol

[0646] EDCI = 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0647] g = grams

[0648] h = hours

[0649] HCl = hydrochloric acid

[0650] HPLC = High Performance Liquid Chromatography

[0651] HOAc = Acetic acid

[0652] HOBT = Hydroxybenzotriazole

[0653] M = mole

[0654] MeOH = methanol

[0655] mg = milligram

[0656] mL = milliliters

[0657] mmol = millimole

[0658] mp = melting point

[0659] m / z = mass-to-charge ratio

[0660] NaCl = Sodium chloride

[0661] Na₂CO₃ = Sodium carbonate

[0662] NMR = Nuclear Magnetic Resonance

[0663] NaOH = Sodium hydroxide

[0664] Na₂SO₄ = Sodium sulfate

[0665] ppm = parts per million

[0666] TFA = Trifluoroacetic acid

[0667] TLC = Thin Layer Chromatography

[0668] TsOH = p-Toluenesulfonic acid

[0669] UV = Ultraviolet light

[0670] wt% = weight percentage

[0671] μM = micromolar

[0672] General Synthesis Method

[0673] The final compound was confirmed by HPLC / MS analysis, and its purity was determined to be >90% by weight. 1 H and 13 C10 NMR spectra were recorded in CDCl3 (residual internal standard CHCl3 = δ 7.26), DMSO-d6 (residual internal standard CD3SOCD2H = δ 2.50), methanol-d4 (residual internal standard CD2HOD = δ 3.31), or acetone-d6 (residual internal standard CD3COCD2H = δ 2.05). Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are in Hertz (Hz). Spin multiplicity is reported as s = singlet, bs = broad singlet, bm = broad multiply, d = doublet, t = triplet, q = quartet, p = quintet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dt = doublet of triplet, td = triplet of doublet, and m = multiply.

[0674] HPLC-MS analysis was performed using gradient elution. Medium-pressure liquid chromatography (MPLC) was performed using silica gel columns in both normal and reversed phases.

[0675] Example 1 - Synthesis of intermediate compounds

[0676] This document describes in detail the synthesis and characterization of several exemplary intermediate compounds or synthons that can be used to prepare a variety of the final compounds of this disclosure. It should be understood that combining the described synthetic methods and intermediate compounds with commonly available starting materials can readily adapt to the synthesis of a variety of compounds of formulas (I)-(XIc), including any of the compounds in Table 1.

[0677] Synthetic intermediate compound 51

[0678]

[0679] Step 1:

[0680] Fe (391 mg, 7.00 mmol) and NH₄Cl (748 mg, 13.99 mmol) were added to a solution of 5-(2-ethoxy-5-nitrophenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (500 mg, 1.40 mmol) in EtOH (10 mL) and H₂O (2 mL), and the reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (430 mg, 93.88% yield) as a yellow solid. MS: m / z = 328.2 (M+1, ESI+).

[0681] Step 2:

[0682] TEA (399 mg, 3.94 mmol) was added to a solution of 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (430 mg, 1.31 mmol) and 2-bromo-2-methylpropionic acid (658 mg, 3.94 mmol) in i-PrOH (10 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)-2-methylpropionic acid (400 mg, 73.65% yield), as a white solid. MS: m / z = 414.3 (M+1, ESI+).

[0683] Step 3:

[0684] SOCl2 (1 g, 8.41 mmol) was added to a solution of 2-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)-2-methylpropionic acid (370 mg, 894.87 μmol) in MeOH (10 mL), and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated, and the residue was poured into water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound methyl 51,2-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)-2-methylpropionate (150 mg, 39.27% ​​yield), as a white solid. MS: m / z = 428.4 (M+1, ESI+).

[0685] Synthetic intermediate compound 52

[0686]

[0687] Step 1:

[0688] A mixture of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (5 g, 12.17 mmol) in H₂O (50 mL) was stirred at 70 °C for 3 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid (4.45 g, 93.18% yield) as a white solid. MS: m / z = 393.1 (M+1, ESI+).

[0689] Step 2:

[0690] A mixture of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonic acid (4.45 g, 11.34 mmol) was added fractionally to fuming nitric acid (20 mL) and DCM (20 mL) at -50 °C. The reaction mixture was then heated to room temperature and stirred for 2 h. The reaction mixture was poured into ice water (100 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-(2-ethoxy-5-nitrophenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (1.05 g, 25.91% yield) as a yellow solid. MS: m / z = 358.2 (M+1, ESI+).

[0691] Step 3:

[0692] To a solution of 2-(2-ethoxy-5-nitrophenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (1.10 g, 3.08 mmol) in EtOH (10 mL) and H₂O (2 mL), Fe (516 mg, 9.23 mmol) and NH₄Cl (540 mg, 9.23 mmol) were added, and the reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (980 mg, 97.25% yield) as a yellow solid. MS: m / z = 328.2 (M+1, ESI+).

[0693] Step 4:

[0694] TEA (909 mg, 8.98 mmol) was added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (980 mg, 2.99 mmol) and 2-bromo-2-methylpropionic acid (1 g, 5.99 mmol) in i-PrOH (10 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionic acid (430 mg, 34.74% yield), as a yellow solid. MS: m / z = 414.2 (M+1, ESI+).

[0695] Step 5:

[0696] SOCl2 (259 mg, 2.18 mmol) was added to a solution of 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionic acid (300 mg, 725.57 μmol) in MeOH (10 mL), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated, and the residue was poured into water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound methyl 52,2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionate (278 mg, 89.63% yield), as a yellow solid. MS: m / z = 428.3 (M+1, ESI+).

[0697] Synthetic intermediate compound 53

[0698]

[0699] Step 1:

[0700] TEA (2.32 g, 22.91 mmol) was added to a solution of 5-(5-amino-2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2.5 g, 7.64 mmol) and 1-bromocyclobutane-1-carboxylic acid (2.05 g, 11.45 mmol) in i-PrOH (30 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give 1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)cyclobutane-1-carboxylic acid (1.5 g, 46.17% yield) as a yellow solid. MS: m / z = 426.2 (M+1, ESI+).

[0701] Step 2:

[0702] SOCl2 (2.10 g, 17.63 mmol) was added to a solution of 1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)cyclobutane-1-carboxylic acid (1.5 g, 3.53 mmol) in MeOH (30 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated, and the residue was poured into water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 53,1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)cyclobutane-1-carboxylic acid methyl ester (1 g, 64.51% yield), as a yellow solid. MS: m / z = 440.2 (M+1, ESI+).

[0703] Synthetic intermediate compound 54

[0704]

[0705] Step 1:

[0706] TEA (2.97 g, 29.32 mmol) was added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (3.2 g, 9.77 mmol) and 1-bromocyclobutane-1-carboxylic acid (3.5 g, 19.55 mmol) in i-PrOH (40 mL), and the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylic acid (2 g, 48.09% yield) as a white solid. MS: m / z = 426.1 (M+1, ESI+).

[0707] Step 2:

[0708] SOCl2 (1.68 g, 14.10 mmol) was added to a solution of 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylic acid (2 g, 4.70 mmol) in MeOH (30 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated, and the residue was poured into water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 54,1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylic acid methyl ester (1 g, 48.40% yield), as a white solid. MS: m / z = 440.2 (M+1, ESI+).

[0709] Synthetic intermediate compound 55

[0710]

[0711] Step 1:

[0712] TEA (464 mg, 4.58 mmol) was added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (500 mg, 1.53 mmol) and 2-bromoacetic acid (255 mg, 1.83 mmol) in i-PrOH (10 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to give (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)glycine (400 mg, 67.95% yield) as a yellow solid. MS: m / z = 386.1 (M+1, ESI+).

[0713] Step 2:

[0714] A solution of (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)glycine (400 mg, 1.04 mmol) in MeOH (10 mL) was mixed with SOCl2 (617.36 mg, 5.19 mmol), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 55, methyl (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)glycine (350 mg, 84.43% yield), as a yellow oil. MS: m / z = 400.1 (M+1, ESI+).

