BACKGROUND
Although inflammation can be a protective mechanism in response to harmful stimuli
such as invasion of pathogens and tissue damages, chronic inflammation is an
10 important underlying factor in many human diseases such as neurodegeneration,
rheumatoid arthritis, autoimmune and inflammatory diseases, and cancer. Similarly,
the activation of cell death pathways, such as necrosis and apoptosis which are
useful in eliminating infected or damaged cells, is also an important underlying
mechanism for human diseases, including acute and chronic neurodegenerative
15 diseases. Receptor-interacting protein kinase 1 (UniProtKB 013546) is a key
regulator of inflammation, apoptosis and necroptosis. Receptor-interacting protein
kinase 1 has an important role in modulating inflammatory responses mediated by
nuclear-factor kappa-light chain enhancer of activated B cells (NF-KB). More recent
research has shown that its kinase activity controls necroptosis, a form of necrotic
20 cell death, which was traditionally thought to be passive and unregulated, and is
characterized by a unique morphology. Further, receptor- interacting protein kinase 1
is part of a pro-apoptotic complex indicating its activity in regulating apoptosis.
The receptor-interacting protein kinase 1 is subject to complex and intricate
25 regulatory mechanisms, including ubiquitylation, deubiquitylation, and
phosphorylation. These regulatory events collectively determine whether a cell will
survive and activate an inflammatory response or die through apoptosis or
necroptosis. Dysregulation of receptor- interacting protein kinase 1 signaling can
lead to excessive inflammation or cell death, and conversely, research has shown
30 that inhibition of receptor interacting protein kinase 1 can be effective therapies for
diseases involving inflammation or cell death.
35 RIPK1 inhibition has been identified as promising principle to address different
diseases like rheumatoid arthritis (RA), psoriasis, multiple sclerosis, Alzheimer's
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disease, inflammatory bowel disease such as Crohn's disease or ulcerative colitis
(UC). To treat some of these diseases like multiple sclerosis (MS) and Alzheimer's
disease, access to the central nervous system (CNS) is required, while for other
diseases like rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) such
5 as Crohn's disease or UC access to the CNS is not essentially required.
The most advanced RIPK1 inhibitor, GSK2982772 (oxazepinone derivative disclosed
in W02014/125444), was evaluated for RA, psoriasis and UC in phase II clinical
trails. Interestingly, during the toxicological evaluation of GSK2982772 in monkeys
central side effects like irregular gait and uncoordinated movement were reported at
10 doses :?:1 00 mg/kg (GSK2982772; Savage, Published Phase I Protocol Amendment,
2017).
[1-(6-Methoxypyrimidin-4-yl)-4-piperidyi]-[(3S)-3-(3,5-difluorophenyl)isoxazolidin-2-
yl]methanone (comparator compound K, see Example section) is a brain
15 permeable, close analogue to the isoxazolidine derivatives claimed in
W02019130230 and W02020043173, and when applied to cynomolgus monkeys
(1 mg/kg, i.v.) severe side effects were observed (hypoactivity followed by
decubitus, hyporeactivity, limb stiffness and hypotonic with phases of prostration).
Histopathological examination revealed bilateral and symmetrical lesions of brain
20 necrosis (i.e., malacia) located in the basal ganglia (globus pallidus) and the
hypothalamic area, consisting of neuronal necrosis, spongiosis, cellular infiltration
dominated by a population of macrophages, and reactive neocapillaries.
For this isoxazolidine derivative, comparator compound K, which showed severe
25 CNS related side effects in the monkey as described above, a TPSA of 68 A2 was
attributed. In the mouse 15 min after i.v. application of 3 mg/kg a brain/blood ratio
of 2.1 and brain levels of 1.58 1-Jg/ml were observed confirming the good brain
permeability of this kind of compounds. 2 h after oral application of 30 mg/kg to the
mouse a brain/plasma ratio of 1.6 was determined.
30
Therefore, to avoid possible CNS-associated side effects this invention relates to
RIPK1 inhibitor compounds with reduced ability to cross the blood-brain-barrier. In
the literature there are some compound properties described that are correlated
with low blood-brain-barrier permeability like the topologic polar surface area
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(TPSA) and the number of hydrogen bond donors (HBD) (Eur. J. Med. Chem. 185
(2020) 111813). Molecules possessing a TPSA of> 75 A2 are considered to show
impaired brain penetration.
