BACKGROUND OF THE INVENTION
10 [0002] The interleukin-17 cytokine family consists of six members (termed IL-17A
through IL-17F) of which IL-17A (also known as CTLA-8) is the primary effector cytokine
of the T-helper-17 (Th17) cell lineage.
[0003] IL-17A is a variably glycosylated, disulfide linked, homodimeric glycoprotein of
34-38 kDa which shares in the order of 50% homology with its closest family member IL-
15 17F, both of which can be secreted either as homodimers or the heterodimer IL-17AF [K.F.
Geoghegan et al., Protein Expression and Purification 2013, 87, 27-34; J.K. Kells and A.
Linden/Immunity 2004, 21, 467-476].
[0004] Activation of na"lve CD4+ T-cells in response to cytokines such as IL-6,
transforming growth factor 13 (TGF-(3), IL-23, STAT3, and RORyt leads to their
20 differentiation to TH17 cells and expression of pro-inflammatory mediators such as IL-17A.
Furthermore, a variety of cell types from the innate and adaptive immune systems have
been identified as sources of IL-17A. These include mast cells, neutrophilic granulocytes,
NK cells, NKT cells, CDS+ T cells, oy T-cells, macrophages, and type 3-innate lymphoid
cells [D.J. Cua and C.M. Tato, Nat Rev lmmunol 2010, 10, 479-489; W. Jin and C. Dong,
25 Emerging Microbes & Infections 2013, 2, e60].
[0005] Cytokines IL-17A, IL-17F, and IL-17AF bind to common heteromeric receptor
complexes IL-17RA and IL-17RC, albeit with different affinities, and although various cell
types have been reported to express the IL-17RA subunit, the highest responses to IL-17A
come from epithelial cells, endothelial cells, keratinocytes, and fibroblasts [T.A. Moseley
30 et ai./Cytokine Growth Factor Reviews. 2003, 14, 155-174; S.L. Gaffen/ Nature Rev
lmmunol 2009, 9, 556-567; R.M. Onishi and S.L. Gaffen/ Immunology 2010, 129, 311-
321].
wo 2021/239745 PCT/EP2021/063937
2
[0006] Binding of IL-17A to its receptor activates various signal transduction pathways
such as nuclear factor (NF)-KB, phosphoinositide 3-kinase (PI3K), activator protein (AP1),
CCAAT/enhancer-binding protein (C/EBP), and mitogen-activated protein kinase (MAPK)
leading to pro-inflammatory gene expression and the secretion of various pro-inflammatory
5 cytokines including IL-1(3, IL-6, IL-8, TNFa, G-CSF, PGE2 and IFN-y as well as numerous
chemokines and other effectors [S.L. Gaffen, Arthritis Research & Therapy 2004, 6, 240-
247; S.L. Gaffe, Nature Rev lmmunol 2009, 9, 556-567; R.M. Onishi and S.L. Gaffen,
Immunology 2010, 129, 311-321]. The attraction and activation of cells of the innate
immune system to the site of inflammation completes the induction of an inflammatory loop
10 which may also be mediated cooperatively with other cytokines such as TN Fa, IFN-y, and
IL-113 [S.L. Gaffen, Arthritis Research & Therapy 2004, 6, 240-247].
[0007] These IL-17 mediated biological processes have been implicated in the pathology
of many human diseases with an immune component or autoimmune pathology, such as
psoriasis, ankylosing spondylitis, axial spondyloarthritis, psoriatic arthritis, eczema,
15 enthesitis-related arthritis, asthma (including severe asthma), chronic obstructive
pulmonary disease (COPD), cystic fibrosis, pulmonary fibrosis, ulcerative colitis, Crohn's
disease, atopic dermatitis, contact dermatitis, dermatomyositis, myocarditis, uveitis,
exophtalmos, autoimmune thyroiditis, Peyronie's disease, coeliac disease, gall bladder
disease, Pilonidal disease, peritonitis, multiple sclerosis, Guillan-Bar Syndrome, irritable
20 bowel syndrome, inflammatory bowel disease, Castleman's disease, pelvic inflammatory
disease, systemic onset juvenille idiopathic arthritis (JIA), rheumatoid arthritis, giant cell
arteritis, graft versus host disease, discoid lupus erythematosus, systemic lupus
erythematosus, lupus nephritis, vasculitis, insulin dependent diabetes type I, autoimmune
diabetes, Necrobiosis Lipoidica Diabeticorum, Pyoderma Gangrenosum, Hidradenitis
25 Suppurativa, Papulopustular Rosacea, Lichen Planus, heart disease including ischaemic
diseases such as myocardial infarction as well as atherosclerosis, intravascular
coagulaton, bone resorption, osteroporosis, peridontitis, hypochlorhydria, pain (particularly
pain associated with inflammation), and also in cancer (Bartlett, HS; Million, RP (2015)
Nat. Rev. Drug Discovery 14:11-12; Santibanez, JF; Bjelica, S (2018) Recent Pat
30 Anticancer Drug Discov. 13(2):133-144). In addition, due to the emerging role of
neuroinflammation in neurodegeneration, IL-17 has also been implicated in the
progression of neurodegenerative disorders such as Alzheimer's disease (Cristiano et al
(2019) Br J Pharmacal. 176(18):3544-3557), and Parkinson's disease (Storelli et al, (2019)
Front Neurol. 24;10:13). Furthermore, due to IL-17A's key regulatory roles in host defense
35 pathological conditions of relevance also include viral, bacterial, fungal and parasitic
infections. An association between serum levels of IL-17 at the time of admission to the
wo 2021/239745 PCT/EP2021/063937
3
intensive care unit and the development of sepsis has also been observed suggesting
increased IL-17 may increase the susceptibility for septic complications and endotoxic
shock associated with infection [Ahmed et al., Eur J Trauma Emerg Surg 2018, 44(4):621-
626]. Its role in sepsis has also been suggeted to extend to patients with sepsis-induced
5 Acute Respiratory Distress Syndrome (ARDS) and acute lung injury [Ding et al.,
Oncotarget 2017, 8(55):93704-93711]. Very recently inhibition of IL-17 has also been
suggested to be used to prevent acute respiratory distress syndrome (ARDS) in
coronavirus disease 2019 (COVID-19) [Pacha, Sallman & Evans., Nat Rev lmmunol 2020,
1:1-2].
