Pyrazole MAGL inhibitors

Abstract

Provided herein are pyrazole compounds and pharmaceutical compositions comprising the compounds. These subject compounds and compositions can be used as modulators of monoacylglycerol lipase (MAGL). In addition, these subject compounds and compositions can be used to treat pain.

Description

[0001] This application is a divisional application of Chinese invention patent application filed on May 22, 2018, with application number 201880033044.0 and invention title "Pyrazole MAGL Inhibitor".

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 510,213, filed May 23, 2017, which is incorporated herein by reference in its entirety. Technical Field

[0004] This application relates to an MAGL inhibitor. Background Technology

[0005] Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzing endocannabinoids in the nervous system, such as 2-AG (2-arachidonicylglycerol), a lipid based on arachidonic esters. Fatty acid amide hydrolase (FAAH) is another enzyme responsible for hydrolyzing endocannabinoids, such as cannabinoids. Summary of the Invention

[0006] This disclosure provides, for example, compounds and compositions that are MAGL modulators, and their use as pharmaceutical agents, methods for their preparation, and pharmaceutical compositions comprising the disclosed compounds as at least one active ingredient. This disclosure also provides the use of the disclosed compounds as pharmaceuticals for inhibiting MAGL activity in warm-blooded animals (such as humans) and / or in the preparation of pharmaceuticals for inhibiting MAGL activity in warm-blooded animals (such as humans).

[0007] One aspect is compounds having formula (I):

[0008]

[0009] in:

[0010] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0011] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0012] R 3 yes

[0013] A is N or C(H);

[0014] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0015] Y is -CH2- or -C(O)-;

[0016] Z is -S-, -O-, or -N(R) 18 )-;

[0017] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 3-8 Cycloalkyl, C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 3-8 Cycloalkyl, C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0018] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0019] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0020] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0021] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0022] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0023] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0024] R 13 Is it H or C? 1-6 alkyl;

[0025] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)OH, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0026] R 15 Is it H or C? 1-6 alkyl;

[0027] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C 1-6 Alkyl group -OH or -CH2CO2H;

[0028] R 17 Is it H or C? 1-6 alkyl;

[0029] R 18 Is it H or C? 1-6 alkyl;

[0030] v is 0 or 1;

[0031] n is 0 or 1;

[0032] m is 0 or 1;

[0033] p is 0, 1, or 2; and

[0034] q is 0, 1, or 2;

[0035] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0036] Another aspect is compounds having formula (I'):

[0037]

[0038] in:

[0039] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0040] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0041] R 3 yes

[0042]

[0043] A is N or C(H);

[0044] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0045] Y is -CH2- or -C(O)-;

[0046] Z is -S-, -O-, or -N(R) 18 )-;

[0047] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0048] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0049] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0050] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0051] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0052] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0053] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0054] R 13 Is it H or C? 1-6 alkyl;

[0055] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0056] R 15 Is it H or C? 1-6 alkyl;

[0057] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, or -CH2CO2H;

[0058] R 17 Is it H or C? 1-6 alkyl;

[0059] R 18 Is it H or C? 1-6 alkyl;

[0060] v is 0 or 1;

[0061] n is 0 or 1;

[0062] m is 0 or 1;

[0063] p is 0, 1, or 2; and

[0064] q is 0, 1, or 2;

[0065] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0066] In some embodiments, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is C(H). In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is N. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 6 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is -S-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is -N(H)-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Z is -S-. In another embodiment, it is a compound having formula (I) or (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -CH2-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein Y is -C(O)-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 13 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 12 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes

[0067] In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 13 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 13It is -CH3. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 12 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 0. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein v is 1. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is -O-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is -N(CH3)-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein X is -CH2N(CH3)CH2-. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 3 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is C(H). In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein A is N. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 6 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 7 It is phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridizinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0068] In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9Heteroaryl. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, or C 1-6 Haloalkoxy group. In another embodiment, it is a compound having formula (I) or (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is -Cl. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (I) or (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 15 It is H. In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (I) or (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 10 and R 11 Each is H.

[0069] In another embodiment, a pharmaceutical composition comprises a compound having formula (I) or (I') as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0070] In another embodiment, a method for treating pain in a patient in need includes administering the patient a therapeutically effective amount of a compound having formula (I) or (I') as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method for treating chronic pain in a patient in need includes administering the patient a therapeutically effective amount of a compound having formula (I) or (I') as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. In another embodiment, a method for treating inflammatory pain in a patient in need includes administering the patient a therapeutically effective amount of a compound having formula (I) or (I') as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0071] In another embodiment, there is a method for treating migraine in a patient in need, the method comprising administering to the patient a therapeutically effective amount of a compound having formula (I) or (I') as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0072] In another embodiment is a method of treating scleroderma in a patient in need, the method comprising administering a therapeutically effective amount of a compound of formula (I) or (I') of the present invention, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0073] In another embodiment, there is a method for treating non-alcoholic fatty liver disease (NASH) in patients in need, the method comprising administering a therapeutically effective amount of a compound having formula (I) or (I') as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof. Detailed Implementation

[0074] This disclosure relates, at least in part, to regulators or inhibitors of MAGL. For example, compounds capable of inhibiting MAGL are provided herein.

[0075] Unless the context clearly indicates otherwise, as used herein and in the appended claims, the singular forms “a / an” and “the” include plural references. Thus, for example, reference to “a reagent” includes multiple such reagents, and reference to “the cell” includes reference to one or more cells (or multiple cells) and their equivalents. When the scope is used herein for physical properties (such as molecular weight) or chemical properties (such as chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments thereof. When referring to a number or numerical range, the term “about” means that the number or numerical range mentioned is an approximation within experimental variability (or statistical experimental error), and therefore the number or numerical range varies between 1% and 15% of said number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude in some other embodiments (e.g., embodiments of any composition, composition, method, or process of the substance described herein) that may be “consistent with” or “substantially composed of” the features described.

[0076] definition

[0077] Unless otherwise specified, the following terms shall have the meanings indicated below as used in the specification and appended claims.

[0078] As used in this article, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x It refers to the number of carbon atoms that make up its specified part (excluding optional substituents).

[0079] "Amino" refers to the -NH2 group.

[0080] "Cyano" refers to the -CN group.

[0081] "Nitro" refers to the -NO2 group.

[0082] "O-" refers to the -O- group.

[0083] "Oxo" refers to the =O group.

[0084] "Thio" refers to the =S group.

[0085] "Imine" refers to the =NH group.

[0086] "Oxime group" refers to the =N-OH group.

[0087] "alkyl" or "alkylene" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl group). In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 1 to 6 carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group is optionally substituted with one or more of the following substituents: halogroup, cyanogroup, nitrogroup, oxogroup, thiogroup, iminogroup, oximegroup, trimethylsilyl, -OR a -SR a -OC(O)-R f -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a )S(O) t R f (where t is 1 or 2), -S(O) t ORa (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0088] "Alkoxy" refers to a group having the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0089] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In other embodiments, the alkenyl group contains 2 to 4 carbon atoms. The alkenyl group is attached to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, the alkenyl group is optionally substituted with one or more of the following substituents: haloyl, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R f -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a )S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a)2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0090] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group has 2 to 4 carbon atoms. The alkynyl group is attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -OR a -SR a -OC(O)-R f -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR f -OC(O)-NR a R f -N(R) a )C(O)R f -N(R) a S(O) t R f (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R f (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, it is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R f It is independently an alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

[0091] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms from 6 to 18, wherein at least one ring in the ring system is fully unsaturated, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2) π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene. Unless otherwise specified in the specification, the term "aryl" or the prefix "ar-" (e.g., in "arylalkyl") is intended to include aryl groups optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, haloalkyl, cyano, nitro, aryl, aralkyl, arylene, arynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -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 OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a)2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0092] "Aryloxy group" refers to a group having the formula -O-aryl that is bonded by an oxygen atom, wherein the aryl group is as defined above.

[0093] "Aryl group" refers to an aryl group having the formula -R c -aryl groups, where R c It is an alkylene chain as defined above, such as methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group is optionally substituted as described above for aryl groups.

[0094] "Arylalkyloxy group" refers to a group having the formula -O-aryl group bonded by an oxygen atom, wherein the aryl group is as defined above.

[0095] "Aryl" refers to a group with the formula -R d -aryl groups, where R d It is an alkenyl chain as defined above. The aryl portion of the aryl group is optionally substituted as described above for the aryl group. The alkenyl chain portion of the aryl group is optionally substituted as defined above for the alkenyl group.

[0096] "Aromaticynyl" refers to a group with the formula -R e -aryl groups, where R e It is an alkynyl chain as defined above. The aryl portion of the arylyl group is optionally substituted as described above for the aryl group. The alkynyl chain portion of the arylyl group is optionally substituted as defined above for the alkynyl chain.

[0097] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused ring or bridged ring systems, having 3 to 15 carbon atoms. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 5 to 7 carbon atoms. The cycloalkyl group is attached to the remainder of the molecule by a single bond. The cycloalkyl group is saturated (i.e., containing only C-C single bonds) or partially unsaturated (i.e., containing one or more double or triple bonds). Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group contains 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 7 carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, the cycloalkyl group contains 3 to 5 carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, the cycloalkyl group comprises 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl). Partially unsaturated cycloalkyl groups are also referred to as "cycloalkenyl". Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless specifically stated otherwise in the specification, the term "cycloalkyl" is intended to include cycloalkyl groups optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, arylenyl, aryynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -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 OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0098] "Halogen" or "halogen" refers to a substituent of bromine, chlorine, fluorine, or iodine.

[0099] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogen groups as defined above.

[0100] "Haloalkoxy" refers to an alkoxy group as defined above that is substituted by one or more halogen groups as defined above.

[0101] "Fluoroalkyl" refers to an alkyl group as defined above, which is substituted with one or more fluorine groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group may optionally be substituted as defined above for alkyl groups.

[0102] "Heterocyclic alkyl" refers to a stable 3- to 18-membered non-aromatic cyclic group comprising 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, the heterocyclic alkyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, including fused, spirocyclic, or bridged ring systems. The heteroatoms in the heterocyclic alkyl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heterocyclic alkyl group is partially or fully saturated. In some embodiments, the heterocyclic alkyl group is attached to the remainder of the molecule by any atom on the one or more rings. Examples of such heterocyclic alkyl groups include, but are not limited to, dioxolane, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the term "heterocyclic alkyl" is intended to include heterocyclic alkyl groups as defined above, optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocyclic alkyl, heteroaryl, heteroarylalkyl, -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(Ra )S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0103] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, wherein at least one ring in the ring system is fully unsaturated, i.e., according to shock theory, it comprises a cyclic, delocalized (4n+2)π-electron system. Heteroaryls include fused-ring or bridged-ring systems. One or more heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. The heteroaryl group is attached to the remainder of the molecule via any atom on the one or more rings. Unless otherwise specified in the specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, optionally substituted with one or more substituents selected from alkyl, alkenyl, ynyl, haloyl, haloalkyl, oxo, thio, cyano, nitro, aryl, aralkyl, aryl-alkenyl, arylynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl, heteroarylalkyl, -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 -Rb -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 OR a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl. b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain.

[0104] "N-Heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen atom, wherein the attachment point of the heteroaryl group to the remainder of the molecule is through a nitrogen atom in the heteroaryl group. The N-heteroaryl group may optionally be substituted as described above for heteroaryl groups.

[0105] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the attachment point of the heteroaryl group to the remainder of the molecule is through a carbon atom in the heteroaryl group. The C-heteroaryl group may optionally be substituted as described above for heteroaryl groups.

[0106] "Heteroaryloxy group" refers to a group having the formula -O-heteroaryl that is bonded by an oxygen atom, wherein the heteroaryl is as defined above.

[0107] "Heteroarylalkyl" refers to a compound with the formula -R c - A heteroaryl group, wherein R cIt is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, then the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for the heteroaryl group.

[0108] "Heteroarylalkoxy" refers to a compound with the formula -OR bonded by an oxygen atom. c - A heteroaryl group, wherein R c It is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, then the heteroaryl group is optionally attached to an alkyl group at the nitrogen atom. The alkylene chain of the heteroaryl alkoxy group is optionally substituted as defined above for the alkylene chain. The heteroaryl portion of the heteroaryl alkoxy group is optionally substituted as defined above for the heteroaryl group.

[0109] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers defined by absolute stereochemistry as (R)- or (S)-. Unless otherwise stated, all stereoisomers of the compounds disclosed herein are intended to be considered in this disclosure. When the compounds described herein contain an alkene double bond, and unless otherwise stated, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, it is intended to include all possible isomers and their racemic and optically pure forms, as well as all tautomers. The term “geometric isomer” refers to the E or Z geometric isomer of the alkene double bond (e.g., cis or trans). The term “positional isomer” refers to a structural isomer surrounding a central ring, such as ortho, meta, and para isomers surrounding a benzene ring.

[0110] "Tautomer" refers to a molecule in which proton transfer from one atom of the molecule to another atom of the same molecule is possible. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerization is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibria include:

[0111]

[0112] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes examples of when the event or situation occurs and examples of when the event or situation does not occur. For example, "optionally substituted aryl" means that the aryl group is substituted or not substituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0113] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. The pharmaceutically acceptable salts of any pyrazole compound described herein are intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0114] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. It also includes salts formed from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Amino acid salts, such as arginine salts, gluconates, and galacturons, are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt.