[0715] Synthetic intermediate compound 56

[0716]

[0717] Step 1:

[0718] TEA (464 mg, 4.58 mmol) was added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (500 mg, 1.53 mmol) and 2-bromopropionic acid (280 mg, 1.83 mmol) in i-PrOH (10 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography to give (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)alanine (360 mg, 59.01% yield) as a yellow solid. MS: m / z = 400.1 (M+1, ESI+).

[0719] Step 2:

[0720] A solution of (360 mg, 901 μmol) of (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)alanine in MeOH (8 mL) was added to SOCl2 (536 mg, 4.51 mmol), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 56, (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)alanine methyl ester (310 mg, 83.19% yield), as a yellow oil. MS: m / z = 414.1 (M+1, ESI+).

[0721] Synthetic intermediate compound 57

[0722]

[0723] TMSCN (453.60 mg, 4.58 mmol) and ZnCl2 (83.08 mg, 610.91 μmol) were added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (1 g, 3.05 mmol) and dihydrofuran-3(2H)-one (525.93 mg, 6.11 mmol) in dioxane (30 mL). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (80 mL). It was extracted with EA (30 mL × 3), washed with brine (80 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give intermediate compound 57,3-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)tetrahydrofuran-3-carboxynitrile (1.09 g, 84.46% yield), as a yellow solid. MS: m / z = 423.2 (M+1, ESI+).

[0724] Synthetic intermediate compound 58

[0725]

[0726] Step 1:

[0727] Br2 (27.56 g, 172.24 mmol) was added fractionally to a mixture of cyclopentanecarboxylic acid (10 g, 86.12 mmol) and red P (1.33 g, 43.06 mmol) at 0 °C, and the reaction mixture was stirred at 60 °C for 6 h. The reaction mixture was diluted with EA (200 mL) and washed with brine (100 mL × 2). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-bromocyclopentane-1-carboxylic acid (12 g, crude product) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),2.31-2.22(m,2H),2.21-2.11(m,2H),1.89-1.83(m,2H),1.78-1.72(m,2H).

[0728] Step 2:

[0729] TEA (741.82 mg, 7.33 mmol) was added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (800 mg, 2.44 mmol) and 1-bromocyclopentane-1-carboxylic acid (943.43 mg, 4.89 mmol) in i-PrOH (15 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EA (40 mL × 3), washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxylic acid (336 mg, 31.29% yield), as a yellow solid. MS: m / z = 440.1 (M+1, ESI+).

[0730] Step 3:

[0731] SOCl2 (2 mL) was added fractionally to a solution of 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxylic acid (336 mg, 764.49 μmol) in MeOH (8 mL), and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated, and the residue was poured into water (30 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate compound 58,1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxylic acid methyl ester (140 mg, 40.38% yield), as a yellow solid. MS: m / z = 454.2 (M+1, ESI+).

[0732] Synthetic intermediate compound 59

[0733]

[0734] Step 1:

[0735] NBS (27.3 g, 153.5 mmol) was added fractionally to a solution of 2-fluoro-3-(trifluoromethyl)aniline (25 g, 139.6 mmol) in DMF (200 mL), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (800 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-bromo-2-fluoro-3-(trifluoromethyl)aniline (27.5 g, 76.6% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ7.32(dd,1H),6.94(t,1H),5.81(br s,2H).

[0736] Step 2:

[0737] Ac₂O (30 g, 294 mmol) was added to a solution of 27.5 g (10⁷ g) of 4-bromo-2-fluoro-3-(trifluoromethyl)aniline in 200 mL of THF, and the mixture was stirred at 60 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give N-(4-bromo-2-fluoro-3-(trifluoromethyl)phenyl)acetamide (30 g, 93.4% yield) as a yellow solid. MS: m / z = 301.8 (M+1, ESI+).

[0738] Step 3:

[0739] CuCN (17.8 g, 200 mmol) was added to a solution of N-(4-bromo-2-fluoro-3-(trifluoromethyl)phenyl)acetamide (30 g, 100 mmol) in DMF (100 mL), and the mixture was stirred at 150 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (800 mL) and extracted with EA (200 mL × 3). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)acetamide (19 g, 77% yield) as a yellow solid. MS: m / z = 246.9 (M+1, ESI+).

[0740] Step 4:

[0741] 5 M HCl (100 mL) was added to a solution of N-(4-cyano-2-fluoro-3-(trifluoromethyl)phenyl)acetamide (19 g, 77 mmol) in EtOH (100 mL), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-amino-3-fluoro-2-(trifluoromethyl)benzonitrile (12.8 g, 80% yield) as a yellow solid. MS: m / z = 205.1 (M+1, ESI+).

[0742] Step 5:

[0743] 4-Amino-3-fluoro-2-(trifluoromethyl)benzonitrile (7.2 g, 35.3 mmol) was added fractionally to a solution of triphosgene (20.3 g, 176.5 mmol) in H₂O (200 mL), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into ice water (200 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give intermediate 59, 3-fluoro-4-isothiocyano-2-(trifluoromethyl)benzonitrile (5.5 g, 62.8% yield), as a colorless oil.

[0744] Example 2 - Synthesis of the final compound

[0745] Details of the synthesis and characterization of several exemplary compounds of this disclosure are described herein. It should be understood that the described synthetic methods and substances are readily adaptable to the synthesis of compounds of various formulas (I)-(XIc), including any of the compounds in Table 1.

[0746] Synthetic compound 1

[0747]

[0748] NaH (29 mg, 730 μmol, 60% purity) was added to a solution of 4-amino-2-(trifluoromethyl)benzonitrile (68 mg, 365 μmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride (100 mg, 243 μmol) was added to the above solution. The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 1, N-(4-cyano-3-(trifluoromethyl)phenyl)-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide (75 mg, 54.97% yield), as a white solid. 1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.07-7.97(m,3H),7.62-7.53(m,2H),7.34(d,1H),4.19-4.14(m,5 H), 2.76 (t, 2H), 1.77-1.68 (m, 2H), 1.31 (t, 3H), 0.92 (t, 3H); MS: m / z=561.4 (M+1, ESI+); HRMS: 561.1527.

[0749] Synthetic compound 5

[0750]

[0751] NaH (55 mg, 1.3 mmol, 60% purity) was added to a solution of 5-amino-3-(trifluoromethyl)pyridinecarboxynitrile (170 mg, 0.9 mmol) in DMF (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride (300 mg, 0.9 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 5,N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide (60 mg, 11.6% yield), as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),8.65(s,1H),8.07-8.00(m,2H),7.90(s,1H),7.34(d,1H),4.19-4.16( m, 5H), 2.77 (t, 2H), 1.77-1.71 (m, 2H), 1.32 (t, 3H), 0.94 (t, 3H); MS: m / z=562.0 (M+1, ESI+); HRMS: 562.1478.

[0752] Synthetic compound 6

[0753]

[0754] NaH (55 mg, 1.3 mmol, 60% purity) was added to a solution of 5-amino-3-(trifluoromethyl)pyridinecarboxynitrile (170 mg, 0.9 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (300 mg, 0.9 mmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 6,N-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (50 mg, 10.0% yield), as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.68(d,1H),8.08-8.05(m,2H),7.90(s,1H),7.37(d,1H),4.19(q,2H),2. 83 (t, 2H), 2.49 (s, 2H), 1.77-1.71 (m, 2H), 1.31 (t, 3H), 0.93 (t, 3H); MS: m / z=562.0 (M+1, ESI+); HRMS: 562.1478.

[0755] Synthetic compounds 7

[0756]

[0757] NaH (29 mg, 730 μmol, 60% purity) was added to a solution of 4-amino-2-(trifluoromethyl)benzonitrile (68 mg, 365 μmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (100 mg, 243 μmol) was added to the above solution. The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 7,N-(4-cyano-3-(trifluoromethyl)phenyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (60 mg, 43.98% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.10-8.06(m,3H),7.71-7.63(m,2H),7.41(d,1H),4.21(q,2H),2.87( t, 2H), 2.52 (s, 3H), 1.80-1.74 (m, 2H), 1.33 (t, 3H), 0.95 (t, 3H); MS: m / z=561.3 (M+1, ESI+); HRMS: 561.1525.