10 [0008] Pre-clinical studies have demonstrated that IL-17A (as well as IL-17F and IL-17C)
is elevated in psoriatic skin [N.J. Wilson et al., Nat lmmunol 2007, 8, 950-957; L.C. Zaba
et al., J Exp Med 2007, 204, 3183-3194; C. Ortega et al, J Leukocyte Bioi 2009, 86, 435-
443; C. Johansen et al., Br J Dermatol 2009, 160, 319-324]. Th17 cells in the peripheral
circulation and lesional skin of patients with psoriasis have also been shown to positively
15 correlate with disease severity as measured by the Psoriasis Area and Severity Index
(PASI) score [L. Zhang et al., Clin lmmunol2010, 135, 108-117]. Serum IL-17A levels are
also significantly correlated with PASI score [H. Takahashi et al., Clin Exp Dermatol 2010,
35, 645-649; S.B. Yilmaz et al. Arch Dermatol Res 2012, 304, 465-469; M. Caproni et al.,
J Clin lmmunol 2009, 29, 210-214].
20 [0009] Animal model studies supported the hypothesis that targeting the IL-17A pathway
would be an effective treatment for psoriasis [L. van der Fits et al., J lmmunol 2009, 182,
5836-5845; K. El Malki et al., J lnvestig Dermatol2013, 133, 441-451; J. Skepner et al., J
lmmunol 2014, 192, 2564-2575] and clinical results with antibodies to IL-17A or IL-17RA
delivered the ultimate validation with excellent efficacy being observed [R.G. Langley et
25 al., N Engl J Med 2014, 371, 326-338; K.B. Gordon et al., N Engl J Med 2016, 375, 345-
356; A.S. Lonnberg et al., Clin Cosmet lnvestig Dermatol 2014, 7, 251-259; S. Coimbra et
al., Core Evid 2014, 9, 89-97; M. Lebwohl et al., N Engl J Med 2015, 373, 1318-1328].
[0010] Elevated levels of IL-17A or IL-17F have been reported in a number of other
diseases including Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA), Ankylosing
30 Spondylitis (AS), Systemic Lupus Erythematosus (SLE), Inflammatory Bowel Disease
(lBO), Multiple Sclerosis (MS), bone erosion, intraperitoneal abscesses, allograft rejection,
angiogenesis, atherosclerosis, and asthma [e.g. S.L. Gaffen, Arthritis Research & Therapy
2004, 6, 240-247; L.A. Tesmer et al., lmmunol Rev 2008, 223, 87-113; US Publ No
20080269467].
wo 2021/239745 PCT/EP2021/063937
4
[0011] The anti-IL-17A therapeutic antibodies Secukinumab and lxekizumab have
shown evidence of positive effects in treating palmoplantar and nail psoriasis; [A. Gottlieb
et al., J Am A cad Dermatol 2016, 76, 70-80; A. Menter et al., J Eur Acad Dermatol Venereal
2017, 31, 1686-1692; C. Paul et al., J Eur Acad Dermatol Venereol2014, 28, 1670-1675];
5 PsA [P. Mease et al., Ann Rheum Dis 2018, 77, 890-897; P. Nash et al., Lancet 2017, 389,
2317-2327] and AS [K. Pavelka et al., Arthritis Res Ther 2017, 19, 285; A. Deodhar et al.,
Arthritis Rheumatol 2018, doi: 10.1 002/art.40753]. A proof of concept study with
Secukinumab in MS has also shown encouraging signs of efficacy [E. Havdrova et al., J
Neurol 2016, 263, 1287-1295].
10 [0012] IL-17A expression has been shown to be increased in SLE patients and
correlated with disease severity [Y. Wang et al., Clin Exp lmmunol2009, 159, 1-10; X.Q.
Chen et al., J Clin lmmunol2010, 30, 221-225].
[0013] In addition, IL-17A has been associated with ocular surface disorders such as
DES [PCT publications W02009089036, W02010062858 and W02011163452; C.S. De
15 Paiva et al., Mucosallmmunol 2009, 2, 243-253] and Th17 cells have been shown to be
elevated in active uveitis and scleritis [A. Amadi-Obi et al., Nat Med 2007, 13, 711-718].
IL-17A levels in tears were associated with clinical severity of dry eye in patients with a
range of systemic autoimmune or inflammatory diseases including Sjogren's syndrome,
Stevens-Johnson syndrome (SJS), SLE, filamentary keratitis, DES, Meibomian gland
20 dysfunction (MGD), and Graft-versus-Host disease (GVHD) [M.H. Kang et al., J Korean
Med Sci 2011, 26, 938-944].
[0014] Several studies have demonstrated that IL-17A is overexpressed in patients with
a range of cancers including gastric carcinoma, medulloblastoma, multiple myeloma,
colorectal carcinoma, Non-Small-Cell Lung Cancer (NSCLC), breast cancer,
25 hepatocellular carcinoma (HCC), and thyroid cancer [X. Meng et al., Turk J Gastroenterol
2018, 29, 45-51; P. Zhou et al., J lnt Med Res 2010, 38, 611-619; D. Lemancewicz et al.,
Med Sci Monit 2012, 18, BR 54-59; S. Le Gouvello et al., Gut 2008, 57, 772-779; B. Pan
et al., Sci Rep 2015, 5, 16053; T. Welte and X. H-F. Zhang, Mediators Inflammation 2015,
804347; J-F. Tu et al., Medicine (Baltimore) 2016, 95, e3220; D.F.G. Carvalho et al., Oncol
30 Lett 2017, 13, 1925-1931]. Increased levels of IL-17A have been shown to correlate with
poor prognosis in several cancer types including malignant thyroid tumor, breast cancer,
pancreatic carcinoma, gastric cancer, NSCLC, colorectal cancer, and head and neck
cancer [S. Punt et al., Oncolmmunol2015, 4, e984547; D.F.G. Carvalho et al., Oncol Lett
2017, 13, 1925-1931; W-C. Chen et al., Histopathology 2013, 63, 225-233; C. Xu et al.,
35 Biomarkers 2014, 19, 287-290; Y. Yamada et al., J Surg Res 2012, 178, 685-691; S. He
wo 2021/239745 PCT/EP2021/063937
5
et al., lnt J Mol Sci 2011, 12, 7424-7437; J-Y. Tseng et al., Clin Cancer Res 2014, 20,
2885-2897; M-H. Lee et al., Oncotarget 2018, 9, 9825-9837].
[0015] Taken together, modulation of the IL-17A pathway, in particular modulation of IL-
17A activity through inhibition of its interaction with the receptor IL-17RA, may be
5 considered a target for the treatment of conditions relating to the immune system and
inflammation, cancer and neurodegenerative disorders.
[0016] WO 2013/116682, WO 2014/066726 and WO 2018/229079 describe classes of
chemical compounds that are stated to modulate the activity of IL-17 and to be useful in
the treatment of medical conditions, including inflammatory disease.
10 [0017] Nevertheless, there is an ongoing need for compounds capable of attenuating I L-
17 A activity.
SUMMARY OF THE INVENTION
[0018] In one aspect, the present invention provides a compound, or a pharmaceutically
15 acceptable salt thereof as defined herein.
