PYRROLO[1,2-b]PYRIDAZINE DERIVATIVES

TWI797366BActive Publication Date: 2023-04-01GILEAD SCIENCES INC
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Authority / Receiving Office
TW · TW
Patent Type
Patents
Current Assignee / Owner
Filing Date
2019-08-13
Publication Date
2023-04-01
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Abstract

This invention discloses a compound of formula (I), its pharmaceutically acceptable salt, its deuterated analogue, its composition, and a method of using the compound to treat diseases.
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Description

[Technical Field] This invention relates to novel compounds as inhibitors of the kinase IRAK4. This invention also relates to methods for preparing such compounds and pharmaceutical compositions comprising such compounds. [Previous Technology] Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threonine kinase that acts as a mediator in the interleukin-1 / TLR signaling cascade. More specifically, IRAK4 is involved in the activation of the Mydoid Differentiation Factor Primary Response Gene 88 (MyD88) signaling cascade and is hypothesized to play a role in inflammatory and fibrotic conditions such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, inflammatory pelvic disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, viral myocarditis, acute and chronic tissue damage, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, and nephropathy (including chronic kidney disease and diabetic nephropathy). Furthermore, IRAK4 plays a role in certain cancers and is hypothesized to act in inflammation associated with gastrointestinal infections, including Clostridium difficile. IL-1R / TLR signaling induces MyD88 activation, which in turn replenishes IRAK4 and IRAK1 to form a signal transduction complex. This complex then interacts with a series of kinases, attachment proteins, and ligases, ultimately leading to the activation of nuclear factor κ light chain enhancer (NF-κB), activator protein-1 (AP1), cyclic AMP-reactive element-binding protein (CREB), and interferon-regulatory factors (IRFs) (including IRF5 and IRF7) in activated B cells, thereby inducing the production of pro-inflammatory cytokines and type I interferons. Therefore, IRAK4 inhibitors can be used to treat inflammatory and fibrotic conditions such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), gout, Lyme disease, arthritis, psoriasis, inflammatory pelvic diseases, systemic lupus erythematosus (SLE), Hughley's syndrome, inflammation associated with gastrointestinal infections (including Clostridium difficile), viral myocarditis, acute and chronic tissue damage, non-alcoholic steatosis (NASH), alcoholic hepatitis, and kidney diseases (including chronic kidney disease and diabetic nephropathy). (Joosten, LAB et al., TOLL-LIKE RECEPTORS AND CHRONIC INFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev. Rheumatol., 346 | 12 June 2016; 344-357, published online 12 May 2016) (Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5+CD11b+MONOCYTE MIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128 | 14 September 2013; 1542-1554), and Type I interferon lesions (Type I) Interferonopathy, such as Aicardi-Goutières syndrome, familial frostbite-like lupus, and retinal vascular disease with leukodystrophy in the brain (Lee-Kirsch et al., TYPE I INTERFERONOPATHIES-AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION, Semin. Immunopathol. (2015) 37:349-357), (Leaf, IA et al., PERICYTE MYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTIC RESPONSES TO TISSUE INJURY, The Journal of Clinical Investigation, 127|January 1, 2017; 321-334), (Seki, E.