Pyrrolo[1,2-b]pyridazine derivatives

Abstract

Compounds of formula (I) are provided; wherein the variable groups are defined herein.

Description

[0001] This application is a divisional application of Chinese invention patent application (filed on February 15, 2018, application number 201880012452.8, PCT application number PCT / US2018 / 018431, entitled "pyrrolo[1,2-b]pyridazine derivatives").

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application Serial No. 62 / 460,013, filed February 16, 2017, the entire disclosure of which is incorporated herein by reference. Technical Field

[0004] This disclosure relates to a novel compound, which is an inhibitor of the kinase IRAK4. This disclosure also relates to methods for preparing said compound and pharmaceutical compositions comprising said compound. Background Technology

[0005] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase that acts as a mediator in the interleukin-1 / Toll-like receptor (IL-1 / TLR) signaling cascade. More specifically, IRAK4 is involved in the activation of the adaptor protein myeloid differentiation primary response gene 88 (MyD88) signaling cascade and is hypothesized to play a role in inflammation-related conditions, as well as oncology and non-alcoholic steatohepatitis (NASH). IL-1R / TLR signaling leads to the activation of MyD88, which recruits IRAK4 and IRAK1 to form a signaling complex. This complex then interacts with a series of kinases, adaptors, and ligases, ultimately resulting in activation of NF-κB cells and the nuclear factor κ-light chain enhancer of activating protein-1, inducing the production of inflammatory cytokines.

[0006] Therefore, IRAK4 inhibitors can be used to treat inflammatory diseases, including autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme arthritis, systemic lupus erythematosus (SLE), Sjögren's syndrome, and viral myocarditis. (Joosten, LAB et al., TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION INRHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev. Rheumatol., 346 | JUNE 201612; 344-357 Published online May 12, 2016) (Valaperti, A. et al., INNATE IMMUNEINTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BYREDUCING CCR5) + CD11b + MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128 | SEPTEMBER 2013 14; 1542-1554), and Type I interferonopathies, such as Aicardi-Goutières syndrome, familial frostbite-like lupus, and retinal vascular disease with leukodystrophy (Lee-Kirsch et al., TYPE I INTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349–357).

[0007] Furthermore, certain cancers, including lymphoma, may contain one or more mutations in the MYD88 adaptor protein, leading to constitutively active signaling cascades that promote tumor cell survival. (Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp. Med. 2015, Vol. 212, No. 13, 2189–2201)

[0008] Therefore, IRAK4 inhibitors can be used to treat cancers, including lymphoma.

[0009] There are currently no approved IRAK4 inhibitory drugs. Therefore, it would be useful to provide IRAK4 inhibitory compounds that have properties suitable for administration as pharmaceuticals to mammals, particularly humans.

[0010] WO2016210034, WO2016210036, WO2015150995, WO2016127024, and WO2016210037 list compounds that are alleged to be used as IRAK4 inhibitors. Summary of the Invention

[0011] This document provides compounds and pharmaceutical compositions that can be used as IRAK4 inhibitors. Some of the compounds disclosed herein can be used in pharmaceutical compositions with at least one pharmaceutically acceptable excipient for the treatment of subjects in need. The compounds of the present invention have also been found to inhibit the production of TNFα, IL-6, IL-1β, and IL-23, all of which are mediators of inflammation. This disclosure also provides compositions comprising pharmaceutical compositions, kits containing said compounds, and methods for using and preparing said compounds.

[0012] In one embodiment of this disclosure, a compound of formula (I) is provided.

[0013]

[0014] in:

[0015] R 1 and R 2 Each is selected independently from:

[0016] C 1-10 Alkyl groups, optionally substituted with Z 1 ;

[0017] C 3-10 Cycloalkyl groups, optionally substituted with Z 1 ;

[0018] 5-10 aryl groups, with optional substitutions including Z 1 ;

[0019] C 6-10 Aryl groups, with optional substitutions including Z 1 ;

[0020] 4-7 member monocyclic heterocyclic groups, with optional substitutions including Z 1 ;

[0021] 6-12 membered bicyclic heterocyclic groups, with optional substitutions including Z 1 ;or

[0022] -N(R 12 (R) 12-S(O)2R 12 -S(O)2N(R) 12 (R) 12 ), or -H;

[0023] R 3 and R 4 Each is selected independently from:

[0024] H, halogen, -NO2, -CN, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -N(R 12 )C(O)-N(R 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0025] C 1-9 Alkyl groups, optionally substituted with Z 1 ;

[0026] C 2-9 The alkynyl group, which may be optionally substituted with Z 1 ;

[0027] C 2-9 Alkenyl, which may be optionally substituted with Z 1 ;

[0028] 5-10 aryl groups, with optional substitutions including Z 1 ;

[0029] C 6-10 Aryl groups, with optional substitutions including Z 1 ;

[0030] 4-12 membered heterocyclic groups, with optional substitutions including Z 1 ;or

[0031] C 3-10 Cycloalkyl groups, optionally substituted with Z 1 ;

[0032] R 5 R6 and R 7 Each is selected independently from:

[0033] H, halogen, -NO2, -CN, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 , or -N(R 12 )S(O)2(R 12 );

[0034] C 1-5 Alkyl groups, optionally substituted with Z 1 ;or

[0035] Cyclopropyl, oxetyl, or aziridine, optionally substituted with Z 1 ;

[0036] Z 1 Independently oxidized, halogenated, -NO2, -N3, -CN, C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R)12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0037] Any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a ;

[0038] Each Z 1a Independently oxidized, halogenated, -NO2, -CN, -N3, C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12-OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0039] Any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1b ;

[0040] Each R 12 Independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C 3-15 cycloalkyl, aryl, heteroaryl, or heterocyclic groups;

[0041] Any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a ;

[0042] Each Z 1b Independently oxidized, hydroxylated, halogenated, -NO2, -N3, -CN, C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -O(C) 1-9 alkyl), -O(C) 2-6 alkenyl), -O(C) 2-6 alkynyl group), -O(C 3-15 cycloalkyl), -O(C 1-8 -Halogenated alkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), -NH2, -NH (C 1-9 alkyl), -NH(C) 2-6 alkenyl), -NH(C) 2-6 alkynyl group), -NH(C 3-15 cycloalkyl), -NH(C 1-8 -Halogenated alkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2, -N(C 2-6 alkenyl)2, -N(C 2-6 2, -N(C)3-15 cycloalkyl)2, -N(C 1-8 -N(haloalkyl)2, -N(aryl)2, -N(heteroaryl)2, -N(heterocyclic)2, -N(C) 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl)(C 2-6 alkenyl), -N(C) 1-9 Alkyl)(C 2-6 alkynyl group), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C) 1-9 Alkyl)(C 1-8 Halogenated alkyl), -N(C) 1-9 Alkyl)(aryl), -N(C) 1-9 Alkyl)(heteroaryl), -N(C) 1-9 Alkyl)(heterocyclic), -C(O)(C 1-9 Alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl group), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 Halogenated alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C 1-9 Alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkynyl group), -C(O)O(C 3-15 cycloalkyl), -C(O)O(C 1-8 Halogenated alkyl), -C(O)O (aryl), -C(O)O (heteroaryl), -C(O)O (heterocyclic), -C(O)NH2, -C(O)NH(C 1-9 Alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 ynyl group), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(C 1-8 Halogenated alkyl), -C(O)NH (aryl), -C(O)NH (heteroaryl), -C(O)NH (heterocyclic), -C(O)N(C 1-9 Alkyl)2、-C(O)N(C 3-15 cycloalkyl)2、-C(O)N(C 2-6 alkenyl)2, -C(O)N(C 2-6 2, -C(O)N(C) 3-15 cycloalkyl)2、-C(O)N(C 1-8Haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclic)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 ynyl group), -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(C 1-8 Halogenated alkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 ), -NHC(O)NH(C 3-15 cycloalkyl), -NHC(O)NH(C 1-8 Halogenated alkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic), -SH, -S(C 1-9 alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkynyl group), -S(C 3-15 cycloalkyl), -S(C 1-8 -Haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclic), -NHS(O)(C 1-9 alkyl), -N(C) 1-9 Alkyl)(S(O)(C) 1-9 Alkyl), -S(O)N(C 1-9 Alkyl)2、-S(O)(C 1-9 Alkyl), -S(O)(NH)(C 1-9 Alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 ynyl group), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8Halogenated alkyl), -S(O) (aryl), -S(O) (heteroaryl), -S(O) (heterocyclic), -S(O)2(C 1-9 Alkyl), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl group), -S(O)2(C 3-15 cycloalkyl), -S(O)2(C 1-8 Halogenated alkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclic), -S(O)2NH(C 1-9 Alkyl), or -S(O)2N(C 1-9 Alkyl)2;

[0043] Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may optionally be substituted with one or more halogens or C. 1-9 Alkyl, C 1-8 Halogenated alkyl groups, -OH, -NH2, -NH(C) 1-9 alkyl), -NH(C) 3-15 cycloalkyl), -NH(C 1-8 -Halogenated alkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2、-NHC(O)(C 3-15 cycloalkyl), -NHC(O)(C 1-8 Halogenated alkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O(C 1-9 Alkyl), -NHC(O)O(C 2-6 ynyl group), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(C 1-8 Halogenated alkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH(C 1-9 Alkyl), -S(O)(NH)(C 1-9 Alkyl), S(O)2(C 1-9 Alkyl), -S(O)2(C 3-15 cycloalkyl), -S(O)2(C 1-8 Halogenated alkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclic), -S(O)2NH(C 1-9 Alkyl), -S(O)2N(C 1-9 Alkyl)2、-O(C 3-15 cycloalkyl), -O(C1-8 Halogenated alkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), or -O (C 1-9 Alkyl); and

[0044] The condition is: when R 1 It is a C3 alkyl group, R 2 To replace C5 alkyl groups containing both F and hydroxyl groups, R 3 R 5 R 6 R 7 For H and R 4 When it is CN, R 1 Replaced by Z 1 ;

[0045] Or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

[0046] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 1-10 Alkyl groups, optionally substituted with Z 1 The condition is: when R 1 It is a C3 alkyl group, R 2 To replace C5 alkyl groups containing both F and hydroxyl groups, R 3 R 5 R 6 R 7 For H and R 4 When it is CN, R 1 Replaced by Z 1 .

[0047] In another implementation, when R 1 Or R 2 C 1-10 Alkyl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, C 6-10 When aryl, 4-7 membered monocyclic heterocyclic, or 6-12 membered bicyclic heterocyclic, in R 1 Or R 2 Two Z atoms attached to the same atom on the group 1 Groups or in R 1 Or R 2 Two Z atoms attached to adjacent atoms on the group 1 The groups together form 3-6 membered cycloalkyl groups or 3-6 membered heterocyclic groups.

[0048] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , or .

[0049] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a methyl group.

[0050] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 6-10 Alkyl groups, optionally substituted with Z 1 .

[0051] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 1-5 Alkyl group, wherein one or more substituents are selected from the following: -Cl, oxo, -CN, C 2-6 alkenyl, C 2-6 Alkyne, cyclopropyl, naphthyl, heteroaryl, monocyclic heterocyclic groups containing nitrogen or sulfur, bicyclic heterocyclic groups, C 7-15 cycloalkyl, -OR 9 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0052] R 9 It is C independently each time it appears. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclic, or heteroaryl groups;

[0053] Each C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups may be optionally substituted with Z. 1a ;

[0054] Wherein C 1-5 Alkyl groups may also be optionally substituted with Z 1 ;and

[0055] Each of the C 2-6 alkenyl, C 2-6 Alkyne, cyclopropyl, naphthyl, heteroaryl, monocyclic heterocyclic groups containing nitrogen or sulfur, bicyclic heterocyclic groups, or C 7-15 cycloalkyl optional substitution has Z 1a .

[0056] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , , or .

[0057] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 1-5 Alkyl groups, optionally substituted with Z 1;

[0058] Wherein C 1-5 Alkyl substitution has one or more Cs 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl;

[0059] Wherein C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl optional substitution with Z 1a ;

[0060] Wherein C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl groups are substituted with one or more of the following groups: halogen, oxo, -CN, C. 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12(R) 12 ); and each of the Cs described herein 2-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 Cycloalkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0061] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 1-5 Alkyl group, optionally substituted with F or -OH and substituted with one or more substituents selected from the following: C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl; wherein the C 4-6 The cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl substituent has two or more substituents selected from the following: -OH and -CH3, and optionally has Z. 1a .

[0062] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0063] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , ,or .

[0064] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , ,or .

[0065] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0066] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 For C7- 10 Cycloalkyl groups, optionally substituted with Z 1 Wherein, when the C7-C 10 When the cycloalkyl group is a bicyclic [2.2.1]heptyl, the C7- 10 Cycloalkyl substitution has at least one of the following: oxo, -Cl, -NO2, -CN, -N3, C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-15 cycloalkyl, C 5-8 Halogenated alkyl, aryl, pyrazolyl, -OR 9 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R12 , or -S(O)2N(R 12 (R) 12 ).

[0067] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for or .

[0068] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 3-10 bridging bicyclic group, which may optionally have one or more Z-substituted groups. 1 Group. An example of this 3-10 bridging bicyclic group is... .

[0069] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 3-10 bridging heterocyclic group, which may optionally have one or more Z-substituted groups. 1 Group. An example of this 3-10 bridging bicyclic group is... .

[0070] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 cycloalkyl groups, which are substituted with one or more -OR groups. 16 ; wherein C 3-6 cycloalkyl optional substitution has Z 1 ;

[0071] R 16 It is C independently each time it appears. 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, aryl, heterocyclic, or heteroaryl; wherein each C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups may be optionally substituted with Z. 1a .

[0072] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C3-6 Cycloalkyl groups, which are substituted with one or more -C(O)-R groups. 11 ; wherein C 3-6 cycloalkyl optional substitution has Z 1 ;

[0073] Where R 11 It is C independently each time it appears. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, aryl, heterocyclic or heteroaryl,

[0074] Each C 1-9 Alkyl substitutions can be selected from -NO2, -N3, -CN, and C. 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 4-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R)12 (R) 12 );and

[0075] Each of the C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups may be optionally substituted with Z. 1a ;

[0076] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, which are substituted with one or more oxo or C-substituted groups. 5-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C(O)OR 12 -C(O)-N(R) 9 (R) 9 -C(O)N(H)(C 4-9 Alkyl), -C(O)N(H)(C 3-10 cycloalkyl), -C(O)N(H) (heterocyclic), -C(O)N(H) (aryl), -C(O)N(H) (heteroaryl)-N(R) 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12-S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0077] Wherein C 5-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C(O)N(H)(C 4-9 Alkyl), -C(O)N(H)(C 3-10 Cycloalkyl), -C(O)N(H) (heterocyclic), -C(O)N(H) (aryl), or -C(O)N(H) (heteroaryl) optionally substituted with Z 1a ; and the C therein 3-6 cycloalkyl optional substitution has Z 1 ;where C 3-6 When the cycloalkyl group is a bicyclo[1.1.1]pentyl, the bicyclo[1.1.1]pentyl group is substituted with one or more oxo, -NO2, -N3, or C groups. 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-15 cycloalkyl, C 5-8 Halogenated alkyl, aryl, pyrazolyl, -OR 16 -C(O)R 11 -C(O)OR 12 -C(O)N(R) 9 (R) 9 -C(O)N(H)(C4 alkyl), -C(O)N(H)(R 16 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12-OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 , or -S(O)2N(R 12 (R) 12 ).

[0078] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for .

[0079] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, wherein the C4 alkyl group is optionally substituted with halogen, -NO2, -CN, -N3, or C4. 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R)12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0080] Wherein C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a ;and

[0081] Wherein C 3-6 cycloalkyl optional substitution has Z 1 ;

[0082] Where C 3-6 When the cycloalkyl group is a bicyclo[1.1.1]pentyl group substituted with a C4 alkyl group, the C4 alkyl group is further substituted with an oxo group, -NO2, -N3, or C4 alkyl group. 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-15 cycloalkyl, C 5-8 Halogenated alkyl, aryl, heteroaryl, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12-OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 , or -S(O)2N(R 12 (R) 12 ).

[0083] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, optionally substituted with Z 1 ; and the C therein 3-6 The cycloalkyl substitution has four or more substituents selected from the following: F, -OH, -Cl, -CN, C. 1-3 Alkyl, C 1-3 fluoroalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy group, -C(O)NH2, -C(O)NH(C 1-3 Alkyl); and -C(O)(C 1-3 (Fluoroalkyl).

[0084] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, which are substituted with C 1-3 fluoroalkyl, or -C(O)(C 1-3 fluoroalkyl), wherein the C 3-6 The cycloalkyl group may also be optionally substituted with Z 1 ; wherein C 1-3 fluoroalkyl or -C(O)(C 1-3 (Fluoroalkyl) further substituted with at least one oxo, -Cl, -NO2, -CN, -N3, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 3-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0085] Wherein C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 3-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1b .

[0086] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, which are substituted with at least one C 1-3 Alkyl or C 1-4 Hydroxyalkyl, wherein the C 3-6 cycloalkyl optional substitution has Z 1 ;

[0087] Wherein C 1-3 Alkyl or C 1-4Further substitution of hydroxyalkyl groups with oxo, chlorine, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0088] Wherein C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1b .

[0089] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 3-6 Cycloalkyl groups, which are substituted with at least one C 1-4 alkoxy or C(O)NH(C) 1-3 Alkyl); wherein the C 3-6 cycloalkyl optional substitution has Z 1 and the C therein 1-4 alkoxy or C(O)NH(C) 1-3 Alkyl groups are further substituted with oxo, halogen, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R)12 (R) 12 ); wherein C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1b .

[0090] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 .

[0091] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 When the 5-10 member heteroaryl group is furanyl, pyranyl, pyrroleyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, oxazolyl, or thiazolyl, the 5-10 member heteroaryl group may optionally be substituted with a 5-12 member bicyclic or a 5-12 member heterobicyclic, wherein the bicyclic and heterobicyclic may be fused, spiro, or bridged.

[0092] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , or .

[0093] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 The aryl group can be imidazole, triazolyl, oxazolyl, isoxazolyl, pyridinyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyridizinyl, isothiazolyl, tetrazolyl, thiophene, furanyl, triazinyl, or an 8-10 member heteroaryl group, with optional substitutions including Z. 1 .

[0094] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , , , , , ,or .

[0095] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , ,or .

[0096] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 6-membered heteroaryl group, with Z optional substitutions. 1 .

[0097] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is pyridine.

[0098] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 4-7 member monocyclic heterocyclic group, with optional substitutions including Z. 1 .

[0099] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , , , , , , or .

[0100] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a nitrogen-containing heterocyclic butyl, morpholino, thiomorpholino, 4-7 sulfonamide, 4-7 cyclic carbamate, 4-7 cyclic carbonate, or 4-7 cyclic sulfide, optionally substituted with Z. 1 .

[0101] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , or .

[0102] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 6-12 membered bicyclic heterocyclic group, with optional substitutions including Z. 1 When the 6-12 membered bicyclic heterocyclic group is 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, the 6-12 membered bicyclic heterocyclic group is substituted with at least one oxygen or C atom. 3-6 cycloalkyl or C(O)(C 1-5 alkyl).

[0103] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 The second ring consists of 6-12 yuan, and its optional substitution is Z. 1 Wherein, when the 6-12 membered bicyclic ring is a bicyclic [2.2.2]octane, the 6-12 membered bicyclic ring is substituted with C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 5-6 membered aryl, 5-6 membered heteroaryl, wherein C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 5-6 membered aryl, and 5-6 membered heteroaryl groups may be further substituted with one or more Z groups.1a Group.

[0104] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is a 6-12 membered bicyclic heterocyclic group, with optional substitutions including Z. 1 Wherein, when the 6-12 membered bicyclic heterocyclic group is 2-oxabicyclo[2.2.2]octane, the 6-12 membered bicyclic heterocyclic group is substituted with C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 5-6 membered aryl, 5-6 membered heteroaryl, wherein C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclic, 5-6 membered aryl, and 5-6 membered heteroaryl groups may be further substituted with one or more Z groups. 1a Group.

[0105] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , , , , , , , , , , , , , , , , ,or .

[0106] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for or .

[0107] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It can be oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl;

[0108] The oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl substituents thereon have one or more substituents selected from the following: -Cl, oxo, -CN, C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-10 Cycloalkyl, aryl, pyridyl, pyridazinyl, 5-10 membered bicyclic heteroaryl, 5-membered heteroaryl, monocyclic heterocyclic groups containing nitrogen or sulfur, bicyclic heterocyclic groups, -OR 9 -C(O)-R 11 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 , or -S(O)2N(R 12 (R) 12 ); wherein C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-10 Cycloalkyl, aryl, pyridyl, pyridazinyl, 5-10 membered bicyclic heteroaryl, 5-membered heteroaryl, monocyclic heterocyclic or bicyclic heterocyclic groups containing nitrogen or sulfur, optionally substituted with Z 1aThe oxocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, and thiazolyl groups are optionally substituted with Z. 1 .

[0109] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It can be oxetane, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl;

[0110] The oxobutyryl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl groups may optionally be substituted with Z. 1 ;

[0111] The oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, and thiazolyl substituents thereon have three or more substituents selected from the following: F, -OH, C. 1-4 Alkyl, C 1-3 Hydroxyalkyl, C 1-4 Fluoroalkyl groups, -(CH2) 1-3 O(C 1-3 Alkyl), -C(O)(C 1-3 fluoroalkyl), -S(O)2(C 1-3 Alkyl), C 3-6 cycloalkyl, C 3-6 Fluorocycloalkyl, oxetanebutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, fluoropyrimidinyl, or methoxypyrimidinyl.

[0112] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl; wherein the pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl group is optionally substituted with Z. 1 The pyrroloalkyl, piperidinyl, pyrazolyl, or thiazolyl substituents thereon are one or more independently selected from the following substituents: -(CH2) 1-3 O(C 1-3 Alkyl), -S(O)2(C 1-3 Alkyl), oxetyl, tetrahydrofuranyl, tetrahydropyranyl or CH2(C 3-6 cycloalkyl); and wherein -(CH2) is mentioned. 1-3 O(C 1-3 Alkyl), -S(O)2(C 1-3 Alkyl), oxetyl, tetrahydrofuranyl, tetrahydropyranyl or CH2(C 3-6(Cycloalkyl) independently substituted with one or more oxo, halogen, -NO2, -CN, -N3, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); wherein C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0113] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 It is an oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl group; wherein the oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl group is optionally substituted with -F or -OH and is substituted with one or more substituents independently selected from the following: C 1-4 Alkyl or C 1-3 Hydroxyalkyl;

[0114] Wherein C 1-4 Alkyl or C 1-3 Hydroxyl alkyl substitution with one or more oxo groups, -Cl, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 7-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 16 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12-S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0115] Any alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1b .

[0116] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, wherein:

[0117] R 1 It is an oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl group; wherein the oxetyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrazolyl, or thiazolyl group is optionally substituted with -F or -OH and is substituted with one or more substituents independently selected from the following: C 1-4 fluoroalkyl, -C(O)(C 1-3 fluoroalkyl), C 3-6 cycloalkyl, C 3-6 Fluorocycloalkyl and fluoropyrimidinyl;

[0118] Wherein C 1-4 fluoroalkyl, -C(O)(C 1-3 fluoroalkyl), C 3-6 cycloalkyl, C 3-6 Fluorocycloalkyl or fluoropyrimidinyl substitution with one or more oxo groups, -Cl, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12)C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0119] Any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1b .

[0120] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 6-10 Aryl groups, with optional substitutions including Z 1 .

[0121] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , ,or .

[0122] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for , ,or .

[0123] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 6-10 aryl, which is substituted with one or more C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 11 -C(O)OR 12 -C(O)NH(C 3-6 cycloalkyl), -C(O)NH(C 4-6 Alkyl), -C(O) heterocyclic group, N(R) 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0124] Wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -C(O)NH(C 3-6 cycloalkyl), -C(O)NH(C 4-6 Alkyl groups or -C(O) heterocyclic groups may be optionally substituted with Z. 1a ;

[0125] Wherein C 6-10 Aryl optional substitution has Z 1 .

[0126] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 6-10 Aryl groups, which are substituted with one or more -C(O)NH(C) groups. 1-3 Alkyl groups, and optionally substituted with Z 1a ;

[0127] The -C(O)NH(C 1-3 Alkyl groups are substituted with one or more oxo, halogen, -NO2, -CN, -N3, or C groups. 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R)12 );

[0128] Wherein C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0129] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 C 6-10 Aryl groups, which are substituted with one or more -C(O)(C 1-3 fluoroalkyl); wherein the -C(O)(C 1-3 (Fluoroalkyl) substitution with one or more oxo groups, -Cl, -NO2, -CN, -N3, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 3-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0130] Wherein C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 3-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b ;and

[0131] Wherein C 6-10 Aryl optional substitution has Z 1 .

[0132] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 -N(R) 12 (R) 12 -S(O)2R 12 -S(O)2N(R) 12 (R) 12 ), or -H.

[0133] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 1 for or .

[0134] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-10 Alkyl groups, optionally substituted with Z 1 .

[0135] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-10 alkyl.

[0136] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is a methyl group.

[0137] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 7-10 Alkyl groups, optionally substituted with Z 1 .

[0138] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-6 Alkyl groups, which are substituted with one or more -O(C) groups. 1-2 Alkyl), -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 Alkyl); wherein the -O(C) 1-2 Alkyl groups are substituted with one or more oxo groups, -Cl, -NO2, -CN, -N3, or C. 2-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 2-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the -O(C 1-2 Alkyl groups are optionally substituted with -F; wherein the -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 Alkyl groups are substituted with one or more oxo, halogen, -NO2, -CN, -N3, or C groups. 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12(R) 12 );

[0139] Wherein C 1-6 Alkyl substitution can be Z 1a ; and each of the Cs described therein 2-9 Alkyl, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 2-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0140] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , , , , , , , or .

[0141] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Alkyl group, wherein one or more substituents are selected from the following: -Cl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bicyclic heterocyclic, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12)C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), or -S(O)2N(R) 12 (R) 12 ); wherein C 4-6 Alkyl groups may also be optionally substituted with Z 1 ;and

[0142] Wherein C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 Cycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bicyclic heterocyclic, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 Alkyl) optional substitution with Z 1a .

[0143] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Alkyl groups, which are substituted with one or more -O(CH2)2R 17 Or -O(CH2)R 17 ;R 17 It is C independently each time it appears. 3-15 Cycloalkyl, aryl, heterocyclic, heteroaryl, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0144] Wherein C3-15 Cycloalkyl, aryl, heterocyclic, and heteroaryl groups may be optionally substituted with Z. 1b ; and the C therein 4-6 Alkyl groups may also be optionally substituted with Z 1 .

[0145] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Alkyl group, wherein the substitutions are five or more substituents selected from the following: F, hydroxyl, -CN, -OCH3, -OCD3, -NHC(O)(C 1-3 Alkyl), -S(O)2(C 1-3 Alkyl), or C 1-2 fluoroalkoxy; and the C therein 4-6 Alkyl substitution can be Z 1 .

[0146] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-3 Alkyl group, wherein one or more substituents are selected from the following: -Cl, C 2-6 alkenyl, C 2-6 Alkyne, cyclopropyl, naphthyl, bicyclic heterocyclic, C 7-15 Cycloalkyl, -O(CH2)2R 17 -O(CH2)R 17 -O(C 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -C(O)(C 1-9 Alkyl), -C(O) (cyclopropyl), -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -N(R)12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), or -S(O)2N(R) 9 (R) 12 );

[0147] Wherein C 1-3 Alkyl groups may also be optionally substituted with Z 1 ;and

[0148] Wherein C 2-6 alkenyl, C 2-6 Alkyne, cyclopropyl, naphthyl, bicyclic heterocyclic, C 7-15 cycloalkyl, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 The cycloalkyl group, -S(O)2 (heterocyclic group), or -S(O)2 (heteroaryl group) can be optionally substituted with Z. 1a .

[0149] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for or .

[0150] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-3 Alkyl group, wherein one or more of the substituents are selected from the following: azirmonobutyl, tetrahydrofuranyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, isothiazolyl, tetraazolyl, furanyl, thiomorpholinyl, 4-7-membered sulfonamide, 4-7-membered cyclic carbamate, 4-7-membered cyclic carbonate, 4-7-membered cyclic sulfide, or 8-10-membered heteroaryl; any one of the optional substitutions has Z 1a ; and the C therein 1-3 Alkyl groups may also be optionally substituted with Z 1 .

[0151] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , or .

[0152] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-3 Alkyl group, wherein the substituted group has one of the following substituents selected from: phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C. 4-6 cycloalkyl;

[0153] The phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C 4-6 Cycloalkyl substitution with one or more oxo groups, -NO2, -N3, -CN, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -O(C) 3-6 alkyl), -O(C) 3-6 cycloalkyl), -O (heterocyclic), -C(O)-R12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 9 (R) 12 );and

[0154] Any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a .

[0155] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-3 Alkyl groups, optionally substituted with Z 1 And the substitution has one of the following substituents selected from: phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C. 4-6 cycloalkyl;

[0156] The phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C 4-6The cycloalkyl substitution has four or more substituents selected from the following: -F, -Cl, -OH, C 1-3 Alkyl, -O(C) 1-2 Alkyl group or -S(O)2NH2.

[0157] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 1-3 Alkyl group, which is oxy-substituted and optionally has one or more substituents selected from the following: halogen, azacyclic butyl, pyrrolidinyl, piperazine, tetrahydrofuranyl, thiomorpholinyl, -CN, C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyclopropyl, C 7-15 cycloalkyl, C 1-8 Halogenated alkyl groups, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 9 (R) 12 ); and the C therein1-3 Alkyl substitution can be Z 1 ;

[0158] Wherein C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyclopropyl, C 7-15 cycloalkyl, C 1-8 Halogenated alkyl, azacyclic butyl, pyrrolidinyl, piperazine, tetrahydrofuranyl, or thiomorpholinyl, optionally substituted with Z 1a .

[0159] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is a C3 alkyl group, and its substitutions include five or more substituents selected from the following: -F, -OH, -OCH3, -CN, -NHC(O)(C 1-3 Alkyl), C 1-2 Fluoroalkoxy, or -S(O)2(C 1-3 alkyl).

[0160] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 3-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0161] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , , , or .

[0162] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for ,or .

[0163] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is cyclopropyl, and its optional substitutions include Z. 1 .

[0164] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C7-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0165] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , or .