[0019] In another aspect, the present invention provides a pharmaceutical composition
comprising a compound of the invention as defined herein, or a pharmaceutically
acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
[0020] In another aspect, the present invention relates to a compound of the invention
20 as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition as defined herein, for use in therapy.
[0021] In another aspect, the present invention relates to a compound of the invention
as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical
composition as defined herein, for use in the treatment of diseases or disorders associated
25 with IL-17A activity.
[0022] In another aspect, the present invention relates to the use of a compound of the
invention as defined herein, or a pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for use in the treatment of diseases or disorders associated
with I L -17 A activity.
30 [0023] In another aspect, the present invention relates to a method of treating a disease
or disorder associated with IL-17A activity, said method comprising administering to a
subject in need of such treatment a therapeutically effective amount of a compound of the
invention as defined herein, or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition as defined herein.
wo 2021/239745 PCT/EP2021/063937
6
[0024] Examples of diseases or disorders associated with IL-17A activity include
diseases with an immune component or autoimmune pathology (such as psoriasis,
ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and
neurodegenerative disorders.
5 [0025] In another aspect, the present invention provides a compound, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined
herein, for use in the treatment of diseases with an immune component or autoimmune
pathology (such as psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid
arthritis), cancer, and neurodegenerative disorders.
10 [0026] In another aspect, the present invention provides the use of a compound, or a
pharmaceutically acceptable salt, in the manufacture of a medicament for use in the
treatment of diseases with an immune component or autoimmune pathology (such as
psoriasis, ankylosing spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and
neurodegenerative disorders.
15 [0027] In another aspect, the present invention provides a method of treating diseases
with an immune component or autoimmune pathology (such as psoriasis, ankylosing
spondylitis, psoriatic arthritis, and rheumatoid arthritis), cancer, and neurodegenerative
disorders, said method comprising administering to a subject in need of such treatment a
therapeutically effective amount of a compound, or a pharmaceutically acceptable salt
20 thereof, or a pharmaceutical composition as defined herein.
[0028] The present invention further provides a method of synthesising a compound, or
a pharmaceutically acceptable salt thereof, as defined herein.
[0029] In another aspect, the present invention provides a compound, or a
pharmaceutically acceptable salt thereof, obtainable by, or obtained by, or directly
25 obtained by a method of synthesis as defined herein.
[0030] In another aspect, the present invention provides novel intermediates as defined
herein which are suitable for use in any one of the synthetic methods set out herein.
[0031] Preferred, suitable, and optional features of any one particular aspect of the
present invention are also preferred, suitable, and optional features of any other aspect.
30 DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0032] Unless otherwise stated, the following terms used in the specification and claims
have the following meanings set out below.
wo 2021/239745 PCT/EP2021/063937
7
[0033] It is to be appreciated that references to "treating" or "treatment" include
prophylaxis as well as the alleviation of established symptoms of a condition. "Treating"
or "treatment" of a state, disorder or condition therefore includes: (1) preventing or delaying
the appearance of clinical symptoms of the state, disorder or condition developing in a
5 human that may be afflicted with or predisposed to the state, disorder or condition but does
not yet experience or display clinical or subclinical symptoms of the state, disorder or
condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying
the development of the disease or a relapse thereof (in case of maintenance treatment) or
at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the
10 disease, i.e., causing regression of the state, disorder or condition or at least one of its
clinical or subclinical symptoms.
[0034] A "therapeutically effective amount" means the amount of a compound that, when
administered to a mammal for treating a disease, is sufficient to effect such treatment for
the disease. The "therapeutically effective amount" will vary depending on the compound,
15 the disease and its severity and the age, weight, etc., of the mammal to be treated.
[0035] The term "alkyl" refers to aliphatic hydrocarbon groups. In this specification the
term "alkyl" includes both straight and branched chain alkyl groups. References to
individual alkyl groups such as "propyl" are specific for the straight chain version only and
references to individual branched chain alkyl groups such as "isopropyl" are specific for
20 the branched chain version only. For example, "C1-6alkyl" includes C1-4alkyl, C1-3alkyl,
propyl, isopropyl and t-butyl. A similar convention applies to other radicals, for example
"phenyiC1-6alkyl" includes phenyiC1-4alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.
[0036] The term "alkylene" includes both straight and branched chain divalent alkyl
groups. For example, "C1-4alkylene" includes methylene (-CH2-), ethylene (-CH2CH2-),
25 propylene and butylene.
[0037] The term "alkoxy" includes both straight and branched chain alkyl groups
singularly bonded to oxygen. For example, "C1-4alkoxy" includes methoxy, ethoxy,
isopropoxy and t-butoxy.
[0038] The term "Cm-n" used as a prefix, refers to any group having m to n carbon atoms.
30 [0039] "Cycloalkyl" means a hydrocarbon ring containing from 3 to 8 carbon atoms, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
bicycle[2.2.2]octane, bicycle[2.1.1]hexane, bicycle[1.1.1]pentane and bicyclo[2.2.1 ]heptyl.
[0040] The term "halo" refers to fluoro, chloro, bromo and iodo.
wo 2021/239745 PCT/EP2021/063937
8
[0041] The term "haloalkyl" or "haloalkoxy" is used herein to refer to an alkyl or alkoxy
group respectively in which one or more hydrogen atoms have been replaced by halogen
(e.g. fluorine) atoms. Examples of haloalkyl and haloalkoxy groups include fluoroalkyl and
fluoroalkoxy groups such as -CHF2, -CH2CF3, or perfluoroalkyl/alkoxy groups such as-
5 CF3, -CF2CF3 or -OCF3.
[0042] The term "heterocyclyl", "heterocyclic" or "heterocycle" means a non-aromatic
saturated or partially unsaturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic
ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3
to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen,
10 oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms,
suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused,
spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such
as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers.
Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl,
15 piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing
heterocycles include tetrahydrothienyl, dihydro-1 ,3-dithiol, tetrahydro-2H-thiopyran, and
hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl,
tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,
tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl,
20 octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For
heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or S02
groups are also included. Examples include the sulfoxide and sulfone forms of
tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1, 1-dioxide and
thiomorpholinyl 1, 1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2
25 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,
2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,
2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are
saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms
selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,
30 tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-
dioxide, thiomorpholinyl, thiomorpholinyl 1, 1-dioxide, piperidinyl, homopiperidinyl,
piperazinyl or homopiperazinyl. Partially unsaturated heterocyclyl rings contain at least
one double bond, such as 1 or 2 double bonds. Examples of partially unsaturated
heterocyclyl rings include 1 ,6-dihydropyridinyl, 1 ,6-dihydropyridazinyl and 2,3-
35 dihydropyrrolyl. As the skilled person would appreciate, any heterocycle may be linked to
another group via any suitable atom, such as via a carbon or nitrogen atom. Suitably, the
wo 2021/239745 PCT/EP2021/063937
9
term "heterocyclyl", "heterocyclic" or "heterocycle" will refer to 4, 5, 6 or 7 membered
monocyclic rings as defined above.