(Garcia Martrinez, et al., TLR4 ENHANCES TGF-β SIGNALING AND HEPATIC FIBROSIS, Nature Medicine, 13|November 11, 2007; 1324-1332), (Garcia Martrinez, et al., HEPATOCYTE MITOCHONDRIAL DNA DRIVES NONALCHOLICSTEATOHEPATITIS BY ACTIVATION OF TLR9, The Journal of Clinical Investigation, 126|March 3, 2016; 859-864). In addition, some cancers, including lymphoma, may contain one or more mutations in the MYD88 attaching protein, thereby generating constitutively active signaling cascades that can promote tumor cell survival. (Kelly et al., IRAK4 INHIBITORS for autoimmunity and lymphoma, J. Exp. Med. 2015, Vol. 212, No. 13, 2189-2201). Therefore, IRAK4 inhibitors can be used to treat cancers including lymphoma. Currently, there are no approved IRAK4 inhibitors. Therefore, it would be useful to provide IRAK4 inhibitory compounds with properties suitable for administration as pharmaceuticals to mammals (specifically, to humans). Considerations for selecting pharmaceutical compounds are multifaceted. Often analyzed are compound characteristics including target potency, pharmacokinetics, pKa, solubility, stability (e.g., metabolic stability), and deviations from the target. WO2016210034, WO2016210036, WO2015150995, WO2016127024 and WO2016210037 list compounds that are claimed to be suitable as IRAK4 inhibitors. [Summary of the Invention] This document provides compounds and pharmaceutical compositions suitable for use as inhibitors of IRAK4. Some compounds of this invention can be used in pharmaceutical compositions with at least one pharmaceutically acceptable excipient for the treatment of individuals in need. The compounds of this invention have also been found to inhibit the production of pro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23, and type I interferons IFNα and IFNβ, all of which are mediators of inflammatory and immune responses. This invention also provides compositions comprising these compounds, including pharmaceutical compositions, kits, and methods of using and preparing these compounds. In one embodiment of the present invention, a compound of formula (I) is provided: wherein Y is selected from: -H, -F, -Cl, -Br, -CN, -CF3, -CF2H, -OH and -OCH3; R1 is selected from C3-10 cycloalkyl groups substituted with X1 as appropriate and 4- to 12-membered heterocyclic groups substituted with X1 as appropriate; wherein each X1 is independently a side oxygen group, a halogroup, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, -O-R12, -C(O)-R12, -C(O)O-R12, -C(O)-N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)C(O)-R12, -N(R12)C(O)O-R12 or -N(R12)C(O)N(R12)(R12); "Het" is selected from 5- to 10-membered heteroaryl groups substituted with X2 as appropriate, or 4- to 12-membered heterocyclic groups substituted with X2 as appropriate; wherein each X2 is selected from oxy group, halogen group, N3, -CN, C1-9 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic groups, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)( R12) and -C(O)N(R12)(R12), wherein any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl, or heterocyclic group is substituted with Z1a as appropriate; R2 is selected from: a) C1-10 alkyl groups substituted with Z1 as appropriate; b) C3-10 cycloalkyl groups substituted with Z1 as appropriate; c) 5- to 10-membered heteroaryl groups substituted with Z1 as appropriate; d) C6-10 aryl groups substituted with Z1 as appropriate; and e) 4- to 12-membered heterocyclic groups substituted with Z1 as appropriate; wherein Z1 is independently a syloxy group, haloyl group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)-R12, -C(O)O-R12, -C(O)-N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)C(O)-R12, -N(R12)C(O)O-R12, -N(R12)C(O)N(R12)(R12), -N(R12)S(O)2(R12), -NR12S(O)2N(R12)(R12), -NR12S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12), -Si(R12)3、-S-R12、-S(O)R12, -S(O)(NH)R12, -S(O)2R12 or -S(O)2N(R12)(R12); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclic group is substituted with Z1a as appropriate; each Z1a is independently a side-oxygen group, halogroup, -NO2, -CN, -N3, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)R12, -C(O)O-R12, -C(O)N(R12)(R12), -N(R12)(R12) -N(R12)2(R12)+, -N(R12)-C(O)R12, -N(R12)C(O)O(R12), -N(R12)C(O)N(R12)(R12), -N(R12)S(O)2(R12), -N(R12)S(O)2-N(R12) (R12), -N(R12)S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12), -Si(R12)3, -S-R12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 or -S(O)2N(R12)( R12); Any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl, aryl, heteroaryl, or heterocyclic group may be substituted with Z1b, as appropriate; each R12 is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclic group; any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be substituted with Z1a, as appropriate; Each Z1b is independently a side oxygen