Different RIPK1 inhibitors were already described (e.g. W02014/125444,
5 W02016/185423), W02016027253 (GSK), W02018/092089).
Denali discloses also benzoxapine derivatives in W02017136727 and
W02018213632. Other chemical classes of RIPK1 inhibitors are bicyclic sulfones
and sulfoxides (W02019086494, Roche), heterocyclic compounds
(W02017069279, Takeda), as well as other benzoxazepinones (W02019204537,
10 Genetech).
Interestingly, in W02016/1 01887 WO 2017/096301, W02020043173 and
W02019/130230 that are also related to isoxazolidine derivatives as RIPK1
inhibitors, compounds with a TPSA up to 102 A2 like example 4 in
W02019/130230 (comparator compound D) are described. Although the TPSA of
15 this compound is well above 75 A2 it, surprisingly, shows still good brain
penetration (brain/plasma ratio 1.1 (2 h after oral application of 30 mg/kg in
mouse)). Therefore, at least reasonable CNS penetration can be expected for the
compounds described in these applications with a TPSA of about/up to 100 A2.
20 To increase the probability of obtaining reduced brain levels this invention is
related to new isoxazolidine derivatives as RIPK1 inhibitors possessing a TPSA
>90 A2 , preferably >1 05 A2, most preferable >120 A2.
To obtain compounds that only poorly penetrate into the CNS polar heterocycles
were implemented in the so called deep pocket 1 (DP1 ). In the literature (J. Med.
25 Chem. 2019, 62, 10, 5096-511 0) replacement of highly potent unsubstituted or
halogen substituted phenyl derivatives in DP1 by heterocycles like 2-, 3- or 4-
pyridyl, pyrazol-3-yl, imidazol-4-yl or 4-oxazolyl derivatives resulted in a significant
drop in enzymatic and cellular activity.
Surprisingly, we could identify compounds with heterocyclic groups in DP1 that
30 showed good potency in the enzymatic ADP-glo and the cellular U937 assay with
a TPSA >90 A2 and showed no CNS related side effects in the monkey.
The invention relates to compounds of formula 1:
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t{
R2
(RJ)m (I)
wherein
R1 represents a 5-6 membered heteroaryl in which 1 to 4 ringatoms are
5 independently selected from -N-, -0- or-S-and wherein R1 is optionally
substituted by 1 to 4 substituents independently selected from
halogen,
-(C1-C4)alkyl,
-O(C1-C4)alkyl,
10 -S(C1-C4)alkyl,
-S(O)(C1-C4)alkyl,
-S(0)2(C1-C4)alkyl,
-O(C 1-C4 )alkyi-R4,
-CN,
15 -(CO)OH,
-(CO)O(C1-C4)alkyl,
-NRaRb,
-(CO)NRaRb, and
-(CO)NRcRd;
20 wherein Ra and Rb are independently from each other H or (C1-C4)alkyl;
and
wherein Rc isH or (C1-C4)alkyl; and
wherein Rd is -(CH2)x-(C3-C7)cycloalkyl or -(CH2)x-(C3-C7)heterocyclyl,
wherein cycloalkyl or heterocyclyl is optionally substituted with 1 to 3
25 substituents selected from (C1-C4)alkyl, (CO)OH or (CO)O(C1-C4)alkyl;
x is an integer 0, 1, 2 or 3;
R2
is a 5-10 membered heteroaryl or 5 to 6 membered heterocycle, wherein 1 to 4
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ring atoms are independently selected from -N-, -0- or -S-, and wherein heteroaryl
or heterocycle is optionally substituted by 1 to 4 substituents selected from
halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyi-OH, -(CO)NReRf and -NReRf, wherein
Re and Rf are independently selected from H, (C1-C4)alkyl or -CO(C1-C4)alkyl; or
5 wherein Re and Rf form together with the nitrogen atom to which they are attached
a 4 to 6 membered ring, which is optionally substituted with oxo;
R3 is halogen or (C1-C2)alkyl;
10 m is an integer 0, 1, 2, 3 or 4;
R4 is OH, CN, -(CO)OH, -(CO)NRgRh or -(CO)O(C1-C4)alkyl;
wherein Rg and Rh are independently selected from H or (C1-C4)alkyl;
15 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
20
In another aspect provided are methods for making the compounds and
intermediates thereof.
In a related aspect, provided herein is a pharmaceutical composition comprising a
compound as described herein and a pharmaceutically acceptable excipient.
In another aspect, provided herein is a method of inhibiting receptor-interacting
25 protein kinase 1. Further provided are methods for treating receptor-interacting
protein kinase 1-mediated disease or disorder comprising administering a
therapeutically effective amount of a compound or a pharmaceutical composition
as described herein to a subject in need thereof. The disclosure also provides
uses of the compounds or compositions thereof in the manufacture of a
30 medicament for the treatment of a disease, disorder or condition that is mediated
by (or mediated, at least in part, by) receptor-interacting protein kinase 1.