[0166] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Cycloalkyl, wherein one or more substituents are selected from the following: -halogenated, oxo-substituted, -CN, C 1-4 Alkyl, C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -O(C) 4-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 5-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -NH(R) 12 ), -N(R 12 (C) 4-9 alkyl), -N(R) 12 (C) 3-10 cycloalkyl), -N(R) 12 (heterocyclic group), -N(R) 12 (aryl), -N(R) 12 (heteroaryl), -N(R) 12 )C(O)O(C 4-9 alkyl), -N(R) 12 )C(O)O(C 3-10 cycloalkyl), -N(R) 12 C(O)O (heterocyclic group), -N(R) 12 )C(O)O(aryl), -N(R) 12 )C(O)O(heteroaryl), -C(O)N(R) 12(C) 5-9 Alkyl), -C(O)N(R) 12 (C) 7-10 cycloalkyl), -C(O)N(R 12 (heterocyclic group), -C(O)N(R) 12 (aryl), -C(O)N(R) 12 (Heteroaryl), -C(O)N(R) 9 (R) 9 -C(O)OR 12 -N(R) 12 )2(R 12 ) + -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)-N( 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)2R 12 -S(O)(NH)R 12 , or -S(O)2N(R 12 (R) 12 ); wherein C 4-6 The cycloalkyl group may also be optionally substituted with Z 1 ; wherein C 1-4 Alkyl substitution can be oxy-, halogenated, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 16 -O(C 4-9 Alkyl), -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 R 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and each of the Cs described herein 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Haloalkyl, -O(C) 4-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 5-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -N(R) 12 (C) 4-9 alkyl), -N(R) 12 (C) 3-10 cycloalkyl), -N(R) 12 (heterocyclic group), -N(R) 12(aryl), -N(R) 12 (heteroaryl), -N(R) 12 )C(O)O(C 4-9 alkyl), -N(R) 12 )C(O)O(C 3-10 cycloalkyl), -N(R) 12 C(O)O (heterocyclic group), -N(R) 12 )C(O)O(aryl), -N(R) 12 )C(O)O(heteroaryl), -C(O)N(R) 12 (C) 5-9 Alkyl), -C(O)N(R) 12 (C) 7-10 cycloalkyl), -C(O)N(R 12 (heterocyclic group), -C(O)N(R) 12 (aryl), -C(O)N(R) 12 (Heteroaryl), aryl, heteroaryl or heterocyclic, optionally substituted with Z 1a .

[0167] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , or .

[0168] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Cycloalkyl, wherein one or more substituents are selected from the following: C 1-4 Hydroxyalkyl, C 1-3 Alkyl group, -(CH2) 1-3 O(C 1-3 Alkyl), -C(O)NH(C 1-4 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl)2、-NHC(O)O(C 1-3 Alkyl), -NHC(O)(C 1-4 hydroxyalkyl); wherein the C 4-6 cycloalkyl optional substitution has Z 1 ;

[0169] The -C(O)NH(C 3-6 Cycloalkyl) substitution with Z 1a ; wherein C 1-4 hydroxyalkyl or -NHC(O)(C1-4 Hydroxyalkyl) substituted with oxo, halogen, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0170] Wherein C 1-3 Alkyl group, -(CH2) 1-3 O(C 1-3 alkyl), -N(C) 1-3 Alkyl)2、-NHC(O)O(C 1-3 Alkyl) substitution with oxo, halogen, -NO2, -CN, -N3, C 3-9 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); wherein -C(O)NH(C 1-4 Alkyl) substitution with oxo, halogen, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R)12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and each of the Cs described herein 3-9 Alkyl, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0171] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , , , or .

[0172] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C4-6 Cycloalkyl groups, which are substituted with one or more -NHC(O)(C 1-3 Alkyl); wherein at least one -NHC(O)(C 1-3 Alkyl groups are substituted with one or more oxo, halogen, -NO2, -CN, -N3, or C groups. 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); wherein C 4-6 cycloalkyl optional substitution has Z 1 ;and

[0173] Wherein C 3-9 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0174] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for .

[0175] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 4-6 Cycloalkyl groups, wherein the substitutions are three or more substituents selected from the following: -OH, C 1-4 Hydroxyalkyl, C 1-3 Alkyl group, -(CH2) 1-3 O(C 1-3 Alkyl), -C(O)NH(C 1-4 Alkyl), -C(O)NH(C 3-6 cycloalkyl), -N(C) 1-3 Alkyl)2、-NHC(O)(C 1-3 Alkyl), -NHC(O)O(C 1-3 Alkyl), or -NHC(O)(C 1-4 hydroxyalkyl); and the C therein 4-6 cycloalkyl optional substitution has Z 1 .

[0176] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 .

[0177] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is an oxazolyl, isoxazolyl, thiadiazolyl, thiazolyl, oxadiazolyl, isothiazolyl, tetrazolyl, thiophenyl, furanyl, or a 6-10 membered heteroaryl; any one of these optional substitutions has Z. 1 ;

[0178] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is a 4-7 member monocyclic heterocyclic group, with optional substitutions including Z. 1 .

[0179] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , or .

[0180] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is an azahexacyclobutane, oxacyclobutane, pyrrolidinyl, morpholinyl, thiomorpholinyl, 4-7 sulfonolactam, 4-7 cyclic carbamate, 4-7 cyclic carbonate, or 4-7 cyclic sulfide; any one of these optionally has Z. 1 .

[0181] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , , or .

[0182] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It can be tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl;

[0183] The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl substituted group has one or more substituents selected from the following: oxo, halogen, -CN, C. 2-4 Alkyl, C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R)12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)2(C 4-9 Alkyl), -S(O)2(C 3-10 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)(NH)R 12 Or -S(O)2N(R) 12 (R) 12 );

[0184] The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group is optionally substituted with Z. 1a ;

[0185] Wherein C 2-4 Alkyl substitutions can be halogenated, followed by -NO2, -CN, -N3, or C. 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0186] Each of the C 3-9 Alkyl, C 5-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -S(O)2(C 4-9 Alkyl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (aryl), or -S(O)2 (heteroaryl) are optionally substituted with Z 1a .

[0187] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for .

[0188] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It can be tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl;

[0189] The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazolyl, or triazolyl group substituted with one or more C1 alkyl groups;

[0190] The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group is optionally substituted with Z. 1 ;

[0191] The C1 alkyl group may be optionally substituted with oxy, halogen, -NO2, -CN, -N3, or C. 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 9 (R) 9 -C(O)N(R) 12 (C) 4-9 Alkyl), -C(O)N(R) 12 (C) 3-10 cycloalkyl), -C(O)N(R 12 (heterocyclic group), -C(O)N(R) 12 (aryl), -C(O)N(R) 12 (heteroaryl), -N(R) 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12-S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -C(O)N(R) 12 (C) 3-10 cycloalkyl), -C(O)N(R 12 (heterocyclic group), -C(O)N(R) 12 (aryl), -C(O)N(R) 12 (Heteroaryl) optional substitution with Z 1a .

[0192] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl; any one of these optional substitutions has Z. 1 The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group substituted with one or more S(O)2(C) groups. 1-3 Alkyl); wherein the S(O)2(C 1-3 Alkyl) substitution with oxo, halogen, -NO2, -CN, -N3, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12)S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0193] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl; any one of these optional substitutions has Z. 1 The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group substituted with one or more C atoms. 1-4 Hydroxyalkyl; wherein the C 1-4 Hydroxyalkyl substitution with oxyhydroxide, halogen, -NO2, -CN, -N3, C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0194] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl; any one of these optional substitutions has Z. 1 The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group is substituted with one or more -CH2C(O)NH(C) groups. 1-6 Alkyl); wherein -CH2C(O)NH(C 1-6 Alkyl) substitution with oxo groups, -Cl, -NO2, -CN, -N3, C 6-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); wherein -CH2C(O)NH(C 1-6 Alkyl) optional substitution with Z 1a ; and the C therein 6-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

[0195] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2It can be tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl;

[0196] The tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrroleyl, pyrazolyl, imidazoleyl, or triazolyl group substituted with one or more -CH2C(O)NH(C) groups. 4-6 Alkyl); and wherein the tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazineyl, pyrroleyl, pyrazolyl, imidazolyl, or triazolyl is optionally substituted with Z. 1 .

[0197] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 C 6-10 Aryl groups, with optional substitutions including Z 1 .

[0198] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 It is a 6-12 membered bicyclic heterocyclic group, with optional substitutions including Z. 1 When the 6-12-membered bicyclic heterocyclic group is 1-oxa-7-azaspiro[3.5]nonyl, the 1-oxa-7-azaspiro[3.5]nonyl group substitutes for one or more Z groups. 1 .

[0199] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for .

[0200] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 -N(R) 12 (R) 12 -S(O)2R 12 -S(O)2N(R) 12 (R) 12 ) or -H.

[0201] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 2 for , , Or -H.

[0202] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R3 Selected from H, halogen, -NO2, -CN, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -N(R 12 )C(O)-N(R 12 (R) 12 -S(O)2R 12 -SR 12 and -S(O)2N(R 12 (R) 12 ).

[0203] In another embodiment, its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 Selected from -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 9 (R) 9 ), -NH(R 9 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -N(R 12 )C(O)-N(R 12 (R) 12 -S(O)2(R) 12 ), -SR 12 Or -S(O)2N(R) 12 (R) 12 );

[0204] Where -N(H)(R) 9 ) is NH(C 1-3 Alkyl), -N(H)(R 9 ) is NH(C 1-4 hydroxyalkyl), or -OR12 -O(C) 1-3 When alkyl), the NH(C) 1-3 Alkyl), NH(C) 1-4 Hydroxyalkyl), or -O(C 1-3 Alkyl groups are further substituted with one or more oxo, halogen, -NO2, -CN, -N3, or C groups. 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0205] Wherein C 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0206] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 for , , or .

[0207] In another embodiment, its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 Selected from -O (C4 alkyl) or -N (H) (C4 alkyl); wherein the -O (C4 alkyl) is optionally substituted with Z. 1a The -N(H) (C4 alkyl) is optionally substituted with oxo, halogen, -NO2, -CN, -N3, or C. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R)12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0208] Wherein C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0209] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 1-9 Alkyl groups, optionally substituted with Z 1 .

[0210] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 1-2 Alkyl groups, optionally substituted with F and further substituted with one or more oxo groups, -Cl, -NO2, -N3, -CN, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0211] Wherein C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0212] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 for .

[0213] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It is a C3 alkyl group, which has one or more Z substitutions. 1 .

[0214] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 4-9 Alkyl groups, optionally substituted with Z 1 .

[0215] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 2-9 The alkynyl group, which may be optionally substituted with Z 1 .

[0216] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 for .

[0217] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 2-9 Alkenyl, which may be optionally substituted with Z 1 .

[0218] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 .

[0219] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 If the 5-10 heteroaryl group is pyridyl, then the pyridyl group is further substituted with one or more Z groups. 1 .

[0220] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 6-10 Aryl groups, with optional substitutions including Z 1 .

[0221] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 6-10 Aryl groups, with optional substitutions including Z 1 ;

[0222] Where C 6-10 When the aryl group is cyanophenyl, the cyanophenyl group is further substituted with one or more oxo, halogen, -NO2, -N3, or C groups. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1a .

[0223] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It is a 4-12 membered heterocyclic group, with optional substitutions including Z. 1 .

[0224] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It is a 4-12 membered heterocyclic group, with optional substitutions including Z. 1 When the 4-12 membered heterocyclic group is a hydroxypyrrolidinyl group, the hydroxypyrrolidinyl group is further substituted with one or more oxo, halogen, -CN, -NO2, -N3, or C groups.1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0225] Wherein C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0226] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R3 C 3-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0227] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 3-6 cycloalkyl groups, which are substituted with one or more Z groups. 1 .

[0228] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 C 7-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0229] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 H, halogen, -NO2, -CN, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -N(R 12 )C(O)-N(R 12 (R) 12 -S(O)2R 12 -SR 12 Or -S(O)2N(R) 12 (R) 12 ).

[0230] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 for or .

[0231] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 For -OR 12 -C(O)-R 12-C(O)-N(R) 12 (R) 12 ), -N(R 9 (R) 9 ), -NH(R 9 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -N(R 12 )C(O)-N(R 12 (R) 12 -S(O)2(R) 12 ), -SR 12 Or -S(O)2N(R) 12 (R) 12 ); where -N(H)(R 9 ) is NH(C 1-3 Alkyl), -N(H)(R 9 ) is NH(C 1-4 hydroxyalkyl), or -OR 12 -O(C) 1-3 When alkyl), the NH(C) 1-3 Alkyl), NH(C) 1-4 Hydroxyalkyl), or -O(C 1-3 Alkyl groups are further substituted with one or more oxo, halogen, -NO2, -CN, -N3, or C groups. 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 4-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0232] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 Selected from -O (C4 alkyl) or -N (H) (C4 alkyl); wherein the -O (C4 alkyl) is optionally substituted with Z. 1a ;

[0233] The -N(H) (C4 alkyl) is optionally substituted with oxo, halogen, -NO2, -CN, -N3, or C. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (V), -N(R) 12 )2(R 12 ) + -N(R) 12 )-C(O)R12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0234] Wherein C 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1a .

[0235] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 1-9 Alkyl groups, optionally substituted with Z 1 .

[0236] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 1-2 Alkyl groups, optionally substituted with F and further substituted with one or more oxo groups, -Cl, -NO2, -N3, -CN, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12-C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1a .

[0237] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It is a C3 alkyl group, which has one or more Z substitutions. 1 .

[0238] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 4-9 Alkyl groups, optionally substituted with Z 1 .

[0239] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 2-9 The alkynyl group, which may be optionally substituted with Z 1 .

[0240] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 2-9 Alkenyl, which may be optionally substituted with Z 1 .

[0241] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 .

[0242] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 for .

[0243] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 When the 5-10 heteroaryl group is pyridyl, the pyridyl group is further substituted with one or more Z groups. 1 .

[0244] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 6-10 Aryl groups, with optional substitutions including Z 1 .

[0245] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 6-10 Aryl groups, with optional substitutions including Z 1 ;

[0246] Where C 6-10 When the aryl group is cyanophenyl, the cyanophenyl group is further substituted with one or more oxo, halogen, -NO2, -N3, or C groups. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); and the C therein 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1a .

[0247] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It is a 4-12 membered heterocyclic group, with optional substitutions including Z. 1 .

[0248] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It is a 4-12 membered heterocyclic group, with optional substitutions including Z. 1 When the 4-12 membered heterocyclic group is a hydroxypyrrolidinyl group, the hydroxypyrrolidinyl group is further substituted with one or more oxo, halogen, -CN, -NO2, -N3, or C groups. 1-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 ), -N(R 12 )S(O)2-N(R 12 (R) 12 ), -N(R 12 )S(O)2O(R 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );

[0249] Wherein C 1-9 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 The alkyl, aryl, heteroaryl, and heterocyclic groups can be substituted with Z. 1a .

[0250] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 3-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0251] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 3-6 cycloalkyl groups, which are substituted with one or more Z groups. 1 .

[0252] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 C 7-10 Cycloalkyl groups, optionally substituted with Z 1 .

[0253] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently selected from H, halogen, -NO2, -CN, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 9 (R) 9 ), NH(R 9 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 , or -N(R 12 )S(O)2(R 12 ).

[0254] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently selected from -NO2, -OR 12 -C(O)-R12 -C(O)-N(R) 12 (R) 12 ), -N(R 9 (R) 9 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 , or -N(R 12 )S(O)2(R 12 ).

[0255] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently C 1-5 Alkyl groups, optionally substituted with Z 1 .

[0256] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently C 1-2 Alkyl groups, optionally substituted with F and substituted with one or more oxo, -Cl, -NO2, -N3, -CN, C 3-9 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )2(R 12 ) + -N(R) 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12-NR 12 S(O)2N(R 12 (R) 12 -NR 12 S(O)₂O(R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), -Si(R 12 )3、-SR 12 -S(O)R 12 -S(O)(NH)R 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); wherein any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z 1a .

[0257] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is a C3 alkyl group, which is substituted with one or more Z groups. 1 .

[0258] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently C 4-5 Alkyl groups, optionally substituted with Z 1 .

[0259] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently cyclopropyl, oxetyl, or azirone, optionally substituted with Z. 1 .

[0260] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 R 6 Or R 7 At least one of them is independently cyclopropyl, oxetyl, or azirone; wherein the cyclopropyl group is substituted with one or more Z groups.1 The oxobutyran or azironebutyran may optionally be substituted with Z. 1 .

[0261] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 R 4 R 5 R 6 Or R 7 No more than two of them are H.

[0262] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 3 It can be H or F.

[0263] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 4 It can be H, F, -CN, or Cl.

[0264] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 5 It can be H or F.

[0265] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 6 It can be H or F.

[0266] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, R 7 It can be H or F.

[0267] In another embodiment or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue, Z 1 Selected from H, halogens, -CN, C 1-9 Alkyl, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12)S(O)2(R 12 ), -OC(O)-N(R) 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and

[0268] Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a .

[0269] Another embodiment of this disclosure provides a pharmaceutical composition comprising the compounds of this disclosure, a pharmaceutically acceptable carrier, and optionally a diluent.

[0270] Another embodiment of this disclosure provides a method for treating inflammation-related diseases or disorders in patients in need, comprising administering to said patient a compound of this disclosure, or a pharmaceutical composition thereof. Detailed Implementation

[0271] definition

[0272] The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0273] A hyphen ("-") not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -C(O)NH2 is attached by a carbon atom. A hyphen before or after a chemical group is for convenience; a chemical group may or may not be depicted with one or more hyphens without losing its usual meaning. A wavy line drawn through the lines in the structure indicates the attachment point of the group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0274] prefix "C" u-v "" indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" indicates that an alkyl group has 1 to 6 carbon atoms.

[0275] The term "about" as used herein includes (and describes) embodiments relating to that value or parameter itself. In some embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In some still embodiments, the term "about" includes the indicated amount ±1%. Furthermore, the term "about X" includes a description of "X". Additionally, the singular forms "a" and "the" include plural references unless the context clearly specifies otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and their equivalents known to those skilled in the art.

[0276] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. Alkyl groups used in this article have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 8 carbon atoms (i.e., C464) 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646) 1-6 Alkyl groups, or 1 to 4 carbon atoms (i.e., C464, C56, C6 ... 1-4 Alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by its chemical name or determined by its molecular formula, it may include isomers having all positions with that number of carbon atoms; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0277] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C64 ... 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl), or 2 to 4 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-4 Alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0278] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C64 ... 2-20 acetylsyl), 2 to 8 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 2-8acetylsyl), 2 to 6 carbon atoms (i.e., C10, C20, C30, C40, C50, C60, C7 ... 2-6 Alkyne group), or 2 to 4 carbon atoms (i.e., C40, C50, C60, C70, C80, C9 ... 2-4 (Alkyne group). The term "alkynyl group" also includes those groups having one triple bond and one double bond.

[0279] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0280] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0281] "alkyl thio" refers to the group "alkyl-S-".

[0282] "Amino" refers to the -NR group. y R y , where each R y The radical is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cycloalkyl or heteroaryl, each of which may optionally be substituted as defined herein.

[0283] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) (including fused systems). The aryl groups used herein have 6 to 20 ring carbon atoms (i.e., C6 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl group, or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthracene. However, aryl groups do not include heteroaryl groups as defined below or any group that overlaps with a heteroaryl group as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl ring system. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic ring system.

[0284] "Cyano" refers to the group -CN.

[0285] "Keto" or "oxo" refers to the group =O.

[0286] "Carbamoyl" refers to the "O-carbamoyl" group (which refers to the group -OC(O)NR). y R z ) and the "N-carbamoyl" group (which refers to the -NR group) y C(O)OR z ), where R y and R zIt is independently selected from hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may be optionally substituted.

[0287] "Carboxyl group" refers to -C(O)OH.

[0288] “Ester” refers to -OC(O)R and -C(O)OR, where R is a substituent; each of them may be optionally substituted, as defined herein.

[0289] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic structure (including fused, bridged, and spirocyclic systems). The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group has at least one double bond). Cycloalkyl groups used herein have 3 to 20 cyclic carbon atoms (i.e., C6 ... 3-20 cycloalkyl groups), 3 to 12 cyclic carbon atoms (i.e., C12+ ... 3-12 cycloalkyl groups), 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 cycloalkyl groups), 3 to 8 cyclic carbon atoms (i.e., C1646-C ... 3-8 cycloalkyl groups, or 3 to 6 cyclic carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 3-6 Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0290] "Halogen" or "halogenated" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihalogenated and trihalogenated alkyl groups refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may, but are not required to, be the same halogen. Examples of halogenated alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0291] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. By way of example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may optionally be substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may optionally be substituted. As used herein, heteroalkyl groups comprise 1-10 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms; and 1-3 heteroatoms, 1-2 heteroatoms, or 1 heteroatom.

[0292] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As described herein, heteroaryls comprise 1 to 20 cyclic carbon atoms (i.e., C2C ... 1-20 (heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C 3-12 (heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 (Heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom, wherein the cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophene, indazole, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, and imidazo[1,5-a]pyridinyl, wherein the heteroaryl can be linked by any ring of the fused system. Any aromatic ring containing at least one heteroatom and having one or more fused rings is considered a heteroaryl, regardless of the connection of the rest of the molecule (i.e., by any of the fused rings). Heteroaryl does not include aryl groups as defined above or overlapping with them.

[0293] "Heterocyclic group" refers to a saturated or unsaturated cycloalkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bicyclic heterocyclic groups, bridged heterocyclic groups, fused heterocyclic groups, and spiro-heterocyclic groups. Heterocyclic groups can be monocyclic or polycyclic, wherein polycyclic groups can be fused, bridged, or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of linkage (i.e., it can be bonded by carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to encompass any non-aromatic ring containing at least one heteroatom, which can be fused to an aryl or heteroaryl ring, regardless of the linkage to the rest of the molecule. The heterocyclic groups used herein have 2 to 20 ring atoms (i.e., 4-20 membered heterocyclic groups), 2 to 12 membered heterocyclic groups (i.e., 4-12 membered heterocyclic groups), 4 to 10 membered heterocyclic groups (i.e., 4-10 membered heterocyclic groups), 4 to 8 membered heterocyclic groups (i.e., 4-8 membered heterocyclic groups), or 4 to 6 membered heterocyclic groups (i.e., 4-6 membered heterocyclic groups); or have 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatomum, wherein the ring heteroatoms are independently selected from nitrogen, sulfur, or oxygen. The heterocyclic group may contain one or more oxo and / or thio groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetane, dioxopentyl, azirone, azirone, morpholinyl, thiomorpholinyl, 4-7 sulfonolactams, 4-7 cyclic carbamates, 4-7 cyclic carbonates, 4-7 cyclic sulfides, and morpholinyl. The term “bridged-heterocyclic group” as used herein refers to a 4- to 10-membered ring moiety connected at two non-adjacent atoms of the heterocyclic group to one or more (e.g., 1 or 2) 4- to 10-membered ring moietyes having at least one heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. “Bridged-heterocyclic group” as used herein includes bicyclic and tricyclic ring systems. Furthermore, as used herein, the term "spiro-heterocyclic" refers to a cyclic system in which the 3- to 10-membered heterocyclic group has one or more additional rings, wherein the one or more additional rings are 3- to 10-membered cycloalkyl groups or 3- to 10-membered heterocyclic groups, and wherein a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclic group. Examples of spiro-heterocyclic rings include bicyclic and tricyclic cyclic systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, dihydroindolyl, and isodihydroindolyl, wherein the heterocyclic group can be bonded to any ring of the fused system.As used herein, a bicyclic heterocyclic group is a heterocyclic group that is attached to another cyclic group at two points, wherein the other cyclic group itself can be a heterocyclic group or a carbocyclic group.

[0294] As used herein, the term "nitrogen- or sulfur-containing heterocyclic group" refers to a heterocyclic group containing at least one nitrogen atom or at least one sulfur atom, or both nitrogen and sulfur atoms, within a ring structure. It should be understood that other heteroatoms, including oxygen, may be present in addition to nitrogen, sulfur, or combinations thereof. Examples of nitrogen- or sulfur-containing heterocyclic groups include morpholino, thiomorpholino, thiazolyl, isothiazolo, oxazolidinone, 1,2-thioheterocyclic pentenyl, piperidinyl, piperazine, etc.

[0295] "Hydroxy" (or hydroxyl) refers to the -OH group. "Hydroxyalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by hydroxyl groups.

[0296] "Nitro" refers to the group -NO2.

[0297] "Sulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0298] "alkylsulfonyl" refers to the group -S(O)2R, where R is a substituent or a defined group.

[0299] "alkylsulfinyl" refers to the group -S(O)R, where R is a substituent or a defined group.

[0300] "Thiocyanate group" refers to -SCN.

[0301] "Mercapto" refers to the group -SR, where R is a substituent or a defined group.

[0302] "Thio" or "thion" refers to the group (=S) or (S).

[0303] Some commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" may also be referred to as "alkylene" or "alkylenyl" and "arylene" or "arylenyl," respectively. Furthermore, unless otherwise defined, in cases where a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last mentioned group contains the atoms that connect said moiety to the remainder of the molecule.

[0304] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the scenario where said event or situation occurs and the scenario where said event or situation does not occur. Furthermore, the term "optionally substituted" refers to the possibility that any one or more hydrogen atoms on a specified atom or group may be partially substituted with or without hydrogen. "Optionally substituted" can be zero to the maximum possible number of substitutions, and each occurrence is independent. When the term "substituted" is used, the substitution must be carried out on the substituted hydrogen atom of the indicated substituent. The optional substitution may be the same as or different from the (desired) substitution.

[0305] When a part is “optionally substituted” and refers to general terms such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,” “cycloalkyl,” “aryl,” or “heteroaryl,” the general term may mean any of the terms specifically listed above, such as (C). 1-3 Alkyl), (C 4-6 alkyl), -O(C) 1-4 Alkyl), (C 3-10 cycloalkyl), O-(C 3-10 Cycloalkyl), etc. For example, "any aryl" includes "aryl" and "-O (aryl)," as well as examples of aryl groups such as phenyl or naphthyl. Furthermore, the term "any heterocyclic" includes the term "heterocyclic" and "O- (heterocyclic)," as well as examples of heterocyclic groups such as oxobutyryl, tetrahydropyranyl, morpholino, piperidinyl, etc. In the same manner, the term "any heteroaryl" includes the term "heteroaryl" and "O- (heteroaryl)," as well as specific heteroaryl groups such as pyridine, etc.

[0306] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imine tautomers. Regardless of which tautomer is exhibited, and regardless of the nature of the equilibrium between the tautomers, those skilled in the art will understand that the compound contains both amide and imine tautomers. Therefore, amide-containing compounds are understood to include their imine tautomers. Similarly, imine-containing compounds are understood to include their amide tautomers.

[0307] Any general formula or structure given in this application is also intended to represent both unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structure described by the general formula given in this application, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to... 2 H (deuterium, D), 3 H (tritium) 11C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. This invention includes compounds of this invention labeled with various isotopes, such as those with radioactive isotopes such as 3 H, 13 C and 14 Compounds incorporating carbon (C) are used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination or for use in patients undergoing radiotherapy.

[0308] This disclosure also includes “deuterated analogues” of Formula I compounds in which one to n hydrogen atoms (where n is the number of hydrogen atoms in the molecule) are replaced with deuterium. Such compounds exhibit enhanced resistance to metabolism and are therefore used to increase the half-life of any Formula I compound (when administered to mammals, specifically humans). See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

[0309] Deuterium-labeled or substituted therapeutic compounds of the present invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (e.g., deuterium) can provide therapeutic advantages based on greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used in PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs are generally prepared using the synthetic routes or examples described below and the steps described in the preparation section, wherein non-isotopically labeled reagents are replaced with readily available isotopically labeled reagents. It is understood that deuterium in this application can be considered a substituent in compounds of formula I.

[0310] The concentration of such heavier isotopes (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds of this invention, any atom not specifically designated as a particular isotope means that it represents any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," it should be understood that the position is hydrogen with its naturally occurring isotopic composition. Therefore, in the compounds of this invention, any atom specifically designated as deuterium (D) means that it represents deuterium.

[0311] In many cases, the compounds of the present invention can form acid and / or base salts due to the presence of amino and / or carboxyl or similar groups.

[0312] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances suitable for the preparation of pharmaceutical compositions intended for veterinary or human medical use.

[0313] The term "pharmaceutically acceptable salt" for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is not undesirable in biological or other respects. "Pharmaceutically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing the acidic salt solution. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be produced according to conventional procedures for preparing acid addition salts from base compounds by dissolving the free base in a suitable organic solvent and treating the solution with an acid. Those skilled in the art will understand the various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. By way of example, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), trienylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkyl)amines, ... Suitable amines include (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0314] The term "substitution" means that any one or more hydrogen atoms on a specified atom or group are partially replaced by other than hydrogen atoms, provided that the replacement does not exceed the normal valence of the specified atom. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidyl, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylthionyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercapto, thionyl, or combinations thereof. This document is not intended to include polymers or similarly indeterminate structures obtained by further defining substituents indefinitely with the appended substituents (e.g., substituted aryl groups having substituted alkyl groups, where the substituted alkyl group itself substitutes for a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, the successive substitution of a substituted aryl group by two other substituted aryl groups is limited to substituted aryl groups (substituted aryl groups) substituted with substituted aryl groups. Similarly, the above definition is not intended to include disallowed substitutions (e.g., substituted methyl groups having five fluorine atoms or heteroaryl groups having two adjacent oxygen ring atoms). These disallowed substitutions are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise stated, when a group is described as optionally substituted, any substitutions in that group are essentially unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, the one or more substituents may also be further substituted by halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl groups, each of which is substituted. In other embodiments, the substituents may be further substituted with halogens, alkyl groups, haloalkyl groups, alkoxy groups, hydroxyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, or heteroaryl groups, none of which are substituted. Those skilled in the art will recognize that the substituents and other portions of the compounds of the general formula herein should be selected to provide sufficiently stable compounds that are pharmaceutically useful for formulation into acceptable stable pharmaceutical compositions. Compounds exhibiting such stability are considered to be within the scope of this invention. Those skilled in the art will understand that any combination of the foregoing definitions and substituents should not result in an inoperable substance or compound.

[0315] As used in this invention, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings / coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents, etc. Such media and agents for pharmaceutically active substances are well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients may also be incorporated into the composition.

[0316] As used in this invention, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings / coatings, antimicrobial and antifungal agents, isotonic agents, and absorption delay agents, etc. Such media and agents for pharmaceutically active substances are well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients may also be incorporated into the composition.

[0317] "Solvates" are formed through the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds are also provided.

[0318] combination

[0319] Patients treated with the IRAK4 inhibitors of this disclosure frequently exhibit diseases or conditions that benefit from treatment with other therapeutic agents. These diseases or conditions may be inflammatory or may be associated with cancer, metabolic disorders, gastrointestinal disorders, etc. Therefore, one aspect of this disclosure is a method for treating inflammatory diseases or conditions, or metabolic disorders, gastrointestinal disorders, or cancer, etc., comprising administering to a patient (specifically a human subject) a combination of the compound of the invention with one or more compounds that can be used to treat the disease.

[0320] In some embodiments, the compounds of this disclosure are formulated in conjunction with one or more other active ingredients. In some embodiments, the other active ingredients are administered in separate dosage forms at substantially the same time. In some embodiments, the other active ingredients are administered sequentially and may be administered at different times in relation to the compounds of this disclosure.