group, hydroxyl group, halogen group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), -NH2, -NH (C1-9 alkyl), -NH (C2-6 alkenyl) -NH (C2-6 alkynyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -N (C2-6 alkenyl)2, -N (C2-6 alkynyl)2, -N (C3-15 cycloalkyl)2, -N (C1-8 haloalkyl)2, -N (aryl)2, -N (heteroaryl)2, -N (heterocyclic)2, -N (C1-9 alkyl)(C3-15 cycloalkyl)-N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 ynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(aryl), -N(C1-9 alkyl)(heteroaryl), -N(C1-9 alkyl)(heterocyclic), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C1-9 alkyl), -C(O) -C(O)O (C2-6 alkenyl), -C(O)O (C2-6 alkynyl), -C(O)O (C3-15 cycloalkyl), -C(O)O (C1-8 haloalkyl), -C(O)O (aryl), -C(O)O (heteroaryl), -C(O)O (heterocyclic), -C(O)NH2, -C(O)NH (C1-9 alkyl), -C(O)NH (C2-6 alkenyl), -C(O)NH (C2-6 alkynyl), -C(O)NH (C3-15 cycloalkyl), -C(O)NH (C1-8 haloalkyl), -C(O)NH (aryl), -C(O)NH (heteroaryl), -C(O)NH (heterocyclic), -C(O)N (C1-9 alkyl)2, -C(O)N (C3- 15-cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 ynyl)2, -C(O)N(C3-15-cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclic)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 ynyl), -NHC(O)(C3-15-cycloalkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclic), -NHC(O)O(C1-9 alkyl) -NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl), -NHC(O)NH (C3-15 cycloalkyl), -NHC(O)NH (C1-8 haloalkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic),-SH, -S(C1-9 alkyl), -S(C2-6 alkenyl), -S(C2-6 ynyl), -S(C3-15 cycloalkyl), -S(C1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclic), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 ynyl), -S(O) -S(O) (C3-15 cycloalkyl), -S(O) (C1-8 haloalkyl), -S(O) (aryl), -S(O) (heteroaryl), -S(O) (heterocyclic), -S(O)2 (C1-9 alkyl), -S(O)2 (C2-6 alkenyl), -S(O)2 (C2-6 ynyl), -S(O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl) or -S(O)2N (C1-9 alkyl)2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be derived from one or more halogen groups, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 ynyl), -NHC(O)O (C3-15 cycloalkyl) -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2 (C1-9 alkyl), -S(O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic) or -O (C1-9 alkyl) substitution; Or its pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs. In one embodiment, R1 is a C3-10 cycloalkyl group substituted with X1, as appropriate. In another embodiment, R1 is selected from cyclohexyl and bicyclo[2.2.2]octane. In another embodiment, R1 is a 4- to 12-member heterocyclic group that is replaced by X1, depending on the situation. In another embodiment, R1 is tetrahydropiperanone. In another embodiment, R1 is oxabicyclo[2.2.2]octane. In one embodiment, "Het" is selected from: In another embodiment, "Het" is: In some embodiments, "Het" is replaced by X2. In one embodiment, X2 is a halogen group, CN, C1-9 alkyl, C3-6 cycloalkyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic group, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12, and -C(O)-N(R12)(R12). In the examples, X2 is selected from -F, CN, C1-4 alkyl, C1-8 haloalkyl, C3-4 cycloalkyl and C1-3 cyanoalkyl. In another embodiment, X2 is selected from methyl, ethyl, -CHF2, -CF3, cyclopropyl, -CH2CHF2 and -CH2CF3. In another embodiment, X2 is CHF2. In another embodiment, R2 is a C1-10 alkyl group that is substituted with Z1 as appropriate. In another embodiment, R2 is a C1-10 alkyl group substituted with one or more -F or -OH or a combination of F and OH, as appropriate. In another embodiment, R2 is a C3-10 cycloalkyl group that is substituted with Z1, as appropriate. In another embodiment, R2 is a C3-8 cycloalkyl group substituted with -OH, -N(R12)C(O)(R12), -N(R12)C(O)O(R12) or -C(O)N(R12)(R12), depending on the situation. In the embodiment, X1 is F. In this embodiment, Y represents CN. In other embodiments, the present invention provides a compound of formula (Ia): wherein R1 is selected from C3-10 cycloalkyl groups substituted with X1 as appropriate and 4- to 12-membered heterocyclic groups substituted with X1 as appropriate; wherein each X1 is independently a syloxy group, a halogen group, -CN, C1-9 alkyl, and C3-15 cycloalkyl; "Het" is selected from 5- to 10-membered