Detailed Description
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Definitions
As used herein, the term "alkyl," by itself or as part of another substituent, refers to a
straight or branched, saturated, aliphatic radical having the number of carbon atoms
indicated. Alkyl can include any number of carbons, such as C1-2, C1-3, C1-4, C1-s, C1-
5 6, C1-7, C1-s, C1-9, C1-1o, C2-3, C2-4, C2-s, C2-6, C3-4, C3-s, C3-6, C4-s, C4-6 and Cs-6. For
example, (C1-4)alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl. Alkyl can also refer to alkyl groups having up to
20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl
groups can be substituted or unsubstituted.
10 As used herein, the term "alkoxy," by itself or as part of another substituent, refers
to a group having the formula -OR, wherein R is alkyl.
As used herein, the term "cycloalkyl," by itself or as part of another substituent,
refers to a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged
15 polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms
indicated.
Cycloalkyl can include any number of carbons, such as C3-6, C4-6, Cs-6, C3-B, C4-B, Css,
C6-B, C3-9, C3-1o, C3-11, and C3-12. Saturated monocyclic cycloalkyl rings include, for
20 example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated
bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]
bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also
be partially unsaturated, having one or more double or triple bonds in the ring.
Representative cycloalkyl groups that are partially unsaturated include, but are not
25 limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1 ,3- and 1,4-
isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1 ,3-, 1,4-
and 1 ,5-isomers), norbornene, and norbornadiene.
When cycloalkyl is a saturated monocyclic C3-6 cycloalkyl, exemplary groups include,
but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl
30 groups can be substituted or unsubstituted.
As used herein, the term "heteroalkyl," by itself or as part of another substituent,
refers to an alkyl group of any suitable length and having from 1 to 3 heteroatoms
such as N, 0 and S, provided that the attachment of the substituent is at a carbon
atom. For example, heteroalkyl can include ethers, thioethers and alkyl-amines.
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The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)and
-S(0)2-. The heteroatom portion of the heteroalkyl can replace a hydrogen of the
alkyl group to form a hydroxy, thio, or amino group. Alternatively, the heteroatom
portion can be inserted between two carbon atoms.
5 As used herein, the term "alkenyl" by itself or as part of another substituent, refers to
a straight chain or branched hydrocarbon having at least 2 carbon atoms and at least
one double bond. Alkenyl can include any number of carbons, such as C2, C2-3, C2-4,
C2-s, C2-6, C2-1, C2-a, C2-9, C2-1o, C3, C3-4, C3-s, C3-6, C4, C4-s, C4-6, Cs, Cs-6, and C6.
Alkenyl groups can have any suitable number of double bonds, including, but not
10 limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not
limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl,
butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1 ,3-pentadienyl, 1 ,4-pentadienyl, 1-
hexenyl, 2-hexenyl, 3-hexenyl, 1 ,3-hexadienyl, 1 ,4-hexadienyl, 1 ,5-hexadienyl, 2,4-
hexadienyl, or 1 ,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.
15 As used herein, the term "alkynyl," by itself or as part of another substituent refers, to
either a straight chain or branched hydrocarbon having at least 2 carbon atoms and
at least one triple bond. Alkynyl can include any number of carbons, such as C2, C2-3,
C2-4, C2-s, C2-6, C2-1, C2-s, C2-9, C2-1o, C3, C3-4, C3-s, C3-6, C4, C4-s, C4-6, Cs, Cs-6, and C6.
Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-
20 butynyl, 2-butynyl, isobutynyl, sec-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl,
isopentynyl, 1 ,3-pentadiynyl, 1 ,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-
hexadiynyl, 1 ,4-hexadiynyl, 1 ,5-hexadiynyl, 2,4-hexadiynyl, or 1 ,3,5-hexatriynyl.
Alkynyl groups can be substituted or unsubstituted.
As used herein, the terms "halo" and "halogen", by themselves or as part of another
25 substituent, refer to a fluorine, chlorine, bromine, or iodine atom.
As used herein, the term "haloalkyl", by itself or as part of another substituent, refers
to an alkyl group where some or all of the hydrogen atoms are replaced with halogen
atoms. As for alkyl groups, haloalkyl groups can have any suitable number of carbon
atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl,
30 etc. In some instances, the term "perfluoro" can be used to define a compound or
radical where all the hydrogens are replaced with fluorine. For example,
perfluoromethyl refers to 1,1, 1-trifluoromethyl.
As used herein, the term "aryl", by itself or as part of another substituent, refers to an
aromatic ring system having any suitable number of carbon ring atoms and any
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suitable number of rings. Aryl groups can include any suitable number of carbon ring
atoms, such as C6, C7, Cs, C9, C10, C11, C12, C13, C14, C1s, or C16, as well as Cs-7, Cs-
10, C6-10, C6-12, or C6-14. Aryl groups can be monocyclic, fused to form bicyclic (e.g.,
benzocyclohexyl), or tricyclic groups, or linked by a bond to form a biaryl g roup.