[0115] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the bioavailability and properties of free acids and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines (such as alkali metals and alkaline earth metals or organic amines). Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following: primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., above.

[0116] As used herein, the terms “treatment,” “treating,” “relief,” and “improvement” are used interchangeably. These terms refer to methods of achieving a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventive benefits). “Therapeutic benefit” means the eradication or improvement of an underlying condition that is being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying condition, such that improvement is observed in the patient even though the underlying condition remains. For preventive benefits, the composition is given to patients at risk of developing a specific disease, or patients who report one or more physical symptoms of a disease, even if the disease has not yet been diagnosed.

[0117] Compound

[0118] The compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) described herein are modulators of MAGL. In some embodiments, these compounds are inhibitors of MAGL. In some embodiments, the compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) described herein, and compositions comprising these compounds, may be used to treat pain, migraine, scleroderma, or nonalcoholic fatty liver disease (NASH).

[0119] In some embodiments, it is a compound having formula (I):

[0120]

[0121] in:

[0122] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0123] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0124] R 3 yes

[0125]

[0126] A is N or C(H);

[0127] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0128] Y is -CH2- or -C(O)-;

[0129] Z is -S-, -O-, or -N(R) 18 )-;

[0130] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 3-8 Cycloalkyl, C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 3-8 Cycloalkyl, C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0131] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0132] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0133] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0134] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0135] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0136] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0137] R 13 Is it H or C? 1-6 alkyl;

[0138] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)OH, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0139] R 15 Is it H or C? 1-6 alkyl;

[0140] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C 1-6 Alkyl group -OH or -CH2CO2H;

[0141] R 17 Is it H or C? 1-6 alkyl;

[0142] R 18 Is it H or C? 1-6 alkyl;

[0143] v is 0 or 1;

[0144] n is 0 or 1;

[0145] m is 0 or 1;

[0146] p is 0, 1, or 2; and

[0147] q is 0, 1, or 2;

[0148] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0149] In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 , R 10It is H, and R 11 It is H. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0150] In another embodiment, it is a compound having formula (I), wherein R 2 It is H. In another embodiment, it is a compound having formula (I), wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (I), wherein R 2 It is -Cl. In another embodiment, it is a compound having formula (I), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 2 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (I), wherein R 2 It is -CF3.

[0151] In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R3 yes In another embodiment, a compound having formula (I) is present, wherein A is N. In another embodiment, a compound having formula (I) is present, wherein A is C(H). In another embodiment, a compound having formula (I) is present, wherein R... 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein Z is -S-. In another embodiment, it is a compound having formula (I), wherein Z is -O-. In another embodiment, it is a compound having formula (I), wherein Z is -N(R)-. 18 In another embodiment, it is a compound having formula (I), wherein Z is -N(H)-. In another embodiment, it is a compound having formula (I), wherein Z is -N(CH3)-. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R13 It is -CH3.

[0152] In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, a compound having formula (I) is present, wherein A is N. In another embodiment, a compound having formula (I) is present, wherein A is C(H). In another embodiment, a compound having formula (I) is present, wherein R... 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein Z is -S-. In another embodiment, it is a compound having formula (I), wherein Z is -O-. In another embodiment, it is a compound having formula (I), wherein Z is -N(R)-. 18 In another embodiment, it is a compound having formula (I), wherein Z is -N(H)-. In another embodiment, it is a compound having formula (I), wherein Z is -N(CH3)-. In another embodiment, it is a compound having formula (I), wherein Y is -CH2-. In another embodiment, it is a compound having formula (I), wherein Y is -C(O)-. In another embodiment, it is a compound having formula (I), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having formula (I), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having formula (I), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having formula (I), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having formula (I), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, q is 2, and p is 1. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl and R 13It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0153] In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 12 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is a halogen. In another embodiment, it is a compound having formula (I), wherein R 12 It is F. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 12 It is C1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 12 It is -CH3 and R 13 It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein X is -O-. In another embodiment, it is a compound having formula (I), wherein X is -N(R)-. 16 In another embodiment, it is a compound having formula (I), wherein X is -N(H)-. In another embodiment, it is a compound having formula (I), wherein X is -N(CH3)-. In another embodiment, it is a compound having formula (I), wherein X is -N(R)-. 16 )-and R 16 It is -C 1-6 Alkyl-OH. In another embodiment, it is a compound having formula (I), wherein X is -CH2N(R 16 CH2-. In another embodiment, it is a compound having formula (I), wherein X is -CH2N(H)CH2-. In another embodiment, it is a compound having formula (I), wherein X is -CH2N(CH3)CH2-. In another embodiment, it is a compound having formula (I), wherein A is N. In another embodiment, it is a compound having formula (I), wherein A is C(H). In another embodiment, it is a compound having formula (I), wherein v is 0. In another embodiment, it is a compound having formula (I), wherein v is 1. In another embodiment, it is a compound having formula (I), wherein R 3 yes

[0154] In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 3-8 Cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14Substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -C 1-6 Alkyl-OH. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6Halogenated alkyl substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 3-8 Cycloalkyl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 3-8 Cycloalkyl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0155] In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (I), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0156] In another embodiment, it is a compound having formula (I), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (I), wherein R 5 It is H. In another embodiment, it is a compound having formula (I), wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (I), wherein R 5 It is -Cl. In another embodiment, it is a compound having formula (I), wherein R 5 It is -F. In another embodiment, it is a compound having formula (I), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 5It is -CH3. In another embodiment, it is a compound having formula (I), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (I), wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (I), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (I), wherein R 5 It is -OCF3.

[0157] In another embodiment, it is a compound having formula (I), wherein R 6 It is H. In another embodiment, it is a compound having formula (I), wherein R 6 It is a halogen. In another embodiment, it is a compound having formula (I), wherein R 6 It is -Cl. In another embodiment, it is a compound having formula (I), wherein R 6 It is -F. In another embodiment, it is a compound having formula (I), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (I), wherein R 6 It is -CH3.

[0158] In some embodiments, it is a compound having formula (I'):

[0159]

[0160] in:

[0161] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0162] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0163] R 3 yes

[0164] A is N or C(H);

[0165] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0166] Y is -CH2- or -C(O)-;

[0167] Z is -S-, -O-, or -N(R) 18 )-;

[0168] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0169] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0170] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0171] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0172] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0173] R10 and R 11 Each is independently H or C 1-6 alkyl;

[0174] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0175] R 13 Is it H or C? 1-6 alkyl;

[0176] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0177] R 15 Is it H or C? 1-6 alkyl;

[0178] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, or -CH2CO2H;

[0179] R 17 Is it H or C? 1-6 alkyl;

[0180] R 18 Is it H or C? 1-6 alkyl;

[0181] v is 0 or 1;

[0182] n is 0 or 1;

[0183] m is 0 or 1;

[0184] p is 0, 1, or 2; and

[0185] q is 0, 1, or 2;

[0186] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0187] In another embodiment, it is a compound having formula (I'), wherein R 1 It is -C(O)OR15 In another embodiment, it is a compound having formula (I'), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having formula (I'), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (I'), wherein R 1 It is -C(O)NR 10 R 11 , R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having formula (I'), wherein R 1 It is -C(O)NR 10 R 11 , R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 1 It is -C(O)NR 10 R 11 , R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 1 It is -C(O)NR 10 R 11 , R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 1 It is -C(O)NR 10 R 11 , R 10 It is -CH3, and R 11 It is -CH3.

[0188] In another embodiment, it is a compound having formula (I'), wherein R 2It is H. In another embodiment, it is a compound having formula (I'), wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (I'), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (I'), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (I'), wherein R 2 It is -CF3.

[0189] In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, a compound having formula (I') is present, wherein A is N. In another embodiment, a compound having formula (I') is present, wherein A is C(H). In another embodiment, a compound having formula (I') is present, wherein R... 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), where Z is -S-. In another embodiment, it is a compound having formula (I'), where Z is -O-. In another embodiment, it is a compound having formula (I'), where Z is -N(R)-. 18In another embodiment, it is a compound having formula (I'), wherein Z is -N(H)-. In another embodiment, it is a compound having formula (I'), wherein Z is -N(CH3)-. In another embodiment, it is a compound having formula (I'), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0190] In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, a compound having formula (I') is present, wherein A is N. In another embodiment, a compound having formula (I') is present, wherein A is C(H). In another embodiment, a compound having formula (I') is present, wherein R... 3 yes In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), where Z is -S-. In another embodiment, it is a compound having formula (I'), where Z is -O-. In another embodiment, it is a compound having formula (I'), where Z is -N(R)-. 18In another embodiment, it is a compound having formula (I'), wherein Z is -N(H)-. In another embodiment, it is a compound having formula (I'), wherein Z is -N(CH3)-. In another embodiment, it is a compound having formula (I'), wherein Y is -CH2-. In another embodiment, it is a compound having formula (I'), wherein Y is -C(O)-. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having formula (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having formula (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having formula (I'), or a solvation, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, q is 2, and p is 1. In another embodiment, it is a compound having formula (I'), wherein R... 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is -CH3 and R13 It is -CH3.

[0191] In another embodiment, it is a compound having formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), wherein R 12 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is a halogen. In another embodiment, it is a compound having formula (I'), wherein R 12 It is F. In another embodiment, it is a compound having formula (I'), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (I'), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 12 It is -CH3 and R 13 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 3 yes In another embodiment, it is a compound having formula (I'), where X is -O-. In another embodiment, it is a compound having formula (I'), where X is -N(R)-. 16In another embodiment, it is a compound having formula (I'), where X is -N(H)-. In another embodiment, it is a compound having formula (I'), where X is -N(CH3)-. In another embodiment, it is a compound having formula (I'), where X is -CH2N(R)-. 16 CH2-. In another embodiment, it is a compound having formula (I'), wherein X is -CH2N(H)CH2-. In another embodiment, it is a compound having formula (I'), wherein X is -CH2N(CH3)CH2-. In another embodiment, it is a compound having formula (I'), wherein A is N. In another embodiment, it is a compound having formula (I'), wherein A is C(H). In another embodiment, it is a compound having formula (I'), wherein v is 0. In another embodiment, it is a compound having formula (I'), wherein v is 1. In another embodiment, it is a compound having formula (I'), wherein R 3 yes

[0192] In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14Substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0193] In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (I'), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0194] In another embodiment, it is a compound having formula (I'), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (I'), wherein R 5 It is H. In another embodiment, it is a compound having formula (I'), wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (I'), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (I'), wherein R 5It is -F. In another embodiment, it is a compound having formula (I'), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (I'), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (I'), wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (I'), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (I'), wherein R 5 It is -OCF3.

[0195] In another embodiment, it is a compound having formula (I'), wherein R 6 It is H. In another embodiment, it is a compound having formula (I'), wherein R 6 It is a halogen. In another embodiment, it is a compound having formula (I'), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (I'), wherein R 6 It is -F. In another embodiment, it is a compound having formula (I'), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (I'), wherein R 6 It is -CH3.

[0196] In another embodiment, there is a compound having formula (I) and having the structure of formula (Ia):

[0197]

[0198] in:

[0199] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0200] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0201] A is N or C(H);

[0202] R 4 It is H, halogen, -OR 7 C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0203] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0204] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0205] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0206] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0207] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0208] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0209] R13 Is it H or C? 1-6 alkyl;

[0210] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0211] R 15 Is it H or C? 1-6 Alkyl; and

[0212] R 17 Is it H or C? 1-6 alkyl;

[0213] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0214] In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes In another embodiment, it is a compound having formula (I), wherein R 3 yes

[0215] In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0216] In another embodiment, it is a compound having formula (Ia), wherein R 2 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is -Cl. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ia), wherein R 2 It is -CF3.

[0217] In another embodiment, it is a compound having formula (Ia), wherein R 12 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is a halogen. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is F. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 13 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 13 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0218] In another embodiment, a compound having formula (Ia) is present, wherein A is C(H). In another embodiment, a compound having formula (Ia) is present, wherein A is N.

[0219] In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4It is -CF3. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes-OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0220] In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (Ia), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0221] In another embodiment, it is a compound having formula (Ia), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is -Cl. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is -F. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is -CH3. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is C 1-6Haloalkoxy groups. In another embodiment, it is a compound having formula (Ia), wherein R 5 It is -OCF3.

[0222] In another embodiment, it is a compound having formula (Ia), wherein R 6 It is H. In another embodiment, it is a compound having formula (Ia), wherein R 6 It is a halogen. In another embodiment, it is a compound having formula (Ia), wherein R 6 It is -Cl. In another embodiment, it is a compound having formula (Ia), wherein R 6 It is -F. In another embodiment, it is a compound having formula (Ia), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ia), wherein R 6 It is -CH3.