[0321] Combination for inflammatory diseases and conditions

[0322] For example, the compounds disclosed herein can be combined with one or more of the following substances: 5-lipoxygenase inhibitors, acetylcholinesterase inhibitors, ACTH receptor agonists, activin receptor antagonists, acyltransferase inhibitors, adrenocorticotropic hormone ligands, AKT1 gene inhibitors, alkaline phosphatase modulators, alkaline phosphatase stimulators, androgen receptor agonists, apolipoprotein C3 antagonists, bactericidal penetrant stimulators, β-adrenergic receptor antagonists, β-glucuronidase inhibitors, B-lymphocyte antigen CD20 inhibitors, bradykinin receptor modulators, BTK kinase inhibitors, calcineurin inhibitors, calcium channel inhibitors, cannabinoid CB1 receptor modulators, cannabinoid CB2 receptor modulators, cannabinoid receptor antagonists, and cannabinoids. Receptor modulators, cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokine antagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3 modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD49b antagonists, CD49d antagonists, CD89 agonists, cell adhesion molecule inhibitors, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, CSF-1 agonists, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, cyclic GMP phosphodiesterase inhibitors, cyclooxygenase 2 inhibitors, cyclooxygenase inhibitors, cyclooxygenase stimulators, cytochrome P450. 3A4 inhibitors, cytotoxic T-lymphocyte protein-4 stimulators, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, DNA polymerase inhibitors, EGFR family tyrosine kinase receptor modulators, eosinophil peroxidase inhibitors, eosinophil activation chemokine ligand inhibitors, EP4 prostaglandin receptor agonists, epidermal growth factor agonists, epidermal growth factor ligands, estrogen receptor β agonists, factor XIII agonists, FGF-10 ligands, FGF2 receptor agonists, CX3CL1 ligand inhibitors, free fatty acid receptor 2 antagonists, GATA 3 transcription factor inhibitors, glucagon-like peptide-2 agonists, glucocorticoid agonists, GM-CSF receptor agonists, G-protein-coupled receptor 84 antagonists, guanylate cyclase receptor agonists, histamine H2 receptor antagonists, histone acetyltransferase inhibitors, histone deacetylase inhibitors, HLAClass II antigen modulators, hydrolase inhibitors, ICAM1 gene inhibitors, ICAM-1 inhibitors, IL-1 gene inhibitors, IL-10 agonists, IL-10 gene stimulators, IL-11 agonists, IL-12 antagonists, IL-12 gene inhibitors, IL-13 antagonists, IL-17 antagonists, IL-2 antagonists, IL-2 receptor α subunit inhibitors, IL-21 antagonists, IL-23 antagonists, IL-6 antagonists, IL-6 gene inhibitors, IL-6 receptor modulators, IL- 7. Antagonists, IL-8 antagonists, immunoglobulin G1 agonists, immunoglobulin G2 modulators, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin α-4 / β-1 antagonists, integrin α-4 / β-7 antagonists, integrin α-E antagonists, integrin antagonists, integrin β-7 antagonists, interferon β ligands, interleukin 17E ligand inhibitors, interleukin ligand inhibitors, interleukin receptor 17A antagonists, interleukin receptor 17B antagonists, interleukin-1 β-ligands, interleukin-1 β-ligand modulators, interleukin-6 ligand inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, JAK2 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, LanC-like protein 2 modulators, leukotriene BLT receptor antagonists, lipoxygenase modulators, L-selectin antagonists, MAdCAM inhibitors, matrix metalloproteinase inhibitors, matrix metalloproteinase modulators, melanocortin agonists, membranous copperamine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, MIP3 α-ligand inhibitors, mitochondrial 10 kDa heat shock protein stimulators, monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, mucin stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, natriuretic peptide receptor C agonists, neuroregulatory protein-4 ligands, nicotinic acetylcholine receptor agonists, nicotinic ACh receptor α 4-subunit modulators, nicotinic ACh receptor α7 subunit stimulators, nicotinic ACh receptor β2 subunit modulators, NK1 receptor antagonists, NKG2D-activated NK receptor antagonists, nuclear factor κB inhibitors, opioid growth factor receptor agonists, opioid receptor antagonists, opioid receptor δ antagonists, oxidoreductase inhibitors, P2X7 purine receptor agonists, p38 MAP kinase inhibitors, PARP inhibitors, PDE4 inhibitors, PDGF receptor agonists, phagocytic stimulating peptide modulators, phosphoMurNAc pentapeptide transferase inhibitors, phospholipase A2 inhibitors, platelet-activating factor receptor antagonists, potassium channel inhibitors, PPAR α agonists, PPAR δ agonists, PPARγ-agonists, protein CYR61 stimulators, protein fimH inhibitors, protein kinase C α inhibitors, protein kinase C β inhibitors, protein kinase C δ inhibitors, protein kinase C ε inhibitors, protein kinase C η inhibitors, protein kinase C Theta inhibitors, protein kinase G inhibitors, protein kinase inhibitors, P-selectin glycoprotein ligand-1 inhibitors, PurH purine biosynthesis protein inhibitors, retinoic acid receptor α agonists, retinoic acid receptor β agonists, retinoid receptor agonists, RNA polymerase inhibitors, SMAD-7 inhibitors, sodium channel inhibitors, somatostatin receptor agonists, sphingosine 1-phosphate phosphatase 1 stimulators, sphingosine 1-phosphate phosphatase modulators, sphingosine kinase 1 inhibitors, sphingosine kinase 2 inhibitors, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors, STAT-3 inhibitors, STAT-4 inhibitors, stem cell antigen-1 inhibitors, superoxide dismutase modulators, superoxide dismutase stimulators, SYK kinase inhibitors, T cell surface glycoprotein CD28 inhibitors, TGF inhibitors. β1 ligand inhibitors, thymosin agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 agonists, TNF α ligand inhibitors, TNF α ligand modulators, TNF antagonists, TPL2 kinase inhibitors, trefoil factor modulators, tryptase inhibitors Inhibitors, tryptophan 5-hydroxylase inhibitors, tumor necrosis factor 14 ligand modulators, TYK2 kinase inhibitors, type I TNF receptor antagonists, type II TNF receptor modulators, unspecified growth factor receptor modulators, vanilloid VR1 agonists, vitamin D3 receptor agonists, cladin inhibitors, abatacept; acemenam; adalimumab; DCCT-10; apremilast; AST-120; balsalazine; balsalazine sodium; baliximab; beclomethasone dipropionate; budesonide; D-9421; budesonide MMX; caprodeco; pegylated certolizumab pegol); Clostridium butyricum; etanercept; fingolimod; glamer acetate; golimumab; infliximab; infliximab biosimilar; infliximab biosimilar; interferon β-1a; bioplasma; lenalidomide; mesalazine; GED-0001; AJG-501; metenkefalin acetate with tridecactideAcetate, Mycophenolate Molecular Ethate; Naltrexone; Natalizumab; Nizoralide; Osalazine; Interleukin; Propionyl-L-Carnitine; Recombinant Interferon β-1a, Serono; Remedymcel-L; Rifaximin; Rituximab; Ropivacaine; Rosiglitazone; Saxaglastine; Secukinumab; SPD-480; Tacrolimus; Tamibarbitine; Tiduglutide; Thalidomide; Tocilizumab; RO-4877533; Tofacitinib; CP-690550; Trichuris suis ova; ASP-1002; Eutectum; Valganciclovir; Vedolizumab; Ziliutone; Anti-CD3 Imaging Agent (Antibody Fragment, Cancer / Autoimmune Disease), ImaginAb; AVX-470; Cyclosporine; CXCR1 / 2 Ligand mAb (Immunology), Eli Lilly; FFP-102; GSK-3050002; INN-108; IR-777; SGM-1019; peg-Iloleukin; PF-06480605; PF-06651600; SER-287; Syn-1002; Thetanix; Tolerogenic dendritic cell therapy (injectable) Crohn's disease), Barcelona Hospital Clinic / Fundacio Clinic; TOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexin V-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD-334; ASP-3291; beclomethasone dipropionate; bertilimumab; cyclosporine; clazakizumab; DLX-105; dolcanatide; E-6011; ETX-201; FFP-104; filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974; GLPG-1205; iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103; JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate; CB-01-05-MMX; LY-3074828; mesalazine with N-acetylcysteine; midismase; morasistem biosimilars with fosfomycin and carbapenems (enteric, Crohn's disease); Reponex; pluripotent adult progenitor cell therapy (ischemic / cerebral palsy).Athersys / Healios; NN-8828; olokizumab; OvaSave; P-28-GST; PDA-002; PF-4236921; PF-547659; Prednisolone; PUR-0110; QBECO; RBX-2660; Naltrexone for modified purposes (low dose, liver disease, Crohn's disease), TaiwanJ; JKB-122; SB-012; sotrastaurin; STNM-01; TAK-114; Tetostrept; Debio-0512; TRK-170; TRX-318; Vexizumab; VB-201; ZP-1848; Zicacisine; ABT-494; alicaforsen; Ampion; BI-655066; briakinumab; Cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodium phosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02; mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib; RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; latuimod; pucanatide; telotristat etiprate; infliximab biosimilar, Samsung Bioepis; AZD-058; and rifabutin with clarithromycin and further with clofazimine.

[0323] In addition, the following non-exhaustive list of compounds and compound classes may be combined with the compounds disclosed herein: 5-lipoxygenase inhibitors, such as zileutone, etalocibm FPL-64170, E-3040, and BU-4601A; acetylcholinesterase inhibitors, such as BL-7040; ACTH receptor agonists, such as metenkefalin acetate with tridecactide acetate and FAR-404; activin receptor antagonists such as follistatin; acyltransferase inhibitors such as AZD-0585; adrenocorticotropic hormone ligands, such as metenkefalin acetate with tridecactide acetate and FAR-404; AKT1 gene inhibitors, such as vidofludimus; alkaline phosphatase modulators such as recombinant human alkaline phosphatase (oral, ulcerative colitis). AM-Pharma; alkaline phosphatase stimulants such as bovine alkaline phosphatase; androgen receptor agonists, such as PB-005; apolipoprotein C3 antagonists, such as AZD-0585; bactericidal penetrant stimulants, such as opebacan; β-adrenergic receptor antagonists, such as NM-001; β-glucuronidase inhibitors, such as KD-018; B-lymphocyte antigen CD20 inhibitors, such as ocrelizumab and rituximab; bradykinin receptor modulators, such as givinostat; calcineurin inhibitors, such as tacrolimus and cyclosporine; calcium channel inhibitors, such as clotrimazole; cannabinoid C Cannabinoid CB2 receptor modulators, such as GWP42003-P and cannabidiol; cannabinoid receptor antagonists, such as fingolimod; cannabinoid receptor modulators, such as GWP42003-P and cannabidiol; cathepsin S inhibitors, such as VBY-129 and VBY-036; CCN protein stimulators, such as CSA-13; CCR3 chemokine antagonists, such as bertilimab; CCR5 chemokine antagonists, such as HGS-1025; CCR9 chemokine antagonists, such as MLN-3126, vercirnon, and CCX-025. CD3 modulators, such as visilizumab; CD40 ligand inhibitors, such as FFP-104; CD40 ligand receptor antagonists, such as FFP-104, FFP-102, and toralizumab; CD49b antagonists, such as visilizumab; CD49d antagonists, such as ELND-004; CD89 agonists, such as HF-1020; cell adhesion molecule inhibitors, such as nastatinumab, alicaforsen (intravenous), ASP-2002, and ISIS-2302.Chemokines CXC ligand inhibitors, such as CXCR1 / 2 ligand mAbs (immunology), Eli Lilly; CHST15 gene inhibitors, such as STNM-01; collagen modulators, such as adipose-derived stem cell therapies (Celution System), Cytori, DCCT-10; CSF-1 agonists, such as saxaglastine and morasistatin biosimilars of fosfomycin and carbapenems (enteric). Crohn's disease; Reponex; CSF-1 antagonists, such as JNJ-40346527; CXC10 chemokine ligand inhibitors, such as 946414-98-8, BMS-936557; CXCR2 chemokine antagonists, such as elubrixin; cyclic GMP phosphodiesterase inhibitors, such as CEL-031; cyclooxygenase 2 inhibitors, such as P-54; cyclooxygenase inhibitors, such as mesalazine, sodium 4-aminosalicylate, AJG-501, AGI-022; cyclooxygenase stimulants, such as nicotine. polacrilex; cytochrome P450 3A4 inhibitors, such as KD-018; cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept; dihydroceramide δ4 desaturase inhibitors, such as ABC-294640; dihydroorotate dehydrogenase inhibitors, such as vidofludimus; DNA polymerase inhibitors, such as valganciclovir; EGFR family tyrosine kinase receptor modulators, such as neuroregulatory protein 4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis), Avexegen Therapeutics / Sonsel Los Angeles; eosinophil peroxidase inhibitors, such as AWEPOPD-01, AWEPO-003; eosinophil activation chemokine ligand inhibitors, such as bertilimab; EP4 prostaglandin receptor agonists, such as KAG-308; epidermal growth factor agonists, such as heparin-EGF-like factor, Scios Nova; epidermal growth factor ligands, such as Hebervis; estrogen receptor β agonists, such as Primberry; factor XIII agonists, such as Caprodex; FGF-10 ligands, such as Repifermin; FGF2 receptor agonists, such as F2A; CX3CL1 ligand inhibitors, such as E-6011; free fatty acid receptor 2 antagonists, such as GLPG-0974; GATA 3 transcription factor inhibitors, such as SB-012; glucagon-like peptide-2 agonists, such as Tiduglutide, ZP-1848, NB-1002; glucocorticoid agonists, such as Budesonide, Beclomethasone dipropionate, Dexamethasone sodium phosphate, AJG-511, DOR-201, D-9421-C;GM-CSF receptor agonists, such as saxaglastine and moraxaglastine biosimilars of fosfomycin and carbapenem (enteric, Crohn's disease), Reponex; G-protein-coupled receptor 84 antagonists, such as GLPG-1205; guanylate cyclase receptor agonists, such as dolcanatide, SP-333; histamine H2 receptor antagonists, such as bismuth, Medeva; histone acetyltransferase inhibitors, such as TIP60 inhibitors (ulcerative colitis / inflammatory bowel disease / autoimmune diseases), University of Pennsylvania; histone deacetylase inhibitors, such as givinostat; HLA class II antigen modulators, such as HLA class II protein modulators (Crohn's disease), Nextera AS; hydrolase inhibitors, such as SC-56938; ICAM1 gene inhibitors, such as alicaforsen; ICAM-1 inhibitors, such as alicaforsen. (Intravenous), ISIS-2302; IL1 gene inhibitors, such as PLR-14; IL-10 agonists, such as peg-ilo-interleukin, AM-0010; IL10 gene stimulators, such as gene therapy (IL-10), Imperial College London; IL-11 agonists, such as olprene interleukin, YM-294; IL-12 antagonists, such as eutecticumab, briakinumab, apimod; IL12 gene inhibitors, such as RDP-58; IL-13 antagonists, such as tralokinumab, anrukinzumab; IL-17 antagonists, such as secukinumab, vidofludimus; IL-2 antagonists, such as dalizumab; IL-2 receptor α subunit inhibitors, such as baliximab, dalizumab, BSX-003, Ro-34-7375; IL-21 antagonists, such as... NN-8828, ATR-107; IL-23 antagonists, such as tildrakizumab, eutecticumab, BI-655066, AMG-139, briakinumab, LY-3074828, apimod; IL-6 antagonists, such as tocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL-6 gene inhibitors, such as YSIL6-T-PS; IL-6 receptor modulators, such as tocilizumab; IL-7 antagonists, such as interleukin-7 receptor modulators (ulcerative colitis / T-cell acute lymphoblastic leukemia), Effimune; IL-8 antagonists, such as elubrixin and clotrimazole; immunoglobulin G1 agonists, such as HF-1020; immunoglobulin G2 modulators, such as PF-547659; inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil.Insulin sensitizers, such as elafibranor, rosiglitazone, HE-3286, EGS-21; integrin α-4 / β-1 antagonists, such as natezumab, TRK-170, felasin; integrin α-4 / β-7 antagonists, such as etrolizumab, vedozumab, abrilumab, carotegast methyl, TRK-170, felasin; integrin α-E antagonists, such as etrolizumab; integrin antagonists, such as vedozumab, ASP-2002; integrin β-7 antagonists, such as etrolizumab; interferon β ligands, such as interferon β-1a, recombinant interferon β-1a, Serono; interleukin 17E ligand inhibitors, such as anti-IL-17BR humanized antibodies (pulmonary fibrosis / asthma / ulcerative colitis), Medical Research Council. Technology; Interleukin ligand inhibitors, such as HE-3286; Interleukin receptor 17A antagonists, such as brodalumab; Interleukin receptor 17B antagonists, such as anti-IL-17BR humanized antibodies (pulmonary fibrosis / asthma / ulcerative colitis), Medical Research Council Technology; Interleukin-1 β ligands, such as K(D)PT, PUR-0110, HMPL-004; Interleukin-1 β-ligand modulators, such as PUR-0110 and HMPL-004; interleukin-6 ligand inhibitors, such as PF-4236921; JAK tyrosine kinase inhibitors, such as tofacitinib and peficitinib; Jak1 tyrosine kinase inhibitors, such as ABT-494, tofacitinib, filgotinib, peficitinib, GLPG-0555, and solcitinib; JAK2 gene inhibitors, such as vidofludimus; Jak3 tyrosine kinase inhibitors, such as tofacitinib and peficitinib; Jun N-terminal kinase inhibitors, such as sermamod; LanC Leukoprotein-2 modulators, such as BT-11; leukotriene BLT receptor antagonists, such as ONO-4057, etalocib, SC-53228, SC-52798; lipoxygenase modulators, such as mesalazine; L-selectin antagonists, such as BNP-001; MAdCAM inhibitors, such as vedolizumab, PF-547659; matrix metalloproteinase inhibitors, such as D-5410; matrix metalloproteinase modulators, such as D-5410; melanocortin agonists, such as ASP-3291; copper amine oxidase inhibitors, such as velpatumab; metalloproteinase-2 inhibitors, such as KD-018, RWJ-68354;Metalloproteinase-9 inhibitors, such as GS-5745; MIP 3 α ligand inhibitors, such as GSK-3050002; mitochondrial 10 kDa heat shock protein stimulants, such as INV-103; monocyte differentiation antigen CD14 inhibitors, such as CD14 anti-inflammatory, Cornell; mTOR inhibitors, such as P-2281; mucin stimulants, such as rebamipide; NAD-dependent deacetylase sirtuin-1 stimulants, such as SRT-2104; natriuretic peptide receptor C agonists, such as pukanatide; neuroregulatory protein-4 ligands, such as neuroregulatory protein 4 (Crohn's disease / ulcerative colitis / necrotizing enterocolitis), Avexegen Therapeutics / Sonsel Los Angeles; nicotinic acetylcholine receptor agonists, such as TC-2403, nicotine gum, nicotine; nicotinic ACh receptor α4 subunit modulators, such as TC-2403; nicotinic ACh receptor α 7-subunit stimulators, such as GTS-21; nicotinic ACh receptor β2 subunit modulators, such as TC-2403; NK1 receptor antagonists, such as KD-018, besylate-nopetran; NKG2 D-activated NK receptor antagonists, such as NNC-0142-002; nuclear factor κB inhibitors, such as KD-018, cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalazine with N-acetylcysteine, P-54; opioid growth factor receptor agonists, such as metenkefalin acetate with tridecactide acetate, FAR-404; opioid receptor antagonists, such as naltrexone, IRT-103; opioid receptor delta antagonists, such as KD-018; oxidoreductase inhibitors, such as olsalazine; P2X7 purine receptor agonists, such as givinostat; p38 MAP kinase inhibitors, such as RDP-58, damartiamide, sermatiamide, and RWJ-68354; PARP inhibitors, such as EB-47 and INO-1003; PDE4 inhibitors, such as apremilast, tetostreptococcal, and CC-1088; PDGF receptor agonists, such as olprene interleukin and YM-294; phagocytic stimulating peptide modulators, such as 99mTc-RP-128; phospho-MurNAc pentapeptide transferase inhibitors, such as SQ-641; phospholipase A2 inhibitors, such as varespladib methyl; platelet-activating factor receptor antagonists, such as desarazin sodium; potassium channel inhibitors, such as clotrimazole; PPARα agonists, such as elafibranor (GFT-1007); and PPARδ agonists, such as elafibranor (GFT-1007).PPARγ agonists, such as rosiglitazone, GED-0507-34-Levo, etalocib; protein CYR61 stimulators, such as CSA-13; protein fimH inhibitors, such as EB-8018; protein kinase Cα inhibitors, such as sotrastaurin (AEB-071); protein kinase Cβ inhibitors, such as sotrastaurin (AEB-071); protein kinase Cδ inhibitors, such as sotrastaurin (AEB-071); protein kinase Cε inhibitors, such as sotrastaurin (AEB-071); protein kinase Cη inhibitors, such as sotrastaurin (AEB-071); protein kinase Cθ inhibitors, such as sotrastaurin (AEB-071); Protein kinase G inhibitors, such as CEL-031; Protein kinase inhibitors, such as TOP-1288; P-selective protein glycoprotein ligand-1 inhibitors, such as SEL-K2; PurH purine biosynthesis protein inhibitors, such as mycophenolate mofetil; Retinyl receptor α agonists, such as tamibarbitine; Retinyl receptor β agonists, such as tamibarbitine; Retinoid receptor agonists, such as tamibarbitine; RNA polymerase inhibitors, such as rifaximin; SMAD-7 inhibitors, such as Mongersen (GED-0301); Sodium channel inhibitors, such as ropivacaine; Somatostatin receptor agonists, such as valproate; Sphingosine 1-phosphophosphatase 1 stimulators, such as APD-334; Sphingosine 1-phosphophosphatase modulators, such as S1P modulators (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis), Akaal Pharma; Sphingosine kinase 1 inhibitors, such as ABC-294640; Sphingosine kinase 2 inhibitors, such as ABC-294640; Sphingosine-1-phosphate receptor-1 agonists, such as ozanimod (RPC-1063) and KRP-203; Sphingosine-1-phosphate receptor-1 antagonists, such as amiselimod (MT-1303); Sphingosine-1-phosphate receptor-1 modulators, such as fingolimod (FTY-720), ozanimod (RPC-1063), and amiselimod. (MT-1303); Sphingosine-1-phosphate receptor-5 modulators, such as ozanimod; STAT3 gene inhibitors, such as vidofludimus; STAT-3 inhibitors, such as TAK-114; STAT-4 inhibitors, such as STAT-4 antisense oligonucleotides (Crohn's disease / colitis), NIAID; stem cell antigen-1 inhibitors, such as Ampion, DMI-9523; superoxide dismutase modulators, such as midismase, LT-0011;Superoxide dismutase stimulators, such as superoxide dismutase; T cell surface glycoprotein CD28 inhibitors, such as abatacept; TGF β1 ligand inhibitors, such as Mongersen and GED-0301; thymosin agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201; TLR-4 antagonists, such as JKB-122 and VB-201; TLR-9 agonists, such as BL-7040 and cobitolimod; TNF Alpha ligand inhibitors, such as adalimumab, pegylated tertuzumab, infliximab biosimilars, infliximab, golimumab, ISIS-104838, CSA-13, DLX-105, adalimumab biosimilars, desarazin sodium, Debio-0512, HMPL-004, DLX-105, infliximab biosimilars, AZD-9773, CYT-020-TNFQb, DOM-0200; TNF α ligand modulators, such as PUR-0110, CDP-571; TNF antagonists, such as etanercept, pegylated tertuzumab, AVX-470, onaspirin; trefoil factor modulators, such as AG-012; trypsin inhibitors, such as APC-2059; tryptophan 5-hydroxylase inhibitors, such as telotristat. etiprate; tumor necrosis factor 14 ligand modulators, such as SAR-252067; type I TNF receptor antagonists, such as DOM-0100; type II TNF receptor modulators, such as etanercept; unspecified growth factor receptor modulators, such as AP-005; vanillin VR1 agonists, such as zirconia; vitamin D3 receptor agonists, such as calcitriol; and clathrin inhibitors, such as larizole acetate and AT-1001.

[0324] In addition, the following non-exhaustive list of compounds and compound classes can be combined with the compounds disclosed herein: 14-3-3 protein η inhibitors, 5-lipoxygenase inhibitors, Abl tyrosine kinase inhibitors, ACTH receptor agonists, adenosine A3 receptor agonists, adenosine deaminase inhibitors, ADP ribosylcyclase-1 modulators, ADP ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, polyproteoglycanase-2 inhibitors, albumin modulators, AP1 transcription factor inhibitors, basigin inhibitors, Bcr protein inhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigen CD20 inhibitors, B-lymphocyte antigen CD20 modulators, and B-lymphocyte stimulator ligand inhibitors. Brachykinin receptor modulators, BRAF gene inhibitors, branched aminotransferase 1 inhibitors, bromine-containing domain protein inhibitors, Btk tyrosine kinase inhibitors, cadherin-11 antagonists, calcineurin inhibitors, calcium channel inhibitors, carbonic anhydrase inhibitors, cathepsin K inhibitors, cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2 chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists, CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4 agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, CD40 ligand receptor modulators, CD52 antagonists, CD 73 agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95 antagonists, cell adhesion molecule inhibitors, choline kinase inhibitors, cluster protein stimulators, complement C5 inhibitors, complement factor stimulators, C-reactive protein inhibitors, CSF-1 antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokine antagonists, cyclin-dependent kinase inhibitor 1 inhibitors, cyclin-dependent kinase-2 inhibitors, cyclin-dependent kinase-4 inhibitors, cyclin-dependent kinase-5 inhibitors, cyclin-dependent kinase-6 inhibitors, cyclin-dependent kinase-7 inhibitors, cyclin-dependent kinase-9 inhibitors Drugs, Cyclooxygenase 2 inhibitors, Cyclooxygenase 2 modulators, Cyclooxygenase inhibitors, Cytosol phospholipase A2 inhibitors, Cytotoxic T-lymphocyte protein-4 modulators, Cytotoxic T-lymphocyte protein-4 stimulators, DHFR inhibitors, Diamine acetyltransferase inhibitors, Dihydroorotate dehydrogenase inhibitors, Elongation factor 2 inhibitors, Eosinophil activation chemokine 2 ligand inhibitors, EP4 prostaglandin receptor antagonists, Erythropoietin receptor agonists, Fas ligands, FGF-2 ligand inhibitors, FK506 binding protein-12 modulators, Folic acid antagonists, Folic acid receptor agonists, Folic acid receptor β antagonists, Folic acid receptor modulators, CX3CL1 (Fractalkine) ligand inhibitors,Fyn tyrosine kinase inhibitors, G protein-coupled receptor 15 antagonists, GABA A receptor modulators, glucocorticoid agonists, glucocorticoid antagonists, glucocorticoid-induced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSF receptor antagonists, GM-CSF receptor modulators, growth regulator protein α ligand inhibitors, Hwith Kwith adenosine triphosphate inhibitors, histamine H4 receptor antagonists, histone deacetylase inhibitors, histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLA class II antigen DQ-2 α modulators, HLA class II antigen inhibitors, HLA class II antigen modulators, Hsp70 family inhibitors, hypoxia-inducible factor-1 inhibitors, IFNB gene stimulators, I-κB kinase β inhibitors, I-κB kinase β inhibitors, and more. B kinase inhibitors, IL-1 antagonists, IL-10 agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17 antagonists, IL-17 receptor modulators, IL-2 agonists, IL-2 antagonists, IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists, IL-6 antagonists, IL-6 receptor modulators, immunoglobulin antagonists, immunoglobulin G1 agonists, immunoglobulin G1 antagonists, immunoglobulin G1 modulators, immunoglobulin G2 antagonists, immunoglobulin G2 modulators, immunoglobulin γ Fc receptor II modulators, immunoglobulin γ Fc receptor IIB antagonists, immunoglobulin κ modulators, immunoglobulin M antagonists, inducible nitric oxide synthase inhibitors, inosine monophosphate dehydrogenase inhibitors, insulin sensitizers, integrin α-1 / β-1 antagonists, integrin α-4 / β-1 antagonists, integrin antagonists, interferon β ligands, interferon γ ligands, interleukin 17A ligand inhibitors, interleukin 17F ligand inhibitors, interleukin 23A inhibitors, interleukin ligands, interleukin receptor 17A antagonists, interleukin-1 β ligand inhibitors, interleukin-10 ligands, interleukin-2 ligands, interleukin-4 ligands, interleukin-6 ligand inhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinase inhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun N-terminal kinase inhibitors, KCNA voltage-gated potassium channel-3 regulators, Kelch-like ECH-associated protein 1 regulators, Kit tyrosine kinase inhibitors, LanC-like protein 2 regulators, LITAF gene inhibitors, lymphocyte functional antigen-3 receptor antagonists, Lyn tyrosine kinase inhibitors, macrophage mannose receptor 1 regulators, MAdCAM inhibitors, MAP kinase regulators, MAP3K2 gene inhibitors, and MAPKAPK5 inhibitors.Matrix metalloproteinase inhibitors, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, MEK-2 protein kinase inhibitors, membrane copper amine oxidase inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, heparin-binding cytokine ligand inhibitors, mitochondrial 10 kDa heat shock protein stimulators, mTOR complex 1 inhibitors, mTOR inhibitors, NAD-ADP-ribosyltransferase stimulators, NAMPT gene inhibitors, NF-κB inhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene stimulators, nicotinic acetylcholine receptor antagonists, NK cell receptor modulators, NKG2AB-activated NK receptor antagonists, NKG2D-activated NK receptor antagonists, nucleoerythrocyte 2-associated factor 2 stimulators, nuclear factor κB inhibitors, nuclear factor κB modulators, nuclear factor κB p105 inhibitors, opioid growth factor receptor agonists, opioid receptor delta antagonists, osteoclast differentiation factor antagonists, osteoclast differentiation factor ligand inhibitors, oxidoreductase inhibitors, p2X7 purine receptor agonists, p38 MAP kinase α inhibitors, p38 MAP kinase inhibitors, PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGF receptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors, phosphoinositol-3 kinase delta inhibitors, phosphoinositol-3 kinase γ inhibitors, phospholipase A2 inhibitors, platelet-activating factor receptor antagonists, PPAR γ-agonists, programmed cell death protein 1 modulators, prostaglandin D synthase stimulators, protein arginine deiminase inhibitors, protein tyrosine kinase inhibitors, PurH purine biosynthesis protein inhibitors, Rho-associated protein kinase 2 inhibitors, Seprase inhibitors, CD24 signal transducer modulators, signal transduction inhibitors, sodium-glucose transporter-2 inhibitors, sphingosine-1 phosphophosphatase modulators, STAT3 gene inhibitors, superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors, Syk tyrosine kinase inhibitors, multiligand glycan-1 inhibitors, T cell receptor antagonists, T cell receptor modulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1 binding protein modulators, ankle protein modulators, T-cell differentiation antigen CD6 inhibitors, T-cell surface glycoprotein CD8 inhibitors, tendinogen modulators, TGF-β agonists, thymosin agonists, TLR-2 antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF α ligand inhibitors, TNF α-ligand modulators, TNF antagonists, TNF gene inhibitors, TNF receptor modulators, TNFSF11 gene inhibitors, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 15 ligand inhibitors,Tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor ligand inhibitors, type I IL-1 receptor antagonists, type I TNF receptor antagonists, type II TNF receptor modulators, unspecified GPCR agonists, VEGF receptor antagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, X-linked inhibitors of apoptosis protein inhibitors, Zap70 tyrosine kinase inhibitors,