[0758] Synthetic compound 8

[0759]

[0760] NaH (44 mg, 1.10 mmol, 60% purity) was added to a solution of 4-amino-2-chlorobenzonitrile (84 mg, 548 μmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride (150 mg, 365 μmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 8, N-(3-chloro-4-cyanophenyl)-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide (90 mg, 46.78% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.14(s,1H),11.33(s,1H),8.04-7.97(m,2H),7.85(d,1H),7.37-7.33(m,2H),7.26(dd,1H),4 .21-4.16(m,5H),2.78(t,2H),1.80-1.70(m,2H),1.32(t,3H),0.95(t,3H); MS: m / z=527.3(M+1,ESI+); HRMS: 527.1263.

[0761] Synthetic compound 9

[0762]

[0763] NaH (44 mg, 1.10 mmol, 60% purity) was added to a solution of 4-amino-2-chlorobenzonitrile (84 mg, 548 μmol) in DMF (10 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, followed by the addition of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (150 mg, 365 μmol). The mixture was stirred at 25 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 9, N-(3-chloro-4-cyanophenyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (85 mg, 44.18% yield), as a white solid. 1 HNMR(400MHz,DMSO-d6)δ11.64(s,1H),8.03-8.00(m,2H),7.85(d,1H),7.38-7.35(m,2H),7.26(d,1H),4.18(q,2H) ,2.83(t,2H),2.48(s,3H),1.77-1.72(m,2H),1.31(t,3H),0.94(t,3H); MS: m / z=527.3(M+1,ESI+); HRMS: 527.1262.

[0764] Synthetic compound 10

[0765]

[0766] Step 1:

[0767] Add Dess-Martin (32.42 g, 76.45 mmol) to a solution of (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (12.5 g, 50.96 mmol) in DCM (300 mL), and stir the reaction mixture at 25 °C for 3 h. Pour the reaction mixture into water (500 mL) and extract with DCM (100 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give (R)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (10 g, 80.66% yield) as a white solid. MS: m / z = 144.2 (M-100+1, ESI+).

[0768] Step 2:

[0769] Phenylmethylamine (5.29 g, 49.33 mmol) was added to a solution of (R)-4-oxopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (10 g, 41.11 mmol) in DCM (300 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. Then, NaBH(OAc)3 (13.07 g, 61.66 mmol) was added to the above reaction mixture, and the mixture was stirred again at 25 °C for 3 h. The reaction mixture was poured into water (500 mL) and extracted with DCM (100 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give (2R)-4-(phenylmethylamino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (10.5 g, 76.38% yield) as a yellow oil. MS: m / z = 335.1 (M+1, ESI+).

[0770] Step 3:

[0771] Pd / C (0.8 g) was added to a solution of (2R)-4-(benzylamino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (7.5 g, 22.46 mmol) in MeOH (80 mL), and the reaction mixture was stirred at 25 °C under H2 for 6 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (2R)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)-2-methyl ester (4.0 g, 76.38% yield) as a yellow oil. MS: m / z = 245.2 (M+1, ESI+).

[0772] Step 4:

[0773] TEA (6.35 g, 49.12 mmol) was added to a solution of (2R)-4-aminopyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (4 g, 16.37 mmol) and CbzCl (4.90 g, 19.65 mmol) in DCM (100 mL), and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into water (150 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give (2R)-4-(((benzyloxy)carbonyl)amino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (5.4 g, 87.15% yield) as a yellow oil. MS: m / z = 279.1 (M-100+1, ESI+).

[0774] Step 5:

[0775] LAH (813 mg, 21.40 mmol) was added fractionally to a solution of (2R)-4-(((benzoxy)carbonyl)amino)pyrrolidine-1,2-dicarboxylic acid 1-(tert-butyl)2-methyl ester (5.4 g, 14.27 mmol) in THF (80 mL) at 0 °C, followed by stirring of the reaction mixture at 25 °C for 3 h. The reaction mixture was slowly poured into ice water (150 mL) and extracted with EA (100 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give (2R)-4-(((benzoxy)carbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.9 g, 58.00% yield) as a colorless oil. MS: m / z = 251.1 (M-100+1, ESI+).

[0776] Step 6:

[0777] To a solution of (2R)-4-(((benzoxy)carbonyl)amino)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (4.5 g, 12.84 mmol) in DCM (30 mL), Dysmart (5.45 g, 12.84 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (30 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give (2R)-4-(((benzoxy)carbonyl)amino)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.9 g, 64.82% yield) as a colorless oil. MS: m / z = 249.2 (M-100+1, ESI+).

[0778] Step 7:

[0779] A solution of (2R)-4-(((benzoxy)carbonyl)amino)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (2.9 g, 8.32 mmol) in THF (20 mL) was mixed with TMSCF3 (1.54 g, 10.82 mmol) and CsF (127 mg, 832 μmol), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give (2R)-4-(((benzoxy)carbonyl)amino)-2-((S)-2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.35 g, 57.55% yield) as a yellow oil. MS: m / z=391.2(M-100+1,ESI+).

[0780] Step 8:

[0781] To a solution of (2R)-4-(((benzoxy)carbonyl)amino)-2-((S)-2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (2.35 g, 4.79 mmol) in DCM (5 mL), 3 M HCl / EA (5 mL) was added, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into aq. NaHCO3 (40 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to give ((5R)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-3-yl)carbamate (1.50 g, 4.71 mmol, 98.38% yield) as a brown oil. MS: m / z = 319.0 (M+1, ESI+).

[0782] Step 9:

[0783] To a solution of ((5R)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidone-3-yl)carbamate (1.50 g, 4.71 mmol) and 4-bromo-2-(trifluoromethyl)benzonitrile (1.77 g, 7.07 mmol) in toluene (25 mL), K₂CO₃ (1.95 g, 14.14 mmol) and RuPhosPd-G₂ (183.02 mg, 235.63 μmol) were added, and the reaction mixture was stirred in N₂ at 110 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give methyl carbamate ((5R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-3-yl)carbamate (869 mg, 37.83% yield) as a yellow oil. MS: m / z = 488.1 (M+1, ESI+).

[0784] Step 10:

[0785] TMSI (1.07 g, 5.35 mmol) was added to a solution of ((5R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidone-3-yl)carbamate (869 mg, 1.78 mmol) in MeCN (10 mL), and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with EA (40 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-((2R)-4-amino-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (70 mg, 11.11% yield) as a grayish-white solid. 1 H NMR(400MHz,MeOD)δ7.81(d,1H),7.03(d,1H),6.97(dd,1H),4.59(d,1H),4.38(q,1H),4.12(t,1 H), 3.88-3.83 (m, 1H), 3.72 (dd, 1H), 2.73-2.65 (m, 1H), 2.48 (d, 1H); MS: m / z=354.0 (M+1, ESI+).

[0786] Step 11:

[0787] To a solution of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (70 mg, 170 μmol) in THF (5 mL), 4-((2R)-4-amino-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (60 mg, 170 μmol) and TEA (51.50 mg, 508.91 μmol) were added, and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into water (20 mL) and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 10, N-((5R)-1-(4-cyano-3-(trifluoromethyl)phenyl)-5-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidine-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (15 mg, 12.15% yield), as a white solid. 1H NMR(400MHz,DMSO-d6)δ7.98-7.95(m,2H),7.83(d,1H),7.36(d,1H),6.86-6.83(m,2H),4.34-4.26(m,2H),4.19(q,2H),3.74-3.64(m,2H),3.17 (t,1H),2.78(t,2H),2.47(s,3H),2.23-2.18(m,1H),2.12-2.07(m,1H), 1.75-1.65(m,2H),1.32(t,3H),0.88(t,3H); MS: m / z=728.3(M+1,ESI+).