[0223] In another embodiment, there is a compound having formula (I) and having the structure of formula (Ib):

[0224]

[0225] in:

[0226] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0227] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0228] Z is -S-, -O-, or -N(R) 18 )-;

[0229] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0230] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0231] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0232] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0233] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0234] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0235] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0236] R 13 Is it H or C? 1-6 alkyl;

[0237] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0238] R 15 Is it H or C? 1-6 alkyl;

[0239] R 17 Is it H or C? 1-6 Alkyl; and

[0240] R 18 Is it H or C? 1-6 alkyl;

[0241] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0242] In another embodiment, it is a compound having formula (Ib), wherein R 3 yes In another embodiment, it is a compound having formula (Ib), wherein R 3 yes In another embodiment, it is a compound having formula (Ib), wherein R 3 yes

[0243] In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11It is H. In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0244] In another embodiment, it is a compound having formula (Ib), wherein R 2 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (Ib), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ib), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 2 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ib), wherein R 2 It is -CF3.

[0245] In another embodiment, it is a compound having formula (Ib), wherein R 12 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is a halogen. In another embodiment, it is a compound having formula (Ib), wherein R 12It is F. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 12 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 13 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 13 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0246] In another embodiment, a compound having formula (Ib) is present, wherein Z is -S-. In another embodiment, a compound having formula (Ib) is present, wherein Z is -O-. In another embodiment, a compound having formula (Ib) is present, wherein Z is -N(R)-. 18 In another embodiment, it is a compound having formula (Ib), where Z is -N(H)-. In another embodiment, it is a compound having formula (Ib), where Z is -N(CH3)-.

[0247] In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0248] In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9Heteroaryl. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (Ib), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0249] In another embodiment, it is a compound having formula (Ib), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is H. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ib), wherein R 5 It is -F. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 5 It is -CH3. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ib), wherein R 5 It is -OCF3.

[0250] In another embodiment, it is a compound having formula (Ib), wherein R 6It is H. In another embodiment, it is a compound having formula (Ib), wherein R 6 It is a halogen. In another embodiment, it is a compound having formula (Ib), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Ib), wherein R 6 It is -F. In another embodiment, it is a compound having formula (Ib), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ib), wherein R 6 It is -CH3.

[0251] In another embodiment, there is a compound having formula (I) and having the structure of formula (Ic):

[0252]

[0253] in:

[0254] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0255] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0256] Z is -S-, -O-, or -N(R) 18 )-;

[0257] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0258] R5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0259] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0260] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0261] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0262] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0263] R 13 Is it H or C? 1-6 alkyl;

[0264] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0265] R 15 Is it H or C? 1-6 alkyl;

[0266] R 17 Is it H or C? 1-6 Alkyl; and

[0267] R 18 Is it H or C? 1-6 alkyl;

[0268] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0269] In another embodiment, it is a compound having formula (Ic), wherein R 3 yes In another embodiment, it is a compound having formula (Ic), wherein R 3 yes In another embodiment, it is a compound having formula (Ic), wherein R 3 yes

[0270] In another embodiment, it is a compound having formula (Ic), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (Ic), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (Ic), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)NR 10 R11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0271] In another embodiment, it is a compound having formula (Ic), wherein R 2 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is a halogen. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ic), wherein R 2 It is -CF3.

[0272] In another embodiment, it is a compound having formula (Ic), wherein R 12 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is a halogen. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is F. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 13 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 13 It is C 1-6Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0273] In another embodiment, it is a compound having formula (Ic), where Z is -S-. In another embodiment, it is a compound having formula (Ic), where Z is -O-. In another embodiment, it is a compound having formula (Ic), where Z is -N(R)-. 18 In another embodiment, it is a compound having formula (Ic), where Z is -N(H)-. In yet another embodiment, it is a compound having formula (Ic), where Z is -N(CH3)-.

[0274] In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups.14 Substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0275] In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9Heteroaryl. In another embodiment, it is a compound having formula (Ic), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0276] In another embodiment, it is a compound having formula (Ic), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ic), wherein R 5 It is H. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is a halogen. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is -F. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (Ic), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ic), wherein R 5 It is -OCF3.

[0277] In another embodiment, a compound having formula (I) has the structure of formula (Id):

[0278]

[0279] in:

[0280] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0281] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6Halogenated alkyl groups;

[0282] A is N or C(H);

[0283] Y is -CH2- or -C(O)-;

[0284] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0285] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0286] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0287] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0288] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0289] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0290] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0291] R 13 Is it H or C? 1-6 alkyl;

[0292] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0293] R 15 Is it H or C? 1-6 alkyl;

[0294] R 17 Is it H or C? 1-6 alkyl;

[0295] n is 0 or 1;

[0296] m is 0 or 1;

[0297] p is 0, 1, or 2; and

[0298] q is 0, 1, or 2;

[0299] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0300] In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0301] In another embodiment, it is a compound having the formula (Id), wherein R 2 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 2 It is a halogen. In another embodiment, it is a compound having the formula (Id), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Id), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 2It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Id), wherein R 2 It is -CF3.

[0302] In another embodiment, it is a compound having the formula (Id), wherein R 12 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is a halogen. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is F. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 13 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 13 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0303] In another embodiment, a compound having formula (Id) is present, wherein A is C(H). In another embodiment, a compound having formula (Id) is present, wherein A is N.

[0304] In another embodiment, it is a compound having the formula (Id), where Y is -CH2-. In another embodiment, it is a compound having the formula (Id), where Y is -C(O)-.

[0305] In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, q is 2, and p is 1.

[0306] In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14Substitution. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0307] In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (Id), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0308] In another embodiment, it is a compound having the formula (Id), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is a halogen. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is -F. In another embodiment, it is a compound having the formula (Id), where R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Id), wherein R 5 It is -OCF3.

[0309] In another embodiment, it is a compound having the formula (Id), wherein R 6 It is H. In another embodiment, it is a compound having the formula (Id), wherein R 6 It is a halogen. In another embodiment, it is a compound having the formula (Id), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Id), wherein R 6 It is -F. In another embodiment, it is a compound having the formula (Id), where R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Id), wherein R 6 It is -CH3.

[0310] In another embodiment, there is a compound having formula (I) and having the structure of formula (Ie):

[0311]

[0312] in:

[0313] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0314] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0315] Y is -CH2- or -C(O)-;

[0316] Z is -S-, -O-, or -N(R) 18 )-;

[0317] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0318] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0319] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0320] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0321] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0322] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0323] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0324] R 13 Is it H or C? 1-6 alkyl;

[0325] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0326] R 15 Is it H or C? 1-6 alkyl;

[0327] R 17 Is it H or C? 1-6 alkyl;

[0328] R 18 Is it H or C? 1-6 alkyl;

[0329] n is 0 or 1;

[0330] m is 0 or 1;

[0331] p is 0, 1, or 2; and

[0332] q is 0, 1, or 2;

[0333] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0334] In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11It is -CH3.

[0335] In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is a halogen. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ie), wherein R 2 It is -CF3.

[0336] In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is a halogen. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is F. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 13 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is C 1-6 Alkyl and R 13It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0337] In another embodiment, it is a compound having the formula (Ie), wherein Y is -CH2-. In another embodiment, it is a compound having the formula (Ie), wherein Y is -C(O)-.

[0338] In another embodiment, it is a compound having the formula (Ie), where Z is -S-. In another embodiment, it is a compound having the formula (Ie), where Z is -O-. In another embodiment, it is a compound having the formula (Ie), where Z is -N(R)-. 18 In another embodiment, it is a compound having the formula (Ie), where Z is -N(H)-. In another embodiment, it is a compound having the formula (Ie), where Z is -N(CH3)-.

[0339] In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, q is 2, and p is 1.

[0340] In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having the formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4It is -CF3. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having formula (Ie), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0341] In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is a halogen. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is -F. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is C 1-6Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ie), wherein R 5 It is -OCF3.

[0342] In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is H. In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is a halogen. In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is -F. In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ie), wherein R 6 It is -CH3.

[0343] In another embodiment, there is a compound having formula (I) and having the structure of formula (If):

[0344]

[0345] in:

[0346] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0347] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0348] Y is -CH2- or -C(O)-;

[0349] Z is -S-, -O-, or -N(R) 18 )-;

[0350] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0351] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0352] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0353] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0354] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0355] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0356] R 13 Is it H or C? 1-6 alkyl;

[0357] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R)17 )C(O)-C 1-6 alkyl;

[0358] R 15 Is it H or C? 1-6 alkyl;

[0359] R 17 Is it H or C? 1-6 alkyl;

[0360] R 18 Is it H or C? 1-6 alkyl;

[0361] n is 0 or 1;

[0362] m is 0 or 1;

[0363] p is 0, 1, or 2; and

[0364] q is 0, 1, or 2;

[0365] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0366] In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)OR 15 In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)NR 10 R 11R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0367] In another embodiment, it is a compound having the formula (If), where R 2 It is H. In another embodiment, it is a compound having the formula (If), where R 2 It is a halogen. In another embodiment, it is a compound having the formula (If), where R 2 It is -Cl. In another embodiment, it is a compound having the formula (If), where R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 2 It is C 1-6 Halogenated alkyl groups. In another embodiment, it is a compound having the formula (If), wherein R 2 It is -CF3.

[0368] In another embodiment, it is a compound having the formula (If), where R 12 It is H. In another embodiment, it is a compound having the formula (If), where R 12 It is a halogen. In another embodiment, it is a compound having the formula (If), where R 12 It is F. In another embodiment, it is a compound having the formula (If), where R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R12 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 13 It is H. In another embodiment, it is a compound having the formula (If), where R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 13 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 12 It is H and R 13 It is H. In another embodiment, it is a compound having the formula (If), where R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having the formula (If), where R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having the formula (If), where R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0369] In another embodiment, it is a compound having the formula (If), where Y is -CH2-. In another embodiment, it is a compound having the formula (If), where Y is -C(O)-.

[0370] In another embodiment, it is a compound having the formula (If), where Z is -S-. In another embodiment, it is a compound having the formula (If), where Z is -O-. In another embodiment, it is a compound having the formula (If), where Z is -N(R)-. 18 In another embodiment, it is a compound having the formula (If), where Z is -N(H)-. In another embodiment, it is a compound having the formula (If), where Z is -N(CH3)-.

[0371] In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 1. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 1, q is 2, and p is 1. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 0, and p is 2. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 1, n is 1, q is 1, and p is 0. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein m is 0, n is 0, q is 2, and p is 1.

[0372] In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7It is -CF3. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0373] In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having the formula (If), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0374] In another embodiment, it is a compound having the formula (If), where R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (If), wherein R 5 It is H. In another embodiment, it is a compound having the formula (If), where R5 It is a halogen. In another embodiment, it is a compound having the formula (If), where R 5 It is -Cl. In another embodiment, it is a compound having the formula (If), where R 5 It is -F. In another embodiment, it is a compound having the formula (If), where R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (If), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (If), where R 5 It is C 1-6 Halogenated alkyl groups. In another embodiment, it is a compound having the formula (If), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (If), where R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (If), wherein R 5 It is -OCF3.

[0375] In another embodiment, a compound having formula (I) has the structure of formula (Ig):

[0376]

[0377] in:

[0378] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0379] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0380] A is N or C(H);

[0381] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0382] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0383] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0384] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0385] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0386] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0387] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0388] R 12 Is it H, halogen, or C? 1-6 alkyl;

[0389] R 13 Is it H or C? 1-6 alkyl;

[0390] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0391] R 15 Is it H or C? 1-6 alkyl;

[0392] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, or -CH2CO2H;

[0393] R 17 Is it H or C? 1-6 Alkyl; and

[0394] v is 0 or 1;

[0395] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0396] In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0397] In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is a halogen. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ig), wherein R 2 It is -CF3.

[0398] In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is a halogen. In another embodiment, it is a compound having the formula (Ig), wherein R 12It is F. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 13 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is H and R 13 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is H and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is H and R 13 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is C 1-6 Alkyl and R 13 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is -CH3 and R 13 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is C 1-6 Alkyl and R 13 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 12 It is -CH3 and R 13 It is -CH3.

[0399] In another embodiment, a compound having formula (Ig) is present, wherein A is N. In another embodiment, a compound having formula (Ig) is present, wherein A is C(H).

[0400] In another embodiment, it is a compound having the formula (Ig), wherein X is -O-. In another embodiment, it is a compound having the formula (Ig), wherein X is -N(R)-. 16 In another embodiment, it is a compound having formula (Ig), wherein X is -N(H)-. In another embodiment, it is a compound having formula (Ig), wherein X is -N(CH3)-. In another embodiment, it is a compound having formula (Ig), wherein X is -CH2N(R)-.16 CH2-. In another embodiment, it is a compound having the formula (Ig), wherein X is -CH2N(H)CH2-. In another embodiment, it is a compound having the formula (Ig), wherein X is -CH2N(CH3)CH2-.

[0401] In another embodiment, a compound having formula (Ig) is used, where v is 0. In yet another embodiment, a compound having formula (Ig) is used, where v is 1.

[0402] In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4It is -Cl. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14Substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ig), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0403] In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is a halogen. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is -F. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is -CH3. In another embodiment, it is a compound having the formula (Ig), wherein R5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ig), wherein R 5 It is -OCF3.

[0404] In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is H. In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is a halogen. In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is -F. In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ig), wherein R 6 It is -CH3.