[0325] 99mTc-labeled annexin V-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494, acalatinib, aceclofenac, acetarib, MS-392, adalimumab, adalimumab biosimilar, adalimumab biosimilar, AK-106, ALX-0061, aminopterin, anakinin, anakinin biosimilar, anakinin biosimilar, ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064, bimekizumab, BiP (rheumatoid arthritis), Kings College London, BLHP-006, blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, cannabinoids, terbutaline, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, pegylated thiotuzumab, CF-101, CFZ-533, CHR-5154, cibinetide, cyclosporine, clazakizumab, CNTO-6785, corticotropin, valproic acid, CR-6086, CreaVax-RA, CWG-92, CWG-9 40. Cx-611, DE-098, Defocut, Rheumavax, Dinosema, Diacerein, Diclofenac, E-6011, Eicosapentaenoic Acid Monoglyceride, Etanercept, Etanercept Biosimilar, Etanercept Biosimilar, Etoduolic Acid, Etocoxib, Filgotinib, Fosdagrocorat, Gerilimzumab, Ginsenoside CK, Givinostat, Goat Polyclonal Antibody, Golimumab, GS-5745, GS-9876, GSK-3196165, HM-71224, HMPL-523, Sodium Hyaluronate, IB-RA (Injectable, for rheumatoid arthritis), Innobioscience, IB-RA (oral, for rheumatoid arthritis), Innobioscience, Ailamod, IMD-2560, Imidazole salicylates, Infliximab, Infliximab modified biologic (Biobetter), Infliximab biosimilar, INSIX RA, Interferon-gamma biosimilar, Interleukin-2(Injectable), Interleukin-2 biosimilar, INV-103, IR-501, itolizumab, JNJ-40346527, Catshuning, KD-025, Ketoprofen and Omeprazole, Leflunomide, Lenzilumab, LLDT-8, Romexicob, LY-3090106, Masatitinib, Mavrilimumab, MBS-2320, MEDI-5117, Meloxicam, Methotrexate, MGD -010, Misoprostol and Diclofenac, MM-A01-01, Monalizumab, MORAb-022, MPC-300-IV, MRC-375, Nabumetone, Namilumab, Naproxen and Emeprazole, Naproxen and Emeprazole Strontium, Ocaratuzumab, Oframumab, OHR-118, Olokizumab, OM-89, Once-daily Naproxen (oral controlled-release), Pain), Alvogen, ONO-4059, Oralgam, ozoralizumab, peficitinib, pebiprofen, PF-06687234, piperidone hydrochloride, piroxicam, prednisolone, prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, rabeximod, RCT-18, recombinant human CD22 monoclonal antibody (intravenous infusion), Lonn RyonnPharma / SinoMab Bioscience (Shenzhen), recombinant human interleukin-1 receptor antagonist (rheumatoid arthritis), Shanghai Fudan Zhangjiang Biomedical, recombinant human interleukin-2 Recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, RhuDex, rifabutin, clarithromycin, and clofazimine, rituximab, rituximab biosimilar, rituximab biosimilar, RPI-78, SAN-300, sarilumab, SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SSS-07, KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079, tarenflurbil (transdermal spray, for dermatology / rheumatoid arthritis), MIKA Pharma / GALENpharma, Technetium Tc 99m tilmanocept, technetium [99Tc]methylene diphosphate, tenoxicam, Debio-0512, tocilizumab, tofacitinib, *Trichoderma suis* oocytes, umbilical cord-derived mesenchymal stem cells (iv, RA / liver disease), Alliancells / ZhongyuanUnion, eutecticumab, VAY-736, VB-201, WF-10, XmAb-5871, YHB-1411-2; 14-3-3 protein η inhibitors, such as anti-AGX-020 mAbs (Rheumatoid arthritis), Augurex; 5-lipoxygenase inhibitors, such as tenoxicam, dabufone, terbufenozide, levofloxacin, ZD-2138, etalocib, tenidap, teposarrin, flurobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0757, T-0799, ZM-216800, L-699333, BU-4601A, SKF-104351, CI-986; Abl tyrosine kinase inhibitors, such as imatinib; ACTH receptor agonists, such as FAR-404, metenkefalin acetate with tridecactide Acetate; adenosine A3 receptor agonists, such as CF-101; adenosine deaminase inhibitors, such as cladribine, pentostatin, FR-221647; ADP ribosylcyclase-1 regulators, such as indatuximab ravtansine; ADP ribosylation factor 6 inhibitors, such as NAV-2729; adrenocorticotropic hormone ligands, such as corticotropin, valproic acid, FAR-404, metenkefalinacetate with tridecactideAcetate; polyprotein polysaccharide-2 inhibitors, such as GIBH-R-001-2; albumin modulators, such as ALX-0061 and ONS-1210; AP1 transcription factor inhibitors, such as T-5224, tarenflurbil, and SP-10030; basilin inhibitors, such as ERG-240; Bcr protein inhibitors, such as imatinib; and B-lymphocyte antigen CD19 inhibitors, such as XmAb-587. 1. MDX-1342; B-lymphocyte antigen CD20 inhibitors, such as ocrelizumab, ocfamumab, rituximab, rituximab biosimilars, vetuzumab, rituximab biosimilars, ocaratuzumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01, CT-P10, TL-011, PF-05280586 IBPM-001RX, IBI-301, AME-133v, BCD-020, BT-D004, SAIT-101; B-lymphocyte antigen CD20 modulators, such as rituximab biosimilars, SBI-087, TRU-015, DXL-625; B-lymphocyte stimulator ligand inhibitors, such as belimumab, RCT-18, blisibimod, tabalumab, acecept, briobacept; bradykinin receptor modulators, such as givinostat; BRAF gene inhibitors, such as bimetinib; branched aminotransferase 1 inhibitors, such as ERG-240; bromine-domain-containing protein inhibitors, such as RVX-297, ZEN-003694; Btk tyrosine kinase inhibitors, such as acalabrutinib, HM-71224, spebrutinib; BTK inhibitors (rheumatoid arthritis), Humanwell. Healthcare / WuxiAppTech, BMS-986142, TAK-020, ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486, CG-026806, GDC-0834; cadherin-11 antagonists, such as RG-6125; calcineurin inhibitors, such as HS-378, cyclosporine; calcium channel inhibitors, such as RP-3128; carbonic anhydrase inhibitors, such as polmacoxib; cathepsin K inhibitors, such as CRA-013783, T-5224, AM-3876, VEL-0230, NPI-2019; cathepsin S inhibitors, such as MIV-247, AM-3876, RWJ-445380, NPI-2019; CCR1 kinase inhibitors. Chemokine antagonists, such as BX-471, BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715, PS-375179; CCR2 chemokine antagonists, such as MK-0812, AZD-6942; CCR3 gene regulators, such as CM-102; CCR5 chemokine antagonists, such as maraviro, OHR-118, NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists, such as sarilumab; CD29 regulators, such as PF-06687234; CD3 regulators, such as otelixizumab; CD39 agonists, such as AAV5-CD39 / CD73. (Rheumatoid Arthritis), Arthrogen; CD4 agonists, such as maraviro; CD4 antagonists, such as tregalizumab, zamumab, MTRX-1011A, BW-4162W94, EP-1645, crixacillinab; CD40 ligand inhibitors, such as dapirolizumab pegol; CD40 ligand receptor antagonists, such as BI-655064, anti-CD40-XTEN, tenesimab; CD40 ligand receptor modulators, such as CFZ-533; CD52 antagonists, such as alenzusmab; CD73 agonists, such as AAV5-CD39 / CD73.(Rheumatoid arthritis), Arthrogen; CD79b modulators, such as MGD-010; CD80 antagonists, such as RhuDex, XENP-9523, ASP-2408, and abatacept modified biologics; CD86 antagonists, such as ES-210, abatacept biosuperior, ASP-2408, and XENP-9523; CD95 antagonists, such as DE-098 and CS-9507; cell adhesion molecule inhibitors, such as natezumab, alicaforsen, NPC-17923, TK-280, and PD-144795; choline kinase inhibitors, such as choline kinase inhibitors (rheumatoid arthritis), UC San Diego; peptidoglycan stimulants, such as alenzumab; complement factor C5 inhibitors, such as eculizumab, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center; complement factor stimulants, such as CM-101; C-reactive protein inhibitors, such as IB-RA. (Oral, rheumatoid arthritis), Innobioscience, ISIS-353512; CSF-1 antagonists, such as masitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578, PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, such as 946414-98-8, BMS-936557; CXCR4 chemokine antagonists, such as praxavir; cyclin-dependent kinase inhibitors, such as CDK-1 / 2 / 5 / 7 / 9 inhibitors (cancer / tumor development / rheumatoid arthritis), BioPatterns; cyclin-dependent kinase inhibitors... Enzyme-2 inhibitors, such as seliciclib and BP-14; cyclin-dependent kinase-4 inhibitors, such as CDK-4 / 6 inhibitors (rheumatoid arthritis) and Teijin; cyclin-dependent kinase-5 inhibitors, such as BP-14; cyclin-dependent kinase-6 inhibitors, such as CDK-4 / 6 inhibitors (rheumatoid arthritis) and Teijin; cyclin-dependent kinase-7 inhibitors, such as BP-14 and seliciclib; cyclin-dependent kinase-9 inhibitors, such as BP-14 and seliciclib; cyclooxygenase 2 inhibitors, such as celecoxib, etoricoxib, polmacoxib, lafluolimus, etodoxacin, meloxicam, IB-RA (injectable, rheumatoid arthritis), Innobioscience, and IB-RA (oral).Rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, romecoxib; cyclooxygenase 2 modulators, such as DRGT-46; cyclooxygenase inhibitors, such as aceclofenac, diclofenac, imidazole salicylate, naproxen etemesil, misoprostol and diclofenac, nabumetone, naproxen and emeprazole, naproxen and emeprazole strontium, once-daily naproxen (oral controlled release), Pain), Alvogen, Perbiprofen, LY-210073, Tenoxicam, Licrofenone, NS-398, Bromfenac, L-746483, LY-255283, Tenidap, Teposalin, Flurobufen, Ibuprofen, Flurbiprofen, SKF-86002, SC-57666, WY-28342, CI-986, Permoprofen; Cytosol phospholipase A2 inhibitors, such as AVX-00 2; Cytotoxic T-lymphocyte protein-4 modulators, such as berazepam and ES-210; cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept, abatacept biosimilars, and BMS-188667; DHFR inhibitors, such as methotrexate, MPI-2505, and MBP-Y003; diamine acetyltransferase inhibitors, such as diminazeneacetate. urate); dihydroorotate dehydrogenase inhibitors, such as DHODH inhibitors (rheumatoid arthritis / autoimmune diseases), East China University of Science and Technology, ASLAN-003, lafluolimus, leflunomide, HWA-486, ABR-224050; elongation factor 2 inhibitors, such as diphenhydramine 2; eosinophil activation chemokine 2 ligand inhibitors, such as CM-102; EP4 prostaglandin receptor antagonists, such as CR-6086; erythropoietin receptor agonists, such as cibinetide; Fas ligands, such as AP-300; FGF-2 ligand inhibitors, such as RBM-007; FK506 binding protein-12 modulators, such as tanciolimus; folic acid antagonists, such as methotrexate, MBP-Y003; folic acid receptor agonists, such as folic acid receptor modulators (chimeric proteins, cancer / rheumatoid arthritis), Proda Biotech; folic acid receptor modulators, such as technetium (99mTc) etarfolatide; CX3CL1 ligand inhibitors, such as E-6011; Fyn tyrosine kinase inhibitors, such as masertinib and lafluolimus; G protein-coupled receptor 15 antagonists, such as GPR15 antagonists (rheumatoid arthritis / HIV-mediated enteropathy), Omeros; GABAAlpha receptor modulators, such as lafluolimus; glucocorticoid agonists, such as prednisolone and fosdagrocorat; glucocorticoid antagonists, such as REC-200; glucocorticoid-induced leucine zipper stimulators, such as ART-G01; GM-CSF ligand inhibitors, such as nanobubumab, MORAb-022, and lenzilumab; GM-CSF receptor antagonists, such as mavrilimumab; GM-CSF receptor modulators, such as GSK-3196165; growth regulator alpha ligand inhibitors, such as T-5224; Hwith Kwith adenosine triphosphate (ATP) inhibitors, such as naproxen and emeprazole, naproxen and emeprazole strontium, ketoprofen and omeprazole, KEO-25001, HC-1004, PN-40020; histamine H4 receptor antagonists, such as toreforant, GD-48; histone deacetylase inhibitors, such as givinostat, CHR-5154; histone deacetylase-6 inhibitors, such as CKD-506; HIV-1 gp120 protein inhibitors, such as maraviro; HLA class II antigen DQ-2 α modulators, such as NexVax2; HLA class II antigen inhibitors, such as HLA-DR1 / DR4 inhibitors (rheumatoid arthritis), Provid; HLA class II antigen modulators, such as ARG-301, recombinant T-cell receptor ligands (rheumatoid arthritis), Artielle; Hsp 70 family inhibitors, such as guanitolimus trihydrochloride; hypoxia-inducible factor-1 inhibitors, such as 2-methoxyestradiol; IFNB gene stimulators, such as ART-102; I-κB kinase beta inhibitors, such as IMD-2560 and IMD-0560; I-κB kinase inhibitors, such as methylbadoxolone; IL-1 antagonists, such as linaloacetate, IBBB-007-IL, antisense oligonucleotides (rheumatoid arthritis), Leiden University Medical Center, recombinant human interleukin-1 receptor antagonists (rheumatoid arthritis), Shanghai Fudan Zhangjiang Biopharmaceutical; IL-10 agonists, such as peg-ileoleukin; IL-11 agonists, such as olprene interleukin; IL-12 antagonists, such as eutecticumab and briakinu. MAB, ddRNAi therapy (rheumatoid arthritis), Medistem / Benitec; IL-15 antagonists, such as AMG-714, BNZ-132-2; IL-17 antagonists, such as ixekizumab, secukinumab, KD-025; IL-17 receptor modulators, such as CNTO-6785; IL-2 agonists, such as interleukin-2 biosimilars; IL-2 antagonists, such as IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,Rheumatoid arthritis), Innobioscience, BNZ-132-2; IL-21 antagonists, such as NN-8828, BNZ-132-2; IL-23 antagonists, such as uterotumab, briakinumab; IL-3 antagonists, such as anti-IL-3 mAbs (rheumatoid arthritis), University of Regensburg; IL-4 agonists, such as SER-130-AMI; IL-6 antagonists, such as olokizumab, clazakizumab, sirukumab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R003, peptide IL-6 antagonists, MEDI-5117, T-5224, humanized anti-IL-6 mAb, tocilizumab biosimilars, IL-6 neutralizing human antibodies, anti-IL6 antibodies, RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, elastomodil, TA-383; IL-6 receptor modulators, such as tocilizumab, tocilizumab biosimilars, RO-4877533; immunoglobulin antagonists, such as elastomodil; immunoglobulin G1 agonists, such as... Canamab, modified infliximab biologics, infliximab biosimilars, BX-2922, STI-002, HF-1020; immunoglobulin G1 antagonists, such as YHB-1411-2; immunoglobulin G1 modulators, such as CFZ-533, lenzilumab; immunoglobulin G2 antagonists, such as denosumab; immunoglobulin G2 modulators, such as PF-547659; immunoglobulin γ Fc receptor II modulators, such as MGD-010; immunoglobulin γ Fc receptor IIB antagonists, such as XmAb-5871; immunoglobulin κ modulators, such as lenzilumab; immunoglobulin M antagonists, such as IB-RA (injectable, for rheumatoid arthritis), Innobioscience, IB-RA (oral,Rheumatoid arthritis), Innobioscience; Inducible nitric oxide synthase inhibitors, such as SKLB-023; Inosine monophosphate dehydrogenase inhibitors, such as mycophenolate mofetil; Insulin sensitizers, such as rosiglitazone, THR-0921, HE-3286, BLX-1002; Integrin α-1 / β-1 antagonists, such as SAN-300; Integrin α-4 / β-1 antagonists, such as natamuzumab; Integrin antagonists, such as PEG-HM-3, CY-9652; Interferon β ligands, Examples include recombinant interferon β-1a and TA-383; interferon-γ ligands, such as interferon-γ biosimilars; interleukin-17A ligand inhibitors, such as ABT-122, bimekizumab, and ABBV-257; interleukin-17F ligand inhibitors, such as bimekizumab; interleukin-23A inhibitors, such as guselkumab; interleukin ligands, such as IPB-007-IL; interleukin receptor 17A antagonists, such as brodalumab; and interleukin-1... β-ligand inhibitors, such as cannabidiol, linacicept, T-5224, geovokizumab, BLX-1002, LY-2189102, PMI-001, K-832, CDP-484; interleukin-10 ligands, such as PF-06687234; interleukin-2 ligands, such as dine-2 interleukin, recombinant interleukin-2, interleukin-2 biosimilars, recombinant human interleukin-2, and interleukin-2. (Injectable); Interleukin-4 ligands, such as Tetravil; Interleukin-6 ligand inhibitors, such as gilimab, PF-4236921; Itk tyrosine kinase inhibitors, such as ARN-4079; JAK tyrosine kinase inhibitors, such as tofacitinib, SHR-0302, cerdulatinib, peficitinib, deuterated tofacitinib analogs, SD-900, CVXL-0074; Jak1 tyrosine kinase inhibitors, such as ABT-494, baricitinib, ruxolitinib, filgotinib, tofacitinib, itac itinib, peficitinib, NIP-585, CS-944X, YJC-50018, GLPG-0555, MRK-12; Jak2 tyrosine kinase inhibitors, such as baricitinib, ruxolitinib, CT-1578; JAK3 gene inhibitors, such as GBL-5b; Jak3 tyrosine kinase inhibitors, such as decernotinib, tofacitinib, peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613; JunN-terminal kinase inhibitors, such as IQ-1S; KCNA voltage-gated potassium channel-3 regulators, such as MRAD-P1; Kelch-like ECH-associated protein 1 regulators, such as dimethyl fumarate; Kit tyrosine kinase inhibitors, such as imatinib and masertinib; LanC-like protein 2 regulators, such as BT-11; LITAF gene inhibitors, such as GBL-5b; lymphocyte functional antigen-3 receptor antagonists, such as afasicept; Lyn tyrosine kinase inhibitors, such as masertinib; macrophage mannose receptor 1 regulators, such as technetium Tc 99m. tilmanocept; MAdCAM inhibitors, such as PF-547659; MAP kinase modulators, such as SKLB-023; MAP3K2 gene inhibitors, such as GBL-5b; MAPKAPK5 inhibitors, such as GLPG-0259; matrix metalloproteinase inhibitors, such as GLPG-0259; MCL1 gene inhibitors, such as seliciclib; MEK protein kinase inhibitors, such as bimetinib, AD-GL0001; MEK-1 protein kinase inhibitors, such as bimetinib; MEK-2 protein kinase inhibitors, such as bimetinib; membrane copper amine oxidase inhibitors, such as BTT-1023, PRX-167700, velpatumab; metalloproteinase-2 inhibitors, such as ERG-240; metalloproteinase-9 inhibitors, such as GS-5745, ERG-240; heparin-binding cytokine ligand inhibitors, such as CAB-102; mitochondrial 10 kDa heat shock protein stimulants, such as INV-103; mTOR complex 1 inhibitors, such as everolimus; mTOR inhibitors, such as everolimus and tanciolimus; NAD-ADP ribosyltransferase stimulants, such as denifedipine-2; NAMPT gene inhibitors, such as ART-D01; NF-κB inhibitor stimulants, such as denosumab; NFAT gene inhibitors, such as T-5224; NFE2L2 gene stimulants, such as methylbardoxazoline; nicotinic acetylcholine receptor antagonists, such as RPI-78 and RPI-MN; NK cell receptor modulators, such as masatitinib; NKG2AB-activated NK receptor antagonists, such as monalizumab; NKG2D-activated NK receptor antagonists, such as NNC-0142-002; nucleoerythrocyte 2-related factor 2 stimulants, such as dimethyl fumarate; nuclear factor κB inhibitors, such as methylbardoxazoline and IB-RA (injectable, for rheumatoid arthritis). InnobioscienceDehydromethylbenzyl quinonemycin, HE-3286, IMD-0560, MP-42, tarenflurbil, VGX-1027, SKLB-023, SP-650003, MG-132, SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005; nuclear factor κB modulators, such as REM-1086; nuclear factor κB p105 inhibitors, such as REM-1086; opioid growth factor receptor agonists, such as metenkefalin acetate with tridecactide acetate, FAR-404; opioid receptor delta antagonists, such as HS-378; osteoclast differentiation factor antagonists, such as denosumab, cyclic peptides (rheumatoid arthritis / osteoporosis). University of Michigan; osteoclast differentiation factor ligand inhibitors, such as denosumab; oxidoreductase inhibitors, such as etodoxacin and imidazole salicylates; P2X7 purine receptor agonists, such as givinostat; p38 MAP kinase α inhibitors, such as VX-745, BMS-582949 prodrug, and BMS-751324; p38 MAP kinase inhibitors, such as BCT-197, losmapimod, and ARRY-797; PDE 4 inhibitors, such as apremilast; PDE 5 inhibitors, such as PDE5 inhibitors (rheumatoid arthritis), University of Rochester; PDGF receptor agonists, such as olprespin; PDGF receptor antagonists, such as imatinib and masitinib; PDGF-B ligand inhibitors, such as SL-1026; PERK gene inhibitors, such as bimetinib; phosphoinositol-3 kinase delta inhibitors, such as duvelisib, RP-6503, CT-732, INK-007, and GNE-293; phosphoinositol-3 kinase gamma inhibitors. Examples of antiphospholipase inhibitors include duvelisib and RP-6503; phospholipase A2 inhibitors, such as AVX-002, human secreted phospholipase A2 type IIA-integrin-binding inhibitory peptide (rheumatoid arthritis / asthma / Alzheimer's disease / cancer), University of California, Davis, AK-106, vareniladine methyl ester, Ro-31-4493, BM-162353, Ro-23-9358, and YM-26734; platelet-activating factor receptor antagonists, such as piperidone hydrochloride; PPARγ agonists, such as rosiglitazone, THR-0921, rosiglitazone XR, and etalocib; programmed cell death protein 1 modulators, such as INSIX RA; ​​prostaglandin D synthase stimulators, such as HF-0220; and protein arginine deiminase inhibitors, such as PAD inhibitors (rheumatoid arthritis).Leiden University Medical Center / LURIS; protein tyrosine kinase inhibitors, such as leflunomide; PurH purine biosynthesis protein inhibitors, such as mycophenolate mofetil; Rho-associated protein kinase 2 inhibitors, such as KD-025; Seprase inhibitors, such as anti-fibroblast-activating protein (FAP) antibody radiotracers (rheumatoid arthritis), Hoffmann-La Roche / Radeburg University; CD24 signal transducer modulators, such as CD24-IgFc; signal transduction inhibitors, such as imatinib; sodium glucose transporter-2 inhibitors, such as THR-0921; sphingosine 1-phosphophosphatase modulators, such as S1P modulators (oral, multiple sclerosis / ulcerative colitis / rheumatoid arthritis); AkaalPharma; STAT3 gene inhibitors, such as methylbadosolone and vidofludimus; superoxide dismutase stimulants, such as imipammonium; SYK family tyrosine kinase inhibitors, such as MK-8457; Syk tyrosine kinase inhibitors, such as fostamatinib, entospletinib, KDDF-201110-06, HMPL-523, cerdulatinib, AB-8779, GS-9876, PRT-2607, CVXL-0074, CG-103065, and CG-026806; multiligand glycan-1 inhibitors, such as indatuximab ravtansine; T-cell receptor antagonists, such as TCR-inhibiting SCHOOL peptide (systemic / local, rheumatoid arthritis / dermatitis / scleroderma), SignaBlok, and CII modified peptides (rheumatoid arthritis). Peking University; T-cell receptor modulators, such as ARG-301; T-cell surface glycoprotein CD28 inhibitors, such as abatacept, beracip, abatacept biosimilars, RhuDex, BMS-188667; T-cell surface glycoprotein CD28 stimulators, such as TAB-08; TAK1 binding protein modulators, such as epigallocatechin 3-gallate; ankle protein modulators, such as short ankle protein modulators (rheumatoid arthritis), KayteeBio; T-cell differentiation antigen CD6 inhibitors, such as itolizumab; T-cell surface glycoprotein CD8 inhibitors, such as tregalizumab; tendinogen modulators, such as Tetravil; TGF β-agonists, such as tregalizumab; thymosin agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201 and P-13; TLR-4 antagonists, such as VB-201 and P-13; TLR-9 antagonists, such as P-13; TNFAlpha ligand inhibitors, such as adalimumab biosimilar YHB-1411-2, adalimumab, infliximab, recombinant humanized anti-TNF-α monoclonal antibody, pegylated tertuzumab, golimumab, ozoralizumab, AT-132, etanercept biosimilar, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-0512, and anti-TNF... Alpha-human monoclonal antibody, modified infliximab biologics, UB-721, KN-002, DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420, GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501, CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2 E7, BAT-1406, XPro-1595, Atsttrin, SSS-07, Golimumab biosimilar, TA-101, Adalimumab biosimilar, BLX-1002, ABX-0401, TAQ-588, Golimumab biosimilar, TeHL-1, placulumab, PMI-001, tgAAV-TNFR:Fc, K-832, CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215, AME-527, Anti-TNF-α mAb, GENZ-38167, BLX-1028, CYT-020-TNFQb, CC-1080, CC-1069; TNF α ligand modulators, such as MM-A01-01, CDP-571, camobucol; TNF antagonists, such as etanercept, pegylated thromuzumab, etanercept biosimilars, etanercept biosimilars, DNX-114, TNF antagonists and IL-12 antagonists.(Rheumatoid Arthritis), Oxford University, BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, onafenib, DE-096, PN-0615, lenalicept, ITF-1779, MDL-201112, BAX-2200, SCB-808, DA-3853, HD-203; TNF gene inhibitors, such as GIBH-R-001-2; TNF receptor modulators, such as recombinant TNF receptor 2-Fc Fusion protein mutants, T-0001, tgAAV-TNFR:Fc; TNFSF11 gene inhibitors, such as denosumab; transcription factor p65 inhibitors, such as REM-1086; transcription factor RelB inhibitors, such as REM-1086; transferrin modulators, such as methotrexate, MBP-Y003; tumor necrosis factor 13C receptor antagonists, such as VAY-736; tumor necrosis factor 15 ligand inhibitors, such as anti-TL1A antibodies (rheumatoid arthritis / inflammatory bowel disease). NIAMS; tumor necrosis factor ligand 13 inhibitors, such as acecept; tumor necrosis factor ligand inhibitors, such as ABBV-257, etanercept biosimilars, ABT-122; type I IL-1 receptor antagonists, such as anakinin, anakinin biosimilars, anakinin biosimilars, AXXO; type I TNF receptor antagonists, such as NM-9405; type II TNF receptor modulators, such as etanercept, SCB-131, etanercept biosimilars, etanercept biosimilars. Drugs, BAX-2200, SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; unspecified GPCR agonists, such as NCP-70X; VEGF receptor antagonists, such as 2-methoxyestradiol and NSC-650853, SL-1026; VEGF-2 receptor antagonists, such as CG-026806; VEGF-2 receptor modulators, such as VEGFR2 neutralizing antibodies (rheumatoid arthritis), University of Rochester; VEGF-B ligand inhibitors, such as CSL-346; X-linked inhibitors of apoptosis protein inhibitors, such as IAP inhibitors (oral), Pharmascience; and Zap70 tyrosine kinase inhibitors, such as MK-8457, CT-5332.

[0326] Combination for metabolic diseases or conditions

[0327] Examples of metabolic disorders include, but are not limited to, diabetes (including type 1 and type 2 diabetes), metabolic syndrome, dyslipidemia, obesity, glucose intolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0328] Examples of therapeutic agents used to treat metabolic disorders include antihypertensive agents and lipid-lowering agents. Other therapeutic agents used to treat metabolic disorders include insulin, sulfonylureas, biguanides, alpha-glucosidase inhibitors, and intestinal hypoglycemic agents. Therefore, one aspect of this disclosure is a method of treating metabolic diseases, comprising administering a compound of this disclosure in combination with one or more compounds that can be used to treat metabolic diseases to a subject in need, particularly a human subject.

[0329] Pharmaceutical Composition

[0330] When the active ingredient can be administered alone, it is preferred to present it in the form of a pharmaceutical formulation (composition). Formulations of the present invention for veterinary and human use comprise at least one of the above-described active ingredients and one or more acceptable carriers, as well as optional other therapeutic components. The carrier must be "acceptable," meaning it must be compatible with the other components in the formulation and physiologically non-toxic to its recipient.

[0331] Formulations include those suitable for the aforementioned routes of administration. These formulations are typically presented in unit dosage forms and can be prepared using any method well-known in the pharmaceutical field. The techniques and formulations described can generally be found in [reference needed]. Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). The method includes the step of mixing the active ingredient with an inactive ingredient (e.g., a carrier, pharmaceutical excipient, etc.) that constitutes one or more auxiliary ingredients. Formulations are typically made by uniformly and densely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then shaping the product if desired.

[0332] In some implementations, the formulation suitable for oral administration is presented as discrete units, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient.

[0333] In some embodiments, the pharmaceutical formulation comprises one or more compounds of the present invention, one or more pharmaceutical carriers or excipients, and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient can be in any form suitable for the intended method of administration. When intended for oral administration, they can be prepared as tablets, lozenges, tablets, aqueous or oil-containing suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral administration can be prepared according to any method of pharmaceutical composition preparation well known in the art, and to obtain a palatable article, the composition may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives. Tablets containing the active ingredient and mixed with a non-toxic pharmaceutical excipient suitable for tablet preparation are acceptable. The excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby achieving a sustained effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate alone, or mixtures thereof with paraffin, may be used.

[0334] The amount of active ingredient combined with an inactive ingredient to produce a dosage form will vary depending on the host being treated and the specific route of administration. For example, in some embodiments, a dosage form for oral administration to humans contains about 1 to 1000 mg of the active substance, formulated with an appropriate and convenient amount of a carrier substance (e.g., an inactive ingredient or excipient substance). In some embodiments, the carrier substance varies from about 5% to about 95% (weight:weight) of the total composition. In some embodiments, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg, or 1 to 50 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions described herein contain no more than about 400 mg of a compound of formula I. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof.

[0335] It should be understood that, in addition to the ingredients specifically mentioned above, the formulations disclosed herein may include other agents conventional in the art for the type of formulation discussed, such as flavoring agents, those suitable for oral administration.