[0788] Synthetic compound 11

[0789]

[0790] K₂CO₃ (168 mg, 1.22 mmol) was added to a solution of 4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl chloride (250 mg, 608.46 μmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (190 mg, 730.15 μmol) in MeCN (10 mL), and the reaction mixture was stirred at 25 °C for 16 h. The residue was filtered and concentrated under reduced pressure, and purified by preparative HPLC to give compound 11, (S)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl)-4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide (102 mg, 26.35% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),7.94-7.90(m,3H),7.82-7.76(m,2H),7.68(s,2H),7.11(d,1H),6.76(s,1H),4.17-4.06(m,7 H), 3.71 (s, 1H), 2.78 (s, 2H), 1.76-1.75 (m, 2H), 1.34 (s, 3H), 1.07 (s, 3H), 0.95 (s, 3H); MS: m / z=635.2 (M+1, ESI+); HRMS: 635.1952.

[0791] Synthetic compound 13

[0792]

[0793] Step 1:

[0794] 4-Amino-2-(trifluoromethyl)benzonitrile (4.5 g, 24.18 mmol) was added fractionally to a solution of triphosgene (8.34 g, 72.53 mmol) in H₂O (50 mL), and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into ice water (100 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-isothiocyano-2-(trifluoromethyl)benzonitrile (1.02 g, 18.49% yield) as a white solid.

[0795] Step 2:

[0796] To a solution of compound 51, namely methyl 2-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)-2-methylpropionate (150 mg, 350.88 μmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (160 mg, 702 μmol) in DMSO (10 mL), isopropyl acetate (3 g, 29.37 mmol) was added, and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 13,4-(3-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-2-(trifluoromethyl)benzonitrile (110 mg, 50.27% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.40(d,1H),8.31(s,1H),8.10(dd,1H),7.62(d,1H),7.50(dd,1H),7.34(d,1H),4.20(q,2H ), 4.16 (s, 3H), 2.77 (t, 2H), 1.77-1.71 (m, 2H), 1.54 (s, 6H), 1.36 (t, 3H), 0.93 (t, 3H); MS: m / z=624.2 (M+1, ESI+); HRMS: 624.1998.

[0797] Synthetic compound 18

[0798]

[0799] Step 1:

[0800] 4-Amino-2-(trifluoromethyl)benzonitrile (4.5 g, 24.18 mmol) was added fractionally to a solution of triphosgene (8.34 g, 72.53 mmol) in H₂O (50 mL), and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into ice water (100 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give 4-isothiocyano-2-(trifluoromethyl)benzonitrile (1.02 g, 18.49% yield) as a white solid.

[0801] Step 2:

[0802] To a solution of compound 52, namely methyl 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionate (278 mg, 650.30 μmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (178 mg, 780.36 μmol) in DMSO (15 mL), isopropyl acetate (1.33 g, 13 mmol) was added, and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 18,4-(3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 24.66% yield), as a white solid. 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.39(d,1H),8.30(s,1H),8.08(dd,1H),7.55-7.53(m,2H),7.34(d,1H),4.18(q,2H),2. 82(t,2H),2.48(s,3H),1.76-1.70(m,2H),1.53(s,6H),1.34(t,3H),0.91(t,3H); MS: m / z=624.1(M+1,ESI+); HRMS: 624.1996.

[0803] Synthetic compound 19

[0804]

[0805] Step 1:

[0806] 5-Amino-3-(trifluoromethyl)pyridinecarboxylonitrile (2.00 g, 10.69 mmol) was added fractionally to a solution of triphosgene (6.14 g, 53.44 mmol) in H₂O (15 mL), and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was poured into ice water (100 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give 5-isothiocyano-3-(trifluoromethyl)pyridinecarboxylonitrile (1.0 g, 40.81% yield) as a yellow oil.

[0807] Step 2:

[0808] To a solution of compound 51, namely methyl 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionate (350 mg, 818.72 μmol) and 5-isothiocyano-3-(trifluoromethyl)pyridinecarboxynitrile (225 mg, 982.47 μmol) in DMSO (5 mL), isopropyl acetate (1.67 g, 16.37 mmol) was added, and the reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 19, namely 5-(3-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioimidazolidine-1-yl)-3-(trifluoromethyl)pyridinecarboxynitrile (158 mg, 30.90% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),9.25(d,1H),8.83(d,1H),7.63(d,1H),7.50(dd,1H),7.35(d,1H),4.20(q,2H),4.16 (s,3H),2.77(t,2H),1.77-1.72(m,2H),1.56(s,6H),1.37(t,3H),0.93(t,3H); MS: m / z=625.2(M+1,ESI+); HRMS: 625.1951.

[0809] Synthetic compound 20

[0810]

[0811] To a solution of compound 52, namely methyl 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionate (200 mg, 467.84 μmol) and 5-isothiocyano-3-(trifluoromethyl)pyridinecarboxynitrile (161 mg, 702 μmol) in NMP (10 mL), isopropyl acetate (5 mL) was added, and the reaction mixture was stirred at 115 °C for 16 h. The reaction mixture was poured into water (150 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 20, namely 5-(3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioimidazolidin-1-yl)-3-(trifluoromethyl)pyridinecarboxylate (105 mg, 35.93% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.25(s,1H),8.82(s,1H),7.54-7.53(m,2H),7.35(d,1H),4.18(q,2H),2.82(t,2 H), 2.48 (s, 3H), 1.73 (q, 2H), 1.55 (s, 6H), 1.34 (t, 3H), 0.93-0.91 (t, 3H); MS: m / z=625.2 (M+1, ESI+); HRMS: 625.1944.

[0812] Synthetic compound 21

[0813]

[0814] To a solution of compound 53, namely methyl 1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)cyclobutane-1-carboxylate (280 mg, 637 μmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (175 mg, 764 μmol) in DMSO (5 mL), isopropyl acetate (1.30 g, 12.74 mmol) was added, and the reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 21, namely 4-(5-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-7-yl)-2-(trifluoromethyl)benzonitrile (80 mg, 19.75% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.38(d,1H),8.25(s,1H),8.06(dd,1H),7. 65(d,1H),7.52(dd,1H),7.36(d,1H),4.21(q,2H),4.12(s,3H),2.76(t,2H),2.6 7-2.61(m,2H),2.45-2.38(m,2H),2.00-1.94(m,1H),1.76-1.69(m,2H),1.58-1. 53 (m, 1H), 1.36 (t, 3H), 0.92 (t, 3H); MS: m / z=636.2 (M+1, ESI+); HRMS: 636.1998.

[0815] Synthetic compound 22

[0816]

[0817] Compound 54, namely methyl 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylate (500 mg, 1.14 mmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (260 mg, 1.14 mmol) in DMSO (20 mL), was mixed with 10 mL of isopropyl acetate, and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water (200 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with water (200 mL) and brine (200 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 22, 4-(5-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-7-yl)-2-(trifluoromethyl)benzonitrile (100 mg, 13.83% yield), as a white solid. 1 H NMR(400MHz, CDCl3)δ9.90(s,1H),8.09(d,1H),8.00-7.98(m,2H),7.88(dd ,1H),7.48(dd,1H),7.27(d,1H),4.36(q,2H),2.97(t,2H),2.76-2.71(m,2 H),2.64-2.54(m,5H),2.31-2.24(m,1H),1.90-1.81(m,2H),1.78-1.70(m, 1H), 1.62(t,3H), 0.99(t,3H); MS: m / z=636.1(M+1,ESI+); HRMS: 636.1992.

[0818] Synthetic compound 23

[0819]

[0820] Isopropyl acetate (3.25 g, 31.85 mmol) was added to a solution of methyl 1-((4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)amino)cyclobutane-1-carboxylate (700 mg, 1.59 mmol) and 5-isothiocyano-3-(trifluoromethyl)pyridinecarboxylonitrile (438 mg, 1.91 mmol) in DMSO (10 mL), and the reaction mixture was stirred at 85 °C for 3 h. The reaction mixture was poured into water (100 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 5-(5-(4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-7-yl)-3-(trifluoromethyl)pyridinecarboxylate (200 mg, 19.72% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),9.22(d,1H),8.76(d,1H),7.67(d,1H ),7.53(dd,1H),7.38(d,1H),4.25-4.14(m,5H),2.76(t,2H),2.68-2.64(m, 2H),2.54-2.46(m,2H),2.04-1.97(m,1H),1.79-1.69(m,2H),1.61-1.56(m ,1H),1.38(t,3H),0.92(t,3H); MS: m / z=637.0(M+1,ESI+); HRMS: 637.1949.