[0043] By "bridged ring systems" is meant ring systems in which two rings share more
than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th
5 Edition, Wiley lnterscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring
systems include, aza-bicyclo[2.2.1 ]heptane, 2-oxa-5-azabicyclo[2.2.1 ]heptane, azabicyclo[
2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.
[0044] By "spiro bi-cyclic ring systems" we mean that the two ring systems share one
common spiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or
10 heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring
systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-
azaspiro[3.3]heptanes and 2-oxa-6-azaspiro[3.3]heptanes.

CLAIMS
5 1. A compound of Formula I
(I)
wherein:
X1, X2, X3, and X4 are each independently CR5 or N;
10 Y is aryl or heteroaryl, each of which is optionally substituted by one or more
15
20
substituents independently selected from halo, C1-4alkyl, C1-4alkoxy, C1-
3alkylene-C1-4alkoxy, C1-3alkylene-N(C1-3alkyl)2, and C1-4haloalkyl; and wherein
when Y is a 5- or 6-membered heteroaryl ring, said ring is optionally fused to a
5- or 6-membered cycloalkyl or heterocyclyl ring, each of which is optionally
substituted by one or more substituents independently selected from from halo,
C1-4alkyl, C1-4alkoxy, C1-3alkylene-C1-4alkoxy, C1-3alkylene-N(C1-3alkyl)2, and C1-
4haloalkyl;
R1 and R2 together with the carbon atom to which they are attached form a 4- to 1 amembered
cycloalkyl ring, wherein the cycloalkyl ring:
a. is optionally substituted with one or more substituents independently
selected from halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, and C1-
4haloalkoxy; and
b. is optionally spiro-attached to one or more independently selected C3-
scycloalkyl groups;
25 R3 is hydrogen, fluoro or C1-4alkyl;
30
(A) a 5- to 10-membered heteroaryl, a C3-7cycloalkyl, or a 3- to 12-
membered heterocyclyl ring, each of which is optionally substituted by
one or more substituents independently selected from hydroxy, halo,
C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
,
C02R10
, C1-3alkylene-R11 , C3-7cycloalkyl, and heterocyclyl, wherein
said C3-7cycloalkyl and heterocyclyl substituents are optionally
5
10
15
20
wo 2021/239745
(B)
(C)
PCT/EP2021/063937
187
substituted with one or more substituents independently selected from
hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7,
C(O)NR8R9
, and C02R10;
C1-6alkyl optionally substituted with hydroxy, halo, C1-4alkoxy, cyano,
NR6R7, C(O)NR8R9 or C02R10;
5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-
membered cycloalkyl or heterocyclyl ring, each of which is optionally
substituted by one or more substituents independently selected from
hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7,
C(O)NR8R9
, C02R10
, C1-3alkylene-R1\ C3-7cycloalkyl, and
heterocyclyl;
(D) a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl
(E)
ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl
ring, each of which rings is optionally substituted by one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R1\ C3-7cycloalkyl, and heterocyclyl; OR
a partially unsaturated heterocyclic ring, optionally fused to a 5- to 6-
membered heteroaryl ring and optionally substituted with one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R1\ C3-7cycloalkyl, and heterocyclyl;
R5 is hydrogen, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl or cyano;
R11 is hydroxy, halo, C1-4alkoxy, cyano, NR12R13, C(O)R14, aryl or heteroaryl;
25 R14 is hydroxy, C1-4alkyl, C1-4alkoxy or NR15R16;
R6, R7, R8
, R9
, R10
, R12, and R13 are independently selected from hydrogen and C1-
4alkyl;
R15 and R16 are independently selected from hydrogen and C1-4alkyl; or
R15 and R16 taken together with the nitrogen atom to which they are attached form a
30 3- to ?-membered heterocyclyl ring, the ring optionally containing a further
heteroatom chosen from 0, S, and Nand being optionally substituted with C1-
4alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, having the following structure:
5
wo 2021/239745 PCT/EP2021/063937
3.
188
wherein X1, X2, X3, X4, Y, R1, R2, R3, and R4 are as defined in claim 1; or a
pharmaceutically acceptable salt thereof.
The compound according to claim 1 or claim 2, wherein X1, X2, X3, and X4 are each
independently CH or N.
4. The compound according to claim 3, wherein X1 is Nand X2, X3, and X4 are CH.
5. The compound according to claim 3, wherein X1, X2, X3, and X4 are all CH.
6. The compound according to claim 1 or claim 2, wherein two of X1, X2, X3, and X4 are
CR5
, and two are N; or three of X1, X2, X3, and X4 are CR5
, and the other is N.
10 7. The compound according to any one of claims 1 to 6, wherein Y is heteroaryl
optionally substituted by one or more substituents independently selected from halo,
C1-4alkyl, C1-4alkoxy, C1-3alkylene-C1-4alkoxy, C1-2alkylene-N(C1-3alkyl)2, and C1-
4haloalkyl.
15
8. The compound according to claim 7, wherein Y is a 5- or 6-membered heteroaryl
ring, said ring being optionally fused to a 5- or 6-membered cycloalkyl or heterocyclyl
ring, each of which is optionally substituted by one or more substituents
independently selected from halo, C1-4alkyl, C1-4alkoxy, C1-3alkylene-C1-4alkoxy, C1-
2alkylene-N(C1-3alkyl)2, and C1-4haloalkyl.
9. The compound according to claim 7, wherein Y is a heteroaryl ring optionally
20 substituted by one or more substituents independently selected from halo, C1-3alkyl,
C1-2alkoxy, C1-2alkylene-C1-2alkoxy, and C1-2haloalkyl.
10. The compound according to claim 7, wherein Y is a 5- to 6-membered heteroaryl
optionally substituted by one or more substituents independently selected from halo
and methyl.
wo 2021/239745 PCT/EP2021/063937
189
11. The compound according to claim 7, wherein Y is a 5- to 6-membered heteroaryl
ring substituted in a position ortho to the NHC(O)- moiety by methyl or ethyl.
12. The compound according to any one of claims 1 to 6, wherein Y is:
~ N
or
5 wherein JVV"V' is the point of attachment to the rest of the compound of Formula I
and Y is optionally substituted by one or more substituents independently selected
from halo, C1-3alkyl, C1-2alkoxy, C1-2alkylene-C1-2alkoxy, and C1-2haloalkyl.