[0336] Veterinary compositions are also provided, which contain at least one active ingredient as defined above and a veterinary carrier.

[0337] Veterinary carriers are materials that can be used to administer compositions and can be solid, liquid, or gaseous materials that are inert or acceptable in the veterinary field and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally, or via any other desired route.

[0338] The effective dose of the active ingredient depends at least on the nature of the condition being treated, its toxicity, whether the compound is used prophylactically (at a lower dose), the method of delivery, and the pharmaceutical formulation, and will be determined by clinicians using routine dose escalation studies.

[0339] route of administration

[0340] One or more compounds of formula I (referred to herein as the active ingredient) or a pharmaceutically acceptable salt thereof may be administered via any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be understood that preferred routes may vary depending on, for example, the recipient's condition. An advantage of the compounds of the present invention is that they are orally bioavailable and can be administered orally. Thus, in one embodiment, the pharmaceutical composition described herein is an oral dosage form. In some embodiments, the pharmaceutical composition described herein is an oral solid dosage form.

[0341] Formulation Example 1

[0342] Prepare hard gelatin capsules containing the following ingredients:

[0343]

[0344] Mix the above ingredients and encapsulate them in hard gelatin capsules.

[0345] Formulation Example 2

[0346] Tablets are prepared using the following ingredients:

[0347]

[0348] The components are mixed and compressed to form tablets.

[0349] Formulation Example 3

[0350] Prepare a dry powder inhaler formulation containing the following components:

[0351]

[0352] Mix the active ingredient with lactose and add the mixture into a dry powder inhaler.

[0353] Formulation Example 4

[0354] Each tablet containing 30mg of active ingredient is prepared as follows:

[0355]

[0356] The active ingredient, starch, and cellulose are thoroughly mixed and passed through a 20-mesh US sieve. A polyvinylpyrrolidone solution is mixed with the resulting powder and then passed through a 16-mesh US sieve. The resulting granules are dried at 50-60°C and passed through a 16-mesh US sieve. Sodium carboxymethyl starch, magnesium stearate, and talc, pre-passed through a 30-mesh US sieve, are then added to the granules, mixed, and compressed on a tableting machine to obtain tablets weighing 120 mg each.

[0357] Formulation Example 5

[0358] Each suppository containing 25 mg of active ingredient is prepared as follows:

[0359]

[0360] The active ingredient is passed through a 60-mesh US sieve and suspended in saturated fatty acid glycerides that have been pre-melted with the minimum amount of heat required. The mixture is then poured into suppository molds with a nominal capacity of 2.0g and allowed to cool.

[0361] Formulation Example 6

[0362] A suspension containing 50 mg of active ingredient per 5.0 mL dose is prepared as follows:

[0363]

[0364] The active ingredients, sucrose, and xanthan gum are mixed and passed through a 10-mesh US sieve, then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring agent, and coloring agent are diluted with some water and added while stirring. Sufficient water is then added to produce the desired volume.

[0365] Formulation Example 7

[0366] Subcutaneous preparations can be prepared as follows:

[0367]

[0368] Formulation Example 8

[0369] Prepare an injectable formulation having the following composition:

[0370]

[0371] Formulation Example 9

[0372] Prepare a topical formulation having the following composition:

[0373]

[0374] Combine all the above ingredients except water and heat to 60°C with stirring. Then, add a sufficient amount of water at 60°C to emulsify the ingredients while stirring vigorously, and then add water to bring the total volume to 100g.

[0375] Formulation Example 10

[0376] Sustained-release composition

[0377]

[0378] The sustained-release formulation of this disclosure can be prepared as follows: the compound, a pH-dependent binder, and any optional excipients are tightly mixed (dry mix). The dry mix is ​​then granulated in the presence of a strong alkaline aqueous solution (sprayed into the mixed powder). The granules are dried, sieved, mixed with an optional lubricant (e.g., talc or magnesium stearate), and compressed into tablets. The preferred strong alkaline aqueous solution is a solution of an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide, preferably sodium hydroxide) in water (optionally containing up to 25% of a water-miscible solvent, such as a lower alcohol).

[0379] For identification, taste masking purposes, and to improve ease of swallowing, the resulting tablets may be coated with an optional film-forming agent. The film-forming agent is typically present in an amount of 2% to 4% of the tablet weight. Suitable film-forming agents are well known in the art and include hydroxypropyl methylcellulose, cationic methacrylate copolymers (dimethylaminoethyl methacrylate / methyl methacrylate-butyl methacrylate copolymer-Eudragit), etc. ® E-Röhm. Pharma, etc. These film-forming agents may optionally contain colorants, plasticizers, and other supplementary ingredients.

[0380] The compressed tablets preferably have a hardness sufficient to withstand compression of 8 kPa. The tablet size depends primarily on the amount of the compound in the tablet. The tablet contains 300 to 1100 mg of the compound's free base. Preferably, the tablet contains 400-600 mg, 650-850 mg, and 900-1100 mg of the compound's free base.

[0381] To influence the dissolution rate, the wet mixing time of the powder containing the compound is controlled. Preferably, the total powder mixing time, i.e., the time the powder is exposed to the sodium hydroxide solution, is 1 to 10 minutes, more preferably 2 to 5 minutes. After granulation, the granules are removed from the granulator and placed in a fluidized bed dryer for drying at approximately 60°C.

[0382] Formulation Example 11

[0383] Tablets are prepared using the following ingredients:

[0384]

[0385] The components are mixed and compressed to form tablets.

[0386] Example

[0387] The following embodiments are included to illustrate specific implementations of this disclosure. Those skilled in the art should understand that the techniques disclosed in the following embodiments represent techniques that work well in the practice of this disclosure and can therefore be considered as specific models constituting its practice. However, based on the content of this disclosure, those skilled in the art should understand that many changes can be made to the disclosed specific implementations without departing from the spirit and scope of this disclosure and still obtaining the same or similar results.

[0388] List of abbreviations and acronyms

[0389]

[0390]

[0391]

[0392]

[0393] 1. General Plan

[0394] Option 1:

[0395]

[0396] Compound of Formula 1.5 can be obtained according to the method outlined in Scheme 1. 1-Aminopyrrole 1.1 can be condensed with a suitable coupling ligand using a suitable catalyst (e.g., HCl, etc.) and a suitable solvent (e.g., EtOH, etc.) to produce a substituted pyrrolo[1,2-b]pyridazine 1.2. Halogenation at the indicated position using a known halogenating agent (e.g., NBS, etc.) can form intermediate 1.3, where X is chlorine, bromine, or iodine, and where intermediate 1.3 can be further substituted with a suitable agent (e.g., selectfluor, etc.) via CH activation or electrophilic aromatic substitution to produce intermediate 1.4. Halogen metal exchange from -X to -M can then be achieved using a suitable agent (e.g., n-BuLi, etc.) or transition metal coupling using a palladium catalyst and a metal source (e.g., B2Pin2, Me6Sn2, etc.) to give intermediate 1.5, where M is a metal, such as tin or boron. Alternatively, the substituted 1-aminopyrrole 1.6 can be converted to pyrrolo[1,2-b]pyridazine heterocycle 1.7 via the above condensation. Heterocycle 1.7 can be converted to a type 1.4 intermediate by halogenation.

[0397] Option 2:

[0398]

[0399] Compound (I) can be assembled by first reacting an amine with intermediate 2.1 at C-4 to give intermediate 2.2. After converting it to an acid 2.3 using a suitable reagent (e.g., LiOH, LiI, and pyridine), a second amine can be introduced using standard amide bond formation conditions (e.g., DIPEA and HATU) to give amide 2.4. The metal-containing substance (1.5) can be coupled to intermediate 2.4 using a suitable catalyst (e.g., a palladium catalyst) to give compound (I).

[0400] Option 3:

[0401]

[0402] Alternatively, compound (I) can be assembled by first adding an amine to carboxylic acid 3.1 using standard amide bond formation (e.g., DIPEA and HATU, etc.) to give amide 3.2. Adding an amine to the C-4 position of 3.2 can generate intermediate 2.4, which can be coupled with intermediate 1.5 using a suitable catalyst such as a palladium catalyst to give compound (I).

[0403] Option 4:

[0404]

[0405] Compound (I) can also be prepared as shown in Scheme 4, first by coupling intermediate 2.2 and heterocycle 1.5 using a suitable catalyst such as a palladium catalyst to obtain compound 4.1. Ester 4.1 can be converted to carboxylic acid 4.2 using known conditions (e.g., LiOH, LiI, and pyridine). Compound (I) can be obtained by adding an amine to intermediate 4.2 using standard amide bond formation conditions (e.g., HATU and DIPEA).

[0406] Option 5:

[0407]

[0408] As shown in Scheme 5, an amine can be added to C-4 of compound 3.1 using a base (e.g., NaH, LiHMDS, etc.) to directly give intermediate 2.3. This can be converted to compound (I) in the same manner as shown in Scheme 2.

[0409] Option 6:

[0410]

[0411] Starting from intermediate 2.4, the compound can react with a suitable reagent (e.g., hexamethyldistin) to give compound 6.1. It can then be coupled with the haloheterocycle 1.4 using a suitable catalyst (e.g., palladium catalyst) to give compound (I).

[0412] Option 7:

[0413]

[0414] In the substitution sequence of the synthesis, compound 2.1 can first be coupled with intermediate 1.5 using a suitable catalyst (e.g., a palladium catalyst) to give the monohalogenated product 7.1. Addition of an amine can produce intermediate ester 7.2, which is then converted to a carboxylic acid to give intermediate 7.3. Addition of an amide using amide bond formation conditions (e.g., DIPEA and HATU, etc.) can produce compound (I).

[0415] Option 8:

[0416]

[0417] Alternatively, as shown in Scheme 8, ester 7.1 can be converted to the corresponding carboxylic acid 8.1 by known hydrolysis conditions (e.g., LiOH, LiI, and pyridine). An amide bond is formed using standard conditions (e.g., DIPEA and HATU) to produce intermediate 8.2, and an amine can then be introduced at the C-4 position to give compound (I).

[0418] Option 9:

[0419]

[0420] Starting from amide intermediate 3.2, coupling with heterocycle 1.5 using a suitable catalyst (e.g., palladium catalyst) can produce monohalogenated intermediate 9.2, which can be converted into compound (I) as described in scheme 8.

[0421] Option 10:

[0422]

[0423] It should also be noted that the synthetic operations of the introduced R groups are possible after their introduction. Scheme 10 shows the synthesis of R... 1 Specific illustrative examples of group changes, where a secondary amine 10.1 reacts to form a methanesulfonamide 10.2. Other functional groups may also be present in R. 1 These groups and operations can be manipulated. These groups and operations may include, but are not limited to, oxidation, elimination, or substitution using suitable reagents known to those skilled in the art. The sequence of synthetic operations may be performed in a manner consistent with the methods outlined in Schemes 1-9 and should not be limited to the final steps of compound preparation.

[0424] Option 11:

[0425]

[0426] After the formation of the amide, R can also be performed. 2 Changes in functional groups. An illustrative example is shown in Scheme 11, but the functional groups present or the synthetic operations performed are not limited to those shown in Scheme 11, wherein methyl ester 11.1 reacts with MeMgX or MeLi to produce the tertiary alcohol 11.2 shown. The sequence of synthetic operations may be carried out in a manner consistent with the methods outlined in Schemes 1-9 and should not be limited to the final step in the preparation of the compound.

[0427] Option 12:

[0428]

[0429] R present on the pyrrolo[1,2-b]pyridazine heterocycle 3 R 4 R 5 R 6 and R 7The manipulation of the group can also be carried out after its connection with the pyridine core. An illustrative example is shown in Scheme 12, although the groups present and the operations performed are not limited to those shown in this scheme. Compounds with a cyano group, such as 12.1, can be converted into the corresponding carboxamide 12.2. The sequence of synthetic operations can be carried out in a manner consistent with the methods outlined in Schemes 1-9 and should not be limited to the final step of compound preparation.

[0430] 2. Synthetic intermediates

[0431] Preparation of intermediate I-1:

[0432]

[0433] 3,3-Diethoxy-2-formylpropionitrile potassium salt (I-1C):

[0434] 1.0 M potassium tert-butoxide / THF (2.2 L, 2.2 mol) was added to a stirred solution of 3,3-diethoxypropane-nitrile (I-1A, 283.80 g, 1.98 mol) and methyl formate (I-1B, 148.80 g, 2.48 mol) in anhydrous THF (1.1 L) at 10 °C. The temperature was maintained between 10 °C and 15 °C throughout the 45-minute addition. After the addition, the resulting slurry was stirred at ambient temperature for 2 hours. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered, and the filter cake was washed with 1 / 1 hexane / THF and dried overnight in a vacuum oven at 60 °C to provide I-1C. 1 H-NMR (CD3OD) is consistent with the desired structure.

[0435] Pyrrolo[1,2-b]pyridazine-3-onitrile (I-1E):

[0436] A stirred suspension of potassium 3,3-diethoxy-2-formylpropionitrile (I-1C, 5.10 g, 24.36 mmol) was cooled to 0 °C and concentrated. HCl (7.11 mL, 85.26 mmol) was added dropwise at a controlled rate, ensuring the internal temperature of the reaction did not exceed 20 °C. After the addition was complete, the reaction was stirred at room temperature for 20 min. A solution of 1-aminopyrrole (I-1D, 1.00 g, 12.18 mmol) in methanol (4.0 mL) was added to the reaction mixture. After the addition, the reaction mixture was refluxed at 90 °C for 2 h. When heating was complete, the reaction was cooled to room temperature and concentrated to approximately half of the initial volume. A saturated aqueous solution of sodium bicarbonate was carefully added to the resulting residue until bubbling ceased. The solution was extracted with two portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and the resulting residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide I-1E.

[0437] 1H NMR (400 MHz, chloroform- d ) δ 8.16-8.03 (m, 2H), 7.93 (ddd, J = 2.6,1.4, 0.6 Hz, 1H), 7.04 (dd, J = 4.5, 2.7 Hz, 1H), 6.84 (dd, J = 4.6, 1.4 Hz,1H).

[0438] 7-Bromopyrrolo[1,2-b]pyridazine-3-onitrile (I-1F):

[0439] N-bromosuccinimide was added in a single addition to a solution of pyrrolo[1,2-b]pyridazine-3-onitrile (I-1E, 840.0 mg, 5.9 mmol) in MeCN (30 mL) at room temperature. The reaction was stirred at room temperature for 30 min, then poured into a saturated aqueous solution of sodium bicarbonate. The solution was concentrated under vacuum to remove acetonitrile. The resulting aqueous layer was extracted with three aliquots of EtOAc. The combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (eluent: EtOAc / hexane) to provide I-1F.

[0440] 1H NMR (400 MHz, chloroform- d ) δ 8.28 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.1Hz, 1H), 7.12 (d, J = 4.8 Hz, 1H), 6.93 (d, J = 4.8 Hz, 1H).

[0441] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborphane-2-yl)pyrrolo[1,2-b]pyridazine-3-onitrile (I-1):

[0442] 7-Bromopyrrolo[1,2-b]pyridazine-3-onitrile (I-1F, 416.5 mg, 1.9 mmol), bis(pinacol)diboron (762.1 mg, 3.0 mmol), potassium acetate (552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II) dichloride (65.8 mg, 0.094 mmol) were added to a microwave-safe flask. Dioxane (8.0 mL) and DMF (4.0 mL) were added, and the reaction mixture was degassed with bubbling argon for 2 minutes. The flask was sealed, and the reaction mixture was heated in a microwave-safe reactor at 120 °C for 60 minutes. After cooling, the reaction mixture was filtered and concentrated under vacuum. The resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with a second portion of EtOAc, and the combined organic layers were dried over sodium sulfate, filtered through a Celite stopper, and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide I-1.

[0443] 1H NMR (400 MHz, chloroform- d ) δ 8.31 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 2.2Hz, 1H), 7.52 (d, J = 4.6 Hz, 1H), 6.84 (d, J = 4.6 Hz, 1H), 1.41 (s, 12H).

[0444] Preparation of intermediate I-2:

[0445]

[0446] 3-Chloropyrrolo[1,2-b]pyridazine (I-2): 1-Aminopyrrole (0.50 g, 6.1 mmol) was dissolved in a 3:1 MeOH:AcOH mixture (16 mL) at room temperature, followed by the addition of 2-chloromalondialdehyde (0.78 g, 7.3 mmol). The resulting mixture was stirred at room temperature for 30 min, then heated to 80°C. o The solution was kept at C for 16 hours. The solvent was removed by rotary evaporation and the crude residue was partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted once with EtOAc. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crude residue was then purified by silica gel chromatography (eluent: EtOAc / hexane) to give the product 3-chloropyrrolo[1,2-b]pyridazine (I-2).

[0447] 1H NMR (400 MHz, chloroform- d ) δ 7.93 (d, J = 2.5 Hz, 1H), 7.75-7.70 (m,1H), 7.69 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 4.3, 2.8 Hz, 1H), 6.45 (dd, J =4.3, 1.4 Hz, 1H).

[0448] Preparation of intermediate I-3:

[0449]

[0450] 4,6-Dibromopyridine-3-carboxylic acid methyl ester (I-3): 4,6-Dichloropyridine-3-carboxylic acid methyl ester (5.0 g, 24.3 mmol) was suspended in hydrogen bromide (33%, in acetic acid, 24 mL). The reaction vessel was sealed and heated to 60 °C for 4 hours. The reaction was cooled to room temperature and diluted with H2O. The resulting solid was filtered and washed with H2O. The solid was then suspended in H2O and alkalized with an aqueous sodium hydroxide solution. The resulting aqueous solution was extracted with EtOAc (3 times). The resulting organic layers were combined, dried over sodium sulfate, and concentrated to provide 4,6-dibromopyridine-3-carboxylic acid methyl ester.

[0451] ES / MS: 296.182 (M+H + ).

[0452] Preparation of intermediate I-4:

[0453]

[0454] 6-Bromo-4-(isopropylamino)pyridine-3-carboxylic acid methyl ester (I-4): Isopropylamine (15.3 mL, 177 mmol) was added to a solution of 4,6-dibromopyridine-3-carboxylic acid methyl ester (7.16 g, 24.3 mmol) in acetonitrile (125 mL) and H₂O (3 mL). The reaction vessel was sealed and heated to 80 °C for 2 hours. The resulting solution was cooled to room temperature and concentrated to dryness. The resulting oil was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide 6-bromo-4-(isopropylamino)pyridine-3-carboxylic acid methyl ester.

[0455] ES / MS: 273.569 (M+H + ).

[0456] ¹H NMR (400 MHz, chloroform-d) δ 8.60 (s, 1H), 8.08 (s, 1H), 6.72 (s, 1H), 3.87 (s, 3H), 3.68 (dq, J = 13.1, 6.5 Hz, 1H), 1.28 (d, J = 6.4 Hz, 6H).

[0457] Preparation of intermediate I-5:

[0458]

[0459] 6-Bromo-4-chloropyridin-3-carboxylic acid. Lithium hydroxide (2.93 g, 119.77 mmol) in water (68 mL) was added to a solution of methyl 6-bromo-4-chloropyridin-3-carboxylic acid (15 g, 59.89 mmol) in methanol (240 mL). The solution was heated to 43 °C overnight and then cooled to room temperature. An aqueous solution of hydrochloric acid (1 M, 120 mL) was added, and volatiles were removed under vacuum. The resulting slurry was filtered and washed with H₂O to provide 6-bromo-4-chloropyridin-3-carboxylic acid.

[0460] ES / MS: 237.967 (M+H + ).

[0461] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.03 (s, 1H).

[0462] (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide. HATU (6.27 g, 16.49 mmol), (R)-4-amino-3-fluoro-2-methylbut-2-ol hydrochloride (2.4 g, 15.23 mmol), and N,N-diisopropylethylamine (5.62 mL, 32.26 mmol) were added to a solution of 6-bromo-4-chloropyridine-3-carboxylic acid (3 g, 12.69 mmol) in DMF (42 mL). The resulting solution was stirred overnight at room temperature and then diluted with ethyl acetate. The organic solution was washed with a saturated aqueous lithium chloride solution (3 times), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0463] ES / MS: 341.089 (M+H + ).

[0464] 1H NMR (400 MHz, DMSO- d 6) δ 8.88 (t, J = 5.5 Hz, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 4.82 (s, 1H), 4.28 (ddd, J = 49.3, 9.4, 2.0 Hz, 1H), 3.84-3.63(m, 1H), 3.40-3.22 (m, 1H), 1.13 (d, J = 7.0 Hz, 6H).

[0465] (R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (I-5). 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[1,2-b]pyridazin-3-onitrile (0.24 g, 0.9 mmol), XPhos Pd G3 (0.05 g, 0.06 mmol), and tripotassium phosphate aqueous solution (2M, 0.59 mL, 1.18 mmol) were added to a solution of (R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (0.2 g, 0.59 mmol) in DME (3.9 mL). The resulting solution was degassed with argon and heated to 120 °C in a microwave reactor for 12 minutes. The crude reaction mixture was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide (R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

[0466] ES / MS: 402.220 (M+H + ).

[0467] Preparation of intermediate I-6:

[0468]

[0469] 6-Chloro-4-(N-(Methylsulfonyl)methylsulfonylamino)pyridine-3-carboxylate: Methanesulfonyl chloride (0.39 mL, 5 mmol) was slowly added to a solution of 4-amino-6-chloropyridine-3-carboxylate (334 mg, 1.67 mmol) and triethylamine (0.7 mL, 5 mmol) in dichloromethane (5 mL). The mixture was stirred overnight. It was diluted with EtOAc (20 mL) and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried and concentrated. The mixture was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0470] ES / MS: 357 [M+H] +

[0471] 6-Chloro-4-(Methylsulfonyl)pyridine-3-carboxylic acid (I-6): Lithium hydroxide (20 mg, 0.8 mmol) was added to a solution of ethyl 6-chloro-4-(N-(Methylsulfonyl)methylsulfonyl)pyridine-3-carboxylic acid (60 mg, 0.17 mmol) in THF / MeOH (1 mL / 0.5 mL). The solution was heated to 50 °C and held for 3 hours, acidified with HCl (1N), and extracted with EtOAc. The organic layer was dried and concentrated to give I-6, which was used without further purification.

[0472] ES / MS: 251 [M+H] +

[0473] Preparation of intermediate I-7:

[0474]

[0475] (2-(4-nitrophenyl)prop-2-yl)carbamate methyl ester (I-7B):

[0476] Methyl chloroformate (0.11 ml, 1.43 mmol) was added to a solution of 2-(4-nitrophenyl)propane-2-amine (I-7A, 250 mg, 1.15 mmol) and pyridine (0.25 ml, 3.15 mmol) in DCM (10 mL) at 0°C. The reaction was gradually heated to room temperature and stirred for 2 days. The reaction was concentrated, diluted with EtOAc, and washed three times with 1N HCl. The organic extract was dried over sodium sulfate to give I-7B.

[0477] ES / MS: 239.0 (M+H + ).

[0478] ¹H NMR (400 MHz, chloroform-d) δ 8.18 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H), 5.20 (s, 1H), 3.58 (s, 3H), 1.66 (s, 6H).

[0479] (2-(4-aminophenyl)prop-2-yl)carbamate methyl ester (I-7):

[0480] A solution of methyl (2-(4-nitrophenyl)prop-2-yl)carbamate (I-7B, 101 mg, 0.424 mmol) in EtOH (10 mL) was degassed under argon and vacuum. Pd / C (10%, 26 mg, 0.0248 mmol) was added and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-7.

[0481] ¹H NMR (400 MHz, chloroform-d) δ 7.21–7.16 (m, 2H), 6.70–6.57 (m, 2H), 5.03 (s, 1H), 3.58 (s, 3H), 3.46 (s, 2H), 1.63 (s, 6H).

[0482] Preparation of intermediate I-8:

[0483]

[0484] (1-(4-nitrophenyl)cyclopropyl)carbamate methyl ester (I-8B):

[0485] Methyl chloroformate (0.1 ml, 1.30 mmol) was added to a solution of 1-(4-nitrophenyl)cyclopropyl-1-amine (I-8A, 250 mg, 1.16 mmol) and pyridine (0.3 ml, 3.72 mmol) in DCM (10 mL) at 0°C. The reaction was gradually heated to room temperature and stirred for 2 days. The reaction mixture was concentrated, diluted with EtOAc, and washed three times with 1N HCl. The organic extract was dried over sodium sulfate to give I-8B.

[0486] 1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.9 Hz, 2H), 5.44 (s, 1H), 3.69 (s, 3H), 1.40 (m, 4H).

[0487] (1-(4-aminophenyl)cyclopropyl)carbamate methyl ester (I-8):

[0488] A solution of methyl (1-(4-nitrophenyl)cyclopropyl)carbamate (I-8B, 227 mg, 0.961 mmol) in EtOH (15 mL) was degassed under argon and vacuum. Pd / C (10%, 60 mg, 0.0564 mmol) was added, and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-8.

[0489] ¹H NMR (400 MHz, chloroform-d) δ 7.08 (dd, J = 33.4, 8.0 Hz, 2H), 6.72–6.56 (m, 2H), 5.44 (s, ¹H), 3.62 (d, J = 4.8 Hz, 3H), 3.09 (d, J = 47.9 Hz, 2H), 1.22 (t, J = 7.0 Hz, 4H).

[0490] Preparation of intermediate I-9:

[0491]

[0492] Methyl(1-(4-nitrophenyl)cyclopropyl)acetamide (I-9B):

[0493] Acetic anhydride (0.12 ml, 1.27 mmol) was added to a solution of 1-(4-nitrophenyl)cyclopropyl-1-amine (I-9A, 250 mg, 1.16 mmol) and pyridine (0.3 ml, 3.72 mmol) in DCM (10 mL) at 0 °C. The reaction was gradually warmed to room temperature and stirred for 2 days. The reaction was concentrated, diluted with EtOAc, and washed three times with 1N HCl. The organic extract was dried over sodium sulfate, filtered, and concentrated to give I-9B.

[0494] ES / MS: 221.0 (M+H + ).

[0495] 1H NMR (400 MHz, chloroform-d) δ 8.13 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 6.15 (s, 1H), 2.04 (s, 3H), 1.40 (s, 4H).

[0496] Methyl(1-(4-aminophenyl)cyclopropyl)acetamide (I-9):

[0497] A solution of methyl(1-(4-nitrophenyl)cyclopropyl)acetamide (I-9B, 217 mg, 0.985 mmol) in EtOH (15 mL) was degassed under argon and vacuum, then Pd / C (10%, 60 mg, 0.0564 mmol) was added and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-9.

[0498] ¹H NMR (400 MHz, chloroform-d) δ 7.06 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 2H), 5.59 (d, J = 8.1 Hz, 1H), 3.72–3.38 (m, 2H), 1.95 (s, 3H), 0.85 (t, J = 7.4 Hz, 4H).

[0499] Preparation of intermediate I-10:

[0500]

[0501] (S)-3-(4-nitro-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-10C):

[0502] A 60% dispersion of sodium hydride in oil (60%, 133 mg, 3.316 mmol) was added to a solution of 4-nitro-1H-pyrazole (I-10A, 250 mg, 2.211 mmol) in DMF (5 mL) at 0 °C. After stirring for 1.5 h, a solution of (R)-3-((methanesulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (I-10B, 704 mg, 2.653 mmol) in 5 mL DMF was added and the mixture was heated at 95 °C overnight. The reaction mixture was diluted with EtOAc and washed twice with brine. The organic extract was dried over sodium sulfate and purified by silica gel chromatography (eluent: EtOAc / hexane) to provide I-10C.

[0503] ¹H NMR (400 MHz, chloroform-d) δ 8.16 (s, ¹H), 8.13–8.01 (m, ¹H), 4.89 (p, J = 5.7 Hz, ¹H), 3.87 (dd, J = 12.0, 6.5 Hz, ¹H), 3.77 (s, ¹H), 3.57 (s, 2H), 2.60–2.34 (m, 2H), 1.48 (s, 9H).

[0504] (S)-4-nitro-1-(pyrrolidone-3-yl)-1H-pyrazole hydrochloride (I-10D):

[0505] 750 μL of HCl (4.0 M dioxane solution) was added to a solution of (S)-3-(4-nitro-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-10C, 248.3 mg, 0.880 mmol) in DCM (3 mL). After 4 hours, HCl (1 mL) and MeOH (1 mL) were added. The reaction mixture was heated at 40 °C overnight. The reaction mixture was concentrated to dryness to give I-10D.

[0506] ES / MS: 183.2 (M+H + ).

[0507] (S)-4-nitro-1-(1-(oxetane-3-yl)pyrrolidine-3-yl)-1H-pyrazole (I-10E):

[0508] AcOH (250 μL) was added to a solution of (S)-4-nitro-1-(pyrrolidone-3-yl)-1H-pyrazole hydrochloride (I-10D, 186 mg, 0.851 mmol), triethylamine (0.12 mL, 0.861 mmol), and 3-oxetane (0.250 mL, 4.267 mmol) in DCE (5 mL). The reaction was stirred at room temperature for 3 hours. Sodium cyanoborohydride (270 mg, 4.296 mmol) was added and the reaction was heated at 55 °C overnight. The reaction was partitioned with DCM and brine. The organic extract was dried over sodium sulfate and the resulting residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to provide I-10E.

[0509] ES / MS: 239.2 (M+H + ).

[0510] 1H NMR (400 MHz, chloroform-d) δ 8.39 (d, J = 0.6 Hz, 1H), 8.05 (d, J = 0.7Hz, 1H), 5.01-4.86 (m, 1H), 4.72 (td, J = 6.6, 2.8 Hz, 2H), 4.67 (t, J = 6.1Hz, 1H), 4.63 (t, J = 6.1 Hz, 1H), 3.77 (tt, J = 6.8, 5.8 Hz, 1H), 2.98 (ddd,J = 17.9, 9.1, 3.8 Hz, 2H), 2.86 (dd, J = 10.2, 6.7 Hz, 1H), 2.63-2.45 (m,2H), 2.30-2.05 (m, 1H).

[0511] (S)-1-(1-(oxetane-3-yl)pyrrolidine-3-yl)-1H-pyrazole-4-amine (I-10):

[0512] A solution of (S)-4-nitro-1-(1-(oxecyclobutan-3-yl)pyrrolidine-3-yl)-1H-pyrazole (I-10E, 82.8 mg, 0.348 mmol) in EtOH (5 mL) was degassed under argon and vacuum, then Pd / C (10%, 22 mg, 0.021 mmol) was added and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-10.

[0513] ES / MS: 209.1 (M+H + ).

[0514] 1H NMR (400 MHz, chloroform-d) δ 7.21 (d, J = 0.9 Hz, 1H), 7.12 (d, J = 1.0Hz, 1H), 4.77 (ddt, J = 9.4, 7.2, 4.7 Hz, 1H), 4.69 (td, J = 6.6, 2.7 Hz,2H), 4.63 (dt, J = 10.4, 6.0 Hz, 2H), 3.82-3.62 (m, 1H), 2.82 (pd, J = 8.8,7.9, 3.9 Hz, 3H), 2.53 (td, J = 8.5, 6.3 Hz, 1H), 2.41 (dtd, J = 13.8, 8.6,5.4 Hz, 1H), 2.25-2.04 (m, 1H).