[0821] Synthetic compound 24

[0822]

[0823] To a solution of compound 54, namely methyl 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylate (500 mg, 1.14 mmol) and 5-isothiocyano-3-(trifluoromethyl)pyridinecarboxylate (261 mg, 1.14 mmol) in DMSO (5 mL), isopropyl acetate (5 mL) was added, and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 24, namely 5-(5-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-7-yl)-3-(trifluoromethyl)pyridinecarboxylate (95 mg, 13.12% yield), as a white solid. 1 H NMR(400MHz, CDCl3)δ9.89(s,1H),9.13(d,1H),8.41(d,1H),8.07(d,1H),7.48(dd,1H),7.27(s,1H),4.36(dd,2H),2.96(t,2H),2.79-2. 73(m,2H),2.64-2.57(m,5H),2.33-2.25(m,1H),1.90-1.72(m,3H),1.62(t,3H),0.99(t,3H); MS: m / z=637.1(M+1,ESI+); HRMS: 637.1945.

[0824] Synthetic compound 25

[0825]

[0826] To a solution of compound 55, namely (350 mg, 876.22 μmol) methyl glycine and 240 mg, 1.05 mmol) 4-isothiocyano-2-(trifluoromethyl)benzonitrile in toluene (10 mL), AcOH (526 mg, 8.76 mmol) was added, and the reaction mixture was stirred at 120 °C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 25, 4-(3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-5-oxo-2-thioimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (86 mg, 16.48% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.39(d,1H),8.17(s,1H),8.00(dd,1H),7.88(d,1H),7.82(dd,1H),7.30(d,1H),4.88(s,2H ), 4.15 (q, 2H), 2.84 (t, 2H), 2.48 (s, 3H), 1.77-1.71 (m, 2H), 1.34 (t, 3H), 0.92 (t, 3H); MS: m / z=596.3 (M+1, ESI+); HRMS: 596.1689.

[0827] Synthetic compound 26

[0828]

[0829] To a solution of compound 56, namely (310 mg, 749.75 μmol) methyl alanine (4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)alanine (205 mg, 900 μmol) in toluene (10 mL), AcOH (450 mg, 7.50 mmol) was added, and the reaction mixture was stirred at 120 °C for 1 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 26, 4-(3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4-methyl-5-oxo-2-thioimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (80 mg, 17.50% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.39(d,1H),8.23(d,1H),8.04(dd,1H),7.75-7.69(m,2H),7.32(d,1H),5.10(q,2H),4.20-4.14( m,2H),2.84(t,2H),2.49(s,3H),1.77-1.72(m,2H),1.43(d,2H),1.34(t,3H),0.92(t,3H); MS: m / z=610.2(M+1,ESI+); HRMS: 610.1841.

[0830] Synthetic compound 27

[0831]

[0832] Triphosgene (272 mg, 916 μmol) was added fractionally to a solution of 5-amino-2-(trifluoromethyl)benzonitrile (341.13 mg, 1.83 mmol) in DCM (15 mL) at -10 °C, and the mixture was stirred at this temperature for 0.5 h. Then, TEA (232 mg, 2.29 mmol) was added, and the mixture was stirred for another 15 min. Subsequently, a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (500 mg, 1.53 mmol) in DCM (15 mL) was added to the above mixture, and the mixture was stirred at -10 °C for 1 h. The mixture obtained by evaporation was purified by preparative HPLC to give compound 27, namely 1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)urea (85 mg, 10.32% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),10.08(s,1H),9.42(s,1H),8.22(d,1H),8.00(d,1H),7.77(dd,1H),7.65(d,1H),7.60(dd,1H),7.11 (d,1H),4.08(dd,2H),2.83(t,2H),2.48(s,3H),1.77-1.71(m,2H),1.29(t,3H),0.92(t,3H); MS: m / z=540.1(M+1,ESI+); HRMS: 540.1967.

[0833] Synthetic compound 28

[0834]

[0835] A mixture of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (350 mg, 1.07 mmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (293 mg, 1.28 mmol) in NMP (6 mL) was stirred at 80 °C for 3 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 28, 1-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)thiourea (140 mg, 23.57% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.53(s,1H),10.47(s,1H),10.37(s,1H),8.33(d,1H),8.10-8.01(m,2H),7.65-7.59(m,2H),7.19(d,1H) ,4.13(dd,2H),2.81(t,2H),2.48(s,3H),1.75-1.69(m,2H),1.33(t,3H),0.90(t,3H); MS: m / z=556.1(M+1,ESI+); HRMS: 556.1739.

[0836] Synthetic compound 29

[0837]

[0838] Step 1:

[0839] Pd₂(dba)₃ (154 mg, 168 μmol), xantphos (49 mg, 84 μmol), and Cs₂CO₃ (1.10 g, 3.37 mmol) were added to a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (500 mg, 1.68 mmol) and tert-butyl aziridine-3-ylcarbamate (319 mg, 1.85 mmol) in toluene (10 mL). The reaction mixture was stirred at 80 °C for 1 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)azacyclobutane-3-yl)carbamate (330 mg, 57.43% yield) as a yellow solid. MS: m / z = 342.1 (M+1, ESI+). Step 2:

[0840] TFA (1.10 g, 9.67 mmol) was added to a solution of (330 mg, 967 μmol) tert-butyl carbamate in DCM (6 mL), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was evaporated under reduced pressure to give 2,2,2-trifluoroacetate of 4-(3-aminoazacyclobutane-1-yl)-2-(trifluoromethyl)benzonitrile (230 mg, 98.71% yield). MS: m / z = 242.2 (M+1, ESI+), as a yellow oil.

[0841] Step 3:

[0842] K₂CO₃ (527 mg, 3.81 mmol) was added to a solution of 2,2,2-trifluoroacetate of 4-(3-aminoazacyclobutane-1-yl)-2-(trifluoromethyl)benzonitrile (230 mg, 954 μmol) and 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (411 mg, 1.00 mmol) in MeCN (10 mL), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC to give compound 29, namely N-(1-(4-cyano-3-(trifluoromethyl)phenyl)azacyclobutane-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (140 mg, 99.2% purity), as a white solid. 1H NMR(400MHz,DMSO-d6)δ11.73(s,1H),8.56(s,1H),7.96-7.94(m,2H),7.78(d,1H),7.38(dd,1H),6.73(d,1H),6.63(dd,1H),4.30-4.18(m, 5H), 3.74-3.70 (m, 2H), 2.82 (t, 2H), 2.48 (s, 3H), 1.75-1.69 (m, 2H), 1.34 (t, 3H), 0.89 (t, 3H); MS: m / z=616.1 (M+1, ESI+); HRMS: 616.1950.

[0843] Synthetic compound 30

[0844]

[0845] Step 1:

[0846] Pd₂(dba)₃ (154 mg, 168 μmol), oxanthracene phosphine (49 mg, 84 μmol), and Cs₂CO₃ (1.10 g, 3.37 mmol) were added to a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (500 mg, 1.68 mmol) and piperidin-4-ylcarbamate (405 mg, 2.02 mmol) in toluene (10 mL). The reaction mixture was stirred at 80 °C for 2 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography to give 1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)carbamate (390 mg, 62.72% yield) as a yellow solid. MS: m / z = 370.2(M+1, ESI+).

[0847] Step 2:

[0848] TFA (1.20 g, 10.56 mmol) was added to a solution of tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)carbamate (390 mg, 1.06 mmol) in DCM (8 mL), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was evaporated under reduced pressure to give 2,2,2-trifluoroacetate of 4-(4-aminopiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (270 mg, 94.97% yield) as a yellow oil. MS: m / z = 270.2 (M+1, ESI+).