[0405] In another embodiment, a compound having formula (I) has the structure of formula (Ih):

[0406]

[0407] in:

[0408] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0409] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0410] A is N or C(H);

[0411] X is -O-, -N(R) 16 - or -CH2N(R) 16 CH2-;

[0412] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0413] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0414] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0415] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0416] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0417] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0418] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C3-8 Cycloalkyl, -C(O)NR 8 R 9 -SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0419] R 15 Is it H or C? 1-6 alkyl;

[0420] R 16 It is H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl group, or -CH2CO2H;

[0421] R 17 Is it H or C? 1-6 Alkyl; and

[0422] v is 0 or 1;

[0423] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0424] In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is -CH3. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0425] In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is H. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is a halogen. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is -CH3. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ih), wherein R 2 It is -CF3.

[0426] In another embodiment, a compound having the formula (Ih) is present, wherein A is N. In another embodiment, a compound having the formula (Ih) is present, wherein A is C(H).

[0427] In another embodiment, it is a compound having the formula (Ih), wherein X is -O-. In another embodiment, it is a compound having the formula (Ih), wherein X is -N(R)-. 16In another embodiment, it is a compound having the formula (Ih), wherein X is -N(H)-. In another embodiment, it is a compound having the formula (Ih), wherein X is -N(CH3)-. In another embodiment, it is a compound having the formula (Ih), wherein X is -CH2N(R)-. 16 In another embodiment, X is a compound having the formula (Ih), wherein X is -CH2N(H)CH2-. In yet another embodiment, X is a compound having the formula (Ih), wherein X is -CH2N(CH3)CH2-.

[0428] In another embodiment, a compound having formula (Ih) is used, where v is 0. In yet another embodiment, a compound having formula (Ih) is used, where v is 1.

[0429] In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4It is a halogen. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R... 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heteroaryl. In another embodiment, it is a compound having the formula (Ih), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0430] In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is H. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is a halogen. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is -F. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 5It is -CH3. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is -CF3. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having the formula (Ih), wherein R 5 It is -OCF3.

[0431] In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is H. In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is a halogen. In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is -F. In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having the formula (Ih), wherein R 6 It is -CH3.

[0432] In another embodiment, there is a compound having formula (I) and having the structure of formula (Ii):

[0433]

[0434] in:

[0435] R 1 It is -C(O)OR 15 or -C(O)NR 10 R 11 ;

[0436] R 2 It is H, halogen, C 1-6 Alkyl, or C 1-6 Halogenated alkyl groups;

[0437] A is N or C(H);

[0438] R 4 It is H, halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R9 C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0439] R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or phenyl;

[0440] R 6 Is it H, halogen, or C? 1-6 alkyl;

[0441] R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 replace;

[0442] Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen attached to them, they form heterocyclic alkyl rings;

[0443] R 10 and R 11 Each is independently H or C 1-6 alkyl;

[0444] Each R 14 Independently selected from halogens, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)NR 8 R 9-SO2-C 1-6 Alkyl groups and -N(R) 17 )C(O)-C 1-6 alkyl;

[0445] R 15 Is it H or C? 1-6 Alkyl; and

[0446] R 17 Is it H or C? 1-6 alkyl;

[0447] Or its solvates, hydrates, tautomers, N-oxides, stereoisomers, or pharmaceutically acceptable salts.

[0448] In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)OR 15 In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)OR 15 And R 15 It is H. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)OR 15 And R 15 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)OR 15 And R 15 It is -CH3. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is H. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is H, and R 11It is -CH3. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is C 1-6 Alkyl, and R 11 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 1 It is -C(O)NR 10 R 11 R 10 It is -CH3, and R 11 It is -CH3.

[0449] In another embodiment, it is a compound having formula (Ii), wherein R 2 It is H. In another embodiment, it is a compound having formula (Ii), wherein R 2 It is a halogen. In another embodiment, it is a compound having formula (Ii), wherein R 2 It is -Cl. In another embodiment, it is a compound having the formula (Ii), wherein R 2 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 2 It is -CH3. In another embodiment, it is a compound having formula (Ii), wherein R 2 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ii), wherein R 2 It is -CF3.

[0450] In another embodiment, a compound having formula (Ii) is provided, wherein A is N. In another embodiment, a compound having formula (Ii) is provided, wherein A is C(H).

[0451] In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, -C(O)NR 8 R 9 C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, -C 1-6 Alkyl-C2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is halogen, -OR 7 C 1-6 Haloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 2-9 Heterocyclic alkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is a halogen. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -Cl. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is -CF3. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Haloalkyl, C 6-10 Aryl, or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14Substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 1-6 Halogenated alkyl group. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is -CF3. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is C 6-10 Aryl or C 1-9 heteroaryl, of which C 6-10 Aryl or C 1-9 The heteroaryl group is optionally surrounded by 1 or 2 R groups. 14 Substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is optionally converted by a halogen or C. 1-6 Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is unsubstituted. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is halogenated or C-shaped. 1-6Halogenated alkyl substitution. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Yes - OR 7 And R 7 It is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, wherein the phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl group is substituted with -Cl or -CF3. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9 Heterocyclic alkyl groups. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0452] In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It can be arbitrarily divided by 1 or 2 Rs 14 Replacement C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 It is unreplaced C 1-9 Heteroaryl. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 Is it by 1 or 2 Rs? 14 Replacement C 2-9Heteroaryl. In another embodiment, it is a compound having formula (Ii), or a solvate, hydrate, tautomer, N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof, wherein R 4 yes

[0453] In another embodiment, it is a compound having formula (Ii), wherein R 5 It is H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is H. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is a halogen. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is -Cl. In another embodiment, it is a compound having the formula (Ii), wherein R 5 It is -F. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is -CH3. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is C 1-6 Haloalkyl. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is -CF3. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is C 1-6 Haloalkoxy groups. In another embodiment, it is a compound having formula (Ii), wherein R 5 It is -OCF3.

[0454] In another embodiment, it is a compound having formula (Ii), wherein R 6 It is H. In another embodiment, it is a compound having formula (Ii), wherein R 6 It is a halogen. In another embodiment, it is a compound having formula (Ii), wherein R 6 It is -Cl. In another embodiment, it is a compound having the formula (Ii), wherein R 6 It is -F. In another embodiment, it is a compound having formula (Ii), wherein R 6 It is C 1-6 Alkyl group. In another embodiment, it is a compound having formula (Ii), wherein R 6 It is -CH3.

[0455] Other embodiments provided herein include combinations of one or more of the specific embodiments described above.

[0456] In some embodiments, the compounds disclosed herein are selected from Examples 1-456.

[0457] In another embodiment, it is a compound having the following structure:

[0458] Where R 4 R 5 R 6 R 12 and R 13 As defined in formula (Ia) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0459] Where R 4 R 5 R 6 R 12 and R 13 As defined in formula (Ia) described herein, and x and y are at least one amino acid (aa).

[0460] In another embodiment, it is a compound having the following structure:

[0461] Where R 4 R 5 R 6 R 12 R 13 And Z as defined in formula (Ib) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0462] Where R 4 R 5 R 6 R 12 R 13 And Z is as defined in formula (Ib) described herein, and x and y are at least one amino acid (aa).

[0463] In another embodiment, it is a compound having the following structure:

[0464] Where R 4 R 5 R 12 R 13And Z as defined in formula (Ic) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0465] Where R 4 R 5 R 12 R 13 And Z is as defined in formula (Ic) described herein, and x and y are at least one amino acid (aa).

[0466] In another embodiment, it is a compound having the following structure:

[0467] Where R 4 R 5 R 6 R 12 R 13 A, Y, m, n, p, and q are as defined in formula (Id) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0468] Where R 4 R 5 R 6 R 12 R 13 A, Y, m, n, p, and q are as defined in formula (Id) described herein, and x and y are at least one amino acid (aa).

[0469] In another embodiment, it is a compound having the following structure:

[0470] Where R 4 R 5 R 6 R 12 R 13 X, Y, Z, m, n, p, and q are as defined in formula (Ie) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0471] Where R 4 R 5 R 6 R 12 R 13 X, Y, Z, m, n, p, and q are as defined in formula (Ie) described herein, and x and y are at least one amino acid (aa).

[0472] In another embodiment, it is a compound having the following structure:

[0473] Where R 4 R 5 R 12 R 13 X, Y, Z, m, n, p, and q are as defined in the formula (If) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0474] Where R 4 R 5 R 12 R 13 X, Y, Z, m, n, p, and q are as defined in the formula (If) described herein, and x and y are at least one amino acid (aa).

[0475] In another embodiment, it is a compound having the following structure:

[0476] Where R 4 R 5 R 6 R 12 A, X, and v are as defined in formula (Ig) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0477] Where R 4 R 5 R 6 R 12 A, X, and v are as defined in formula (Ig) described herein, and x and y are at least one amino acid (aa).

[0478] In another embodiment, it is a compound having the following structure:

[0479] Where R 4 R 5 R 6 A, X, and v are as defined in formula (Ih) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0480] Where R 4 R 5 R 6A, X, and v are as defined in formula (Ih) described herein, and x and y are at least one amino acid (aa).

[0481] In another embodiment, it is a compound having the following structure:

[0482] Where R 4 R 5 and R 6 As defined in formula (Ii) described herein, and x and y are at least one amino acid (aa). In another embodiment, a compound having the following structure is provided:

[0483] Where R 4 R 5 and R 6 As defined in formula (Ii) described herein, and x and y are at least one amino acid (aa).

[0484] This article describes inhibitors of monoacylglycerol lipase (MAGL) having the structures of formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii). In one embodiment, the inhibitor of MAGL is a covalent inhibitor of MAGL, i.e., a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) reacts with serine residues of MAGL to form modified serine residues, which include retaining groups of formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii); in this embodiment, leaving groups of formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are removed from the compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii). In another embodiment, the covalent inhibitor of MAGL reacts irreversibly with the serine residues of MAGL to form modified serine residues.

[0485] The retained group portion of a compound having formula (Ia) is The retained group portion of a compound having formula (Ib) is The retained group portion of a compound having formula (Ic) is The retained group portion of a compound having formula (Id) is The retained group portion of a compound having formula (Ie) is The retained group portion of a compound having the formula (If) is The retained group portion of a compound having formula (Ig) is The retained group portion of a compound having formula (Ih) is The retained group portion of a compound having formula (Ii) is

[0486] The leaving group moiety of compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) is:

[0487]

[0488] Preparation of compounds

[0489] The compounds used in the reactions described herein were prepared using organic synthesis techniques, from commercially available chemicals, and / or from compounds described in chemical literature. "Commercially available chemicals" are derived from standard commercial sources, including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, Wisconsin, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, Illinois), Avocado Research (Lancashire, UK), BDH (Toronto, Canada), Bionet (Cornwall, UK), Chemservice (Westchester, Pennsylvania), Combi-blocks (San Diego, California), Crescent Chemical Co. (Hapak, NY), eMolecules (San Diego, California), and Fisher Chemical Co. Scientific Co. (Pittsburgh, Pennsylvania), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, California), Key Organics (Cormwick, UK), Lancaster Synthesis (Wyndham, New Hampshire), Matrix Scientific (Columbia, South Carolina), Maybridge Chemical Co. Ltd. (Cormwick, UK), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer (Waterbury, CN), Polyorganix (Houston, Texas), and Pierce Chemical Co.(Rockford, Illinois), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, South Carolina), Spectrum Chemicals (Gardina, California), Sundia Meditech (Shanghai, China), TCI USA (Portland, Oregon), Trans World Chemicals, Inc. (Rockville, Maryland), and Wuxi (Shanghai, China).

[0490] Suitable reference books and papers that detail the synthesis of reactants that can be used to prepare the compounds described in this article, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd ed., Academic Press, New York, 1983; HO House, "Modern Synthetic Reactions," 2nd ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; TL. Gilchrist, "Heterocyclic Chemistry," 2nd ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and..." Structure, 4th edition, Wiley-Interscience, New York, 1992. Other suitable references and papers detailing the synthesis of reactants that can be used to prepare the compounds described herein, or providing references to articles describing such preparations, include, for example, Fuhrhop, J. and Penzlin G., “Organic Synthesis: Concepts, Methods, Starting Materials,” Second, Revised and Enlarged Edition (1994), John Wiley & Sons, ISBN: 3-527-29074-5; Hoffman, RV, “Organic Chemistry, An Intermediate Text” (1996), Oxford University Press, ISBN 0-19-509618-5; Larock, RC."Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd Edition (1999), Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," 4th Edition (1992), John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (ed.), "Modern Carbonyl Chemistry" (2000), Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups (Pattel's 1992 Guide to Functional Group Chemistry) "(1992) Interscience ISBN: 0-471-93022-9; Solomons, TWG "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC"Intermediate Organic Chemistry," 2nd edition (1993), Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999), John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000), John Wiley & Sons, over 55 volumes; and "Chemistry of Functional Groups," John Wiley & Sons, 73 volumes.

[0491] Specific and similar reactants are also identified by the known chemicals index compiled by the American Chemical Society's Chemical Abstracts Service, which is available in most public and university libraries, as well as through online databases (American Chemical Society, Washington, D.C.). Chemicals known in the catalogue but not commercially available are optionally prepared by custom chemical synthesis companies, many of which offer custom synthesis services to standard chemical suppliers (such as those listed above). References for the preparation and selection of pharmaceutical salts of the compounds described herein are PHStahl & C.G. Wermuth, “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0492] Other forms of the compounds disclosed in this article

[0493] Isomers

[0494] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and corresponding mixtures thereof. In some cases, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers and corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of racemic mixtures. In some embodiments, the compounds described herein are prepared as their independent stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomers, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomer salts). In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that does not cause racemization.