heteroaryl groups substituted with X2 as appropriate and 4- to 12-membered heterocyclic groups substituted with X2 as appropriate; wherein each X2 is selected from a syloxy group, a halogen group, N3, -CN, C1-9 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic groups, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12) R12) and -C(O)N(R12)(R12), wherein any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl, or heterocyclic group is substituted with Z1a as appropriate; each Z1a is independently a side-oxygen group, halogroup, -NO2, -CN, -N3, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)R12, -C(O)O-R12, -C(O)N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)-C(O)R12, -N(R12)C(O)O(R12), -N(R12)C(O)N(R12)(R12), -N(R12)S(O)2(R12), -N(R12)S(O)2-N(R12)(R12), -N(R12)S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12), -Si(R12)3, -S-R12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 or -S(O)2N(R12)(R12); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclic group is substituted with Z1b as appropriate; Each R12 is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclic; wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is substituted by Z1a as appropriate; each Z1b is independently a side oxygen group, hydroxyl group, halogen group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl).-O (aryl), -O (heteroaryl), -O (heterocyclic), -NH2, -NH (C1-9 alkyl), -NH (C2-6 alkenyl), -NH (C2-6 ynyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -N (C2-6 alkenyl)2, -N (C2-6 ynyl)2, -N (C3-15 cycloalkyl)2, -N (C1-8 haloalkyl)2, -N (aryl)2, -N (heteroaryl)2, -N (heterocyclic)2, -N (C1-9 alkyl)(C3-15 cycloalkyl), -N (C1-9) Alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 ynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(aryl), -N(C1-9 alkyl)(heteroaryl), -N(C1-9 alkyl)(heterocyclic), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkyl), -C(O)O(C2-6 alkyl), -6-alkenyl), -C(O)O(C2-6 ynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclic), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 ynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclic), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2 Alkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclic)2, -NHC(O) (C1-9 alkyl), -NHC(O) (C2-6 alkenyl), -NHC(O) (C2-6 alkynyl), -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl),-NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl) -NHC(O)NH (C3-15 cycloalkyl), -NHC(O)NH (C1-8 haloalkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic), -SH, -S (C1-9 alkyl), -S (C2-6 alkenyl), -S (C2-6 ynyl), -S (C3-15 cycloalkyl), -S (C1-8 haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclic) Cycloyl), -NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 ynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(aryl), -S(O) -S(O) (heteroaryl), -S(O) (heterocyclic), -S(O)2 (C1-9 alkyl), -S(O)2 (C2-6 alkenyl), -S(O)2 (C2-6 ynyl), -S(O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl) or -S(O)2N (C1-9 alkyl)2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be derived from one or more halogen groups, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), - NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 ynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic)The following are substitutions: -NHC(O)NH (C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), S(O)2 (C1-9 alkyl), -S(O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), or -O (C1-9 alkyl); or pharmaceutically acceptable salts, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof. The present invention also provides pharmaceutical compositions comprising a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, and a pharmaceutically acceptable carrier. The present invention also provides a method for treating an inflammatory condition in a patient requiring treatment. The method comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or (Ia) as described above. In another embodiment, the method comprises administering to the patient requiring treatment a composition comprising a therapeutically effective compound of formula (I) or (Ia). In some embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), psoriasis, or rheumatoid arthritis.