[0515] Preparation of intermediate I-11:

[0516]

[0517] (R)-4-(dibenzylamino)-3-fluoro-2-methylbut-2-yl acetate:

[0518] DMAP (16.2 mg, 0.13 mmol) and triethylamine (0.56 mL, 4.0 mmol) were added to a solution of (R)-4-(dibenzylamino)-3-fluoro-2-methylbut-2-ol (800.0 mg, 2.6 mmol) and acetic anhydride (0.276 mL, 2.9 mmol). The reaction mixture was heated to 100 °C until complete consumption of the starting material was observed by mass spectrometry. Once complete, the reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (eluent: EtOAc / hexane) to provide the desired product.

[0519] ES / MS: 344.2 (M+H + ).

[0520] (R)-4-amino-3-fluoro-2-methylbut-2-yl acetate (I-11):

[0521] Pd(OH)₂ / carbon was added to a solution of 4-(dibenzylamino)-3-fluoro-2-methylbut-2-yl acetate (748.0 mg, 2.2 mmol) in EtOH (8.0 mL) and EtOAc (8.0 mL). The atmosphere was purged and backfilled three times with hydrogen, and then maintained under hydrogen atmosphere during the reaction. After three hours, the reaction mixture was filtered and concentrated under vacuum to provide I-11, which was used without further purification.

[0522] ES / MS: 164.0 (M+H + ).

[0523] Preparation of intermediate I-12:

[0524] (3-acetamidobicyclo[1.1.1]pentan-1-yl) tert-butyl carbamate

[0525]

[0526] (3-Acetamidobicyclo[1.1.1]pentan-1-yl)tert-butyl carbamate: A saturated aqueous solution of sodium bicarbonate (15 mL) and acetic anhydride (0.73 mL, 7.7 mmol) were added to a solution of (3-aminobicyclo[1.1.1]pentan-1-yl)tert-butyl carbamate (303 mg, 1.5 mmol) in CH2Cl2 (7.5 mL) at 0 °C. The biphasic solution was warmed to room temperature and stirred for 24 hours. The mixture was extracted with CH2Cl2 (3 times). The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The resulting substance was used without further purification.

[0527] 1H NMR (400 MHz, chloroform-d) δ 5.80 (s, 1H), 4.93 (s, 1H), 2.31 (s, 6H), 1.94 (s, 3H), 1.44 (s, 9H).

[0528] Preparation of intermediate I-13:

[0529]

[0530] 6-Chloro-4-(((1S)-3-fluorocyclohexyl)amino)pyridine-3-carboxylic acid ethyl ester: Dissolve 0.13 g (0.44 mmol) of 6-chloro-4-(((1S,3S)-3-hydroxycyclohexyl)amino)pyridine-3-carboxylic acid ethyl ester in DCM (6 mL) and adjust to 0. o C. DAST (0.069 mL, 0.52 mmol) was then added dropwise over a period of 1 minute. After 5 minutes, the reaction mixture was quenched by adding saturated sodium bicarbonate aqueous solution (1 mL, poured into water (5 mL)) and extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to give a crude residue, which was further purified by silica gel chromatography (eluent: EtOAc / hexane) to provide the desired product.

[0531] ES / MS: 301.4 [M+H + ].

[0532] Preparation of intermediate I-14

[0533]

[0534] (1r,4r)-4-(oxazol-5-yl)cyclohexane-1-amine hydrochloride (I-14): p-Toluenesulfonylmethylisocyanate (430 mg, 2.2 mmol) was added to a solution of ((1r,4r)-4-formylcyclohexyl)carbamate (500 mg, 2.2 mmol) in MeOH (10 mL), and the resulting mixture was heated at 65 °C for 12 hours. The mixture was poured into water (10 mL) and extracted with 2 x 20 mL EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give pure ((1r,4r)-4-(oxazol-5-yl)cyclohexyl)carbamate. It was then dissolved in HCl (4.0 M dioxane solution, 4 mL, 16 mmol) and stirred at room temperature for 3 hours. The reaction mixture was then concentrated directly to dryness to give I-14 HCl salt, which was used without further purification.

[0535] ES / MS: 167.1 [M+H] +

[0536] Preparation of intermediate I-15

[0537]

[0538] (1r,4r)-4-(4-methyloxazol-5-yl)cyclohexane-1-amine hydrochloride (I-15): (1r,4r)-4-(4-methyloxazol-5-yl)cyclohexane-1-amine hydrochloride is prepared in the same manner as described in I-14, except that p-toluenesulfonylmethylisocyanate is replaced with 1-methyl-1-toluenesulfonylmethylisocyanate.

[0539] ES / MS: 181.1 [M+H] +

[0540] Preparation of intermediate I-16

[0541]

[0542] 1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-amine hydrochloride (I-16): 1-(oxazol-5-yl)-2-oxabicyclo[2.2.2]octane-4-amine hydrochloride was prepared in the same manner as described in I-14, with (1-formyl-2-oxabicyclo[2.2.2]octane-4-yl)carbamate tert-butyl ester instead of ((1r,4r)-4-formylcyclohexyl)carbamate tert-butyl ester.

[0543] ES / MS: 195.1 [M+H]+

[0544] Preparation of intermediate I-17

[0545]

[0546] 1-(4-methyloxazol-5-yl)-2-bicyclo[2.2.2]octaneoxazolidinyl[2.2.2]octane-4-amine hydrochloride (I-17): 1-(4-methyloxazol-5-yl)-2-oxazolidinyl[2.2.2]octane-4-amine hydrochloride was prepared in the same manner as described in I-16, except that p-toluenesulfonylmethylisocyanate was replaced with 1-methyl-1-toluenesulfonylmethylisocyanate.

[0547] ES / MS: 209.1 [M+H] +

[0548] Preparation of intermediate I-18

[0549]

[0550] 5-(5-nitropyridin-2-yl)oxazole: XPhos Pd G3 (43 mg, 0.051 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)oxazole (132 mg, 0.68 mmol), and K3PO4 (0.5 M aqueous solution, 1.5 mL, 0.77 mmol) were added to a solution of 2-bromo-5-nitropyridinium (125 mg, 0.62 mmol) in DME (2.5 mL). The resulting mixture was heated in a microwave reactor at 120 °C for 20 min, then poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give 5-(5-nitropyridin-2-yl)oxazole.

[0551] ES / MS: 192.0 [M+H] +

[0552] 6-(Oxazol-5-yl)pyridin-3-amine (I-18): 5-(5-nitropyridin-2-yl)oxazole (178 mg, 0.093 mmol) was dissolved in THF (3 mL), followed by the addition of a saturated aqueous solution of NH4Cl (1 mL) and iron (312 mg, 5.6 mmol), and the resulting mixture was heated to reflux and held for 2 hours. The mixture was then filtered through a celite pad, washed with MeOH (5 mL), added to water (5 mL), and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give I-18, which was used without further purification.

[0553] ES / MS: 162.1 [M+H] +

[0554] Preparation of intermediate I-19

[0555]

[0556] 4-Methyl-5-(5-nitropyridin-2-yl)oxazole: 1-Methyl-1-toluenesulfonylmethylisocyanate (825 mg, 3.9 mmol) was added to a solution of 5-nitropyridin-2-carboxaldehyde (500 mg, 3.3 mmol) in MeOH (10 mL), and the resulting mixture was heated at 65 °C for 12 hours. The mixture was poured into water (10 mL) and extracted with 2 x 20 mL EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0557] ES / MS: 206.1 [M+H] +

[0558] 6-(4-Methyloxazol-5-yl)pyridin-3-amine (I-19): 4-Methyl-5-(5-nitropyridin-2-yl)oxazol (200 mg, 0.098 mmol) was dissolved in THF (3 mL), followed by the addition of a saturated aqueous solution of NH4Cl (1 mL) and iron (327 mg, 5.8 mmol). The resulting mixture was heated to reflux and held for 2 hours. The mixture was then filtered through a celite pad, washed with MeOH (5 mL), added to water (5 mL), and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give I-19, which was used without further purification.

[0559] ES / MS: 176.1 [M+H] +

[0560] Preparation of intermediate I-20

[0561]

[0562] 5-Ethoxy-6-(oxazol-5-yl)pyridine-3-amine (I-20): XPhos Pd G3 (33 mg, 0.038 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)oxazole (99 mg, 0.51 mmol), and K3PO4 (0.5 M aqueous solution, 1.2 mL, 0.58 mmol) were added to a solution of 6-bromo-5-ethoxypyridine-3-amine (100 mg, 0.51 mmol) in DME (2 mL). The resulting mixture was heated in a microwave reactor at 120 °C for 20 min, then poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give the desired product, which was used without further purification.

[0563] ES / MS: 206.1 [M+H] +

[0564] Preparation of intermediate I-21

[0565]

[0566] (2-Formylpyrimidin-5-yl)carbamate benzyl ester: K₂CO₃ (1.40 g, 10.1 mmol) and benzyl chloroformate (0.79 mL, 5.58 mmol) were added to a solution of 2-(diethoxymethyl)pyrimidin-5-amine (1.00 g, 5.07 mmol) in 1:1 THF:water (12 mL), and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product, which was then dissolved in acetone (10 mL) and 1N HCl (6 mL) and stirred at room temperature for 16 hours. Acetone was removed by rotary evaporation and the resulting mixture was partitioned between a saturated aqueous sodium bicarbonate solution (10 mL) and EtOAc (25 mL). The aqueous solution was then extracted once more with EtOAc (25 mL). The combined organic matter was dried over magnesium sulfate, filtered, and concentrated to give benzyl (2-formylpyrimidin-5-yl)carbamate, which was used without further purification.

[0567] ES / MS: 258.1 [M+H] +

[0568] (2-(oxazol-5-yl)pyrimidin-5-yl)carbamate benzyl ester: p-Toluenesulfonylmethylisocyanate (171 mg, 0.88 mmol) was added to a solution of (2-formylpyrimidin-5-yl)carbamate (225 mg, 0.88 mmol) in BnOH (4 mL), and the resulting mixture was heated at 65 °C for 16 hours. The mixture was poured into water (10 mL) and extracted with 2 x 30 mL EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue still contained a significant amount of BnOH, which was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0569] ES / MS: 297.2 [M+H] +

[0570] 2-(Oxazol-5-yl)pyrimidin-5-amine (I-21): 10% Pd / C (323 mg, 0.015 mmol) was added to a solution of (2-(oxazol-5-yl)pyrimidin-5-yl)carbamate benzyl ester (225 mg, 0.076 mmol) in EtOH (10 mL) in a 50 mL round-bottom flask. The headspace was purged with hydrogen, and then a hydrogen balloon was applied to the reaction flask. After 13 hours, the reaction mixture was filtered through a Celite filter, washed with EtOH (2 x 15 mL), and the resulting EtOH solution was concentrated to dryness to give crude I-21, which was used without further purification.

[0571] ES / MS: 163.1 [M+H] +

[0572] Preparation of intermediate I-22

[0573]

[0574] 3-(oxazol-5-ylmethyl)cyclobut-1-amine hydrochloride (I-22): 3-(oxazol-5-ylmethyl)cyclobut-1-amine hydrochloride was prepared in the same manner as described in I-14, with tert-butyl carbamate ((1r,4r)-4-formylcyclohexyl)carbamate replaced by the known compound (3-(2-oxoethyl)cyclobutyl)carbamate.

[0575] ES / MS: 153.1 [M+H] +

[0576] Preparation of intermediate I-23

[0577]

[0578] ((1r,4r)-4-(hydrazine carbonyl)cyclohexyl)carbamate tert-butyl ester: CDI (1.25 g, 7.7 mmol) as a single solid moiety was added to a solution of (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (1.5 g, 6.2 mmol) in THF (60 mL), and the resulting mixture was stirred at room temperature for 16 hours. Then, hydrazine hydrate (1.05 g, 21 mmol) as a single moiety was added and stirred for 30 minutes. The reaction mixture was then filtered, the filter cake was washed with THF (1 x 50 mL), and dried under vacuum to give the desired product, which was used without further purification.

[0579] ES / MS: 258.0 [M+H] +

[0580] ((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate tert-butyl ester: Trimethyl orthoformate (1.3 mL, 12 mmol) and BF3 were added to a solution of ((1r,4r)-4-(hydrazine carbonyl)cyclohexyl)carbamate (556 mg, 2.2 mmol) in DMF (10 mL) under argon atmosphere. OEt2 (0.01 mL, 0.011 mmol). The reaction mixture was heated to 50 °C and maintained for 4 hours, then cooled to room temperature. DIPEA (0.23 mL, 1.3 mmol) was added, and the mixture was stirred for 12 hours. Once complete, the reaction mixture was poured into water (15 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0581] ES / MS: 268.0 [M+H] +

[0582] (1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexane-1-amine hydrochloride (I-23): Then, ((1r,4r)-4-(1,3,4-oxadiazol-2-yl)cyclohexyl)carbamate tert-butyl ester (100 mg, 0.37 mmol) was dissolved in HCl (4.0 M dioxane solution, 4 mL, 16 mmol) and stirred at room temperature for 3 hours. The reaction mixture was then concentrated directly to dryness to give I-23 HCl salt, which was used without further purification.

[0583] ES / MS: 168.1 [M+H] +

[0584] Preparation of intermediate I-24

[0585]

[0586] ((1r,4r)-4-(2-formylhydrazide-1-carbonyl)cyclohexyl)carbamate tert-butyl: Formylhydrazide (80 mg, 1.3 mmol), HATU (469 mg, 1.2 mmol), and finally DIPEA (0.45 mL, 2.6 mmol) were added to a solution of (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid (250 mg, 1.0 mmol) in DMF (2 mL), and the resulting mixture was stirred at room temperature for 15 min. Once complete, the reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0587] ES / MS: 285.9 [M+H] +

[0588] ((1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate tert-butyl ester: Lawesson's reagent (301 mg, 0.74 mmol) was added to a solution of ((1r,4r)-4-(2-formylhydrazine-1-carbonyl)cyclohexyl)carbamate tert-butyl ester (193 mg, 0.68 mmol) in dioxane (5 mL), and the resulting reaction mixture was heated to 100°C and maintained for 3 hours. Once complete, the reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0589] ES / MS: 284.0 [M+H] +

[0590] (1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexane-1-amine hydrochloride (I-24): Then, ((1r,4r)-4-(1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate tert-butyl ester (59 mg, 0.21 mmol) was dissolved in HCl (4.0 M dioxane solution, 4 mL, 16 mmol) and stirred at room temperature for 7 hours. The reaction mixture was then concentrated directly to dryness to give I-24 HCl salt, which was used without further purification.

[0591] ES / MS: 184.1 [M+H] +

[0592] Preparation of intermediate I-25

[0593]

[0594] ((3R,6S)-6-formyltetrahydro-2H-pyran-3-yl)tert-butyl carbamate: DIPEA (2.3 mL, 13 mmol) as a single moiety was added to a solution of ((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)tert-butyl carbamate (200 mg, 0.87 mmol) in DCM (5 mL) at -10 °C, followed by dropwise addition of a solution of pyridine-SO3 (1:1) complex (2.1 g, 13 mmol) in DMSO (7 mL) over 2 minutes. The reaction vessel was transferred to a 0 °C bath and stirred for 1.5 h, then warmed to room temperature over 2.5 h. The reaction mixture was then adjusted to -10 °C, and pyridine-SO3 (1:1) complex (400 mg, 2.4 mmol) as a single moiety was added, followed by warming of the reaction mixture to room temperature over 2 h. Once complete, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (2 x 30 mL), dried over magnesium sulfate, filtered, concentrated, and the resulting crude aldehyde was used without further purification.

[0595] ES / MS: 230.0 [M+H] +

[0596] ((3R,6S)-6-(oxazol-5-yl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester: p-Toluenesulfonylmethylisocyanate (170 mg, 0.87 mmol) was added to ((3R,6S)-6-formyltetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (200 mg, 0.87 mmol) in MeOH (5 mL), and the resulting mixture was heated at 65°C for 14 hours. The mixture was poured into water (10 mL) and extracted with 2 x 20 mL EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0597] ES / MS: 269.1 [M+H] +

[0598] (3R,6S)-6-(oxazol-5-yl)tetrahydro-2H-pyran-3-amine hydrochloride (I-25): Then, ((3R,6S)-6-(oxazol-5-yl)tetrahydro-2H-pyran-3-yl)carbamate tert-butyl ester (73 mg, 0.27 mmol) was dissolved in HCl (4.0 M dioxane solution, 4 mL, 16 mmol) and stirred at room temperature for 6 hours. The reaction mixture was then concentrated directly to dryness to give I-25 HCl salt, which was used without further purification.

[0599] ES / MS: 169.1 [M+H] +

[0600] Preparation of intermediate I-26

[0601]

[0602] (4-(2-methyloxazol-5-yl)cyclohexyl-3-en-1-yl)carbamate tert-butyl ester: XPhos Pd G3 (18 mg, 0.022 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)oxazol (109 mg, 0.52 mmol) and K3PO4 (0.5 M aqueous solution, 1.3 mL, 0.65 mmol) were added to a solution of 4-((tert-butoxycarbonyl)amino)cyclohexyl-1-yl trifluoromethanesulfonic acid (150 mg, 0.43 mmol) in DME (3 mL). The resulting mixture was heated in a microwave reactor at 120 °C for 20 min, then poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to obtain the desired product.

[0603] ES / MS: 279.2 [M+H] +

[0604] (4-(2-methyloxazol-5-yl)cyclohexyl)tert-butyl carbamate: 10% Pd / C (107 mg, 0.10 mmol) was added to a solution of (140 mg, 0.50 mmol) tert-butyl carbamate in EtOH (6 mL) in a 50 mL round-bottom flask. The headspace was purged with hydrogen, and then a hydrogen balloon was applied to the reaction flask. After 2 hours, the reaction mixture was filtered through a Celite filter, washed with EtOH (2 x 15 mL), and the resulting EtOH solution was concentrated to dryness to give the desired product, which was used without further purification.

[0605] ES / MS: 281.2 [M+H] +

[0606] 4-(2-methyloxazol-5-yl)cyclohexane-1-amine hydrochloride (I-26): tert-butyl 4-(2-methyloxazol-5-yl)cyclohexyl)carbamate (141 mg, 0.50 mmol) was then dissolved in HCl (4.0 M dioxane solution, 4 mL, 16 mmol) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated directly to dryness to give I-26 HCl salt, which was used without further purification.

[0607] ES / MS: 181.1 [M+H] +

[0608] Preparation of intermediate I-27

[0609]

[0610] N,N-Dibenzyl-O-(tert-butyldimethylsilyl)-L-serine methyl ester: TBS-Cl (1.7 g, 11 mmol), DMAP (61 mg, 0.50 mmol), and DIPEA (3.5 mL, 20 mmol) were added to a solution of dibenzyl-L-serine methyl ester (2.0 g, 10 mmol) in DCM (10 mL), and the resulting solution was stirred at room temperature for 3 hours. Once complete, the reaction mixture was poured into water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0611] ES / MS: 414.4 [M+H] +

[0612] (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(dibenzylamino)ethyl)cycloprop-1-ol: Ti(OEt)4 (0.11 mL, 0.36 mmol) was added to a solution of N,N-dibenzyl-O-(tert-butyldimethylsilyl)-L-serine methyl ester (500 mg, 1.1 mmol) in THF (8 mL) at 0 °C, followed by dropwise addition of EtMgBr solution (3.0 M ether solution, 1.2 mL, 3.6 mmol) diluted to a total volume of 4 mL with THF. After stirring for 16 hours, Ti(OEt)4 (0.29 mL, 0.97 mmol) was added, followed by dropwise addition of EtMgBr solution (3.0 M ether solution, 1.2 mL, 3.6 mmol) diluted to a total volume of 4 mL with THF. After 20 minutes, the starting ester was fully consumed, and the reaction was quenched by carefully adding saturated NH4Cl aqueous solution (5 mL), adding EtOAc (20 mL), and stirring the reaction mixture vigorously for 20 minutes. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0613] ES / MS: 412.5 [M+H] +

[0614] (S)-2-(1-(benzyloxy)cyclopropyl)-2-(dibenzylamino)ethyl-1-ol: NaH (60% dispersion, 102 mg, 2.5 mmol in mineral oil) was added to a solution of (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(dibenzylamino)ethyl)cyclopropyl-1-ol (349 mg, 0.85 mmol) in THF (8 mL) at 0 °C, followed by the addition of benzyl bromide (0.12 mL, 1.0 mmol). The reaction mixture was then warmed to room temperature for 2 hours. Benzyl bromide (1.0 mL, 8.5 mmol) and TBAI (63 mg, 0.17 mmol) were added as a single component, and the resulting reaction mixture was stirred for 16 hours. Once complete, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give (S)-N,N-dibenzyl-1-(1-(benzyloxy)cyclopropyl)-2-((tert-butyldimethylsilyl)oxy)ethyl-1-amine (425 mg, 0.85 mmol), which was then dissolved in THF (5 mL) at room temperature and treated with TBAF (1.0 MTHF solution, 1.0 mL, 1.0 mmol). After 24 hours, the reaction mixture was poured into water (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0615] ES / MS: 388.4 [M+H] +

[0616] (R)-1-(2-amino-1-fluoroethyl)cycloprop-1-ol (I-27): (Diethylamino)sulfur trifluoride (0.14 mL, 1.0 mmol) was added dropwise to a solution of (S)-2-(1-(benzyloxy)cyclopropyl)-2-(dibenzylamino)ethyl-1-ol (328 mg, 0.85 mmol) in THF (6 mL) at 0 °C in a Teflon bottle. The reaction mixture was warmed to room temperature over 4 hours, then poured into a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (eluent: EtOAc / hexane) to give (R)-N,N-dibenzyl-2-(1-(benzyloxy)cyclopropyl)-2-fluoroethyl-1-amine. 10% Pd / C (270 mg, 0.25 mmol) was added to a solution of (R)-N,N-dibenzyl-2-(1-(benzyloxy)cyclopropyl)-2-fluoroethyl-1-amine (330 mg, 0.85 mmol) in EtOH (8 mL) and EtOAc (2 mL) in a 50 mL round-bottom flask. The headspace was purged with hydrogen, and then a hydrogen balloon was applied to the reaction flask. After 16 hours, the reaction mixture was filtered through a Celite filter, washed with EtOH (2 x 15 mL), and the resulting EtOH solution was concentrated to dryness to give I-27, which was used without further purification.

[0617] ES / MS: 120.1 [M+H] +

[0618] Preparation of intermediate I-28

[0619]

[0620] 3,3-Difluoro-4-(((trifluoromethyl)sulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (I-28B):

[0621] At -10 o Pyridine (2.2 ml, 21.35 mmol) was added to a solution of tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (I-28A, 939 mg, 4.188 mmol) in DCM (40 mL). Trifluoromethanesulfonic anhydride (1 M dichloromethane solution, 10.5 ml) was added via a feeding funnel over ~10 minutes. At -10 °C... oC. Stir for another 2 hours. Quench the reaction with 1 M citric acid to pH 4.5 (~5 mL). Separate the organic layer and extract the aqueous solution with DCM. Dry the combined organic extracts with sodium sulfate to give I-28B.

[0622] 1H NMR (400 MHz, chloroform-d) δ 5.16 (s, 1H), 4.05–3.65 (m, 4H), 1.48 (s, 9H).

[0623] 19F NMR (376 MHz, chloroform-d) δ -75.01 (d, J = 33.7 Hz), -78.87, -108.16 (dd, J = 246.8, 81.5 Hz), -120.31 (dd, J = 308.9, 247.6 Hz).

[0624] 3,3-Difluoro-4-(4-nitro-1H-pyrazole-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-28C):

[0625] In 0 o C. A solution of 4-nitro-1H-pyrazole (I-28C, 250 mg, 2.211 mmol) in DMF (5 mL) was added to a 60% dispersion of sodium hydride in oil (138 mg, 3.45 mmol). After stirring for 1 hour, a solution of 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester (I-28B, 943 mg, 2.653 mmol) in 5 mL DMF was added and stirred at 95°C. o Heat at C overnight. Dilute the reaction mixture with EtOAc and wash twice with brine. Dry the organic extract with sodium sulfate and purify by silica gel chromatography (eluent: EtOAc / hexane) to provide I-28C.

[0626] ¹H NMR (400 MHz, chloroform-d) δ 8.16 (s, ¹H), 8.13–8.01 (m, ¹H), 4.89 (p, J = 5.7 Hz, ¹H), 3.87 (dd, J = 12.0, 6.5 Hz, ¹H), 3.77 (s, ¹H), 3.57 (s, 2H), 2.60–2.34 (m, 2H), 1.48 (s, 9H).

[0627] 4-(4-amino-1H-pyrazole-1-yl)-3,3-difluoropyrrolidine-1-carboxylic acid tert-butyl ester (I-28):

[0628] A solution of tert-butyl 3,3-difluoro-4-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (I-28C, 165 mg, 0.518 mmol) in EtOH (15 mL) was degassed under argon and vacuum. Pd / C (10%, 28 mg, 0.026 mmol) was added and the mixture was stirred for 2 days under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-28.

[0629] ES / MS: 288.9 (M + ).

[0630] ¹H NMR (400 MHz, chloroform-d) δ 7.30 (s, ¹H), 7.20 (d, J = 5.8 Hz, ¹H), 4.92–4.69 (m, ¹H), 4.01 (dd, J = 13.6, 6.5 Hz, 2H), 3.95–3.76 (m, 2H), 1.47 (d, J = 3.8 Hz, 9H).

[0631] Preparation of intermediate I-29

[0632]

[0633] (3R,4R)-3-(4-amino-1H-pyrazole-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester is prepared similarly to I-28, but in the first step, (3R,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester is used instead of 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

[0634] ES / MS: 270.9 (M + ).

[0635] 1H NMR (400 MHz, chloroform-d) δ 7.29 (s, 1H), 7.13 (d, J = 15.0 Hz, 1H), 5.26 (dd, J = 50.9, 21.6 Hz, 1H), 4.82 (d, J = 14.0 Hz, 1H), 4.06-3.38 (m,6H), 1.49 (s, 9H).

[0636] 19F NMR (376 MHz, chloroform-d) δ -177.64, -182.29 (m)

[0637] Preparation of intermediate I-30

[0638]

[0639] (3R,4S)-3-(4-amino-1H-pyrazole-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester is prepared similarly to I-28, but in the first step, (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester is used instead of 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

[0640] ES / MS: 271.9 (M+H + ).

[0641] ¹H NMR (400 MHz, chloroform-d) δ 7.21 (d, J = 14.5 Hz, 2H), 5.23 (ddd, J = 53.9, 7.0, 3.6 Hz, 1H), 4.84 (d, J = 27.9 Hz, 1H), 4.04 (dt, J = 15.3, 9.5 Hz, 1H), 3.99–3.59 (m, 3H), 2.73 (s, 2H), 1.50 (s, 9H).

[0642] 19F NMR (376 MHz, chloroform-d) δ -179.08 -204.08 (m)

[0643] Preparation of intermediate I-31

[0644]

[0645] (3S,4R)-3-(4-amino-1H-pyrazole-1-yl)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester is prepared similarly to I-28, but in the first step, (3R,4R)-3-fluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester is used instead of 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester.

[0646] ES / MS: 270.9 (M + ).

[0647] ¹H NMR (400 MHz, chloroform-d) δ 7.21 (d, J = 14.1 Hz, 2H), 5.47–5.04 (m, 1H), 5.00–4.71 (m, 1H), 4.18–3.99 (m, 1H), 3.99–3.52 (m, 2H), 2.73 (s, 2H), 1.50 (s, 9H).

[0648] 19F NMR (376 MHz, chloroform-d) δ-193.69 (ddd, J = 60.6, 32.8, 24.6 Hz).

[0649] Preparation of intermediate I-32

[0650]

[0651] 2-(4-Nitrophenyl)prop-2-yl)carbamate 2-chloroethyl ester (EC-I-5B):

[0652] In 0 o C. Add 2-chloroethyl chloroformate (0.15 ml, 1.45 mmol) to a solution of 2-(4-nitrophenyl)propane-2-amine (250 mg, 1.154 mmol) and N,N-diisopropylethylamine (0.5 ml, 2.87 mmol) in DCM (5 mL). The reaction mixture was gradually heated to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM and washed with 1N HCl and brine. The organic extract was dried over sodium sulfate to give I-32B.

[0653] 3-(2-(4-nitrophenyl)prop-2-yl)oxazolidin-2-one (I-32C):

[0654] Add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.85 ml, 5.69 mmol) to a solution of 2-(4-nitrophenyl)prop-2-yl)carbamate (I-32B, 330.8 mg, 1.154 mmol) in CH3CN (5 mL). The reaction was carried out at 80 °C. o Heat at C for 3 hours. Dilute the reaction mixture with EtOAc and wash with 1N HCl and brine. Dry the organic extract with sodium sulfate to give I-32C.

[0655] ES / MS: 251.0 (M+H + ).

[0656] ¹H NMR (400 MHz, chloroform-d) δ 8.24–8.15 (m, 2H), 7.60–7.51 (m, 2H), 4.34 (dd, J = 8.5, 7.2 Hz, 2H), 3.72–3.63 (m, 2H), 1.74 (s, 6H).

[0657] 3-(2-(4-aminophenyl)prop-2-yl)oxazolidin-2-one (I-32):

[0658] Calcium chloride (185 mg, 1.667 mmol) and iron powder (326 mg, 5.838 mmol) were added to a suspension of 3-(2-(4-nitrophenyl)prop-2-yl)oxazolidin-2-one (I-32C, 278 mg, 1.111 mmol) in EtOH (20 mL). 2 mL of water was added and the reaction mixture was heated to 60 °C. o C. Incubate overnight. Filter the reaction mixture through a Celite stopper and wash with EtOAc. Wash the filtrate with saturated NaHCO3 solution and brine, and dry over sodium sulfate to give product I-32.

[0659] ¹H NMR (400 MHz, chloroform-d) δ 7.19 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 8.6 Hz, 2H), 4.26–4.07 (m, 2H), 3.47–3.23 (m, 2H), 1.74 (s, 6H).

[0660] Preparation of intermediate I-33

[0661]

[0662] 3-(1-(4-aminophenyl)cyclopropyl)oxazolidin-2-one (I-33):

[0663] 3-(1-(4-aminophenyl)cyclopropyl)oxazolidin-2-one is prepared similarly to I-32, but in the first step, 2-(4-nitrophenyl)propane-1-amine is replaced with 1-(4-nitrophenyl)propane-2-amine.

[0664] ES / MS: 219.1 (M+H + ).

[0665] ¹H NMR (400 MHz, chloroform-d) δ 7.23–7.17 (m, 2H), 6.68–6.58 (m, 2H), 4.21 (dd, J = 8.8, 7.3 Hz, 2H), 3.56–3.43 (m, 2H), 1.36–1.23 (m, 2H), 1.20–1.06 (m, 2H).