[0495] Labeled compounds

[0496] In some embodiments, the compounds described herein are present in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds (as a pharmaceutical composition). Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are the same as those listed herein, but except that one or more atoms are replaced by atoms having an atomic weight or mass number different from those normally found in nature. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, respectively.2 H, 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, and 36 Cl. The compounds described herein, and their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, or derivatives (other isotopes containing the aforementioned isotopes and / or other atoms) are all within the scope of this invention. Certain isotope-labeled compounds, such as those combined with radioactive isotopes (e.g., 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium-containing (i.e....) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, heavy isotopes such as deuterium (i.e., 2 H) substitution produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. In some embodiments, the isotopically labeled compound, its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative is prepared by any suitable method.

[0497] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0498] Pharmaceutically acceptable salts

[0499] In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts of themselves. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts (as a pharmaceutical composition).

[0500] In some embodiments, the compounds described herein have acidic or basic groups and thus react with a number of inorganic or organic bases, as well as any of inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by reacting the purified compound in its free form with a suitable acid or base alone and isolating the salts thus formed.

[0501] solvates

[0502] In some embodiments, the compounds described herein are present as solvates. In some embodiments, methods of treating a disease are performed by administering such solvates. Methods of treating a disease by administering such solvates (as pharmaceutical compositions) are further described herein.

[0503] The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during a crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent (including, but not limited to, dioxane, tetrahydrofuran, or MeOH). Furthermore, the compounds provided herein are present in both unsolvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0504] prodrug

[0505] In some embodiments, the compounds described herein are in the form of prodrugs. Methods for treating diseases by administering such prodrugs are also described herein. Methods for treating diseases by administering such prodrugs (as pharmaceutical compositions) are further described herein.

[0506] In some embodiments, the prodrug comprises a compound in which a polypeptide chain of one or more amino acid residues (e.g., two, three, or four) amino acid residues is covalently linked via an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of the compound described herein. The amino acid residues include, but are not limited to, 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, chain-locked lysine, isochain-locked lysine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. In other embodiments, the prodrug comprises a compound in which an oligonucleotide of one or more nucleic acid residues (e.g., two, three, or four) is covalently linked to the compound described herein.

[0507] Pharmaceutically acceptable prodrugs of the compounds described herein also include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts, and sulfonates. In some embodiments, compounds having a free amino, amide, hydroxyl, or carboxyl group are converted into prodrugs. For example, a free carboxyl group is derived into an amide or alkyl ester. In some cases, all of these prodrug moieties are bound to groups (including, but not limited to, ether, amine, and carboxylic acid functional groups).

[0508] Hydroxyl prodrugs include esters, such as, but not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonates, sulfate esters, and disulfide-containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetate, and phosphoryloxymethoxycarbonyl compounds, as outlined in Advanced Drug Delivery Reviews 1996, 19, 115.

[0509] Amine-derived prodrugs include, but are not limited to, the following groups and combinations of groups:

[0510]

[0511] And sulfonamides and phosphonamides.

[0512] In some cases, sites on any aromatic ring portion are susceptible to various metabolic reactions, so incorporating appropriate substituents into the aromatic ring structure can reduce, minimize, or eliminate this metabolic pathway.

[0513] Pharmaceutical Composition

[0514] In some embodiments, compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein are administered as pure chemicals. In some embodiments, compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein are combined with pharmaceutically suitable or acceptable carriers (also referred to herein as pharmaceutically suitable (or acceptable) excipients, physiologically suitable (or acceptable) excipients, or physiologically suitable (or acceptable) carriers) selected based on a chosen administration route and standard pharmaceutical practice (such as, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub, Easton, PA (2005))).

[0515] Therefore, this document provides a pharmaceutical composition comprising at least one compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide, together with one or more pharmaceutically acceptable carriers. One or more carriers (or one or more excipients) are acceptable or suitable if the carrier is compatible with the other components of the composition and is harmless to the recipient of the composition (i.e., the subject).

[0516] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (I), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ia), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ib), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ic), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Id), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ie), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (If), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ig), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ih), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having formula (Ii), or a pharmaceutically acceptable salt thereof.

[0517] Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ia), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ib), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ic), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Id), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (If), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ig), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ih), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable excipient and a compound having formula (Ii), or a pharmaceutically acceptable salt thereof.

[0518] In some embodiments, compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein are substantially pure because they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or byproducts generated, for example, in one or more steps of the synthetic method.

[0519] These dosage forms include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), vaginal, ocular, or aerosol administration, although the most appropriate form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound used. For example, the disclosed compositions are formulated to unit doses and / or formulated for oral or subcutaneous administration.

[0520] Exemplary pharmaceutical compositions are used in the form of pharmaceutical formulations, such as solid, semi-solid, or liquid forms, comprising one or more of the disclosed compounds (as active ingredients, in the form of a mixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application). In some embodiments, the active ingredient is compounded, for example, with a generally non-toxic, pharmaceutically acceptable carrier for use in tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The active target compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect against the progression or condition of the disease.

[0521] In some embodiments used to prepare solid compositions (such as tablets), the major active ingredient is mixed with a pharmaceutical carrier, such as a conventional tableting component (e.g., corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum), and other pharmaceutical diluents (e.g., water) to form a solid preformation composition containing a homogeneous mixture of the disclosed compound or a non-toxic, pharmaceutically acceptable salt thereof. When these preformation compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, making the composition easily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0522] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) intended for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate), and / or any of the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethyl cellulose, hydroxypropyl methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants. (3) Disintegrants, such as glycerin; (4) Disintegrants, such as crosvidone, croscarboxymethyl cellulose sodium, starch glycolate sodium, agar, calcium carbonate, potato starch or cassava starch, alginic acid, certain silicates, and sodium carbonate; (5) Solution blockers, such as paraffin; (6) Absorption promoters, such as quaternary ammonium compounds; (7) Wetting agents, such as sodium docusate, cetyl alcohol, and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof; and (10) Colorants. In the case of capsules, tablets, and pills, in some embodiments, the composition contains a buffer. In some embodiments, similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose (or milk sugars) and high molecular weight polyethylene glycol.

[0523] In some embodiments, tablets are made by compression or molding, optionally with one or more auxiliary ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or croscarmellose sodium), surfactants, or dispersants. In some embodiments, molded tablets are prepared by molding a mixture of a subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) are scored or prepared with coatings and shells (such as enteric coatings and other coatings).

[0524] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage form contains inert diluents (such as water or other solvents), solubilizers and emulsifiers (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol), oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0525] In some embodiments, in addition to the subject composition, the suspension also contains a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth gum, and mixtures thereof.

[0526] In some embodiments, the dosage form for rectal or vaginal administration is presented as a suppository prepared by mixing the subject composition with one or more suitable non-irritating excipients or carriers (including, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylates), and is solid at room temperature but liquid at body temperature, and thus melts in the body cavity and releases the active agent.

[0527] Dosage forms for transdermal administration of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In some embodiments, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and, as needed, with any preservative, buffer, or propellant.

[0528] In some embodiments, in addition to the subject composition, ointments, pastes, creams, and gels contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0529] In some embodiments, in addition to the subject composition, the powder and spray contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, the spray additionally contains conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0530] In some embodiments, the compounds described herein are formulated as eye drops for ocular administration.

[0531] The compositions and compounds disclosed herein can alternatively be administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. In some embodiments, non-aqueous suspensions (e.g., fluorocarbon propellants) are used. In some embodiments, sonic atomizers are used because they minimize the reagent's exposure to shear, which leads to degradation of the compounds contained in the subject composition. Typically, aqueous aerosols are prepared by formulating the subject composition together with conventionally pharmaceutically acceptable carriers and stabilizers in aqueous solutions or suspensions. Carriers and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), harmless proteins (like serum albumin), sorbitol esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0532] Pharmaceutical compositions suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically acceptable sterile isotonic or non-aqueous aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, wherein the sterile powders are now reconstituted into sterile injectable solutions or dispersions prior to use. In some embodiments, the sterile injectable solutions or dispersions contain antioxidants, buffers, antibacterial agents, solutes (making the dosage form isotonic with the intended recipient's blood), or suspending agents or thickeners.

[0533] Examples of suitable aqueous and non-aqueous carriers for use in pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate) and cyclodextrins. For example, by using coating materials (such as lecithin), by maintaining the desired particle size (in the case of dispersions), and by using surfactants to maintain appropriate flowability.

[0534] Enteric drug formulations were also considered, including the disclosed compounds, enteric-coated materials, and their pharmaceutically acceptable carriers or excipients. Enteric-coated materials are polymers that are substantially insoluble in the acidic environment of the stomach and primarily soluble in intestinal fluid at a specific pH. The small intestine is the portion of the gastrointestinal tract (digestive tract) between the stomach and large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is approximately 5.5, the jejunum is approximately 6.5, and the terminal ileum is approximately 7.5. Therefore, enteric materials are insoluble at pH values ​​up to, for example, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.2, about 8.4, about 8.6, about 8.8, about 9.0, about 9.2, about 9.4, about 9.6, about 9.8, or about 10.0. Exemplary enteric materials include cellulose phthalate acetate (CAP), hydroxypropyl methyl phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), cellulose trimellitate acetate, hydroxypropyl methyl succinate, cellulose acetate succinate, cellulose hexahydrophthalate, cellulose propionate, cellulose maleate, cellulose butyrate, cellulose propionate, copolymers of methyl methacrylate and methyl methacrylate, copolymers of methyl acrylate, methyl methacrylate and methacrylate, copolymers of methyl vinyl ether and maleic anhydride (Gantrez ES series), ethyl methacrylate-methyl methacrylate-trimethylammonium chloride ethyl acrylate copolymers, natural resins (such as corn gluten, shellac, and copal collophorium), and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L30D, etc.). L100, Eudragit S100, Kollicoat EMM30D, Estacryl30D, Coateric, and Aquateric. The solubility of each of the above materials is known or readily measurable in vitro.

[0535] The dosage of a composition comprising at least one compound having the formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein varies depending on the patient's (e.g., human) condition (i.e., stage of disease), overall health status, age, and other factors.

[0536] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dose and suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provides an amount of one or more compositions sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes, such as more frequent complete or partial remission, or longer disease-free and / or overall survival, or reduction in symptom severity). The optimal dose is typically determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends on the patient's body mass, weight, or blood volume.

[0537] Oral dosage typically ranges from about 1.0 mg to about 1000 mg, once to four times or more daily.

[0538] method

[0539] This document discloses methods for modulating MAGL activity. Considered methods include, for example, exposing the enzyme to compounds described herein. In some embodiments, the compounds used by one or more of the foregoing methods are one of the genera, subgenera, or specific compounds described herein, such as compounds having the formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii). In some embodiments, compounds having the formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are provided herein, wherein the compound is an MAGL inhibitor. In some embodiments, compounds having the formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are provided herein, wherein the compound is a selective MAGL inhibitor. The ability of the compounds described herein to modulate or inhibit MAGL is evaluated using procedures known in the art and / or described herein. Another aspect of this disclosure provides a method for treating patients with diseases associated with MAGL expression or activity. In some embodiments, compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are provided herein, wherein the compound is selective in inhibiting MAGL compared to inhibiting other serine hydrolases. In some embodiments, compounds having formulas (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) are provided herein, wherein the compound is 10, 100, or 1000-fold selective in inhibiting MAGL compared to inhibiting other serine hydrolases.

[0540] In another embodiment, a method for treating pain in a patient includes administering to a patient in need a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to treat the pain. In another embodiment, a method for treating neuropathic pain in a patient includes administering to a patient in need a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to treat the neuropathic pain. In another embodiment, a method for treating inflammatory pain in a patient includes administering to a patient in need a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to treat the inflammatory pain. In another embodiment, a method for treating chronic pain in a patient includes administering to a patient in need a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvation, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof, to treat the chronic pain.

[0541] In another embodiment, it is a method for treating migraine in a patient in need, the method comprising administering a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0542] In another embodiment, it is a method of treating scleroderma in a patient in need, the method comprising administering a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0543] In another embodiment, it is a method for treating non-alcoholic fatty liver disease (NASH) in a patient in need, the method comprising administering a therapeutically effective amount of a compound having formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii) as described herein, or a solvate, hydrate, tautomer, N-oxide, or pharmaceutically acceptable salt thereof.

[0544] In some embodiments, the disclosed compound used by one or more of the foregoing methods is one of the genera, subgenera or specific compounds described herein, such as compounds having the formula (I), (I'), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii).

[0545] The disclosed compounds are administered to patients (animals and humans) requiring this treatment at doses that will provide optimal pharmaceutical efficacy. It should be understood that the required dose for any specific application will vary from patient to patient, not only with the specific compound or composition chosen, but also with the route of administration, the nature of the condition being treated, the patient's age and condition, any subsequent concomitant medications or special diet followed by the patient, and other factors. The appropriate dose is ultimately determined by the attending physician. For the treatment of the aforementioned clinical conditions and diseases, the compounds disclosed herein are administered orally, subcutaneously, topically, parenterally, via inhalation spray, or rectally in dosage forms containing conventional, non-toxic, and pharmaceutically acceptable carriers, adjuvants, and mediators. Parenteral administration includes subcutaneous injection, intravenous injection, or intramuscular injection or infusion techniques.