Implementation Method

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, Wherein Y is selected from: -H, -F, -Cl, -Br, -CN, -CF3, -CF2H, -OH, and -OCH3; R1 is selected from C3-10 cycloalkyl groups substituted with X1 as appropriate and 4- to 12-membered heterocyclic groups substituted with X1 as appropriate; wherein each X1 is independently a side-oxygen group, a halogen group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, -O-R12, -C(O)-R12, -C(O)O-R12, -C(O)-N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)C(O)-R12, -N( R12)C(O)O-R12 or -N(R12)C(O)N(R12)(R12); "Het" is selected from: wherein each X2 is selected from alkyl, halogen, N3, -CN, C1-9 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12) and -C(O)N(R12)(R12), wherein any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl or heterocyclic group is substituted by Z1a as appropriate; R2 is selected from: a) as appropriate a) Z1-substituted C1-10 alkyl groups; b) Z1-substituted C3-10 cycloalkyl groups, as appropriate; c) Z1-substituted 5- to 10-membered heteroaryl groups, as appropriate; d) Z1-substituted C6-10 aryl groups, as appropriate; and e) Z1-substituted 4- to 12-membered heterocyclic groups, as appropriate; wherein Z1 is independently a side-oxygen group, a halogroup, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)-R12, -C(O)O-R12, -C(O)-N(R12)(R12), -N(R12)(R12), -N(R12)2(R12). +、-N(R12)C(O)-R12、-N(R12)C(O)O-R12、-N(R12)C(O)N(R12)(R12、-N(R12)S(O)2(R12、-NR12S(O)2N(R12)(R12、-NR12S(O)2O(R12、-OC(O)R12、-OC(O)OR12、-OC(O)-N(R12)(R12、-Si(R12)3、-S-R12、-S(O)R12、-S(O)(NH)R12、-S(O)2R12 or-S(O)2N(R12)(R12); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl,The heteroaryl or heterocyclic group is substituted with Z1a as appropriate; each Z1a is independently a side oxygen group, a halogroup, -NO2, -CN, -N3, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)R12, -C(O)O-R12, -C(O)N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)-C(O)R12, -N(R12)C(O)O(R12), -N(R12)C(O)N(R12)(R12), -N(R12)S(O)2(R12), -N(R12) S(O)2-N(R12)(R12), -N(R12)S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12), -Si(R12)3, -S-R12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 or -S(O)2N(R12)(R12); wherein any alkyl, alkenyl, ynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclic group is substituted with Z1b as appropriate; each R12 is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, aryl, heteroaryl or heterocyclic group; wherein any alkyl, alkenyl, ynyl, Cycloalkyl, aryl, heteroaryl, or heterocyclic groups are substituted by Z1a as appropriate; each Z1b is independently a side oxygen group, hydroxyl group, halogen group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 ynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), -NH2, -NH (C1-9 alkyl), -NH (C2-6 alkenyl), -NH (C2-6 ynyl), -NH (C3-15 cycloalkyl), -NH (C1-8 Halogenated groups, -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 ynyl)2, -N(C3-15 cycloalkyl)2, -N(C1-8 haloalkyl)2, -N(aryl)2, -N(heteroaryl)2, -N(heterocyclic)2, -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 ynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(aryl)-N(C1-9 alkyl)(heteroaryl), -N(C1-9 alkyl)(heterocyclic), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 ynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclic) -C(O)NH2, -C(O)NH (C1-9 alkyl), -C(O)NH (C2-6 alkenyl), -C(O)NH (C2-6 alkynyl), -C(O)NH (C3-15 cycloalkyl), -C(O)NH (C1-8 haloalkyl), -C(O)NH (aryl), -C(O)NH (heteroaryl), -C(O)NH (heterocyclic), -C(O)N (C1-9 alkyl)2, -C(O)N (C3-15 cycloalkyl)2, -C(O)N (C2-6 alkenyl)2, -C(O)N (C2-6 alkynyl)2, -C(O)N (C3-15 cycloalkyl)2, -C(O)N (C1-8 haloalkyl)2, -C(O)N (aryl)2, -C (O)N(heteroaryl)2, -C(O)N(heterocyclic)2, -NHC(O) (C1-9 alkyl), -NHC(O) (C2-6 alkenyl), -NHC(O) (C2-6 ynyl), -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 ynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -N HC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl), -NHC(O)NH (C3-15 cycloalkyl), -NHC(O)NH (C1-8 haloalkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic), -SH, -S (C1-9 alkyl), -S (C2-6 alkenyl), -S (C2-6 alkynyl), -S (C3-15 cycloalkyl), -S (C1-8 haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclic)-NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 ynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclic), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 ynyl), -S (O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl) or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is, as appropriate, derived from one or more halogroups, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1- -9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -S(O) The following substitutions are allowed: (NH)(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclic), -S(O)2NH(C1-9 alkyl), -S(O)2N(C1-9 alkyl)2, -O(C3-15 cycloalkyl), -O(C1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclic) or -O(C1-9 alkyl); and unless otherwise defined, the aforementioned heterocyclic groups have 1 to 5 cyclic heteroatoms independently selected from nitrogen, sulfur or oxygen.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is a C3-10 cycloalkyl group substituted with X1 as appropriate.

3. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is selected from cyclohexyl and bicyclo[2.2.2]octane.

4. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is a 4- to 12-membered heterocyclic group substituted with X1 as appropriate.

5. A compound of claim 4 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is tetrahydropiperanone.

6. The compound of claim 4 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is oxabicyclo[2.2.2]octane.

7. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein "Het" is X2 substituted.

8. The compound of claim 7 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue, wherein X2 is a halogen group, CN, C1-9 alkyl, C3-6 cycloalkyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic group, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12 and -C(O)-N(R12)(R12).

9. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is selected from -F, CN, C1-4 alkyl, C1-8 haloalkyl, C3-4 cycloalkyl and C1-3 cyanoalkyl.

10. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is selected from methyl, ethyl, -CHF2, -CF3, cyclopropyl, -CH2CHF2 and -CH2CF3.

11. The compound of claim 7 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is -CHF2.

12. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R2 is a C1-10 alkyl group substituted with Z1 as appropriate.

13. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R2 is, where appropriate, a C1-10 alkyl group substituted with one or more -F or -OH or combinations of F and OH.

14. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R2 is a C3-10 cycloalkyl group substituted with Z1 as appropriate.

15. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R2 is, where appropriate, a C3-8 cycloalkyl group substituted with -OH, -N(R12)C(O)(R12), -N(R12)C(O)O(R12) or -C(O)N(R12)(R12).

16. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X1 is F.

17. The compound of any one of claims 1 to 11, wherein Y is CN.

18. A compound of formula (Ia) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, in, R1 is selected from C3-10 cycloalkyl groups substituted with X1 as appropriate and 4- to 12-membered heterocyclic groups substituted with X1 as appropriate; wherein each X1 is independently a syloxy group, a halogen group, -CN, C1-9 alkyl, and C3-15 cycloalkyl; "Het" is selected from: wherein each X2 is selected from a syloxy group, a halogen group, N3, -CN, C1-9 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic groups, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12) and -C(O)N(R12)(R12), wherein any alkyl group Alkenyl, alkynyl, cycloalkyl, haloalkyl, or heterocyclic groups are substituted with Z1a as appropriate; each Z1a is independently a side-oxygen group, halogroup, -NO2, -CN, -N3, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O-R12, -C(O)R12, -C(O)O-R12, -C(O)N(R12)(R12), -N(R12)(R12), -N(R12)2(R12)+, -N(R12)-C(O)R12, -N(R12)C(O)O(R12), -N(R12)C(O)N(R12)(R12), -N(R12)S(O)2(R12) 2) -N(R12)S(O)2-N(R12)(R12), -N(R12)S(O)2O(R12), -OC(O)R12, -OC(O)OR12, -OC(O)-N(R12)(R12), -Si(R12)3, -S-R12, -S(O)R12, -S(O)(NH)R12, -S(O)2R12 or -S(O)2N(R12)(R12); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclic group is substituted with Z1b as appropriate; each R12 is independently H, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, aryl, heteroaryl or heterocyclic group; wherein any The alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic groups are substituted by Z1a as appropriate; each Z1b is independently a side oxygen group, hydroxyl group, halogen group, -NO2, -N3, -CN, C1-9 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, C1-8 haloalkyl, aryl, heteroaryl, heterocyclic, -O (C1-9 alkyl), -O (C2-6 alkenyl), -O (C2-6 alkynyl), -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), -NH2, -NH (C1-9 alkyl), -NH (C2-6 alkenyl), -NH (C2-6 alkynyl), -NH (C3-15 cycloalkyl),-NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -N (C2-6 alkenyl)2, -N (C2-6 ynyl)2, -N (C3-15 cycloalkyl)2, -N (C1-8 haloalkyl)2, -N (aryl)2, -N (heteroaryl)2, -N (heterocyclic)2, -N (C1-9 alkyl)(C3-15 cycloalkyl), -N (C1-9 alkyl)(C2-6 alkenyl), -N (C1-9 alkyl)(C2-6 ynyl), -N (C1-9 alkyl)(C3-15 cycloalkyl), -N (C1-9 alkyl)(C1-8 haloalkyl), -N (C1-9) Alkyl)(aryl), -N(C1-9 alkyl)(heteroaryl), -N(C1-9 alkyl)(heterocyclic), -C(O)(C1-9 alkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 ynyl), -C(O)(C3-15 cycloalkyl), -C(O)(C1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)O(C1-9 alkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 ynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl ... -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 ynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclic), -C(O)N(C1-9 alkyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 ynyl)2, -C(O)N(C3-15 cycloalkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(aryl) 2. -C(O)N (heteroaryl) 2. -C(O)N (heterocyclic) 2. -NHC(O) (C1-9 alkyl), -NHC(O) (C2-6 alkenyl), -NHC(O) (C2-6 ynyl), -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkenyl), -NHC(O)O (C2-6 ynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl)-NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -NHC(O)NH (C2-6 alkenyl), -NHC(O)NH (C2-6 alkynyl), -NHC(O)NH (C3-15 cycloalkyl), -NHC(O)NH (C1-8 haloalkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic), -SH, -S (C1-9 alkyl), -S (C2-6 alkenyl), -S (C2-6 alkynyl), -S (C3-15 cycloalkyl), -S (C1-8 haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclic) -N(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(NH)(C1-9 alkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 ynyl), -S(O)(C3-15 cycloalkyl), -S(O)(C1-8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclic), -S(O)2(C1-9 alkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 ynyl), -S(O)2(C3-15 cycloalkyl), -S(O) -S(O)2 (C1-8 alkyl halogroup), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl) or -S(O)2N (C1-9 alkyl)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is derived from one or more alkyl groups, C1-9 alkyl, C1-8 alkyl halogroup, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 alkyl halogroup), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl)2, -N (C3-15 cycloalkyl)2, -NHC(O) (C3-15 cycloalkyl), -N HC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 alkynyl), -NHC(O)O (C3-15 cycloalkyl), -NHC(O)O (C1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C1-9 alkyl), -S(O)(NH) (C1-9 alkyl), S(O)2 (C1-9 alkyl), -S(O)2 (C3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl),The following substitutions are used: -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl), -S(O)2N (C1-9 alkyl)2, -O (C3-15 cycloalkyl), -O (C1-8 haloalkyl), -O (aryl), -O (heteroaryl), -O (heterocyclic), or -O (C1-9 alkyl); and unless otherwise defined, the aforementioned heterocyclic groups have 1 to 5 cyclic heteroatoms independently selected from nitrogen, sulfur, or oxygen.