[0666] Preparation of intermediate I-34

[0667]

[0668] 1-(2-(4-aminophenyl)prop-2-yl)pyrrolidine-2-one (I-34):

[0669] 1-(2-(4-aminophenyl)prop-2-yl)pyrrolidine-2-one is prepared similarly to I-32, but in the first step, 2-chloroethyl chloroformate is replaced with 4-chlorobutyryl chloride.

[0670] ES / MS: 218.9 (M + ).

[0671] 1H NMR (400 MHz, chloroform-d) δ 7.12 (d, J = 8.5 Hz, 2H), 6.63 (d, J = 8.6Hz, 2H), 3.69 (d, J = 20.0 Hz, 2H), 3.30 (t, J = 7.0 Hz, 2H), 2.36 (t, J =8.1 Hz, 2H), 1.89 (tt, J = 7.7, 6.8 Hz, 2H), 1.72 (s, 6H).

[0672] Preparation of intermediate I-35

[0673]

[0674] 3-(5-nitropyrimidin-2-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (I-35C):

[0675] Triethylamine (0.4 mL, 2.870 mmol) was added to a solution of 2-chloro-5-nitropyrimidine (0.200 g, 1.254 mmol) and 6-oxa-3-azabicyclo[3.1.1]heptane-4-methylbenzenesulfonate (0.394 g, 1.452 mmol) in 2 Me-THF (6 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned with DCM and water. The organic extract was washed with brine and dried over sodium sulfate to give I-35C.

[0676] ES / MS: 223.0.9 (M+H + ).

[0677] 1H NMR (400 MHz, chloroform-d) δ 9.18 (s, 1H), 4.80 (d, J = 6.6 Hz, 2H), 4.08 (d, J = 13.8 Hz, 2H), 3.97 (d, J = 13.9 Hz, 2H), 3.37 (q, J = 7.4 Hz,1H), 1.95 (d, J = 9.2 Hz, 1H).

[0678] 2-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)pyrimidin-5-amine (I-35)

[0679] A solution of 3-(5-nitropyrimidin-2-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (I-35C, 264 mg, 1.263 mmol) in EtOH (15 mL) was degassed under argon and vacuum. Pd / C (10%, 66 mg, 0.062 mmol) was added and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-35.

[0680] ES / MS: 193.1 (M+H + ).

[0681] ¹H NMR (400 MHz, chloroform-d) δ 8.05 (s, 2H), 4.74 (d, J = 6.5 Hz, 2H), 3.98–3.69 (m, 5H), 3.26 (q, J = 7.2 Hz, 1H), 3.18 (s, 2H), 1.99 (d, J = 8.7 Hz, 1H).

[0682] Preparation of intermediate I-36

[0683]

[0684] 3-(5-nitropyridin-2-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (I-36C):

[0685] Triethylamine (0.4 mL, 2.870 mmol) was added to a solution of 2-chloro-5-nitropyridine (I-36A, 0.200 g, 1.261 mmol) and 6-oxa-3-azabicyclo[3.1.1]heptane-4-methylbenzenesulfonate (I-36B, 0.396 g, 1.461 mmol) in 2Me-THF (6 mL). The reaction was stirred at room temperature. 321 mg of I-36B and trimethylamine (0.4 mL) were added and the solution was stirred at 50 °C. o Heating at C for 2 days.

[0686] The reaction was partitioned with DCM and water. The organic extract was washed with brine and dried over sodium sulfate to give I-36C.

[0687] ES / MS: 222.1 (M+H + ).

[0688] 1H NMR (400 MHz, chloroform-d) δ 9.14 (d, J = 2.7 Hz, 1H), 8.31 (dd, J =9.5, 2.7 Hz, 1H), 6.55 (d, J = 9.5 Hz, 1H), 4.83 (d, J = 6.6 Hz, 2H), 4.34-3.52 (m, 4H), 3.37 (dt, J = 9.4, 6.8 Hz, 1H), 1.98 (d, J = 9.1 Hz, 1H).

[0689] 6-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)pyridine-3-amine (I-36):

[0690] A solution of 3-(5-nitropyridin-2-yl)-6-oxa-3-azabicyclo[3.1.1]heptane (I-36C, 245 mg, 1.108 mmol) in EtOH (15 mL) was degassed under argon and vacuum. Pd / C (10%, 60 mg, 0.056 mmol) was added and the mixture was stirred overnight under a hydrogen balloon. The reaction mixture was filtered through a Celite stopper, washed with EtOAc, and the filtrate was concentrated to give I-36.

[0691] ES / MS: 192.2 (M+H + ).

[0692] 1H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 2.9 Hz, 1H), 7.07 (dd, J =8.7, 2.9 Hz, 1H), 6.46 (d, J = 8.9 Hz, 1H), 4.76 (d, J = 6.6 Hz, 2H), 3.80-3.61 (m, 5H), 3.26 (q, J = 7.1 Hz, 1H), 2.05 (d, J = 8.6 Hz, 1H).

[0693] Preparation of intermediate I-37

[0694]

[0695] Pyrrolo[1,2-b]pyridazine: (E)-3-(dimethylamino)propenal (0.7 mL, 7 mmol) was added to a solution of 1H-pyrrolo-1-amine (500 mg, 6.09 mmol) in acetic acid (4 mL). The resulting mixture was stirred at room temperature for 18 hours and diluted with CH2Cl2. The organic layer was washed with water and a saturated aqueous solution of NaHCO3. The aqueous layer was re-extracted with CH2Cl2 and the resulting organic layer was dried over magnesium sulfate and carefully concentrated. The resulting yellow oil was purified by bulb-to-bulb distillation to provide the product.

[0696] ES / MS: 119.0 (M+H + ).

[0697] ¹H NMR (400 MHz, chloroform-d) δ 8.05–7.99 (m, ¹H), 7.81–7.69 (m, 2H), 6.88 (dd, J = 4.3, 2.7 Hz, ¹H), 6.52 (dd, J = 9.2, 4.3 Hz, 2H).

[0698] 7-Bromopyrrolo[1,2-b]pyridazine (I-37) was prepared by adding N-bromosuccinimide (150 mg, 0.84 mmol) to a solution of pyrrolo[1,2-b]pyridazine (100 mg, 0.85 mmol) in CH2Cl2 (1.5 mL) and acetonitrile (0.5 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min and then directly loaded onto a SiO2 column for purification (eluent: EtOAc / hexane) to provide the desired product.

[0699] ES / MS: 199.0 (M+H + ).

[0700] Preparation of intermediate I-38

[0701]

[0702] 6-Chloro-4-((4-hydroxybicyclo[2.2.2]octane-1-yl)amino)pyridine-3-carboxylic acid methyl ester (I-38): Cesium carbonate (1.98 g, 6.08 mmol) was added to a solution of 4,6-dichloropyridine-3-carboxylic acid methyl ester (870 mg, 4.22 mmol) and 1-aminobicyclo[2.2.2]octane-4-ol hydrochloride (500 mg, 2.81 mmol) in nitrile (12 mL). The resulting slurry was heated to 120 °C and held for 24 hours. The mixture was cooled, diluted with EtOAc, and filtered. The solids were washed with EtOAc and the combined filtrates were concentrated and purified by silica gel chromatography (eluent: 2-5% MeOH / CH2Cl2) to provide the desired product.

[0703] ES / MS: 311.3 (M+H + ).

[0704] Preparation of intermediate I-39

[0705]

[0706] 4-(3,3-Difluoropyrrolidone-1-yl)cyclohexane-1-amine hydrochloride (I-39):

[0707] A suspension of (4-oxocyclohexyl)carbamate tert-butyl ester (0.5 g, 2.34 mmol), 3,3-difluoropyrrolidine hydrochloride (0.37 g, 2.56 mmol), acetic acid (0.21 g, 3.5 mmol), and sodium triacetoxyborohydride (0.75 g, 3.5 mmol) in MeOH (3 mL) and DCE (6 mL) was stirred overnight. The suspension was diluted with EtOAc and washed with a saturated sodium bicarbonate solution. The organic layer was dried and concentrated. It was used without further purification.

[0708] ES / MS: 205 (M+H + ).

[0709] Preparation of intermediate I-40

[0710]

[0711] ((1r,3r)-3-((2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)carbamate tert-butyl ester:

[0712] Methanesulfonic anhydride (0.64 g, 4 mmol) was added to a solution of ((1r,3r)-3-(hydroxymethyl)cyclobutyl)carbamate (0.62 g, 3 mmol), trimethylamine (0.86 mL, 6 mmol), and 4-(dimethylamino)pyridine (38 mg, 0.3 mmol) in DCM (5 mL). The mixture was stirred for 16 hours, then diluted with EtOAc and washed with NaHCO3 (saturated). The organic layer was dried and concentrated. The crude mixture, 2-hydroxypyridine, and potassium carbonate (0.74 g, 5 mmol) were dissolved in DMSO. The mixture was heated at 70 °C for 16 hours. It was cooled and filtered. The filtrate was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA was added to obtain the product.

[0713] ES / MS: 279 (M+H + ).

[0714] 1-(((1r,3r)-3-aminocyclobutyl)methyl)pyridine-2(1H)-keto hydrochloride (I-40):

[0715] 250 mg, 0.9 mmol, of tert-butyl ((1r,3r)-3-((2-oxopyridin-1(2H)-yl)methyl)cyclobutyl)carbamate was dissolved in 3 mL of 4M HCl / dioxane. After 2 hours, the solvent was removed. It was used without further purification.

[0716] Preparation of intermediate I-41

[0717]

[0718] (R)-(2-fluoro-3-((methylcarbamoyl)oxy)propyl)tert-butyl carbamate:

[0719] A solution of (R)-(2-fluoro-3-hydroxypropyl)carbamate tert-butyl ester (170 mg, 0.88 mmol), 4-nitrophenyl chloroformate (710 mg, 3.5 mmol), and 4-(dimethylamino)pyridine (430 mg, 3.5 mmol) in DCM (5 mL) and pyridine (5 mL) was stirred overnight at room temperature. Methylamine was added to the mixture and the resulting mixture was stirred. Once complete, the solvent was removed and the crude material was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA was added to obtain the product.

[0720] ES / MS: 251 (M+H+ ).

[0721] Methylcarbamate (R)-3-amino-2-fluoropropyl ester hydrochloride (I-41):

[0722] (R)-(2-fluoro-3-((methylcarbamoyl)oxy)propyl)carbamate tert-butyl ester was dissolved in 4M HCl / dioxane and stirred for 2 hours. The solvent was removed and the resulting substance was used without further purification.

[0723] Preparation of intermediate I-42

[0724]

[0725] (3-(azidomethyl)-3-hydroxycyclobutyl)carbamate tert-butyl ester:

[0726] Methanesulfonic anhydride (1.59 g, 9 mmol) was added to a mixture of tert-butyl (3-hydroxy-3-(hydroxymethyl)cyclobutyl)carbamate (1.8 g, 8 mmol) and N-ethyldiisopropylamine (3.6 mL, 21 mmol) in DCM (20 mL) and stirred overnight. The mixture was diluted with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated. The mixture was dissolved in DMF and sodium azide (1.58 g, 24 mmol) was added to the suspension. It was stirred at 65 °C for 8 hours, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated. It was used without further purification.

[0727] ES / MS: 243 (M+H + ).

[0728] ((3-amino-1-hydroxycyclobutyl)methyl)carbamate methyl ester hydrochloride:

[0729] A solution of tert-butyl (3-(azidomethyl)-3-hydroxycyclobutyl)carbamate (2 g, 8.3 mmol), triphenylphosphine (3.2 g, 12 mmol), and ammonium hydroxide (4.6 mL, 33 mol) in THF (15 mL) / MeOH (15 mL) / H₂O (3 mL) was stirred overnight at room temperature. The solid was filtered and the filtrate was concentrated. The residue was dissolved in 20 mL of DCM, and trimethylamine (4.8 mL, 34 mmol) and methyl chloroformate (1.1 mL, 14 mmol) were added to the mixture. It was stirred for 1 hour. MeOH (3 mL) was added and the solvent was removed. The mixture was purified by a rapid SiO₂ column (eluent: EtOAc / hexane). The product was dissolved in 2 mL of 4 N HCl / dioxane. After 1 hour, the solvent was removed. It was used without further purification.

[0730] (((1S,3s)-3-((2-chloro-5-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)-1-hydroxycyclobutyl)methyl)carbamate methyl ester:

[0731] (((1R,3r)-3-((2-chloro-5-((((R)-2-fluoro-3-hydroxy-3-methylbutyl)carbamoyl)pyridin-4-yl)amino)-1-hydroxycyclobutyl)methyl)carbamate methyl ester:

[0732] (R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (25 mg, 0.09 mmol), ((3-amino-1-hydroxycyclobutyl)methyl)carbamate hydrochloride (36 mg, 0.17 mmol), and N-ethyldiisopropylamine (0.06 mL, 0.34 mmol) were dissolved in 1 mL MeCN. The mixture was heated at 80°C for 24 hours. The solvent was removed, and the mixture was then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA).

[0733] ES / MS: 433.4 (M+H + ).

[0734] ES / MS: 433.4 (M+H + ).

[0735] Preparation of intermediate I-43

[0736]

[0737] 6-Chloro-4-((3-hydroxy-3-(((methoxycarbonyl)amino)methyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester:

[0738] Ethyl 4,6-dichloropyridine-3-carboxylate (0.8 g, 3.6 mmol), methyl ((3-amino-1-hydroxycyclobutyl)methyl)carbamate hydrochloride (1.25 g, 5.4 mmol), and N-ethyldiisopropylamine (1.9 mL, 10.9 mmol) were dissolved in 10 mL MeCN. The mixture was heated at 60 °C for 24 hours. The solvent was removed, and the mixture was then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and neutralized with saturated sodium bicarbonate solution to obtain the product.

[0739] ES / MS: 358.7 (M+H + ).

[0740] 6-Chloro-4-((3-fluoro-3-(((methoxycarbonyl)amino)methyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester (I-43):

[0741] Di(2-methoxyethyl)aminosulfur trifluoride (0.3 mL, 1.7 mmol) was added to a solution of 6-chloro-4-((3-hydroxy-3-(((methoxycarbonyl)amino)methyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester (500 mg, 1.4 mmol) in 5 mL of DCM. The mixture was stirred for 20 minutes. It was diluted with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated, then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA).

[0742] ES / MS: 360.3 (M+H + ).

[0743] Preparation of intermediate I-44

[0744]

[0745] 6-Chloro-4-((3-hydroxy-3-(hydroxymethyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester:

[0746] Add 4,6-dichloropyridine-3-ethyl carboxylate (0.58 g, 2.6 mmol), 3-amino-1-(hydroxymethyl)cyclobutanol (0.81 g, 5.3 mmol), and N-ethyldiisopropylamine (1.8 mL, 10.5 mmol) to 5 mL of MeCN in a flask. Heat the mixture at 80°C for 48 hours. Remove the solvent and then purify by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and neutralized with saturated sodium bicarbonate solution to obtain the product.

[0747] ES / MS: 301.2 (M+H + ).

[0748] 4-((3-(azidomethyl)-3-hydroxycyclobutyl)amino)-6-chloropyridine-3-carboxylic acid ethyl ester:

[0749] Add p-toluenesulfonic anhydride (1.63 g, 5 mmol) to a solution of ethyl 6-chloro-4-((3-hydroxy-3-(hydroxymethyl)cyclobutyl)amino)pyridine-3-carboxylate (0.75 g, 2 mmol) and N-ethyldiisopropylamine (1.1 mL, 6 mmol) in DCM (5 mL). Stir overnight. Dilute with EtOAc and wash with saturated NaHCO3 and brine. Dry and concentrate the organic layer. Dissolve the residue in DMF and add sodium azide (0.53 g, 8 mmol) to the suspension. Stir at 65 °C for 8 hours. Dilute with EtOAc and wash with saturated NaHCO3 and brine. Dry and concentrate the organic layer. Use without further purification.

[0750] ES / MS: 326.3 (M+H + ).

[0751] 6-Chloro-4-((6-oxo-5-oxa-7-azaspiro[3.4]octane-2-yl)amino)pyridine-3-carboxylic acid ethyl ester (I-44):

[0752] A solution of ethyl 4-((3-(azidomethyl)-3-hydroxycyclobutyl)amino)-6-chloropyridine-3-carboxylate (0.6 g, 1.84 mmol), triphenylphosphine (0.73 g, 2.8 mmol), and ammonium hydroxide (1 mL, 7 mol) in THF (5 mL) / MeOH (5 mL) / H2O (1 mL) was stirred overnight. The solid was filtered and the filtrate was concentrated. The residue was dissolved in 10 mL of DCM and 1,1'-carbonyldiimidazole (272 mg, 2 mmol) was added to the mixture. It was stirred for 16 hours, diluted with EtOAc, and washed twice with 20 mL of 0.5 N HCl. The organic layer was dried and concentrated. The mixture was purified on a rapid column (50% EtOAc / hexane).

[0753] ES / MS: 326.2 (M+H + ).

[0754] Preparation of intermediate I-45

[0755]

[0756] ((1r,4r)-4-(5-(trimethylsilyl)isoxazol-3-yl)cyclohexyl)tert-butyl carbamate:

[0757] NH₂OH-HCl (0.2 g, 2.9 mmol) was added to a solution of ((1r,4r)-4-formylcyclohexyl)carbamate (0.5 g, 2.2 mmol) in methanol (10 mL) and water (9 mL). Then 2.9 mL of 1N sodium hydroxide was added. The reaction mixture was stirred overnight at room temperature. Water (30 mL) was added, and the precipitate was filtered and washed with water to give a white solid. The solid and trimethylsilylacetylene (0.62 mL, 4.4 mmol) were dissolved in THF, and 2.1 mL of 13% sodium hypochlorite solution was added to the solution. The mixture was stirred for 16 hours. It was diluted with EtOAc and washed with saturated Na₂S₂O₃. The organic layer was dried and concentrated, and purified by rapid column chromatography (eluent: EtOAc / hexane).

[0758] ES / MS: 338.9 (M+H + ).

[0759] (1r,4r)-4-(isoxazo-3-yl)cyclohexane-1-amine hydrochloride (I-45):

[0760] A solution of ((1r,4r)-4-(5-(trimethylsilyl)isoxazol-3-yl)cyclohexyl)tert-butyl carbamate (0.45 g, 1 mmol) in 4 mL EtOH and 1.5 mL 28% NH4OH was stirred for 16 hours. The solvent was removed and purified by rapid column chromatography (eluent: EtOAc / hexane). The product was collected and dissolved in 5 mL of 4M HCl dioxane solution. The mixture was stirred for 3 hours. The solvent was removed and the product was dried under vacuum. It was used without further purification.

[0761] Preparation of intermediate I-46

[0762]

[0763] 6-Chloro-4-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester:

[0764] A solution of 4,6-dichloropyridine-3-carboxylic acid ethyl ester (0.45 g, 2 mmol), ((1r,3r)-3-aminocyclobutyl)methanol (0.56 g, 4 mmol), and N-ethyldiisopropylamine (1.4 mL, 8 mmol) in 5 mL MeCN was heated at 80°C for 16 hours. The solvent was removed, and the solution was then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA).

[0765] ES / MS: 285.3 (M+H + ).

[0766] 6-Chloro-4-(((1r,3r)-3-((toluenesulfonyloxy)methyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester:

[0767] To a solution of ethyl 6-chloro-4-(((1r,3r)-3-(hydroxymethyl)cyclobutyl)amino)pyridine-3-carboxylate (0.58 g, 2 mmol) and N-ethyldiisopropylamine (0.89 mL, 5 mmol) in DCM (5 mL), p-toluenesulfonic anhydride (1.33 g, 4 mmol) was added. The mixture was stirred overnight, then diluted with EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated. The solvent was removed, and the mixture was then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and neutralized with saturated sodium bicarbonate solution to obtain the product.

[0768] ES / MS: 439.5 (M+H +).

[0769] 4-(((1r,3r)-3-((1H-1,2,4-triazol-1-yl)methyl)cyclobutyl)amino)-6-chloropyridine-3-carboxylic acid ethyl ester (I-46):

[0770] 1,2,4-triazole (28 mg, 0.4 mmol) and 60% sodium hydride (14.6 mg, 0.36 mmol) were suspended in 1 mL NMP. After 10 minutes, 6-chloro-4-(((1r,3r)-3-((toluenesulfonyloxy)methyl)cyclobutyl)amino)pyridine-3-carboxylic acid ethyl ester (100 mg, 0.23 mmol) was added to the suspension. The mixture was stirred for 16 hours, then diluted with EtOAc and washed with brine. The organic layer was dried and concentrated. The mixture was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA).

[0771] ES / MS: 336.2 (M+H + ).

[0772] Preparation of intermediate I-47

[0773]

[0774] 4-((4-aminobicyclo[2.2.2]octane-1-yl)amino)-6-chloropyridine-3-carboxylic acid ethyl ester hydrochloride:

[0775] Ethyl 4,6-dichloropyridine-3-carboxylate (1 g, 5 mmol), tert-butyl (4-aminobicyclo[2.2.2]octane-1-yl)carbamate (2.18 g, 9 mmol), and N-ethyldiisopropylamine (1.58 mL, 9 mmol) were mixed in 3 mL of NMP. The mixture was heated at 90°C for 16 hours. The solvent was removed, and the mixture was purified by rapid column chromatography (eluent: EtOAc / hexane). The product was collected and dissolved in 20 mL of 4 M HCl dioxane solution. The mixture was stirred for 2 hours. The solvent was removed, and the mixture was used without further purification.

[0776] ES / MS: 324.3 (M+H + ).

[0777] 6-Chloro-4-((4-morpholinobicyclo[2.2.2]octane-1-yl)amino)pyridine-3-carboxylic acid ethyl ester (I-47):

[0778] Add 2-bromoethyl ether (215 mg, 0.93 mmol) to a solution of 4-((4-aminobicyclo[2.2.2]octane-1-yl)amino)-6-chloropyridin-3-carboxylic acid ethyl ester hydrochloride (150 mg, 0.45 mmol) and N-ethyldiisopropylamine (0.32 mL, 1.85 mmol) in ACN. In a sealed tube, heat at 110 °C. o Heating at C for 16 hours. Solvent removed, then purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA).

[0779] ES / MS: 394.7 (M+H + ).

[0780] 3. Examples of Operation and Compound Examples

[0781] Operation 1: Example 1:

[0782] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide

[0783]

[0784] 6-Chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylic acid ethyl ester: A mixture of 4,6-dichloropyridine-3-carboxylic acid ethyl ester (150 mg, 0.68 mmol), 3-methyloxetane-3-amine hydrochloride (101 mg, 0.818 mmol), and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol) in dimethylacetamide (4 mL) was heated at 100 °C for 16 hours. The reaction was cooled to room temperature. Water and EtOAc were added. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate. The mixture was filtered and the solvent was evaporated to give the crude product, which was purified by silica gel chromatography (eluent: EtOAc / hexane).

[0785] ES / MS: 271.4 (M+H + ).

[0786] 6-Chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylic acid: Ethyl 6-chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylic acid (113 mg, 0.42 mmol) was dissolved in 2 mL of ethanol. Water (1 mL) was added, followed by lithium hydroxide (30 mg, 1.25 mmol), and the mixture was stirred at room temperature. Once complete, the ethanol was removed under reduced pressure and 2N HCl was added. The product was extracted into ethyl acetate. Once the solvent was removed under reduced pressure, the crude product was obtained and used without further purification.

[0787] ES / MS: 243.1 (M+H + ).

[0788] (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide: A mixture of 6-chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylic acid (40 mg, 0.17 mmol), (R)-4-amino-3-fluoro-2-methylbut-2-ol hydrochloride (31 mg, 0.20 mmol), 1-[di(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (75.21 mg, 0.20 mmol), and N,N-diisopropylethylamine (0.09 ml, 0.49 mmol) in 0.6 mL DMF was stirred at room temperature for 1 hour. Water was added, and the product was extracted into ethyl acetate. The ethyl acetate solution was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: EtOAc / hexane).

[0789] ES / MS: 346.2 (M+H + ).

[0790] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide (Example 1):

[0791] A mixture of (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide (15 mg, 0.043 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrrolo[1,2-b]pyridazine-3-onitrile (I-1) (18 mg, 0.067 mmol), XPhos Pd G3 (4 mg), and 2M tripotassium phosphate (0.07 ml) in 1 mL DME was degassed with argon for 3 min, then capped and heated in a microwave oven at 120°C for 20 min. The crude material was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA was added to obtain the product, which is trifluoroacetate.

[0792] ES / MS: 453.2 (M+H + ). 1H NMR (400 MHz, acetonitrile-d3) δ 9.76 (s, 1H), 8.64(s, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.58 (d, J = 2.2 Hz, 1H), 8.00 (d, J = 5.1Hz, 1H), 7.77 (s, 1H), 7.42 (s, 1H), 7.16 (d, J = 5.1 Hz, 1H), 4.86 (d, J =6.5 Hz, 2H), 4.72 (d, J = 6.5 Hz, 2H), 1.83 (s, 3H), 1.27 (d, J = 2.0 Hz, 6H).

[0793] Alternatively, borate oxidation and Suzuki cross-coupling can be performed in series:

[0794]

[0795] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide (Example 1):

[0796] A mixture of 7-bromopyrrolo[1,2-b]pyridazine-3-onitrile (I-1F) (32 mg, 0.144 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (59 mg, 0.23 mmol), potassium acetate (43 mg, 0.44 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (5 mg, 0.01 mmol), dioxane (0.32 ml), and DMF (0.16 ml) was degassed with argon for 3 minutes. The vial was capped, and the mixture was heated in a microwave at 120°C for 20 minutes. The bottle was opened, and (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((3-methyloxetane-3-yl)amino)nicotinamide (28 mg, 0.14 mmol), XPhos Pd G3 (11 mg, 0.013 mmol), 2M tripotassium phosphate (0.13 ml), and 0.8 mL DME were added. The mixture was degassed with argon for 3 minutes, then capped and heated in a microwave oven at 120°C for 20 minutes. The crude material was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA was added to obtain the product, which is trifluoroacetate.

[0797] Operation 2: Example 2:

[0798] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3R)-3-hydroxycyclohexyl)amino)nicotinamide

[0799]

[0800] (R)-4,6-Dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide: 4,6-Dichloropyridine-3-carboxylic acid (3.0 g, 16 mmol) and (R)-4-amino-3-fluoro-2-methylbut-2-ol HCl salt (2.7 g, 17 mmol) were suspended in DMF (60 mL) at room temperature. HATU (7.13 g, 18.8 mmol) was added as a single fraction to the resulting suspension, followed by DIPEA (2.7 mL, 16 mmol) as a single fraction, and the reaction mixture was stirred at room temperature for 1 hr. The solvent was removed, and the resulting residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted twice more with EtOAc. The organic layers were then combined, dried over magnesium sulfate, filtered, and concentrated. The resulting crude residue was then purified by silica gel chromatography (eluent: EtOAc / hexane) to give the desired product.

[0801] ES / MS: 295.2 (M+H + ).

[0802] 6-Chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3R)-3-hydroxycyclohexyl)amino)nicotinamide: (R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (0.53 g, 1.8 mmol) and (1R,3S)-3-aminocyclohexane-1-ol were added to a microwave-safe bottle, followed by the addition of DMA (5 mL) and DIPEA (0.80 mL, 4.5 mmol). The resulting solution was heated to 160 °C in a microwave reactor. o The mixture was kept at C for 40 min. The reaction mixture was then poured into water and extracted three times with EtOAc. The organic layers were then combined, dried, filtered, and concentrated. The resulting crude residue was then purified by silica gel chromatography (eluent: EtOAc / hexane / MeOH) to obtain the desired product. Note: In some cases, heating to 160°C in a microwave reactor was performed. o It is necessary to keep it warm for 3 hours.

[0803] ES / MS: 374.3 (M+H + ).

[0804] 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3R)-3-hydroxycyclohexyl)amino)nicotinamide (Example 2): 6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-(((1S,3R)-3-hydroxycyclohexyl)amino)nicotinamide (0.018 g, 0.048 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrrolo[1,2-b]pyridazin-3-onitrile (0.023 g, 0.087 mmol) were added to a microwave-safe bottle, followed by the addition of DME (0.8 mL) and XPhos Pd G3 (4.1 mg, 0.005 mL). 0.5 M aqueous solution (0.19 mL, 0.096 mmol) and K3PO4 (0.5 M aqueous solution, 0.19 mL, 0.096 mmol). The resulting mixture was purged with argon for 2 minutes, sealed, and heated to 120 °C in a microwave reactor. o Maintain at C for 10 min. Filter the reaction mixture and purify by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and freeze-dried to obtain the final product, which was a TFA salt.

[0805] ES / MS: 481.4 (M+H + ).

[0806] 1H NMR (400 MHz, methanol-d4) δ 8.76 (d, J = 2.2 Hz, 1H), 8.67 (d, J =2.2 Hz, 1H), 8.54 (s, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.21 (d, J= 5.1 Hz, 1H), 4.61-4.28 (m, 1H), 4.14-3.75 (m, 3H), 3.48 (td, J = 15.6,15.2, 9.4 Hz, 1H), 2.32 (d, J = 12.5 Hz, 1H), 2.00 (d, J = 37.3 Hz, 3H),1.70-1.34 (m, 4H), 1.29 (d, J = 1.6 Hz, 6H).

[0807] Alternatively, the final steps can be performed in series: borate 7-bromopyrrolo[1,2-b]pyridazine-3-onitrile (I-1F) as described in Operation 1 above, followed by a terminating Suzuki coupling.

[0808] Operation 3: Example 3:

[0809] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((1r,4r)-4-(2-hydroxypropyl-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide

[0810]

[0811] 6-Chloro-4-(isopropylamino)pyridine-3-carboxylic acid methyl ester: Isopropylamine (4.17 mL, 48.5 mmol) was added to 4,6-dichloropyridine-3-carboxylic acid methyl ester (2.0 g, 9.7 mmol) in MeCN (40.0 mL) and water (1.12 mL). The reaction mixture was heated to 50 °C and held for 18 hours, then cooled and concentrated under vacuum. The residue was absorbed in EtOAc and washed with brine. The organic layer was separated, dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (eluent: EtOAc / hexane) to provide the desired product.

[0812] ES / MS: 229.3 [M+H + ].

[0813] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridine-3-carboxylic acid methyl ester: 6-chloro-4-(isopropylamino)pyridine-3-carboxylic acid methyl ester (300.0 mg, 1.3 mmol), I-1 (459.0 mmol, 1.7 mmol), XPhos Pd G3 (111.0 mg, 0.13 mmol), and K3PO4 (557.0 mg, 2.6 mmol) were added to a microwave-safe bottle and placed under argon atmosphere. DME (6.0 mL) and water (5.2 mL) were added to the bottle, and the suspension was degassed with bubbling argon for 60 seconds. The bottle was sealed and heated in a microwave reactor at 120°C for 10 minutes. After cooling, the reaction mixture was concentrated under vacuum, and the resulting residue was absorbed in EtOAc and filtered through a celite pad. The solution was washed with brine, dried over sodium sulfate, filtered, concentrated under vacuum, and purified by silica gel chromatography (eluent: EtOAc / hexane) to provide the desired product.