[0546] This article also considers combination therapies, such as co-administering the disclosed compounds and additional active agents as part of a specific treatment regimen designed to provide a beneficial effect through the combined action of these therapeutic agents. The beneficial effect of such a combination includes, but is not limited to, the synergistic pharmacokinetic or pharmacodynamic effects produced by the combination of therapeutic agents. These therapeutic agents are typically administered in combination over a defined time period (usually weeks, months, or years, depending on the chosen combination). Combination therapies are intended to cover the sequential administration of multiple therapeutic agents, i.e., each therapeutic agent is administered at different times, and the administration of these therapeutic agents or at least two of these therapeutic agents in a substantially simultaneous manner.

[0547] Simultaneous administration is achieved, for example, by administering a single dosage form or composition (e.g., tablets or capsules of each therapeutic agent in a fixed proportion) or multiple single dosage forms of each therapeutic agent (e.g., capsules). The sequential or substantially simultaneous administration of each therapeutic agent is achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents may be administered via the same or different routes. For example, the first therapeutic agent in a selected combination may be administered intravenously, while the other therapeutic agents in the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered intravenously.

[0548] Combination therapy also encompasses the further administration of therapeutic agents as described above in combination with other bioactive ingredients and non-pharmacological therapies. When combination therapy further includes non-pharmacological treatment, this treatment is administered at any appropriate time, provided that the beneficial effects from the combined action of the therapeutic agent and non-pharmacological treatment are achieved. For example, where appropriate, when non-pharmacological treatment is temporarily removed from the administration of the therapeutic agent, it may still provide beneficial effects for several days or even weeks.

[0549] The combined components are administered to the patient simultaneously or sequentially. It will be understood that these components are contained in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredient may be contained in a separate drug carrier, as in conventional oral dosage forms administered simultaneously or sequentially.

[0550] In some embodiments, for the intended treatment of pain, the disclosed compound is co-administered with another pain treatment agent such as an opioid, a cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2 inhibitor, acetaminophen, and / or a nonsteroidal anti-inflammatory drug. For example, additional pain treatment agents co-administered include morphine, codeine, hydromorphone, hydrocodone, hydroxymorphone, fentanyl, tramadol, and levonorgestrel.

[0551] In some embodiments, for the intended treatment of pain, the disclosed compounds are co-administered, including aspirin, naproxen, ibuprofen, disalicylate, diflunisal, dextro-ibuprofen, fenprofen, ketoprofen, oxapazine, loxoprofen, indomethacin, tometetin, sulphurin, etodoxacin, ketoroxyprofen, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, celecoxib, parecoxib, rimonaban, and / or etoricoxib.

[0552] The following examples are provided merely as illustrations of various embodiments and should not be construed as limiting the invention in any way.

[0553] Example

[0554] List of abbreviations

[0555] As used above, and throughout the description of this invention, unless otherwise stated, the following abbreviations should be understood to have the following meanings:

[0556] ACN or MeCN acetonitrile

[0557] Bn benzyl

[0558] BOC or Boc tert-butyl carbamate

[0559] CDI 1,1'-carbonyldiimidazole

[0560] Cy cyclohexyl

[0561] DCE (dichloroethane) (ClCH2CH2Cl)

[0562] DCM (dichloromethane (CH2Cl2))

[0563] DIPEA or DIEA diisopropylethylamine

[0564] DMAP 4-(N,N-dimethylamino)pyridine

[0565] DMF dimethylformamide

[0566] DMA N,N-dimethylacetamide

[0567] DMSO (dimethyl sulfoxide)

[0568] equivalent

[0569] Et ethyl

[0570] EtOH (ethanol)

[0571] Ethyl acetate (EtOAc)

[0572] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0573] HPLC (High Performance Liquid Chromatography)

[0574] LAH Lithium Aluminum Hydrogen

[0575] Memethyl

[0576] MeOH methanol

[0577] MS mass spectrometry

[0578] NMM N-methylmorpholine

[0579] NMR nuclear magnetic resonance

[0580] PMB p-methoxybenzyl

[0581] TEA Triethylamine

[0582] TFA (trifluoroacetic acid)

[0583] THF tetrahydrofuran

[0584] TLC (Thin-Layer Chromatography)

[0585] I. Chemical Synthesis

[0586] Unless otherwise specified, reagents and solvents are used as received from commercial suppliers. Anhydrous solvents and dried glassware are used for synthetic transformations sensitive to moisture and / or oxygen. Yields are not optimized. Reaction times are approximate and not optimized. Unless otherwise specified, column chromatography and thin-layer chromatography (TLC) are performed on silica gel. Spectra are given in ppm (δ) and coupling constants (J) are reported in Hertz. For proton spectra, the solvent peak is used as a reference peak.

[0587] Example 1: 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0588]

[0589] Step 1: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0590]

[0591] In a flask, 1H-pyrazole-3-carboxylic acid (5.00 g, 44.6 mmol, 1.00 equivalent), tert-butanol (50 mL), di-tert-butyl dicarbonate (39.0 g, 179 mmol, 4.01 equivalent), triethylamine (27.0 g, 268 mmol, 6.00 equivalent), and DMAP (1.10 g, 9.00 mmol, 0.20 equivalent) were added. The resulting solution was stirred overnight at 65 °C and quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), the organic layers were combined, washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.2 g (crude) of di-tert-butyl 1H-pyrazole-1,3-dicarboxylic acid as a yellow oil. LCMS (ESI, m / z): 169 [M+H-Boc] + .

[0592] Step 2: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0593]

[0594] A flask was filled with 1H-pyrazole-1,3-di-tert-butyl ester (5.00 g, 18.6 mmol, 1.00 equivalent), MeOH (30 mL), NaOH (2.50 g, 62.5 mmol, 3.35 equivalent), and water (5 mL). The resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The mixture was extracted with EtOAc (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 3.05 g (crude) of 1H-pyrazole-3-di-butyl ester as a yellow solid. LCMS (ESI, m / z): 169 [M+H] + .

[0595] Step 3: Preparation of 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride

[0596]

[0597] Triphosgene (210 mg, 1.00 mmol, 1.00 equivalent), DCM (10 mL), and 1-[(4-chlorophenyl)methyl]piperazine (206 mg, 0.698 mmol, 0.70 equivalent) were charged into a flask. DIPEA (516 mg, 3.99 mmol, 4.00 equivalent) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 2 h and quenched with water (20 mL). The mixture was extracted with DCM (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 250 mg (crude) of 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride as a yellow oil.

[0598] Step 4: Preparation of tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0599]

[0600] In a flask, 4-(4-chlorobenzyl)piperazine-1-carbonyl chloride (250 mg, 0.920 mmol, 1.00 equivalent), THF (10 mL), tert-butyl 1H-pyrazole-3-carboxylate (155 mg, 0.920 mmol, 1.01 equivalent), DIPEA (237 mg, 1.83 mmol, 2.00 equivalent), and DMAP (22.0 mg, 0.180 mmol, 0.20 equivalent) were added. The resulting solution was stirred overnight at 60 °C and quenched with water (5 mL). The mixture was extracted with EtOAc (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide 260 mg (70% yield) of tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a yellow oil. LCMS (ESI, m / z): 405 [M+H] + .

[0601] Step 5: Preparation of 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0602]

[0603] In a flask, tert-butyl 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid (260 mg, 0.861 mmol, 1.00 equivalent), DCM (10 mL), and TFA (1 mL) were added. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The crude product was purified by preparative HPLC to provide 66.6 mg (30% yield) of 1-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a yellow solid. 1 H NMR (400MHz, CD3OD) δ8.08(s,1H),7.34-7.39(m,4H),6.75(s,1H),3.68-4.14(m,4H),3.52-3.77(m,2H),2.47-2.70(m,4H). LCMS (ESI, m / z): 349[M+H] + .

[0604] Example 2: 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0605]

[0606] Step 1: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0607]

[0608] A flask was filled with 1H-pyrazole-3-carboxylic acid (5.00 g, 44.6 mmol, 1.00 equivalent), tert-butanol (50 mL), di-tert-butyl dicarbonate (39.0 g, 179 mmol, 4.01 equivalent), triethylamine (27.0 g, 268 mmol, 6.00 equivalent), and DMAP (1.10 g, 9.00 mmol, 0.20 equivalent). As described in step 1 of Example 1, the resulting solution was stirred overnight at 65 °C and quenched with water (20 mL) to provide 11.2 g (crude) of di-tert-butyl 1H-pyrazole-1,3-dicarboxylic acid as a yellow oil. LCMS (ESI, m / z): 169 [M+H-Boc] + .

[0609] Step 2: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0610]

[0611] A flask was filled with 1H-pyrazole-1,3-di-tert-butyl ester (5.00 g, 18.6 mmol, 1.00 equivalent), MeOH (30 mL), NaOH (2.50 g, 62.5 mmol, 3.35 equivalent), and water (5 mL). As described in step 2 of Example 1, the resulting solution was stirred overnight at room temperature and quenched with water (10 mL) to provide 3.05 g (crude) of 1H-pyrazole-3-di-butyl ester as a yellow solid. LCMS (ESI, m / z): 169 [M+H] + .

[0612] Step 3: Preparation of tert-butyl 4-(3-phenoxybenzyl)piperazine-1-carboxylate

[0613]

[0614] A flask was loaded with 3-phenoxybenzaldehyde (5.00 g, 25.2 mmol, 1.00 equivalent), tert-butyl piperazine-1-carboxylate (4.25 g, 22.8 mmol, 0.90 equivalent), and DCE (100 mL). The mixture was stirred at room temperature for 1 h, and then sodium triacetoxyborohydride (10.6 g, 50.0 mmol, 1.98 equivalent) was added. The resulting solution was stirred overnight at room temperature and quenched with water (50 mL). The mixture was extracted with DCM (3 x 50 mL), the organic layers were combined, washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide 8.80 g (95% yield) of 4-(3-phenoxybenzyl)piperazine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 369 [M+H] + .

[0615] Step 4: Preparation of 1-(3-phenoxybenzyl)piperazine

[0616]

[0617] A flask was filled with 8.80 g (23.9 mmol, 1.00 equivalent) of 4-(3-phenoxybenzyl)piperazine-1-carboxylic acid tert-butyl ester, 1,4-dioxane (50 mL), and concentrated hydrochloric acid (5 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure to provide 6.03 g (crude product) of 1-(3-phenoxybenzyl)piperazine as a white solid. LCMS (ESI, m / z): 269 [M+H] + .

[0618] Step 5: Preparation of 4-(3-phenoxybenzyl)piperazine-1-carbonyl chloride

[0619]

[0620] In a flask, 1-(3-phenoxybenzyl)piperazine (200 mg, 0.751 mmol, 1.00 equivalent), DCM (10.0 mL), and triphosgene (135 mg, 0.451 mmol, 0.70 equivalent) were added dropwise. DIPEA (388 mg, 3.00 mmol, 4.00 equivalent) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 5 h and quenched with water (20 mL). As described in step 3 of Example 1, the mixture was extracted with DCM (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 217 mg (crude) of 4-[(3-phenoxyphenyl)methyl]piperazine-1-carbonyl chloride as a yellow oil.

[0621] Step 6: Preparation of tert-butyl 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0622]

[0623] In a flask, 4-[(3-phenoxyphenyl)methyl]piperazine-1-carbonyl chloride (217 mg, 0.661 mmol, 1.00 equivalent), THF (10 mL), tert-butyl 1H-pyrazole-3-carboxylate (110 mg, 0.652 mmol, 1.00 equivalent), DMAP (16.2 mg, 0.131 mmol, 0.20 equivalent), and DIPEA (169 mg, 1.31 mmol, 2.00 equivalent) were added. The resulting solution was stirred overnight at 60 °C and quenched with water (20 mL). As described in step 4 of Example 1, the mixture was extracted with EtOAc (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to provide 120 mg (40% yield) of 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a yellow oil. LCMS (ESI, m / z): 463 [M+H] +

[0624] Step 7: Preparation of 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0625]

[0626] In a flask, tert-butyl 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid (120 mg, 0.261 mmol, 1.00 equivalent), DCM (5 mL), and TFA (1 mL) were charged. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure as described in step 5 of Example 1. The crude product was purified by preparative HPLC to provide 81.6 mg (77% yield) of 1-(4-(3-phenoxybenzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white powder. 1H NMR: (400MHz, CD3OD) δ8.15(s,1H),7.33-7.48(m,3H),7.11-7.27(m,2H),7.06-7.11(s,1H),6.99-7.06(m,2 H), 6.90-6.99 (m, 1H), 6.75-6.90 (m, 1H), 3.82-4.13 (s, 4H), 3.70-3.82 (d, J = 8.2Hz, 2H), 2.60-2.93 (s, 4H). LCMS (ESI, m / z): 407[M+H] + .

[0627] Example 3: 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0628]

[0629] Step 1: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0630]

[0631] As described in step 1 of Example 1, 1H-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equivalent), DMAP (2.15 g, 17.6 mmol, 0.20 equivalent), triethylamine (27.0 g, 267 mmol, 3.00 equivalent), di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equivalent), and tert-butanol (100 mL) were charged into a flask. The resulting solution was stirred at 80 °C for 4 h and concentrated under reduced pressure to provide 25.0 g (crude product) of 1H-pyrazole-1,3-di-tert-butyl dicarboxylic acid as a red oil. LCMS (ESI, m / z): 269 [M+H] + .