13. The compound according to any one of claims 1 to 12, wherein R1 and R2 together
with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl
10 ring, wherein the cycloalkyl ring:
a. is optionally substituted with one or more substituents independently
selected from halo, C1-2alkyl, C1-2alkoxy, and C1-2haloalkyl; and
b. is optionally spiro-attached to a C3-scycloalkyl group.
14. The compound according to any one of claims 1 to 12, wherein R1 and R2 together
15 with the carbon atom to which they are attached form a group selected from:
wherein * is the carbon atom to which R1 and R2 are attached, each occurrence of
R17 is independently selected from halo, C1-2alkyl, C1-2alkoxy, and C1-2haloalkyl, and
m is 0,1, 2 or3.
20 15. The compound according to any one of claims 1 to 12, wherein R1 and R2 together
with the carbon atom to which they are attached form the following group:
wo 2021/239745 PCT/EP2021/063937
190
wherein * is the carbon atom to which R1 and R2 are attached, and each R17 is
independently selected from hydrogen, fluoro, methyl, and trifluoromethyl.
16. The compound according to any one of claims 1 to 15, wherein R3 is hydrogen.
5 17. The compound according to any one of claims 1 to 16, wherein R4 is:
10
15
20
25
30
(A) a 5- to 10-membered heteroaryl or C3-7cycloalkyl ring, each of which
is optionally substituted by one or more substituents independently
selected from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl,
cyano, NR6R7, C(O)NR8R9
, C02R10 , C1-3alkylene-R11 , C3-7cycloalkyl,
(B)
(C)
and heterocyclyl, wherein said C3-7cycloalkyl and heterocyclyl
substituents are optionally substituted with one or more substituents
independently selected from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-
4haloalkyl, cyano, NR6R7, C(O)NR8R9
, and C02R10;
C1-6alkyl optionally substituted with hydroxy, halo, C1-4alkoxy, cyano,
NR6R7 or C02R10;
5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-
membered cycloalkyl or heterocyclyl ring, each of which is optionally
substituted by one or more substituents independently selected from
hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7,
C(O)NR8R9
, C02R10
, C1-3alkylene-R11, C3-7cycloalkyl, and
heterocyclyl;
(D) a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl
(E)
ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl
ring, each of which rings is optionally substituted by one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R11, C3-7cycloalkyl, and heterocyclyl; or
a partially unsaturated heterocyclic ring, optionally fused to a 5- to 6-
membered heteroaryl ring and optionally substituted with one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
wo 2021/239745 PCT/EP2021/063937
191
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R11, C3-7cycloalkyl, and heterocyclyl.
18. The compound according to any one of claims 1 to 16, wherein R4 is:
(A) a 5- to 10-membered heteroaryl or C3-7cycloalkyl ring, each of which
5 is optionally substituted by one or more substituents independently
selected from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl,
cyano, NR6R7, C(O)NR8R9
, C02R10 , C1-3alkylene-R11 , C3-7cycloalkyl,
and heterocyclyl, wherein said C3-7cycloalkyl and heterocyclyl
substituents are optionally substituted with one or more substituents
10
15
20
25
(C)
independently selected from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-
4haloalkyl, cyano, NR6R7, C(O)NR8R9
, and C02R10;
5- to 6-membered heteroaryl ring, said ring being fused to a 5- or 6-
membered cycloalkyl or heterocyclyl ring, each of which is optionally
substituted by one or more substituents independently selected from
hydroxy, halo, oxo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7,
C(O)NR8R9
, C02R10
, C1-3alkylene-R11 , C3-7cycloalkyl, and heterocyclyl;
(D) a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl
(E)
ring, said ring being fused to a phenyl or 5- to 6-membered heteroaryl
ring, each of which rings is optionally substituted by one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R11 , C3-7cycloalkyl, and heterocyclyl; OR
a partially unsaturated heterocyclic ring, optionally fused to a 5- to 6-
membered heteroaryl ring and optionally substituted with one or more
substituents independently selected from hydroxy, halo, oxo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, cyano, NR6R7, C(O)NR8R9
, C02R10
, C1_
3alkylene-R11 , C3-7cycloalkyl, and heterocyclyl.
19. The compound according to any one of claims 1 to 16, wherein R4 is a 5- to 10-
membered heteroaryl, C3-7cycloalkyl, or 3- to 12-membered heterocyclyl ring, each
30 of which is optionally substituted by one or more substituents independently selected
from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-2fluoroalkyl, cyano, NR6R7, C(O)NR8R9
,
and C1-3alkylene-R11 .
20. The compound according to claim 18, wherein R4 is a 5- to 6-membered monocyclic
heteroaryl ring, or a 9- to 1 0-membered bicyclic heteroaryl ring, optionally substituted
5
10
wo 2021/239745 PCT/EP2021/063937
21.
22.
192
by one or more substituents independently selected from fluoro, chloro, methyl,
methoxy, trifluoromethoxy, cyano, NR6R7
, cyclopropyl, and CH2-R11 .
The compound according to claim 18, wherein R4 is a partially unsaturated
heterocyclic ring, optionally fused to a 5- to 6-membered heteroaryl ring and
optionally substituted with one or more substituents independently selected from
hydroxy, halo, oxo, C1-2alkyl, C1-2alkoxy, C1-2haloalkyl, and cyano.
The compound according to any one of claims 1 to 16, wherein R4 is selected from
one of the following groups:
~
-o/~~)~
(R18)p
wo 2021/239745 PCT/EP2021/063937
193
wherein:
J'IJVV' is the point of attachment to the rest of the compound of Formula I;
R18 is independently selected from hydroxy, halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl,
cyano, NR6R7, C1-3alkylene-R11, and C3-7cycloalkyl;
5 R19 is independently selected from hydrogen, C1-4alkyl, C1-3alkylene-R11, and C3-
7cycloalkyl; and
pis 0, 1 or 2;
wherein when R4 is a bicyclic group and p is 1 or 2, then each R18 substituent may
be present on either ring of the bicyclic group.
10 23. The compound according to claim 22, wherein R18 is independently selected from
hydroxy, fluoro, chloro, methyl, methoxy, CF3, NR6R7, C1-3alkylene-R11, and
cyclopropyl; and R19 is independently selected from hydrogen, methyl, and
cyclopropyl.
24. The compound according to any one of claims 1 to 23, wherein R5 is selected from
15 hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, and cyano.
25. The compound according to claim 1, wherein the compound has one of the
structural Formulae lA, IB, IC or 10 shown below:
(lA) (I B)
(I C) (I D)
wo 2021/239745 PCT/EP2021/063937
194
wherein X1 to X4 and R4 are as defined in any one of claims 1 to 24; each R17 is
independently selected from halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, and C1-
4haloalkoxy; R20 and R21 are independently selected from hydrogen, halo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy; and n is 0 to 4.