[0849] Step 3:

[0850] K₂CO₃ (554 mg, 4.01 mmol) was added to a solution of 2,2,2-trifluoroacetate of 4-(4-aminopiperidin-1-yl)-2-(trifluoromethyl)benzonitrile (270 mg, 1.00 mmol) and 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (411 mg, 1.00 mmol) in MeCN (10 mL), and the reaction mixture was stirred at 25 °C for 1 h. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by preparative HPLC to give compound 30, namely N-(1-(4-cyano-3-(trifluoromethyl)phenyl)piperidin-4-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (185 mg, 28.58% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),7.99-7.96(m,2H),7.86-7.78(m,2H),7.36(dd,1H),7.25(d,1H),7.19(dd,1H),4.20(q,2H),3.89(d,2H),3 .36(s,1H),3.06(t,2H),2.83(t,2H),2.49(s,3H),1.76-1.68(m,4H),1. 44-1.32 (m, 5H), 0.90 (t, 3H); MS: m / z=644.1 (M+1, ESI+); HRMS: 644.2261.

[0851] Synthetic compound 31

[0852]

[0853] Step 1:

[0854] Pd₂(dba)₃ (77 mg, 84 μmol), xanthylphosphine (146 mg, 253 μmol), and Cs₂CO₃ (1.65 g, 5.05 mmol) were added to a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (500 mg, 1.68 mmol) and pyrrolidone-3-ylcarbamate-tert-butyl ester (408 mg, 2.19 mmol) in toluene (20 mL). The reaction mixture was stirred at 80 °C for 3 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)carbamate (531 mg, 88.76% yield) as a yellow solid. MS: m / z = 356.1 (M+1, ESI+).

[0855] Step 2:

[0856] To a solution of tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)carbamate (531 mg, 1.49 mmol) in DCM (8 mL), 3 M HCl / EA (4 mL) was added, and the reaction mixture was stirred at 25 °C for 2 h. The mixture was evaporated under reduced pressure to give (3-aminopyrrolidine-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (300 mg, 78.66% yield) as a yellow solid. MS: m / z = 256.1 (M+1, ESI+).

[0857] Step 3:

[0858] TEA (119 mg, 1.18 mmol) was added to a solution of 4-(3-aminopyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (100 mg, 391.79 μmol) and 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (161 mg, 392 μmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was poured into water (60 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-(1-(4-cyano-3-(trifluoromethyl)phenyl)pyrrolidine-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (130 mg, 52.70% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.13(d,1H),7.99-7.97(m,2H),7.76(d,1H),7.36 (d,1H),6.80-6.75(m,2H),4.21(q,2H),3.94-3.90(m,1H),3.54-3.46(m,2H),3.39-3.3 3(m,1H),3.25(dd,1H),2.83(t,2H),2.49(s,3H),2.14-2.06(m,1H),1.97-1.89(m,1H), 1.78-1.69(m,2H),1.36(t,3H),0.91(t,3H); MS: m / z=630.1(M+1,ESI+); HRMS: 630.2106.

[0859] Synthetic compound 32

[0860]

[0861] Step 1:

[0862] Pd₂(dba)₃ (46 mg, 51 μmol), xanthylphosphine (88 mg, 152 μmol), and Cs₂CO₃ (987 mg, 3.03 mmol) were added to a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (300 mg, 1.01 mmol) and (2-oxopyrrolidone-3-yl)carbamate (263 mg, 1.31 mmol) in toluene (20 mL). The reaction mixture was stirred at 80 °C for 3 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (315 mg, 84.44% yield) as a yellow solid. MS: m / z = 314.0 (M-56+1, ESI+).

[0863] Step 2:

[0864] To a solution of tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)-2-oxopyrrolidone-3-yl)carbamate (310 mg, 839 μmol) in DCM (8 mL), 3 M HCl / EA (4 mL) was added, and the reaction mixture was stirred at 25 °C for 2 h. The mixture was evaporated under reduced pressure to give 4-(3-amino-2-oxopyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (220 mg, 97.36% yield) as a yellow solid. MS: m / z = 270.0 (M+1, ESI+). Step 3:

[0865] TEA (248 mg, 2.45 mmol) was added to a solution of 4-(3-amino-2-oxopyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (220 mg, 817 μmol) and 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (336 mg, 817 μmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was poured into water (60 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 32, namely N-(1-(4-cyano-3-(trifluoromethyl)phenyl)-2-oxopyrrolidone-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (150 mg, 28.52% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.69(s,1H),8.40-8.36(m,2H),8.19(d,1H),8.03 -7.97(m,3H),7.37(d,1H),4.44-4.37(m,1H),4.21(q,2H),3.88(t,1H),3. 78-3.71(m,1H),2.83(t,2H),2.48(s,3H),2.34-2.27(m,1H),1.86-1.68(m ,3H),1.34(t,3H),0.90(t,3H); MS: m / z=644.1(M+1,ESI+); HRMS: 644.1901.

[0866] Synthetic compound 33

[0867]

[0868] Step 1:

[0869] Pd₂(dba)₃ (77 mg, 84 μmol), xanthylphosphine (146 mg, 253 μmol), and Cs₂CO₃ (1.65 g, 5.05 mmol) were added to a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (500 mg, 1.68 mmol) and (438 mg, 2.19 mmol) in toluene (20 mL). The reaction mixture was stirred at 80 °C for 3 h. The resulting mixture was cooled to room temperature and poured into water (60 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)-5-oxopyrrolidine-3-yl)carbamate (522 mg, 83.96% yield) as a yellow solid. MS: m / z = 370.1 (M+1, ESI+).

[0870] Step 2:

[0871] To a solution of tert-butyl (1-(4-cyano-3-(trifluoromethyl)phenyl)-5-oxopyrrolidone-3-yl)carbamate (522 mg, 1.41 mmol) in DCM (10 mL), 3 M HCl / EA (5 mL) was added, and the reaction mixture was stirred at 25 °C for 2 h. The mixture was evaporated under reduced pressure to give 4-(4-amino-2-oxopyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (378 mg, 99.34% yield) as a yellow solid. MS: m / z = 270.1 (M+1, ESI+).

[0872] Step 3:

[0873] TEA (426 mg, 4.21 mmol) was added to a solution of 4-(4-amino-2-oxopyrrolidone-1-yl)-2-(trifluoromethyl)benzonitrile hydrochloride (378 mg, 1.40 mmol) and 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonyl chloride (577 mg, 1.40 mmol) in DCM (20 mL), and the reaction mixture was stirred at 25 °C for 3 h. The resulting mixture was poured into water (60 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 33, namely N-(1-(4-cyano-3-(trifluoromethyl)phenyl)-5-oxopyrrolidone-3-yl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide (170 mg, 18.81% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),8.37-8.31(m,2H),8.15(d,1H),7.98-7.96(m,2H),7.89(dd,1H),7.36(dd,1H),4.23-4.05(m,4H),3.77( dd,1H),2.84-2.77(m,3H),2.49(s,3H),2.41(dd,1H),1.77-1.68(m,2H),1.34(t,3H),0.91(t,3H); MS: m / z=644.2(M+1,ESI+); HRMS: 644.1899.

[0874] Synthetic compound 34

[0875]

[0876] To a solution of compound 57, namely 3-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)tetrahydrofuran-3-carboxynitrile (1.09 g, 2.58 mmol) and 4-amino-2-(trifluoromethyl)benzonitrile (576.27 mg, 3.10 mmol) in toluene (20 mL), TCDI (551.74 mg, 3.10 mmol) was added, and the reaction mixture was stirred at 105 °C for 22 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and DMA (2 mL) and EtOH (20 mL) were added to the residue. The mixture was heated to 70 °C and hydrogen chloride (2 M, 4 mL) was added, followed by stirring at this temperature for 2 h. The resulting mixture was poured into water (200 mL) and extracted with EA (50 mL × 3), washed with brine (200 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give compound 34, namely 4-(1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4-oxo-2-thio-7-oxa-1,3-diazaspiro[4.4]non-3-yl)-2-(trifluoromethyl)benzonitrile (60 mg, 3.57% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.39(d,1H),8.26(s,1H),8.07(dd,1H ),7.63-7.61(m,2H),7.32(d,1H),4.33(d,1H),4.17(q,2H),4.00(d,1H),3.7 8(dd,1H),3.54(dd,1H),2.82(t,2H),2.58(t,2H),2.48(s,3H),1.76-1.71( m, 2H), 1.34 (t, 3H), 0.91 (t, 3H); MS: m / z=652.4 (M+1, ESI+); HRMS: 652.1942.