[0632] Step 2: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0633]

[0634] A flask was packed with 1H-pyrazole-1,3-dicarboxylic acid 1,3-di-tert-butyl ester (25.0 g, 93.2 mmol, 1.00 equivalent), NaOH (5.60 g, 140 mmol, 1.50 equivalent), water (80 mL), and MeOH (240 mL). The resulting solution was stirred at room temperature for 2 h and concentrated under reduced pressure as described in step 2 of Example 1. The residue was separated by silica gel column chromatography to provide 10.0 g (64% yield) of 1H-pyrazole-3-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 169 [M+H] + .

[0635] Step 3: Preparation of 2-morpholino-4-(trifluoromethyl)benzaldehyde

[0636]

[0637] Under nitrogen atmosphere, 2-fluoro-4-(trifluoromethyl)benzaldehyde (3.00 g, 15.6 mmol, 1.00 equivalent), potassium carbonate (8.62 g, 62.4 mmol, 4.00 equivalent), morpholine (2.72 g, 31.2 mmol, 2.00 equivalent), and DMSO (40 mL) were charged into a flask. The resulting solution was stirred overnight at 100 °C and then quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL), the organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used to provide 1.86 g (46% yield) of 2-(morpholino-4-yl)-4-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m / z): 260 [M+H] + .

[0638] Step 4: Preparation of tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid

[0639]

[0640] In a flask, 0.600 g (2.31 mmol, 1.00 equivalent) of 2-(morpholino-4-yl)-4-(trifluoromethyl)benzaldehyde, 0.646 g (3.47 mmol, 1.50 equivalent) of piperazine-1-carboxylate, and 20 mL of DCM were added. The mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (1.96 g, 9.23 mmol, 4.00 equivalent) was added as described in step 3 of Example 2. The residue was separated by chromatography to provide 0.920 g (93% yield) of ...+ .

[0641] Step 5: Preparation of 4-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine

[0642]

[0643] As described in step 5 of Example 1, tert-butyl 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (920 mg, 2.14 mmol, 1.00 equivalent), trifluoroacetic acid (10 mL), and DCM (30 mL) were charged into a 250 mL round-bottom flask to provide 700 mg (99% yield) of 4-(2-(piperazine-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine as a brown oil. LCMS (ESI, m / z): 330 [M+H] + .

[0644] Step 6: Preparation of 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl chloride

[0645]

[0646] Triphosgene (226 mg, 0.760 mmol, 0.50 equivalent) and DCM (10 mL) were charged into a flask. As described in step 3 of Example 1, 4-(2-(piperazin-1-ylmethyl)-5-(trifluoromethyl)phenyl)morpholine (500 mg, 1.52 mmol, 1.00 equivalent) and DIPEA (588 mg, 4.56 mmol, 3.00 equivalent) were added at 0 °C to provide 500 mg (84% yield) of 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl chloride as a yellow oil. LCMS (ESI, m / z): 392 [M+H] + .

[0647] Step 7: Preparation of tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0648]

[0649] As described in step 4 of Example 1, a flask was charged with 4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl chloride (400 mg, 1.02 mmol, 1.00 equivalent), tert-butyl 1H-pyrazole-3-carboxylate (190 mg, 1.13 mmol, 1.10 equivalent), DMAP (62.0 mg, 0.510 mmol, 0.50 equivalent), DIPEA (396 mg, 3.07 mmol, 3.00 equivalent), and THF (10 mL). The residue was chromatographically separated to provide 300 mg (56% yield) of tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate as a white solid. LCMS (ESI, m / z): 524 [M+H] + .

[0650] Step 8: Preparation of 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0651]

[0652] As described in step 5 of Example 1, tert-butyl 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid (140 mg, 0.270 mmol, 1.00 equivalent), TFA (1 mL), and DCM (10 mL) were charged into a flask to provide crude product (250 mg). The residue was purified by preparative HPLC to provide 78.2 mg (63% yield) of 1-(4-(2-morpholino-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1 HNMR(400MHz, methanol-d4)□□8.14(d,J=2.6Hz,1H),7.73(d,J=8.2Hz,1H),7.41-7.42(m ,2H),6.83(d,J=2.6Hz,1H),3.81-3.88(m,10H),3.01-3.02(m,4H),2.71(br,4H). LCMS (ESI, m / z): 468[M+H] + .

[0653] Example 4: 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0654]

[0655] Step 1: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0656]

[0657] As described in step 1 of Example 1, 1H-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equivalent), DMAP (2.15 g, 17.6 mmol, 0.20 equivalent), triethylamine (27.0 g, 267 mmol, 3.00 equivalent), and di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equivalent) in tert-butanol (100 mL) were added to a flask to provide 25.0 g (crude) of 1H-pyrazole-1,3-dicarboxylic acid, a red oily substance. LCMS (ESI, m / z): 269 [M+H] + .

[0658] Step 2: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0659]

[0660] As described in step 2 of Example 1, 1H-pyrazole-1,3-di-tert-butyl 1,3-carboxylic acid (25.0 g, 93.2 mmol, 1.00 equivalent) and NaOH (5.60 g, 140 mmol, 1.50 equivalent) in water (80 mL) and MeOH (240 mL) were added to a flask to provide 10.0 g (64% yield) of 1H-pyrazole-3-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 169 [M+H] + .

[0661] Step 3: Preparation of 1H-pyrazole-1,3-dicarboxylic acid 3-(tert-butyl)-1-(4-nitrophenyl) ester

[0662]

[0663] A flask was filled with tert-butyl 1H-pyrazole-3-carboxylate (2.42 g, 14.4 mmol, 1.00 equivalent), DCM (20 mL), 4-nitrophenyl chloroformate (2.90 g, 14.4 mmol, 1.00 equivalent), and triethylamine (4.36 g, 43.1 mmol, 3.00 equivalent). The resulting solution was stirred at room temperature for 3 h and concentrated under reduced pressure to provide 4.80 g (crude product) of 1H-pyrazole-1,3-dicarboxylate 3-(tert-butyl)-1-(4-nitrophenyl) ester as a yellow oil. LCMS (ESI, m / z): 334 [M+H] + .

[0664] Step 4: Preparation of 2-morpholino-4-(trifluoromethyl)benzaldehyde

[0665]

[0666] Under nitrogen atmosphere, a flask was filled with 5.00 g (26.0 mmol, 1.00 equivalent) of 2-fluoro-4-(trifluoromethyl)benzaldehyde, 10.8 g (78.1 mmol, 3.00 equivalent) of potassium carbonate, 6.79 g (78.0 mmol, 3.00 equivalent) of morpholine, and 50 mL of DMSO. The resulting solution was stirred overnight at 80 °C and quenched with 50 mL of water as described in step 3 of Example 3 to provide 4.00 g (59% yield) of 2-morpholino-4-(trifluoromethyl)benzaldehyde as a yellow solid. LCMS (ESI, m / z): 260 [M+H] + .

[0667] Step 5: Preparation of tert-butyl 4-methyl-4-((2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylic acid

[0668]

[0669] In a 100-mL round-bottom flask, 2-morpholino-4-(trifluoromethyl)benzaldehyde (2.50 g, 9.64 mmol, 1.00 equivalent), MeOH (25 mL), AcOH (1.70 g, 28.3 mmol, 3.00 equivalent), and tert-butyl 4-amino-4-methylpiperidin-1-carboxylate (2.46 g, 11.5 mmol, 1.20 equivalent) were added. The resulting solution was stirred at room temperature for 30 min. Sodium cyanoborohydride (1.78 g, 28.3 mmol, 3.00 equivalent) was added. The resulting solution was stirred overnight at room temperature and quenched with water (30 mL). The resulting solution was extracted with DCM (3 x 30 mL), the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography to produce 3.51 g (80% yield) of tert-butyl 4-methyl-4-((2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m / z): 458 [M+H] + .

[0670] Step 6: Preparation of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylic acid

[0671]

[0672] In a 100-mL round-bottom flask, tert-butyl 4-methyl-4-((2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (3.51 g, 7.67 mmol, 1.00 equivalent), paraformaldehyde (2.30 g, 76.7 mmol, 10.0 equivalent), triethylamine (2.30 g, 22.7 mmol, 3.00 equivalent), and DCE (30 mL) were added. The resulting solution was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (4.80 g, 22.6 mmol, 3.00 equivalent) was added. As described in step 3 of Example 2, the resulting solution was stirred overnight at room temperature and quenched with water (30 mL) to produce 3.39 g (94% yield) of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a yellow oil. LCMS(ESI, m / z): 472 [M+H] + Step 7: Preparation of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylic acid

[0673]

[0674] As described in step 5 of Example 1, tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate (3.39 g, 7.19 mmol, 1.00 equivalent), DCM (20 mL), and TFA (5 mL) were charged into a flask to produce 3.50 g (crude product) of tert-butyl 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylate as a white solid. LCMS (ESI, m / z): 372 [M+H] + .

[0675] Step 8: Preparation of tert-butyl 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0676]

[0677] As described in step 3 of Example 4, a flask was charged with 3-tert-butyl 1-(4-nitrophenyl) 1H-pyrazole-1,3-dicarboxylic acid ester (3.50 g, 9.43 mmol, 1.00 equivalent), DCM (20 mL), 4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carboxylic acid tert-butyl ester (6.28 g, 18.7 mmol, 2.00 equivalent), and triethylamine (2.86 g, 28.3 mmol, 3.00 equivalent) to provide 4.58 g (80% yield) of 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a yellow oil. LCMS (ESI, m / z): 566 [M+H] + .

[0678] Step 9: Preparation of 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0679]

[0680] As described in step 5 of Example 1, tert-butyl 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidin-1-carbonyl)-1H-pyrazole-3-carboxylic acid (4.58 g, 8.10 mmol, 1.00 equivalent), DCM (50 mL), and TFA (10 mL) were charged into a flask. The crude product (3.50 g) was purified by preparative HPLC to provide 694.3 mg (17% yield) of 1-(4-methyl-4-(methyl(2-morpholino-4-(trifluoromethyl)benzyl)amino)piperidin-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1 H NMR (300MHz, methanol-d4) δ8.08(d,J=2.6Hz,1H),7.84d,J=8.4Hz,1H),7.49-7.52(m,2H),6.78(d,J=2.6Hz,1H),4.12-4.25(m,4H) ,3.84-3.87(m,4H),3.54-3.65(m,2H),2.93-3.07(m,4H),2.41(br,3H),2.11-2.16(m,2H),2.03-2.10(m,2H),1.41(br,3H). LCMS (ESI, m / z): 510[M+H] + .

[0681] Example 5: 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0682]

[0683] Step 1: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0684]

[0685] As described in step 1 of Example 1, 1H-pyrazole-3-carboxylic acid (10.0 g, 89.2 mmol, 1.00 equivalent), 4-dimethylaminopyridine (2.15 g, 17.6 mmol, 0.20 equivalent), triethylamine (27.0 g, 267 mmol, 3.00 equivalent), and di-tert-butyl dicarbonate (80.0 g, 366 mmol, 4.00 equivalent) in tert-butanol (100 mL) were added to a flask to provide 25.0 g (crude) of 1H-pyrazole-1,3-di-tert-butyl dicarboxylic acid as a red oil. LCMS (ESI, m / z): 269 [M+H] + .

[0686] Step 2: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0687]

[0688] As described in step 2 of Example 1, 1H-pyrazole-1,3-di-tert-butyl 1,3-carboxylic acid (25.0 g, 93.2 mmol, 1.00 equivalent) and NaOH (5.60 g, 140 mmol, 1.50 equivalent) in water (80 mL) and MeOH (240 mL) were added to a flask to provide 10.0 g (64% yield) of 1H-pyrazole-3-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 169 [M+H] + .

[0689] Step 3: Preparation of tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

[0690]

[0691] In a flask, 2-bromo-4-(trifluoromethyl)benzaldehyde (500 mg, 1.98 mmol, 1.00 equivalent), triethylamine (600 mg, 5.93 mmol, 3.00 equivalent), and piperazine-1-carboxylic acid tert-butyl ester (443 mg, 2.38 mmol, 1.20 equivalent) were added in DCE (10 mL). The resulting solution was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (1.26 g, 5.94 mmol, 3.00 equivalent) was added. As described in step 3 of Example 2, the resulting solution was stirred overnight at room temperature and quenched with water (10 mL). The residue was chromatographically separated to provide 680 mg (81% yield) of 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 423 [M+H] + .

[0692] Step 4: Preparation of tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

[0693]

[0694] Under nitrogen atmosphere, tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (680 mg, 1.61 mmol, 1.00 equivalent), zinc cyanide (374 mg, 3.22 mmol, 2.00 equivalent), and tetra(triphenylphosphine)palladium (170 mg, 0.150 mmol, 0.10 equivalent) in DMF (10 mL) were charged into a flask. The resulting solution was stirred overnight at 120 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 30 mL), and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to chromatographic separation to provide 230 mg (39% yield) of tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS(ESI, m / z): 370 [M+H] + .