5 26. The compound according to claim 1, wherein the compound has one of the structural
formulae IE, IF, IG, IH, IJ, IK, IL or IM shown below:
(IF)
(I G)
0
(IK)
wo 2021/239745 PCT/EP2021/063937
195
wherein Y, R1, R2, R3
, R4 and R5 are as defined in any one of claims 1 to 24; each
R17 is independently selected from halo, C1-4alkyl, C1-4alkoxy, C1-4haloalkyl, and C1-
4haloalkoxy; R20 and R21 are independently selected from hydrogen, halo, C1-4alkyl,
C1-4alkoxy, C1-4haloalkyl, and C1-4haloalkoxy; and n is 0 to 4.
5 27. The compound according to claim 25 or claim 26, wherein R20 and R21 are
independently selected from hydrogen, fluoro, methyl, trifluoromethyl, and methoxy;
and n is 0.
28. The compound according to claim 26 or claim 27, wherein each R5 is hydrogen.
29. The compound according to claim 1, wherein the compound is selected from one of
10 the following compounds:
N-((S)-2-((4-(1 ,2-dimethyl-6-oxo-1 ,6-dihydropyridin-3-yl)phenyl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((4-(1 ,2-dimethyl-6-oxo-1 ,6-dihydropyridin-3-yl)-3-fluorophenyl)amino)-1-
(( 1 r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
15 1-methyi-N-((S)-1-((1 r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(7 -oxo-6, 7 -dihydro-1 Hpyrrolo[
2, 3-c ]pyridi n-4-yl) phenyl)am i no )ethyl)-1 H-pyrazole-5-carboxam ide;
1-methyi-N-((S)-1-(( 1 r,4S)-4-methylcyclohexyl)-2-oxo-2-((4-(2-oxo-1 ,2-
d i hyd ropyrid i n-4-yl) phenyl)am i no )ethyl)-1 H-pyrazole-5-carboxam ide;
N-((S)-2-((4-(imidazo[1 ,2-a]pyridin-5-yl)phenyl)amino )-1-((1 r,4S)-4-
20 methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((4-(3,5-dimethyl-1 H-pyrazol-4-yl)phenyl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
1-methyi-N-( (S)-1-( ( 1 r,4S)-4-methylcyclohexyl)-2-oxo-2-( ( 4-(3-(2-oxo-2-(pyrrolidin-
1-yl)ethyl)pyridin-4-yl)phenyl)am ino )ethyl)-1 H-pyrazole-5-carboxamide;
25 N-((S)-2-(( 1 I ,21-dimethyi-61-0X0-1 I ,61-dihydro-[3,31-bipyridin]-6-yl)amino)-1-((1 r,4S)-
4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-( (S)-2-( (31
, 51-dimethyl-[3,41-bi pyridi n]-6-yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-
2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-(( 1 I ,21-dimethyi-61-0X0-1 I ,61-dihydro-[3,31-bipyridin]-6-yl)amino)-1-((1 r,4S)-
30 4-methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
N-( (S)-2-( (31
, 51-dimethyl-[3,41-bi pyridi n]-6-yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-
2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
1-methyi-N-( (S)-1-( ( 1 r,4S)-4-methylcyclohexyl)-2-oxo-2-( ( 4-(tetrahydro-2 H-pyran-4-
yl)phenyl)am ino )ethyl)-1 H-pyrazole-5-carboxam ide;
wo 2021/239745 PCT/EP2021/063937
196
N-( (S)-2-( ( 4-( 4-hydroxytetrahydro-2 H-pyran-4-yl)phenyl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( (S)-2-( ( 4-(3, 6-dihydro-2 H-pyran-4-yl)phenyl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
5 N-((S)-2-((4-(3,5-dimethylisoxazol-4-yl)phenyl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( (S)-2-( (5-(3, 5-dimethylisoxazol-4-yl)pyridin-2-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-(1-(4,4-difluorocyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-
1 0 oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((5-(3,5-dimethyl-1 H-pyrazol-4-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-(1-(4,4-dimethylcyclohexyl)-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
15 N-(1-(4,4-difluorocyclohexyl)-2-((4-(1 ,2-dimethyl-6-oxo-1 ,6-dihydropyridin-3-
yl)phenyl)am ino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-(2-((4-(1 ,2-dimethyl-6-oxo-1 ,6-dihydropyridin-3-yl)phenyl)amino)-1-(4,4-
dimethylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-(1-cyclooctyl-2-((4-(3,5-dimethylpyridin-4-yl)phenyl)amino)-2-oxoethyl)-1-methyl-
20 1 H-pyrazole-5-carboxamide;
N-( 1-cyclooctyl-2-( ( 4-(3, 5-dimethyl-1 H-pyrazol-4-yl)phenyl)am ino )-2-oxoethyl)-1-
methyl-1 H-pyrazole-5-carboxamide;
N-(1-Cyclooctyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-oxoethyl)-1-
methyl-1 H-pyrazole-5-carboxamide;
25 N-((S)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( 1-cyclooctyl-2-( ( 4-( 1 ,2-dimethyl-6-oxo-1, 6-di hydropyridin-3-yl)phenyl)am ino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
30 oxoethyl)-1-isopropyl-1 H-pyrazole-5-carboxam ide;
N-( ( S)-2-( (5-(3, 5-Dimethylisoxazol-4-yl)pyridin-2-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
N-( ( S)-2-( (5-(3, 5-dimethylisoxazol-4-yl)pyridin-2-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1 H-pyrazole-5-carboxamide;
35 N-(( S)-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
wo 2021/239745 PCT/EP2021/063937
197
N-( ( S)-2-( (5-(3, 5-dimethylisoxazol-4-yl)pyridin-2-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
N-( 1-Cycl ooctyl-2 -( ( 5-( 1 , 4-d i methyl-1 H-pyrazol-5-yl) pyri di n-2 -yl) ami no )-2 -oxoethyl)-
1-methyl-1 H-pyrazole-5-carboxamide;
5 (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
1 0 oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
(S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
15 (S)-N-(1-Cyclohexyl-2-((4-(1 ,2-dimethyl-6-oxo-1 ,6-dihydropyridin-3-
yl)phenyl)am ino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( ( S)-2-( (5-(3, 5-Dimethylisoxazol-4-yl)pyridin-2-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2 -oxoethyl)-4-methyl-1 ,2, 5-oxad iazole-3-carboxam ide;
(S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
20 oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-isopropyl-1 H-pyrazole-5-carboxam ide;
25 (S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-(( S)-2-((5-(1 ,4-Dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
30 methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
N-(( S)-2-((5-(1 ,4-Dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
(S)-N-(1-Cycloheptyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-4-methyl-1 ,2, 5-oxadiazole-3-carboxamide;
35 (S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
wo 2021/239745 PCT/EP2021/063937
198
(S)-N-(1-Cyclohexyl-2-((5-(3,5-dimethylisoxazol-4-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1 , 2, 3,4-tetrahyd ropyrrolo[1 , 2 -a] pyrazi ne-6-carboxam ide;
N-(( S)-2-((5-(1 ,4-Dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
5 ( S)-N-(1-Cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
( S)-N-(1-Cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
( S)-N-(1-Cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
1 0 oxoethyl)-4-methyl-1 ,2,5-oxadiazole-3-carboxamide;