[0877] Synthetic compound 38

[0878]

[0879] To a solution of compound 58, namely methyl 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxylate (140 mg, 309 μmol) and 4-isothiocyano-2-(trifluoromethyl)benzonitrile (85 mg, 370 μmol) in NMP (8 mL), isopropyl acetate (4 mL) was added, and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 38, namely 4-(1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4-oxo-2-thio-1,3-diazaspiro[4.4]non-3-yl)-2-(trifluoromethyl)benzonitrile (130 mg, 64.82% yield), as a white solid. 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),8.38(d,1H),8.29(d,1H),8.08(dd, 1H),7.65-7.60(m,2H),7.36(d,1H),4.19(q,2H),2.95(t,2H),2.58(s,3H ),2.32-2.27(m,2H),2.23-2.18(m,2H),1.81-1.72(m,4H),1.46-1.42(m, 2H), 1.35 (t, 3H), 0.93 (t, 3H); MS: m / z=650.4 (M+1, ESI+); HRMS: 650.2159.

[0880] Synthetic compound 47

[0881]

[0882] To a solution of compound 52, namely methyl 2-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)-2-methylpropionate (540 mg, 1.26 mmol) and compound 59, namely 3-fluoro-4-isothiocyano-2-(trifluoromethyl)benzonitrile (1.55 g, 6.3 mmol) in NMP (8 mL), isopropyl acetate (2 mL) was added, and the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 47, namely 4-(3-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4,4-dimethyl-5-oxo-2-thioimidazolidin-1-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (90 mg, 11% yield), as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.30-8.25(m,2H),7.61-7.58(m,2H),7.34(d,1H),4.18(q,2H),2.83(t,2H), 2.48(s,3H),1.76-1.70(m,2H),1.54(dd,6H),1.33(t,3H),0.91(t,3H); MS: m / z=642.4(M+1,ESI+); HRMS: 642.1904.

[0883] Synthetic compound 48

[0884]

[0885] To a solution of compound 54, namely methyl 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclobutane-1-carboxylate (600 mg, 1.36 mmol) and compound 59, namely 3-fluoro-4-isothiocyano-2-(trifluoromethyl)benzonitrile (1.67 g, 6.8 mmol) in NMP (8 mL), isopropyl acetate (2 mL) was added, and the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was poured into water (80 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with water (80 mL) and brine (80 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 48, namely 4-(5-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-7-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (120 mg, 13.5% yield), as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.68(s,1H),8.26-8.20(m,2H),7.63-7.61(m,2H) ,7.37(dd,1H),4.19(q,2H),2.82(t,2H),2.68-2.62(m,1H),2.58-2.52(m, 2H),2.49-2.44(m,4H),2.02-1.95(m,1H),1.78-1.69(m,2H),1.60-1.56(m ,1H),1.35(t,3H),0.91(t,3H); MS: m / z=654.4(M+1,ESI+); HRMS: 654.1901.

[0886] Synthetic compound 49

[0887]

[0888] Compound 57, namely 3-fluoro-4-isothiocyano-2-(trifluoromethyl)benzonitrile (1.57 g, 6.39 mmol), was added to a solution of compound 57, namely 3-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)tetrahydrofuran-3-carboxynitrile (900 mg, 2.13 mmol), in THF (50 mL). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOH (50 mL) and DMA (5 mL), and then 2N HCl (5 mL) was added to the above solution. The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (80 mL), extracted with EA (30 mL × 3), washed with brine (80 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give compound 49, 4-(1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4-oxo-2-thio-7-oxa-1,3-diazaspiro[4.4]non-3-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (135 mg, 9.46% yield), as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H),8.29-8.20(m,2H),7.72-7.67(m,2H) ,7.32(d,1H),4.40(dd,1H),4.18(q,2H),4.03-3.96(m,1H),3.80(q,1H),3. 61-3.51(m,1H),2.83(t,2H),2.72-2.52(m,2H),2.48(s,3H),1.78-1.69(m ,2H),1.34(t,3H),0.92(t,3H); MS: m / z=670.4(M+1,ESI+); HRMS: 670.1849.

[0889] Synthetic compound 50

[0890]

[0891] Step 1:

[0892] TMSCN (454 mg, 4.58 mmol) and ZnCl2 (83 mg, 610.91 μmol) were added to a solution of 2-(5-amino-2-ethoxyphenyl)-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazine-4(3H)-one (1 g, 3.05 mmol) and cyclopentanone (514 mg, 6.11 mmol) in dioxane (30 mL), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and poured into water (80 mL), extracted with EA (30 mL × 3), washed with brine (80 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxynitrile (1.15 g, 89.53% yield). MS: m / z = 421.3 (M+1, ESI+), as a yellow solid.

[0893] Step 2:

[0894] Compound 59, namely 3-fluoro-4-isothiocyano-2-(trifluoromethyl)benzonitrile (1 g, 2.38 mmol), was added to a solution of 1-((4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)amino)cyclopentane-1-carboxynitrile (50 mL) in THF. The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOH (50 mL) and DMA (5 mL), and then 2N HCl (5 mL) was added to the above solution. The resulting mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water (80 mL), extracted with EA (30 mL × 3), washed with brine (80 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give compound 50, 4-(1-(4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl)-4-oxo-2-thio-1,3-diazaspiro[4.4]non-3-yl)-3-fluoro-2-(trifluoromethyl)benzonitrile (126 mg, 7.94% yield), as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.26(s,2H),7.65(s,2H),7.32(d,1H),4.18(q,2H),2.82(t,2H),2.48(s,3H),2.32 -2.20(m,4H),1.76-1.71(m,4H),1.50-1.43(m,2H),1.34(t,3H),0.92(t,3H); MS: m / z=668.5(M+1,ESI+); HRMS: 668.2057.

[0895] Example 3 - Human PDE-5A1 Inhibition Analysis

[0896] This embodiment illustrates the in vitro inhibition of human PDE-5A1 by exemplary compounds of this disclosure (e.g., as described herein).

[0897] Material

[0898] Sildenafil citrate (catalog number LKT-S3313, Axxora, San Diego, CA), vardenafil hydrochloride trihydrate (catalog number SML2103, Sigma-Aldrich, St. Louis, MO), PDE analysis buffer (catalog number 60393, BPS bioscience, San Diego, CA), PDE binder (catalog number 60390, BPS bioscience, San Diego, CA), and PDE binder diluent (cGMP, catalog number 60392, BPS bioscience, San Diego, CA) were used for analysis. The test compounds were supplied by Ildong Pharmaceuticals Co., Ltd.

[0899] Experimental protocol

[0900] The enzymes and substrates used in this experiment are summarized in Table 2.

[0901]

[0902] First, the compounds were serially diluted in 100% DMSO to maximum concentrations of 1 mM and 0.1 mM. Then, each intermediate compound dilution (in 100% DMSO) was directly diluted 10-fold to an analytical buffer of 10% DMSO, and 5 μL of the dilution was added to 50 μL of the reaction mixture, resulting in a final DMSO concentration of 1% for all reactions.

[0903] The enzyme reaction was carried out at room temperature for 60 minutes in a 50 μL mixture containing PDE analysis buffer, 100 nM FAM-cGMP, PDE enzyme (Table 2), and the test compound.

[0904] After the enzyme reaction, 100 μL of binding solution (1:100 diluted with binding agent diluent) was added to each reaction and the reaction was allowed to proceed at room temperature for 60 minutes.