[0814] ES / MS: 336.2 [M+H + ].

[0815] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridine-3-carboxylic acid: methyl 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridine-3-carboxylic acid (100.0 mg, 0.30 mmol) and lithium iodide (399.1 mg, 3.0 mmol) were added to a microwave-safe flask, followed by the addition of pyridine (3.0 mL). The flask was sealed and heated in a microwave reactor to 150 °C for 60 minutes. After cooling, the reaction mixture was concentrated under vacuum. The residue was absorbed in water and acidified to pH ~4 by slow addition of 2N HCl. The resulting solid was separated by filtration and washed with water and a minimum amount of EtOAc. The solid was dried under vacuum to provide the desired compound, which was used without further purification.

[0816] ES / MS: 322.2 [M+H + ].

[0817] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((1r,4r)-4-(2-hydroxypropyl-2-yl)cyclohexyl)-4-(isopropylamino)nicotinamide (Example 3): 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)pyridine-3-carboxylic acid (15.0 mg, 0.047 mmol), trans-2-(4-amino-cyclohexyl)-prop-2-ol (7.7 mg, 0.049 mmol), and HATU (18.6 mg, 0.049 mmol) were added to a round-bottom flask. The solids were dissolved in DMF (1.0 mL), and then DIPEA (17.5 µL, 0.098 mmol) was added. The reaction mixture was stirred at room temperature for 60 minutes. The reaction was filtered and purified directly by reversed-phase high-performance liquid chromatography (eluent: water / MeCN). 0.1% TFA) to provide the final compound.

[0818] ES / MS: 461.4 [M+H + ].

[0819] 1H NMR (400 MHz, chloroform- d) δ 9.99 (d, J = 7.5 Hz, 1H), 9.03 (s, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 5.0 Hz, 1H), 3.93 (h, J= 6.4 Hz, 1H), 3.89-3.77 (m, 1H), 2.08 (d, J = 12.2 Hz, 2H), 1.93 (d, J =12.5 Hz, 2H), 1.43 (d, J = 6.4 Hz, 6H), 1.40-1.21 (m, 3H), 1.19 (s, 6H).

[0820] Operation 4: Example 4:

[0821] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(pyridin-3-ylamino)nicotinamide

[0822]

[0823] 6-Chloro-4-(pyridin-3-ylamino)pyridine-3-carboxylic acid: Dissolve 3-aminopyridine (0.41 g, 4.4 mmol) in THF (7 mL) and adjust to -78°C. o C. Add LiHMDS (1.0 M THF solution, 6.3 mL, 6.3 mmol) dropwise and incubate the resulting solution at -78°C. o Stir at C for 30 minutes. Then add dropwise 4,6-dichloropyridine-3-carboxylic acid (0.40 g, 2.1 mmol) suspended in THF (3 mL) and incubate the resulting mixture at -78°C. o Stir for 5 minutes, then remove the cold bath and warm the reaction mixture to room temperature and stir for 16 hours. The reaction is then quenched with a 1.0M HCl aqueous solution and the organic solvent is removed by rotary evaporation. The resulting aqueous residue is diluted with water and the pH is adjusted to 4-5 using a 1.0M HCl aqueous solution and a 1.0M NaOH aqueous solution. At this point, the solid is filtered, washed with MeOH, and dried to obtain the desired product.

[0824] ES / MS: 250.0 [M+H + ].

[0825] (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(pyridin-3-ylamino)nicotinamide: 6-chloro-4-(pyridin-3-ylamino)pyridine-3-carboxylic acid (0.050 g, 0.20 mmol) and (R)-4-amino-3-fluoro-2-methylbut-2-ol HCl salt (0.063 g, 0.40 mmol) were suspended in DMF (2 mL) at room temperature. HATU (0.16 g, 0.42 mmol) was added as a single fraction to the resulting suspension, followed by DIPEA (0.09 mL, 0.50 mmol) as a single fraction, and the reaction mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted twice more with EtOAc. The organic layers were then combined, dried, filtered, and concentrated. The resulting crude residue was then purified by silica gel chromatography (eluent: EtOAc / hexane / MeOH) to obtain the desired product.

[0826] ES / MS: 353.1 [M+H + ].

[0827] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(pyridin-3-ylamino)nicotinamide (Example 4): (R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(pyridin-3-ylamino)nicotinamide (25 mg, 0.071 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[1,2-b]pyridazin-3-onitrile (34 mg, 0.13 mmol) were added to a microwave-safe bottle, followed by the addition of DME (0.8 mL), XPhos Pd G3 (6.0 mg, 0.007 mmol) and K3PO4 (0.5 M aqueous solution, 0.28 mL, 0.14 mmol). The resulting mixture was purged with argon for 2 minutes, sealed, and heated to 120°C in a microwave reactor. o Maintain at C for 10 min. Filter the reaction mixture and purify by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and freeze-dried to obtain the final product.

[0828] ES / MS: 460.2 [M+H + ].

[0829] 1H NMR (400 MHz, methanol-d4) δ 8.77 (d, J = 2.3 Hz, 1H), 8.77 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.62 (dd, J = 4.9, 1.4 Hz, 1H), 8.57 (d, J = 2.2Hz, 1H), 8.22 (s, 1H), 8.08 (ddd, J = 8.2, 2.6, 1.4 Hz, 1H), 7.84 (d, J = 5.1Hz, 1H), 7.73 (ddd, J = 8.2, 4.9, 0.8 Hz, 1H), 7.16 (d, J = 5.0 Hz, 1H), 4.47(ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.99 (ddd, J = 36.4, 14.5, 2.1 Hz, 1H), 3.62-3.45 (m, 1H), 1.30 (d, J = 1.6 Hz, 6H).

[0830] Operation 5: Example 5:

[0831] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(6-(2-hydroxypropyl-2-yl)spiro[3.3]hept-2-yl)-4-(isopropylamino)nicotinamide

[0832]

[0833] 6-Chloro-N-(6-(2-hydroxypropyl-2-yl)spiro[3.3]hept-2-yl)-4-(isopropylamino)nicotinamide: 50 mg, 0.14 mmol of methyl 6-(6-chloro-4-(isopropylamino)pyridin-3-carboxymethyl)spiro[3.3]heptane-2-carboxylic acid (as outlined in steps 1 and 2 of operation 2) was dissolved in THF (2 mL) and adjusted to 0.05 mmol using an ice / water bath. o C. Then, MeMgI (3.0 M ether solution, 0.14 mL, 0.41 mmol) was added dropwise and the resulting mixture was kept at 0°C. o Stir at C for 15 minutes. Then at 0... oC. Add more MeMgI (3.0 M ether solution, 0.27 mL, 0.42 mmol) dropwise, and stir the resulting mixture for 30 minutes, during which time quench it dropwise with water. Extract the mixture with EtOAc, wash the combined organic layers with brine, dry over magnesium sulfate, filter, concentrate, and purify by silica gel chromatography (eluent: EtOAc / hexane) to obtain the desired product.

[0834] ES / MS: 366.3 [M+H + ].

[0835] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(6-(2-hydroxypropyl-2-yl)spiro[3.3]hept-2-yl)-4-(isopropylamino)nicotinamide (Example 5): 6-chloro-N-(6-(2-hydroxypropyl-2-yl)spiro[3.3]hept-2-yl)-4-(isopropylamino)nicotinamide (0.024 g, 0.066 mmol) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[1,2-b]pyridazin-3-onitrile (0.032 mg, 0.12 mmol) were added to a microwave-safe bottle, followed by the addition of DME (0.8 mL), XPhos Pd G3 (5.6 mg, 0.007 mmol), and Na3PO4 (0.5 M aqueous solution). 0.26 mL, 0.13 mmol). The resulting mixture was purged with argon for 2 minutes, sealed, and heated to 120 °C in a microwave reactor. o Maintain at C for 10 min. Filter the reaction mixture and purify by RP-HPLC (eluent: water / MeCN). 0.1% TFA). The product fractions were combined and freeze-dried to obtain the final product.

[0836] ES / MS: 473.3 [M+H + ].

[0837] 1H NMR (400 MHz, methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.65 (d, J =2.2 Hz, 1H), 8.53 (s, 1H), 7.97 (d, J = 5.0 Hz, 1H), 7.81 (s, 1H), 7.20 (d, J= 5.1 Hz, 1H), 4.44-4.28 (m, 1H), 4.13 (hept, J = 6.5 Hz, 1H), 2.62-2.48 (m,1H), 2.37-2.20 (m, 2H), 2.18-1.93 (m, 5H), 1.90-1.78 (m, 1H), 1.39 (d, J =6.4 Hz, 6H), 1.08 (s, 3H), 1.07 (s, 3H).

[0838] Operation 6: Example 6:

[0839] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide

[0840]

[0841] 6-Bromo-4-(isopropylamino)pyridine-3-carboxylic acid: An aqueous solution of lithium hydroxide (2.5 M, 3.7 mL, 9.25 mmol) was added to a solution of methyl 6-bromo-4-(isopropylamino)pyridine-3-carboxylic acid (1.25 g, 4.58 mmol) in methanol (16 mL). The solution was heated to 45°C and held for 2.5 hours, then cooled to room temperature. An aqueous solution of hydrochloric acid (1 M, 9.1 mL) was added, and volatiles were removed under vacuum. The resulting slurry was filtered and washed with H₂O to provide 6-bromo-4-(isopropylamino)pyridine-3-carboxylic acid.

[0842] ES / MS: 259.419 (M+H + ).

[0843] 6-Bromo-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide: HATU (95 mg, 0.25 mmol), tetrahydropyran-4-amine hydrochloride (32 mg, 0.23 mmol), and DIPEA (0.10 mL, 0.57 mmol) were added to a solution of 6-bromo-4-(isopropylamino)pyridine-3-carboxylic acid (50 mg, 0.19 mmol) in CH2Cl2 (2 mL). The resulting solution was stirred at room temperature for 1 hour and diluted with CH2Cl2. The organic solution was washed with saturated ammonium chloride aqueous solution (twice), dried over sodium sulfate, and concentrated to provide 6-bromo-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide.

[0844] ES / MS: 344.139 (M+H + ).

[0845] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrrolo[1,2-b]pyridazin-3-onitrile (73 mg, 0.27 mmol), XPhos Pd G3 (15 mg, 0.018 mmol), and tripotassium phosphate (2M, 0.25 mL, 0.50 mmol) were added to a solution of 6-bromo-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide (66 mg, 0.19 mmol) in DME (2.5 mL). The resulting solution was degassed with argon and heated to 150°C for 30 minutes. Add SiliaMetS® Thiol (50 mg) to the reaction mixture and filter the resulting slurry, washing with DMF. Purify the crude solution by preparative RP-HPLC (eluent: water / MeCN). 0.1% TFA) to provide 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)nicotinamide, which is a TFA salt.

[0846] ES / MS: 405.379 (M+H + ).

[0847] 1H NMR (400 MHz, methanol-d4) δ 8.74 (d, J = 2.2 Hz, 1H), 8.65 (d, J =2.2 Hz, 1H), 8.55 (s, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.84 (s, 1H), 7.20 (d, J= 5.1 Hz, 1H), 4.12 (ddt, J = 15.2, 11.0, 5.3 Hz, 2H), 4.05-3.94 (m, 2H), 3.53 (td, J = 11.8, 2.1 Hz, 2H), 1.99-1.88 (m, 2H), 1.67 (qd, J = 11.9, 4.4Hz, 2H), 1.39 (d, J = 6.4 Hz, 6H).

[0848] Operation 7: Example 7:

[0849] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(oxecyclobutane-3-yl)nicotinamide

[0850]

[0851] 6-(3-Cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(oxetane-3-yl)nicotinamide. Starting with bromo-4-(isopropylamino)pyridine-3-carboxylic acid (I-4) (30 mg, 0.12 mmol), 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(isopropylamino)-N-(oxetane-3-yl)nicotinamide was prepared following the procedure described in Example 6, using oxetane-3-amine (14 mg, 0.19 mmol) instead of tetrahydropyran-4-amine hydrochloride. The resulting TFA salt was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The resulting substance was purified by silica gel chromatography (eluent: EtOAc / hexane / MeOH) to provide the product as a free base.

[0852] ES / MS: 377.235 (M+H + ).

[0853] 1H NMR (400 MHz, methanol-d4) δ 8.63 (s, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.13 (s, 1H), 7.80 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 4.9 Hz, 1H), 5.09 (dt, J = 7.7, 6.7 Hz, 1H), 4.93 (t, J = 7.0 Hz, 2H), 4.72 (t, J = 6.6 Hz, 2H), 3.87 (p, J = 6.3 Hz, 1H), 1.33 (d, J = 6.3 Hz, 6H).

[0854] Operation 8: Example 8:

[0855] 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((5-oxopyrrolidine-3-yl)amino)nicotinamide

[0856]

[0857] 6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((5-oxopyrrolidin-3-yl)amino)nicotinamide (Example 8): 6-chloro-N-((R)-2-fluoro-3-hydroxy-3-methylbutyl)-4-((5-oxopyrrolidin-3-yl)amino)nicotinamide (obtained as described in Operation 2, replacing (1R,3S)-3-aminocyclohexane-1-ol with 4-aminopyrrolidin-2-one) (30 mg, 0.084 mmol), (3-cyanopyrrolo[1,2-b]pyridazin-7-yl)boronic acid (19 mg, 0.1 mmol), and Pd-PEPPSI™-IPent catalyst (6.6 mg, 0.008 mmol) were added to a microwave tube. Add dimethoxyethane (1 mL) and tripotassium phosphate aqueous solution (1 M, 0.25 mL). Heat the reaction mixture in a microwave reactor to 120 °C and maintain for 20 min, then cool to room temperature. Purify by RP-HPLC (eluent: water / MeCN). 0.1% TFA) yielded the title compound, which is a TFA salt.

[0858] ES / MS: 466.28 [M+H] + .

[0859] 1 H NMR (400 MHz, methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.69 (d, J =2.1 Hz, 1H), 8.64 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.87 (s, 1H), 7.22 (d, J= 5.1 Hz, 1H), 4.84-4.68 (m, 1H), 4.42 (ddd, J = 49.0, 9.4, 2.1 Hz, 1H), 4.07-3.72 (m, 2H), 3.61-3.40 (m, 2H), 2.99 (dd, J = 17.1, 8.0 Hz, 1H), 2.48(dd, J = 17.1, 4.7 Hz, 1H), 1.28 (d, J = 1.7 Hz, 6H).

[0860] Operation 9: Example 9:

[0861] 7-(5-(((1,1-tetrahydrothiophene-3-yl)methyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

[0862]

[0863] 7-(5-(((1,1-tetrahydrothiophene-3-yl)methyl)carbamoyl)-4-(isopropylamino)pyridin-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 9): Eight drops of 30% hydrogen peroxide solution were added to a mixture of 6-(3-cyanopyrrolo[1,2-b]pyridazine-7-yl)-N-((1,1-tetrahydrothiophene-3-yl)methyl)-4-(isopropylamino)nicotinamide (obtained according to the method described in Operation 1) (5 mg, 0.011 mmol) and potassium carbonate (15 mg, 0.11 mmol) in DMSO (0.5 mL). After stirring at ambient temperature for 10 min, the mixture was purified by RP-HPLC (eluent: water / MeCN). 0.1% TFA) yielded the title compound, which is a TFA salt.

[0864] ES / MS: 471.21 [M+H] + .

[0865] 1H NMR (400 MHz, methanol-d4) δ 8.91 (d, J = 2.2 Hz, 1H), 8.68 (d, J =2.3 Hz, 1H), 8.55 (s, 1H), 7.97 (d, J = 5.0 Hz, 1H), 7.80 (s, 1H), 7.11 (d, J= 5.0 Hz, 1H), 4.15 (p, J = 6.4 Hz, 1H), 3.54 (qd, J = 13.7, 6.4 Hz, 2H), 3.26-3.02 (m, 2H), 2.97-2.73 (m, 2H), 2.50-2.29 (m, 1H), 2.08-1.81 (m, 1H),1.40 (d, J = 6.4 Hz, 6H).

[0866] Operation 10: Example 10:

[0867] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methanesulfonylamino)nicotinamide

[0868]

[0869] (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methanesulfonylamino)nicotinamide (Example 10): (R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methanesulfonylamino)nicotinamide (Example 10) was prepared as shown in Operation 1, with 6-chloro-4-(methanesulfonylamino)pyridine-3-carboxylic acid (I-6) instead of 6-chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylic acid.

[0870] Example 10: ES / MS: 461.1 [M+H] + .

[0871] 1H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.55 (d, J = 11.5 Hz, 2H), 8.34 (s, 1H), 7.78 (s, 1H), 7.11 (d, J = 5.0 Hz, 1H), 4.52-4.25 (m, 1H), 4.01(dd, J = 35.5, 14.9 Hz, 1H), 3.50 (td, J = 14.8, 9.4 Hz, 1H), 2.01 (s, 1H), 1.27 (s, 7H).

[0872] Operation 11: Example 11:

[0873] (R)-4-amino-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

[0874]

[0875] (R)-4-amino-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (Example 11): (R)-4-amino-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (Example 11) was prepared as shown in Operation 1, with 4-amino-6-chloropyridine-3-carboxylate ester instead of 6-chloro-4-((3-methyloxetane-3-yl)amino)pyridine-3-carboxylate ethyl ester.

[0876] Example 11: ES / MS: 383.2 [M+H] + .

[0877] 1H NMR (400 MHz, methanol-d4) δ 8.73 (d...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. in: R 1 Selected from: a) C 1-10 Alkyl groups, optionally substituted with Z 1 ; b) C 3-10 Cycloalkyl groups, optionally substituted with Z 1 ; c) 5-10 heteroaryl groups, with optional substitutions including Z 1 ; d)C 6-10 Aryl groups, with optional substitutions including Z 1 ; e) 4-7 membered monocyclic heterocyclic groups, with optional substitutions including Z 1 ; f) 6-12 membered bicyclic heterocyclic groups, with optional substitutions including Z 1 ;or g)-H; R 2 Selected from: a) C 1-10 Alkyl groups, optionally substituted with Z 1 ; b) C 3-10 Cycloalkyl groups, optionally substituted with Z 1 ; c) 5-10 heteroaryl groups, with optional substitutions including Z 1 ; e) 4-7 membered monocyclic heterocyclic groups, with optional substitutions including Z 1 ; g)-H; R 3 Selected from: a) H, halogens, -CN; b) C 1-9 alkyl; R 4 Selected from: a) H, halogens, -CN, -C(O)-N(R) 12 (R) 12 ); b)C 1-9 alkyl; e) 5-10 heteroaryl groups, with optional substitutions including Z 1 ; R 5 R 6 and R 7 Each is selected independently from: a) H, halogens, -CN; b) C 1-5 alkyl; Z 1 Independently oxidized, halogenated, -CN, C 1-9 Alkyl, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -OC(O)R 12 -OC(O)OR 12 -OC(O)-N(R) 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); Any alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a ; Each Z 1a Independently oxidized, halogenated, -CN, C 1-9 Alkyl, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ), or -S(O)2N(R 12 (R) 12 ); Any alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1b ; Each R 12 Independently for H and C 1-9 Alkyl, C 2-6 alkenyl, C 3-15 Cycloalkyl, heteroaryl, or heterocyclic groups; Any alkyl, alkenyl, cycloalkyl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a ; Each Z 1b Independently oxidized, hydroxylated, halogenated, -CN, C 1-9 Alkyl, -O(C) 1-9 alkyl); in, C in the above group definition 6-10 Aryl or aryl refers to phenyl; Among them, in Z 1 Z 1a R 12 In the definition: heteroaryl refers to an aromatic group having a monocyclic ring containing 3 to 8 carbon ring atoms and 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur; and heterocyclic refers to a saturated or unsaturated cycloalkyl group having 1 to 5 cyclic heteroatoms independently selected from nitrogen, oxygen and sulfur, having 4 to 10 cyclic atoms. The condition is: when R 1 It is a C3 alkyl group, R 2 To replace C5 alkyl groups containing both F and hydroxyl groups, R 3 R 5 R 6 R 7 For H and R 4 When it is CN, R 1 Replaced by Z 1 .

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 1 C 1-10 Alkyl groups, optionally substituted with Z 1 The condition is: when R 1 It is a C3 alkyl group, R 2 To replace C5 alkyl groups containing both F and hydroxyl groups, R 3 R 5 R 6 R 7 For H and R 4 When it is CN, R 1 Replaced by Z 1 .

3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 1 It is a methyl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 1 C 6-10 Alkyl groups, optionally substituted with Z 1 .

5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 1 C 1-5 Alkyl group, wherein one or more substituents are selected from the following: -Cl, oxo, -CN, cyclopropyl, heteroaryl, monocyclic heterocyclic group containing nitrogen or sulfur, bicyclic heterocyclic group, C 7-15 cycloalkyl, -OR 9 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 ); R 9 It is C independently each time it appears. 1-9 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, heterocyclic, or heteroaryl groups; Each C 1-9 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 3-15 Cycloalkyl, heterocyclic, or heteroaryl groups may be optionally substituted with Z. 1a .

6. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 1 C 1-5 Alkyl groups, optionally substituted with Z 1 ; Wherein C 1-5 Alkyl substitution has one or more Cs 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl; Wherein C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl optional substitution with Z 1a ; Wherein C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl groups are substituted with one or more of the following groups: halogen, oxo, -CN, C. 2-6 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 9 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ) or -S(O)2N(R 12 (R) 12 ); and the C therein 2-6 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

7. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 1 C 1-5 Alkyl group, optionally substituted with F or -OH and substituted with one or more substituents selected from the following: C 4-6 Cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl; wherein the C 4-6 The cycloalkyl, oxetyl, tetrahydrofuranyl, tetrahydropyranyl, or phenyl substituents have two or more substituents selected from the following: -OH and -CH3, and optionally have Z. 1a .

8. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 1 It is -H.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 2 C 1-10 Alkyl groups, optionally substituted with Z 1 .

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 2 C 1-10 alkyl.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 2 C 7-10 Alkyl groups, optionally substituted with Z 1 .

12. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-6 Alkyl groups, which are substituted with one or more -O(C) groups. 1-2 Alkyl), -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 alkyl); The -O(C) 1-2 Alkyl groups are substituted with one or more oxo groups, -Cl, -CN, or C. 2-9 Alkyl, C 3-15 cycloalkyl, C 2-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ) or -S(O)2N(R 12 (R) 12 ); and the -O(C 1-2 Alkyl groups may be optionally substituted with -F; The -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 Alkyl groups are substituted with one or more oxo, halogen, -CN, or C groups. 3-9 Alkyl, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)R 12 -C(O)OR 12 -C(O)N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )-C(O)R 12 -N(R) 12 )C(O)O(R 12 ), -N(R 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ) or -S(O)2N(R 12 (R) 12 ); Wherein C 1-6 Alkyl substitution can be Z 1a ;and Each of the C 2-9 Alkyl, C 3-9 Alkyl, C 3-15 cycloalkyl, C 1-8 Haloalkyl, C 2-8 The alkyl, aryl, heteroaryl, or heterocyclic groups may be substituted with Z. 1b .

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 4-6 Alkyl group, wherein one or more substituents are selected from the following: -Cl, C 3-15 Cycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bicyclic heterocyclic, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 -S(O)2(C) 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), or -S(O)2N(R) 12 (R) 12 ); Wherein C 3-15 Cycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bicyclic heterocyclic, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), -NHC(O)(C 1-3 Alkyl), or -S(O)2(C 1-3 Alkyl) optional substitution with Z 1a .

14. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 4-6 Alkyl groups, which are substituted with one or more -O(CH2)2R 17 Or -O(CH2)R 17 ; R 17 It is C independently each time it appears. 3-15 Cycloalkyl, aryl, heterocyclic, heteroaryl, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ) or -S(O)2N(R 12 (R) 12 ); Wherein C 3-15 Cycloalkyl, aryl, heterocyclic, and heteroaryl groups may be optionally substituted with Z. 1b ;and Wherein C 4-6 Alkyl groups may also be optionally substituted with Z 1 .

15. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 4-6 Alkyl group, wherein the substitutions are five or more substituents selected from the following: F, hydroxyl, -CN, -OCH3, -OCD3, -NHC(O)(C 1-3 Alkyl), -S(O)2(C 1-3 Alkyl), or C 1-2 fluoroalkoxy; and Wherein C 4-6 Alkyl substitution can be Z 1 .

16. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-3 Alkyl group, wherein one or more substituents are selected from the following: -Cl, cyclopropyl, bicyclic heterocyclic, C 7-15 Cycloalkyl, -O(CH2)2R 17 -O(CH2)R 17 -O(C 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -C(O)(C 1-9 Alkyl), -C(O) (cyclopropyl), -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 -S(O)2(C) 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 Cycloalkyl), -S(O)2 (heterocyclic), -S(O)2 (heteroaryl), or -S(O)2N(R) 9 (R) 12 ); The cyclopropyl, bicyclic heterocyclic, and C 7-15 cycloalkyl, -O(C) 3-9 alkyl), -O(C) 3-10 cycloalkyl), -O (heterocyclic), -O (aryl), -O (heteroaryl), -N (R) 12 )C(O)(C 4-9 alkyl), -N(R) 12 )C(O)(C 3-10 cycloalkyl), -N(R) 12 )C(O)(heterocyclic group), -N(R) 12 )C(O)(aryl), -N(R) 12 )C(O)(heteroaryl), -S(O)2(C 4-9 Alkyl), -S(O)2(aryl), -S(O)2(C 3-10 The cycloalkyl group, -S(O)2 (heterocyclic group), or -S(O)2 (heteroaryl group) can be optionally substituted with Z. 1a .

17. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-3 Alkyl group, wherein one or more of the substituents are selected from the following: azirmonobutyl, tetrahydrofuranyl, triazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyrimidinyl, pyrazinyl, isothiazolyl, tetraazolyl, furanyl, thiomorpholinyl, 4-7-membered sulfonamide, 4-7-membered cyclic carbamate, 4-7-membered cyclic carbonate, 4-7-membered cyclic sulfide, or 8-10-membered heteroaryl; any one of the optional substitutions has Z 1a ;and Wherein C 1-3 Alkyl groups may also be optionally substituted with Z 1 .

18. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-3 Alkyl group, wherein the substituted group has one of the following substituents selected from: phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C. 4-6 cycloalkyl; The phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C 4-6 Cycloalkyl substitution has one or more oxo, -CN, C 4-9 Alkyl, C 3-15 cycloalkyl, C 1-8 Halogenated alkyl, aryl, heteroaryl, heterocyclic, -O(C) 3-6 alkyl), -O(C) 3-6 cycloalkyl), -O (heterocyclic), -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 ) or -S(O)2N(R 9 (R) 12 );and Any alkyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1b .

19. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-3 Alkyl groups, optionally substituted with Z 1 And the substitution has one of the following substituents selected from: phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C. 4-6 cycloalkyl; The phenyl, oxetyl, tetrahydropyranyl, morpholinyl, piperidinyl, imidazolyl, pyridinyl, thiophene, or C 4-6 The cycloalkyl substitution has four or more substituents selected from the following: -F, -Cl, -OH, C 1-3 Alkyl, -O(C) 1-2 Alkyl group or -S(O)2NH2.

20. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 2 C 1-3 Alkyl group, which is oxy-substituted and optionally has one or more substituents selected from the following: halogen, azacyclic butyl, pyrrolidinyl, piperazine, tetrahydrofuranyl, thiomorpholinyl, -CN, C 1-9 Alkyl, cyclopropyl, C 7-15 cycloalkyl, C 1-8 Halogenated alkyl groups, -OR 12 -C(O)-R 12 -C(O)OR 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )C(O)N(R 12 (R) 12 ), -N(R 12 )S(O)2(R 12 -NR 12 S(O)2N(R 12 (R) 12 -OC(O)R 12 -OC(O)-N(R) 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 9 (R) 12 ); Wherein C 1-9 Alkyl, cyclopropyl, C 7-15 cycloalkyl, C 1-8 Halogenated alkyl, azacyclic butyl, pyrrolidinyl, piperazine, tetrahydrofuranyl, or thiomorpholinyl, optionally substituted with Z 1a .

21. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 2 It is a C3 alkyl group, and its substitutions include five or more substituents selected from the following: -F, -OH, -OCH3, -CN, -NHC(O)(C 1-3 Alkyl), C 1-2 Fluoroalkoxy, or -S(O)2(C 1-3 alkyl).

22. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 2 It is -H.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 3 Selected from H, halogens, and -CN.

24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 3 C 1-9 alkyl.

25. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 3 C 1-2 alkyl.

26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 3 It is a C3 alkyl group.

27. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 3 C 4-9 alkyl.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 H, halogen, -CN, or -C(O)-N(R) 12 (R) 12 ).

29. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 4 -C(O)-N(R) 12 (R) 12 ).

30. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 C 1-9 alkyl.

31. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 4 C 1-2 alkyl.

32. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 It is a C3 alkyl group.

33. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 C 4-9 alkyl.

34. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 .

35. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R 4 It is a 5-10 member heteroaryl group, with optional substitutions including Z. 1 ; When the 5-10 heteroaryl group is pyridyl, the pyridyl group is further substituted with one or more Z groups. 1 .

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 R 6 Or R 7 At least one of them is independently selected from H, halogen, -CN.

37. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 R 6 Or R 7 At least one of them is independently C 1-5 alkyl.

38. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 R 6 Or R 7 At least one of them is independently C 1-2 Alkyl group, -CN.

39. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 R 6 Or R 7 At least one of them is independently a C3 alkyl group.

40. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 R 6 Or R 7 At least one of them is independently C 4-5 alkyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 3 It can be H or F.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 4 It can be H, F, -CN, or Cl.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 5 It can be H or F.

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 6 It can be H or F.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R 7 It can be H or F.

46. ​​The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: Z 1 Selected from H, halogens, -CN, C 1-9 Alkyl, C 3-15 Cycloalkyl, aryl, heteroaryl, heterocyclic, -OR 12 -C(O)-R 12 -C(O)-N(R) 12 (R) 12 ), -N(R 12 (R) 12 ), -N(R 12 )C(O)-R 12 -N(R) 12 )C(O)OR 12 -N(R) 12 )S(O)2(R 12 ), -OC(O)-N(R) 12 (R) 12 -S(O)2R 12 Or -S(O)2N(R) 12 (R) 12 );and Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be optionally substituted with Z. 1a .

47. The compounds selected from Table 1 or their pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47, a pharmaceutically acceptable carrier, and optionally a diluent.

49. Use of any compound of claims 1-47 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof in the preparation of a medicament for treating inflammatory diseases.

50. The use of claim 49, wherein the inflammatory disease is selected from autoimmune diseases, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme arthritis, systemic lupus erythematosus (SLE), Sjögren's syndrome, and viral myocarditis.

51. Selected from the following intermediate compounds: , , ,and , Where X is chlorine, bromine, or iodine, and the other variables are as defined in claim 1.

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