N-( ( S)-2-( (2-(3, 5-dimethylisoxazol-4-yl)pyrimidin-5-yl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
( S)-N-(1-Cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-3-methylisoxazole-4-carboxamide;
15 ( S)-N-(1-Cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-3-( methoxym ethyl) isoxazole-4-carboxam ide;
N-( ( S)-2-( (6-(3, 5-dimethylisoxazol-4-yl)pyridin-3-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
6-(( S)-2-(1-Ethyl-1 H-pyrazole-5-carboxamido )-2-((1 r,4S)-4-
20 methylcyclohexyl)acetamido)-3',5'-dimethyl-[3,4'-bipyridine] 1'-oxide;
3-ethyi-N-( (S)-1-( ( 1 r,4S)-4-methylcyclohexyl)-2-( (5-(5-methylpyrimidin-4-yl)pyridin-
2 -yl) ami no )-2 -oxoethyl) isoxazole-4-carboxam ide;
(S)-N-( 1-cycloheptyl-2-( (5-( 1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-2-
oxoethyl)-1-ethyl-1 H-1 ,2, 3-triazole-5-carboxamide;
25 N-( (S)-2-( (5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2-yl)amino )-1-
(( 1 r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (5-(3, 5-dimethyi-4H-1 ,2 ,4-triazol-4-yl)pyridin-2-yl)am ino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(1-(4,4-difluorocyclohexyl)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-
30 yl)amino)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
1-methyi-N-((S)-2-((4-methyl-5-(1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-
( ( 1 r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1 H-pyrazole-5-carboxamide;
35 N-((S)-2-((2-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyrimidin-5-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
wo 2021/239745 PCT/EP2021/063937
199
(S)-N-(1-cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(1-cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
5 (S)-N-( 1-cycloheptyl-2 -( ( 5-( 5-( m ethoxymethyl)-3-methyl isoxazol-4-yl) pyrid in-2-
yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-( (S)-2-( (3'-methoxy-2'-methyl-[3,4'-bipyridin]-6-yl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( (S)-2-( (2', 3'-dimethyl-[3,4'-bi pyridi n]-6-yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-
1 0 2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-( (S)-2-( (2', 5'-dimethyl-[3,4'-bi pyridi n]-6-yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-
2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
15 N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((2-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyrimidin-5-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
(S)-N-(1-cycloheptyl-2-((5-(1-ethyl-4-methyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-
20 yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( ( 5-(3, 5-d i methyl isoxazol-4-yl) pyrazi n-2 -yl)am i no )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
25 N-((S)-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-(1-cycloheptyl-2-((5-(1-cyclopropyl-4-methyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-
yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( ( 5-(3, 5-d i methyl isoxazol-4-yl)-3-fl uoropyrid i n-2 -yl)am i no )-2-
30 oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( ( 5-(3, 5-d i methyl isoxazol-4-yl)-3-fl uoropyrid i n-2 -yl)am i no )-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( ( 5-(3, 5-d i methyl isoxazol-4-yl)-3-fl uoropyrid i n-2 -yl)am i no )-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
35 (S)-N-(1-cycloheptyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyrimidin-2-yl)amino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
wo 2021/239745 PCT/EP2021/063937
200
(S)-N-( 1-cycloheptyl-2-( (5-( 4-hydroxy-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-
2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
5 N-((S)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-1 ,2,3-triazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( (6-(3, 5-d i methyl isoxazol-4-yl) pyrid i n-3-yl) ami no )-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( (6-(3, 5-d i methyl isoxazol-4-yl) pyrid i n-3-yl) ami no )-2-
10 oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( (6-(3, 5-d i methyl isoxazol-4-yl) pyrid i n-3-yl) ami no )-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
(S)-N-( 1-cycloheptyl-2 -( (6-(3, 5-d i methyl isoxazol-4-yl) pyrid i n-3-yl) ami no )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
15 (S)-N-(1-cycloheptyl-2-((5-(4-cyclopropyl-1-methyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-
yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(2-( (5-( 4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-1-cycloheptyl-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-(2-( (5-( 4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-1-cycloheptyl-2-
20 oxoethyl)-3-ethyl isoxazole-4-carboxam ide;
(S)-N-(2-( (5-( 4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-1-cycloheptyl-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cyclohexyl-2-( (5-( 1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
25 (S)-N-(1-cyclohexyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino )-1-((1 r,4S)-4-
30 methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
(S)-N-( 1-cyclohexyl-2-( (5-( 1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-2-
oxoethyl)-3-methylisoxazole-4-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (5-( 4-(hydroxymethyl)-1-methyl-1 H-pyrazol-5-yl)pyridin-2-
yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
35 (S)-N-(1-cyclopentyl-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
wo 2021/239745 PCT/EP2021/063937
201
N-(1-(bicyclo[2.2.1 ]heptan-2-yl)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-
yl)amino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-(2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-2-oxo-1-((1 r,4r)-4-
(trifluoromethyl)cyclohexyl)ethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
5 N-(2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-2-oxo-1-((1 r,4r)-4-
(trifluoromethyl)cyclohexyl)ethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
N-(2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-2-oxo-1-((1 r,4r)-4-
(trifluoromethyl)cyclohexyl)ethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((5-(1 ,4-dimethyl-1 H-1 ,2,3-triazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
1 0 methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-5-fluoropyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
(S)-N-(1-cycloheptyl-2-((5-(1-(2-( dimethylamino )-2-oxoethyl)-4-methyl-1 H-1 ,2,3-
triazol-5-yl)pyridin-2-yl)am ino )-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
15 N-((S)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-isopropylisoxazole-4-carboxamide;