19. A compound of claim 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is, where appropriate, a C3-10 cycloalkyl group substituted with X1.

20. The compound of claim 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is selected from cyclohexyl and bicyclo[2.2.2]octane.

21. A compound of claim 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is a 4- to 12-membered heterocyclic group substituted with X1, as appropriate.

22. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is tetrahydropiperanone.

23. The compound of claim 21 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R1 is oxabicyclo[2.2.2]octane.

24. The compound of claim 18 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein "Het" is selected from:

25. A compound of any one of claims 20 to 24, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein "Het" is X2 substituted.

26. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is a halogen group, CN, C1-9 alkyl, C3-6 cycloalkyl, C3-15 cycloalkyl, C1-8 haloalkyl, 4- to 12-membered heterocyclic group, -O-R12, C1-6 cyanoalkyl, C1-6 alkyl ether, -OC(O)R12, -OC(O)OR12 and -C(O)-N(R12)(R12).

27. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is fluorinated, CN, C1-4 alkyl, C1-8 haloalkyl, C3-4 cycloalkyl and C1-3 cyanoalkyl.

28. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is methyl, ethyl, -CHF2, -CF3, cyclopropyl, -CH2CHF2 or -CH2CF3.

29. The compound of claim 25 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein X2 is -CHF2.

30. A pharmaceutical composition comprising a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, and a pharmaceutically acceptable carrier.

31. Use of any compound of claims 1 to 29 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof or a composition of claim 30, for the manufacture of a medicament for the treatment of inflammatory conditions in patients in need.

32. As claimed in claim 31, wherein the inflammatory condition is selected from IBD, SLE, psoriasis and rheumatoid arthritis.

33. A compound selected from the compounds shown in the table below:

34. Any compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein "Het" is selected from:

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