[0695] Step 5: Preparation of tert-butyl 4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate

[0696]

[0697] In a flask, tert-butyl 4-(2-cyano-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (230 mg, 0.620 mmol, 1.00 equivalent), sodium azide (203 mg, 3.12 mmol, 5.00 equivalent), and ammonium chloride (198 mg, 3.70 mmol, 6.00 equivalent) were added to DMF (10 mL). The resulting solution was stirred overnight at 120 °C and quenched with water (10 mL). The resulting solution was extracted with EtOAc (3 x 30 mL), and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to chromatographic separation to provide 140 mg (55% yield) of tert-butyl 4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate as a white solid. LCMS(ESI, m / z): 413[M+H] + .

[0698] Step 6: Preparation of 1-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine

[0699]

[0700] As described in step 4 of Example 2, tert-butyl 4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carboxylate (140 mg, 0.340 mmol, 1.00 equivalent), 1,4-dioxane (10 mL), and concentrated hydrochloric acid (3 mL) were added to a flask to provide 130 mg (crude) of 1-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine as a white solid. LCMS (ESI, m / z): 313 [M+H] + .

[0701] Step 7: Preparation of tert-butyl 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0702]

[0703] Under nitrogen atmosphere, triphosgene (38.0 mg, 0.130 mmol, 0.40 equivalents) and tert-butyl 1H-pyrazole-3-carboxylate (70.0 mg, 0.420 mmol, 1.30 equivalents) were added dropwise to DCM (10 mL) in a flask. DIPEA (122 mg, 0.960 mmol, 3.00 equivalents) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 2 h. As described in step 3 of Example 1, 1-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine (100 mg, 0.320 mmol, 1.00 equivalent) was added to provide 90.0 mg (55% yield) of 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 507 [M+H] + .

[0704] Step 8: Preparation of 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0705]

[0706] As described in step 5 of Example 1, tert-butyl 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid (90.0 mg, 0.180 mmol, 1.00 equivalent) and TFA (3 mL) in DCM (10 mL) were charged into a flask to provide crude product (100 mg), which was purified by preparative HPLC. The purification yielded 22.3 mg (28% yield) of 1-(4-(2-(1H-tetrazol-5-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1 H NMR (300MHz, methanol-d4) δ 8.30 (s, 1H), 8.14 (d, J = 2.7Hz, 1H), 7.76-7.87 (m, 2H), 6.78 (d, J = 2.7Hz, 1H), 4.44 (s, 2H), 4.18 (br, 4H), 3.24 (br, 4H). LCMS (ESI, m / z): 451[M+H] + .

[0707] Example 6: 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0708]

[0709] Step 1: Preparation of 2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzaldehyde

[0710]

[0711] As described in step 3 of Example 3, 2-fluoro-4-(trifluoromethyl)benzaldehyde (400 mg, 2.08 mmol, 1.00 equivalent), DMSO (10 mL), potassium carbonate (861 mg, 6.24 mmol, 3.00 equivalent), and 1-cyclopropylpiperazine (524 mg, 4.16 mmol, 2.00 equivalent) were charged into a flask under nitrogen atmosphere to provide a crude product. The residue was subjected to chromatographic separation to provide 460 mg (74% yield) of 2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m / z): 299 [M+H] + .

[0712] Step 2: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0713]

[0714] As described in step 1 of Example 1, 1H-pyrazole-3-carboxylic acid (10.0 g, 89.3 mmol, 1.00 equivalent), DMAP (2.18 g, 17.9 mmol, 0.20 equivalent), triethylamine (27.1 g, 268 mmol, 3.00 equivalent), di-tert-butyl dicarbonate (77.8 g, 357 mmol, 4.00 equivalent), and tert-butanol (100 mL) were added to a flask to provide 25.0 g (crude) of 1H-pyrazole-1,3-di-tert-butyl dicarboxylic acid as a red oil. LCMS (ESI, m / z): 269 [M+H] + .

[0715] Step 3: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0716]

[0717] As described in step 2 of Example 1, a flask was charged with 1H-pyrazole-1,3-dicarboxylic acid 1,3-di-tert-butyl ester (25.0 g, 93.3 mmol, 1.00 equivalent), NaOH (5.60 g, 140 mmol, 1.50 equivalent), water (80 mL), and MeOH (240 mL) to provide the crude product. The residue was subjected to chromatographic separation to provide 10.0 g (64% yield) of 1H-pyrazole-3-carboxylic acid tert-butyl ester as a white solid. LCMS (ESI, m / z): 169 [M+H] +

[0718] Step 4: Preparation of tert-butyl 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0719]

[0720] Triphosgene (1.24 g, 4.18 mmol, 0.70 equivalent) and DCM (20 mL) were charged into a flask. 1H-pyrazole-3-carboxylic acid tert-butyl ester (1.00 g, 5.95 mmol, 1.00 equivalent) was added at 0 °C. DIPEA (3.07 g, 23.8 mmol, 4.00 equivalent) was added at 0 °C. The mixture was stirred at room temperature for 2 h at 0 °C. 1-Benzylpiperazine (1.26 g, 7.15 mmol, 1.20 equivalent) was added at 0 °C as described in step 3 of Example 1 to provide the crude product. The residue was chromatographically separated to provide 1.35 g (61% yield) of 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a yellow oil. LCMS (ESI, m / z): 371 [M+H] + .

[0721] Step 5: Preparation of tert-butyl 1-(piperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0722]

[0723] A flask was filled with 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester (1.00 g, 2.70 mmol, 1.00 equivalent), MeOH (10 mL), EtOAc (10 mL), and carbon-supported palladium (0.400 g). Hydrogen was introduced. The resulting solution was stirred at room temperature for 3 h and the catalyst was filtered off. The filtrate was concentrated under reduced pressure to provide 0.690 g (crude product) of 1-(piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a colorless oil. LCMS (ESI, m / z): 281 [M+H] + .

[0724] Step 6: Preparation of tert-butyl 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylate

[0725]

[0726] In a flask, 2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzaldehyde (92.2 mg, 0.309 mmol, 1.00 equivalent), 1-[(piperazin-1-yl)carbonyl]-1H-pyrazole-3-carboxylic acid tert-butyl ester (130 mg, 0.464 mmol, 1.50 equivalent), and DCE (10 mL) were charged. The resulting solution was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (262 mg, 1.24 mmol, 4.00 equivalent) was added as described in step 3 of Example 2 to provide the crude product. The residue was subjected to chromatographic separation to provide 140 mg (81% yield) of 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylic acid tert-butyl ester as a yellow oil. LCMS(ESI, m / z): 563 [M+H] + .

[0727] Step 7: Preparation of 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0728]

[0729] As described in step 5 of Example 1, tert-butyl 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylic acid (140 mg, 0.250 mmol, 1.00 equivalent), DCM (12 mL), and TFA (2 mL) were charged into a flask. The crude product (127 mg) was purified by preparative HPLC to provide 53.2 mg (42% yield) of 1-(4-(2-(4-cyclopropylpiperazin-1-yl)-4-(trifluoromethyl)benzyl)piperazin-1-carbonyl)-1H-pyrazole-3-carboxylic acid as a white solid. 1 H NMR (400MHz, methanol-d4) δ8.14 (s, 1H), 7.70 (d, J = 8.4Hz, 1H), 7.42-7.44 (m, 2H), 6.83 (s, 1H), 3.99 (br,4H),3.87(s,2H),3.15(br,8H),2.69-2.70(m,4H),2.28-2.34(m,1H),0.65-0.84(m,4H). LCMS (ESI, m / z): 507[M+H] + .

[0730] Example 7: 1-(4-(3-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)-1H-pyrazole-3-carboxylic acid

[0731]

[0732] Step 1: Preparation of 3-(pyrrolidone-1-yl)-4-(trifluoromethyl)benzaldehyde

[0733]

[0734] Under a nitrogen atmosphere, a flask was charged with 3-bromo-4-(trifluoromethyl)benzaldehyde (380 mg, 1.50 mmol, 1.00 equivalent), pyrrolidine (160 mg, 2.25 mmol, 1.50 equivalent), tris(dibenzylacetone)palladium (77.6 mg, 0.0750 mmol, 0.05 equivalent), dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl (52.5 mg, 0.110 mmol, 0.07 equivalent), cesium carbonate (978 mg, 3.00 mmol, 3.00 equivalent), and toluene (10 mL). The resulting solution was stirred overnight at 80 °C and quenched with water (20 mL). The mixture was extracted with DCM (3 x 30 mL), the organic layers were combined, washed with water (3 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by chromatography to provide 84.0 mg (23% yield) of 3-(pyrrolidone-1-yl)-4-(trifluoromethyl)benzaldehyde as a yellow oil. LCMS (ESI, m / z): 244 [M+H] + .

[0735] Step 2: Preparation of 1H-pyrazole-1,3-dicarboxylic acid di-tert-butyl ester

[0736]

[0737] As described in step 1 of Example 1, 1H-pyrazole-3-carboxylic acid (20.0 g, 179 mmol, 1.00 equivalent), di-tert-butyl dicarbonate (158 g, 714 mmol, 4.00 equivalent), DMAP (4.35 g, 35.7 mmol, 0.20 equivalent), triethylamine (54.1 g, 536 mmol, 3.00 equivalent), and tert-butanol (200 mL) were added to a flask to provide 20.0 g (crude) of 1H-pyrazole-1,3-di-tert-butyl dicarboxylic acid as a yellow oil. LCMS (ESI, m / z): 169 [M+H-Boc] + .

[0738] Step 3: Preparation of 1H-pyrazole-3-carboxylic acid tert-butyl ester

[0739]

[0740] As described in step 2 of Example 1, a flask was filled with 1H-pyrazole-1,3-di-tert-butyl ester (20.0 g, 74.6 mmol, 1.00 equivalent), MeOH (80 mL), NaOH (10.0 g, 250 mmol, 3.35 equivalent), and water (40 mL) to provide 6.70 g (crude) of 1H-pyrazole-3-di-butyl ester as a yellow solid. LCMS (ESI, m / z): 169 [M+H] + .

[0741] Step 4: Preparation of tert-butyl 1-(4-benzylpiperazine-1-carbonyl)-1H-pyrazole-3-carboxylate

[0742]

[0743] A flask was loaded with 1H-pyrazole-3-carboxylic acid tert-butyl ester (1.68 g, 10.0 mmol, 1.00 equivalent), triphosgene (1.49 g, 5.00 mmol, 0.50 equivalent), and DCM (20 mL). Then, DIPEA (3.87 g, 30.0 mmol, 3.00 equivalent) was added dropwise at 0 °C. The resulting solution was stirred at room temperature for 2...

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pain associated with MAGL expression or activity in a patient: in: R 1 Yes -C(O)OR 15 or -C(O)NR 10 R 11 ; R 2 H, halogen, C 1-6 Alkyl, or C 1-6 Haloalkyl; R 3 yes A is C(H); Y is -CH2-; R 4 H, halogen, -OR 7 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, -C(O)NR 8 R 9 , C 3-8 Cycloalkyl, C 2-9 Heterocycloalkyl, -C 1-6 Alkyl-C 2-9 Heterocycloalkyl, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein C 3-8 Cycloalkyl, C 2-9 Heterocycloalkyl, -C 1-6 Alkyl-C 2-9 Heterocycloalkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally substituted by 1 or 2 R 14 replace; R 5 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, or phenyl; R 6 It is H; R 7 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-OH, C 2-9 Heterocycloalkyl, C 6-10 Aryl, or C 1-9 Heteroaryl, wherein C 2-9 Heterocycloalkyl, C 6-10 Aryl, or C 1-9 The heteroaryl group is optionally substituted by 1 or 2 R 14 replace; Each R 8 and each R 9 Independently selected from H and C 1-6 Alkyl; or R 8 and R 9 Together with the nitrogen to which they are attached, they combine to form a heterocycloalkyl ring; R 10 and R 11 Each independently is H or C 1-6 alkyl; R 12 is H, halogen, or C 1-6 alkyl; R 13 Is H or C 1-6 alkyl; Each R 14 independently selected from halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -C 1-6 Alkyl-OH, C 3-8 Cycloalkyl, -C(O)OH, -C(O)NR 8 R 9 、-SO2-C 1-6 Alkyl, and -N(R 17 )C(O)-C 1-6 alkyl; R 15 Is H or C 1-6 alkyl; R 17 Is H or C 1-6 alkyl; n is 0 or 1; m is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2.

2. The use according to claim 1, wherein m is 1, n is 1, q is 1, and p is 1.

3. The use as claimed in claim 1, wherein R 13 It's H.

4. The use as claimed in claim 1, wherein R 12 It's H.

5. The use as claimed in claim 1, wherein R 6 It's H.

6. The use as claimed in claim 1, wherein R 4 yes 7. The use as claimed in claim 1, wherein R 5 It is -CF3.

8. The use as claimed in claim 1, wherein R 2 It's H.

9. The use as claimed in claim 1, wherein R 1 It is -C(O)OH.

10. The use according to claim 1, wherein the compound is selected from:

11. The use according to claim 1, wherein the compound is:

12. The use according to claim 1, wherein the compound is:

13. The use according to claim 1, wherein the compound is:

14. The use according to claim 1, wherein the compound is:

15. The use according to claim 1, wherein the pain is migraine.

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