3-(tert-butyi)-N-( (S)-2-( (5-( 1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)am ino )-1-
( ( 1 r, 48)-4-methylcyclohexyl)-2 -oxoethyl) isoxazole-4-carboxam ide;
N-((S)-2-((5-(4-cyano-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
20 methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-(trifluoromethyl)isoxazole-4-carboxamide;
(S)-N-( 1-cycloheptyl-2-oxo-2-( (5-( 1 , 3,4-trimethyl-1 H-pyrazol-5-yl)pyridin-2-
yl)amino )ethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
25 N-( (S)-2-( (5-(3, 5-dimethylisothiazol-4-yl)pyridin-2-yl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
N-( (S)-2-( (5-(3, 5-dimethylisothiazol-4-yl)pyridin-2-yl)am ino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (5-( 4-(hydroxymethyl)-1-methyl-1 H-pyrazol-5-yl)pyridin-2-
30 yl)amino )-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((5-(4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
N-((S)-2-((5-(4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
35 N-((S)-2-((5-(4-chloro-1-methyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
wo 2021/239745 PCT/EP2021/063937
202
(S)-N-( 1-cycloheptyl-2-( (5-( 4-(hydroxymethyl)-1-methyl-1 H-pyrazol-5-yl)pyridin-2-
yl) ami no )-2 -oxoethyl)-3-ethyl isoxazole-4-carboxam ide;
N-( (S)-2-( (6-(3, 5-dimethylisoxazol-4-yl)pyridin-3-yl)amino )-1-( ( 1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
5 N-((S)-2-((6-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-3-yl)amino)-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1 H-pyrazole-5-carboxamide;
1-ethyi-N-((S)-2-((5-(4-(hydroxymethyl)-1-methyl-1 H-pyrazol-5-yl)pyridin-2-
yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1 H-pyrazole-5-carboxamide;
N-( (S)-2-( (6-(3, 5-dimethylisoxazol-4-yl)pyridin-3-yl)amino )-1-( ( 1 r,4S)-4-
1 0 methylcyclohexyl)-2-oxoethyl)-1-isopropyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cyclohexyl-2-( (6-(3, 5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)am ino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (6-(3, 5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-2-
oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxamide;
15 (S)-N-(1-cycloheptyl-2-((6-(3,5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino)-2-
oxoethyl)-1-methyl-1 H-1 ,2,3-triazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (6-(3, 5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-2-
oxoethyl)-3-ethylisoxazole-4-carboxamide;
N-((S)-2-((6-(3,5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-1-((1 r,4S)-4-
20 methylcyclohexyl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
N-((S)-2-((6-(3,5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-1-ethyl-1 H-pyrazole-5-carboxam ide;
N-((S)-2-((6-(3,5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-1-((1 r,4S)-4-
methylcyclohexyl)-2-oxoethyl)-3-ethylisoxazole-4-carboxamide;
25 (S)-N-(1-cycloheptyl-2-oxo-2-(( 1 I ,21 ,41-trimethyi-61-0X0-1 I ,61-dihydro-[3,31-bipyridin]-
6-yl)ami no )ethyl)-1-methyl-1 H-pyrazole-5-carboxam ide;
1-methyi-N-((S)-1-(( 1 r,4S)-4-methylcyclohexyl)-2-oxo-2-(( 1 I ,21 ,41-trimethyi-61-0X0-
1 I, 61-dihydro-[3, 31-bipyridin]-6-yl)am ino )ethyl)-1 H-pyrazole-5-carboxam ide;
(S)-N-( 1-cycloheptyl-2-oxo-2-( (5-( 1 , 3, 5-trimethyl-1 H-pyrazol-4-yl)pyridin-2-
30 yl)amino )ethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
1-methyi-N-((S)-1-(( 1 r,4S)-4-methylcyclohexyl)-2-oxo-2-((5-(1 ,3,5-trimethyl-1 Hpyrazol-
4-yl)pyridin-2-yl)amino)ethyl)-1 H-pyrazole-5-carboxamide;
(S)-N-( 1-cycloheptyl-2-( (6-(3, 5-dimethyl-1 H-pyrazol-4-yl)pyridin-3-yl)amino )-2-
oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
35 1-methyi-N-(( S)-2-((5-(1-methyl-4-(trifluoromethyl)-1 H-pyrazol-5-yl)pyridin-2-
yl)am ino )-1-( ( 1 r,4S)-4-methylcyclohexyl)-2-oxoethyl)-1 H-pyrazole-5-carboxamide;
or
wo 2021/239745 PCT/EP2021/063937
203
N-(2-((5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)pyridin-2-yl)amino )-1-
( dispiro[2.1.25.23]nonan-4-yl)-2-oxoethyl)-1-methyl-1 H-pyrazole-5-carboxamide;
or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising a compound according to any one of
5 claims 1 to 29, or a pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients.
31. A compound according to any one of claims 1 to 29, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according to claim 30, for
use in therapy.
10 32. A compound according to any one of claims 1 to 29, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according to claim 30, for
use in the treatment of acute lung injury, Alzheimer's Disease, ankylosing
spondylitis, axial spondyloarthritis and other spondyloarthropathies, arthritis, asthma
(including severe asthma), atopic dermatitis, autoimmune diabetes other
15 autoimmune disorders, autoimmune thyroiditis, bone resorption, cancer (both solid
tumours such as melanomas, sarcomas, squamous cell carcinomas, transitional call
cancers, ovarian cancers and hematologic malignancies and in particular acute
myelogenous leukaemia, chronic lymphocytic leukemia, gastric cancer, and colon
cancer), Castleman's disease, contact dermatitis, Crohn's Disease, chronic
20 myelogenous leukemia, chronic obstructive pulmonary disease (COPD), coeliac
disease, cystic fibrosis, dermatomyositis, discoid lupus erythematosus, eczema,
enthesitis-related arthritis, endotoxic shock associated with infection, exophthalmos,
fibrosing disorders including pulmonary fibrosis, gall bladder disease, giant cell
arteritis, graft-versus-host disease, heart disease including ischaemic diseases such
25 as myocardial infarction as well as atherosclerosis, hepatoblastomas,
hypochlorhydia, immune mediated inflammatory disorders of the central and
peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome,
infections (viral, bacterial, fungal, and parasitic), inflammatory bowel disease,
intravascular coagulation, irritable bowel syndrome, liver fibrosis, Iyme arthritis,
30 meningoencephalitis, myocarditis, meningoencephalitis, osteoporosis, pancreatitis,
Parkinson's disease, pelvic inflammatory disease, pain (particularly pain associated
with inflammation), periodontitis, peritonitis, Peyronie's Disease, Pilonidal disease,
psoriasis, psoriatic arthritis (PsA), renal fibrosis, rheumatoid arthritis, scleroderma or
systemic sclerosis, stroke, surgical adhesions, systemic lupus erythematosus (SLE),
wo 2021/239745 PCT/EP2021/063937
204
systemic onset juvenile idiopathic arthritis (JIA), trauma (surgery), transplant
rejection, Type I diabetes, ulcerative colitis, uveitis or vasculitis.