[0905] Fluorescence intensity was measured using a Tecan Infinite M1000 microplate reader at excitation at 485 nm and emission at 528 nm.

[0906] Data Analysis

[0907] PDE activity analysis was performed twice at each concentration. Fluorescence intensity was converted to fluorescence polarization using Tecan Magellan6 software. Fluorescence polarization (FP) was calculated for the absence of the compound in each dataset. t ) was defined as 100% activity. In the absence of PDEs and compounds, the fluorescence polarization value (FP) in each dataset was... b The activity is defined as 0%. The percentage of activity in the presence of the compound is calculated according to Equation 1:

[0908]

[0909] Fluorescence polarization in the presence of FP= compounds.

[0910] Subsequently, nonlinear regression analysis of the sigmoid dose-response curves generated by Equation 2 was used to plot the activity % values ​​relative to a series of compound concentrations:

[0911]

[0912] Where Y = percentage of activity, B = minimum percentage of activity, T = maximum percentage of activity, X = logarithm of the compound, and Hill Slope = slope factor or Hill coefficient. The IC50 is determined by the concentration that induces the half-maximum percentage of activity. 50 value.

[0913] result

[0914] The results are listed in Table 3, where IC 50 The values ​​are displayed as a range.

[0915]

[0916] As illustrated by this example, the test compound exhibited excellent inhibitory activity against PDE-5.

[0917] Example 4 - Androgen receptor (AR) reporter analysis

[0918] This embodiment illustrates the in vitro antagonistic activity against the androgen receptor (AR) exhibited by exemplary compounds of this disclosure (e.g., as described herein). The procedures and results of this embodiment were performed and obtained by Thermofisher Scientific.

[0919] Test compounds

[0920] Receive the test compound in 100% DMSO at a desired starting concentration of 1000× (or higher). If the compound is provided at a concentration higher than 1000×, perform an initial dilution in 100% DMSO to bring the compound concentration to 1000×. The 1000× test compound is then serially diluted in 100% DMSO (in logarithmic increments of 10.5).

[0921] Matrix-loaded solution

[0922] The matrix-loaded solution consists of three Life Technologies reagents: Solution A (10 mM LiveBlazer) TM -FRET B / G matrix), solution B and solution C.

[0923] Androgen receptor (AR) antagonist screening via R1881 activation

[0924] AR-UAS-bla GripTite TM 293 cells were thawed and resuspended in analytical medium (phenol red-free DMEM, 2% CD-treated FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U / mL / 100 μg / mL Pen / Strep) up to a concentration of 312,500 cells / mL. 4 μL of a 10× serial dilution of cyproterone acetate (control antagonist starting concentration, 3,160 nM) or the compound was added to the appropriate wells of a poly-D-lysine analytical plate. 32 μL of cell suspension was added to the wells, and the plate was pre-incubated for 30 minutes at 37°C / 5% CO2 in a humidified incubator with the compound and control antagonist. 4 μL of a predetermined EC80 concentration of 10× control agonist R1881 was added to the wells containing the control antagonist or the compound. The plate was incubated at 37°C / 5% CO2 for 16 to 24 hours in a humidified incubator. Add 8 μL of 1 μM matrix loading solution to each well and incubate the plate at room temperature for 2 hours. The plate is then placed in a Tecan Safire fluorescent disc reader. 2Read from )

[0925] result

[0926] The results are listed in Table 4, where IC 50 The values ​​are displayed as a range.

[0927]

[0928]

[0929] Example 5 - Androgen receptor (AR) radioligand binding analysis

[0930] This embodiment also illustrates the in vitro antagonistic activity against the androgen receptor (AR) exhibited by exemplary compounds of this disclosure (e.g., as described herein), and demonstrates the binding affinity of the exemplary compounds.

[0931] program

[0932] The methods used in this study are adapted from the steps in the following literature.

[0933] Human androgen receptors obtained from human LNCaP cells were used in modified HEPES buffer, pH 7.4. 70 μg aliquots (adjusted if necessary) were mixed with 0.5 nM [ 3 [H]-ethylestradiolone was incubated at 4°C for 20 hours. Nonspecific binding was estimated in the presence of 1 μM testosterone. The receptor was filtered and washed, and the filters were then counted to determine [H]. 3 [H] Specific binding to estradiolone (historical values: Kd = 0.71 nM; specific binding = 75%; Bmax = 0.25 pmol / mg protein). (See, for example, Traish, AM et al., Binding of 7a,17a-dimethyl-19-nortestosterone (Mibolerone) to androgen and progesterone receptors in human and animal tissues. Endocrinology. 118(4):1327-1333, 1986).

[0934] Compounds were screened at 10 μM.

[0935] In the presence of IC, the IC was determined using MathIQ™ (ID BusinessSolutions Ltd., UK) via nonlinear least squares regression analysis. 50 value.

[0936] result

[0937] The results are listed in Table 6, where the following values ​​are expressed as ranges: IC 50 (nM) concentration range: (A) refers to IC50 concentration range. 50 ≤50nM; (B) refers to 50nM <IC 50 ≤200; and (C) refers to IC 50 >200nM.

[0938]

[0939]

[0940] As illustrated by this embodiment, the exemplary compounds of this disclosure exhibit potent AR-inhibiting activity and binding affinity.

[0941] 6. Equivalents and incorporation by reference

[0942] Although the invention has been specifically shown and described with reference to preferred embodiments and various alternative embodiments, those skilled in the art will understand that various changes may be made to its form and details without departing from the spirit and scope of the invention.

[0943] All references, authorized patents and patent applications cited in the text of this specification are incorporated herein by reference in their entirety for all purposes.

Claims

1. Compounds of formula (I): Or its pharmaceutically acceptable salt or stereoisomer, wherein: The compound is a compound of formula (IVa) or formula (IVb), a compound of formula (VIIa) or formula (VIIb), a compound of formula (VIIIa) or formula (VIIIb): or , or , or , Where R 1 It is -CH3, R 2 It is -CH2CH2CH3, R 3 It is -OCH2CH3, R 4 Choose the group consisting of -Cl and -CF3. R 14 Is it H or F? X 1 Is it CH or N? X 2 It is CH. X 3 It is CH. Z 1 It is either O or S independently. R 8 It is H or CH3. R 9 It is H or CH3. Where R 8 and R 9 Together with the attached carbon atom, it forms a spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic tetrahydrofuranyl group, and A is selected from covalent bonds, -NHC(O)R 5 -、-NR 6 C(Z 1 )NR 7 -、-NR 11 S(O)2-、 .

2. The compound of claim 1, wherein the compound is a compound of formula (IVc) or a compound of formula (IVd): or Or its pharmaceutically acceptable salts or stereoisomers.

3. The compound of claim 2, wherein the compound is selected from the group consisting of: and , Or its pharmaceutically acceptable salts or stereoisomers.

4. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R 8 It is CH3; and R 9 It is CH3.

5. The compound of claim 2, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers.

6. The compound of claim 2, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers.

7. The compound of claim 2, wherein the compound is a compound of formula (IVc): ， Or its pharmaceutically acceptable salts or stereoisomers.

8. The compound of claim 7, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers.

9. The compound of claim 1, wherein the compound is a compound of formula (VIIc): Or its pharmaceutically acceptable salts or stereoisomers.

10. The compound of claim 9, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers.

11. The compound of claim 1, wherein the compound is a compound of formula (VIIIc): Or its pharmaceutically acceptable salts or stereoisomers.

12. The compound of claim 11, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salts or stereoisomers.

13. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compound as described in any one of claims 1-12 or a pharmaceutically acceptable salt or stereoisomer thereof.

14. Use of the compound of any one of claims 1-12 or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition of claim 13, in the preparation of a medicament for regulating androgen receptors and / or inhibiting PDE-5.

15. The use as described in claim 14, wherein the drug is used to inhibit androgen receptors.

16. The use as described in claim 14, wherein the drug is used to inhibit PDE-5.

Images