5 Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups
include benzyl, having a methylene linking group. Some aryl groups have from 6 to
12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have from
6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6
ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.
10 Unless otherwise specified, "substituted aryl" groups can be substituted with one or
more halo, hydroxy, amino, alkylamine, amido, acyl, nitro, cyano, and/or alkoxy
groups.
As used herein, the term "heteroaryl", by itself or as part of another substituent,
15 refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly
containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are heteroatoms
such as N, 0, or S.
The heteroatoms can be oxidized to form moieties such as, but not limited to, -
S(O)- and -S(0)2-. Heteroaryl groups can include any number of ring atoms, such
20 as Cs-6, C3-B, C4-B, Cs-7, Cs-s, C6-B, C3-9, C3-1o, C3-11, Cs-1o, or C3-12, wherein at least
one of the carbon atoms is replaced by a heteroatom. Any suitable number of
heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1
to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5.
25 For example, heteroaryl groups can be Cs-8 heteroaryl, wherein 1 to 4 carbon ring
atoms are replaced with heteroatoms; or Cs-8 heteroaryl, wherein 1 to 3 carbon
ring atoms are replaced with heteroatoms; or Cs-6 heteroaryl, wherein 1 to 4
carbon ring atoms are replaced with heteroatoms; or Cs-6 heteroaryl, wherein 1 to
3 carbon ring atoms are replaced with heteroatoms. The heteroaryl group can
30 include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole,
pyrazine, pyrimidine, pyridazine, triazine (1 ,2,3-, 1 ,2,4- and 1 ,3,5-isomers),
thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl
groups can also be fused to aromatic ring systems, such as a phenyl ring, to form
members including, but not limited to, benzopyrroles such as indole and isoindole,
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benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline),
benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and
cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include
heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be
5 substituted or unsubstituted. The heteroaryl groups can be linked via any position
on the ring. For example, pyrrole includes 1-, 2- and 3-pyrrole, pyridine includes 2-
, 3- and 4-pyridine, imidazole includes 1-, 2-, 4- and 5-imidazole, pyrazole includes
1-, 3-, 4- and 5-pyrazole, triazole includes 1-, 4- and 5-triazole, tetrazole includes
1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5- and 6- pyrimidine, pyridazine
10 includes 3- and 4-pyridazine, 1 ,2,3-triazine includes 4- and 5-triazine, 1 ,2,4-
triazine includes 3-, 5- and 6-triazine, 1 ,3,5-triazine includes 2-triazine, thiophene
includes 2- and 3-thiophene, furan includes 2- and 3-furan, thiazole includes 2-, 4-
and 5-thiazole, isothiazole includes 3-, 4- and 5-isothiazole, oxazole includes 2-, 4-
and 5-oxazole, isoxazole includes 3-, 4- and 5-isoxazole, indole includes 1-, 2- and
15 3-indole, isoindole includes 1- and 2-isoindole, quinoline includes 2-, 3- and 4-
quinoline, isoquinoline includes 1-, 3- and 4-isoquinoline, quinazoline includes 2-
and 4-quinoazoline, cinnoline includes 3- and 4-cinnoline, benzothiophene
includes 2- and 3-benzothiophene, and benzofuran includes 2- and 3-benzofuran.

Claims
5 1. A compound of formula 1:
t(
R2
(R3)m (I)
wherein
R1 represents a 5-6 membered heteroaryl in which 1 to 4 ringatoms are
10 independently selected from -N-, -0- or-S-and wherein R1 is optionally
substituted by 1 to 4 substituents independently selected from
halogen,
-(C1-C4)alkyl,
-O(C1-C4)alkyl,
15 -S(C1-C4)alkyl,
-S(O)(C1-C4)alkyl,
-S(0)2(C1-C4)alkyl,
-O(C1-C4)alkyi-R4,
-(CO)OH,
20 -CN,
-(CO)O(C1-C4)alkyl,
-NRaRb,
-(CO)NRaRb, and
-(CO)NRcRd;
25 wherein Ra and Rb are independently from each other H or (C1-C4)alkyl; and
wherein Rc isH or (C1-C4)alkyl; and
wherein Rd is -(CH2)x-(C3-C7)cycloalkyl or -(CH2)x-(C3-C7)heterocyclyl,
wherein cycloalkyl or heterocyclyl is optionally substituted with 1 to 3
R2
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354
substituents selected from (C1-C4)alkyl, (CO)OH or (CO)O(C1-C4)alkyl;
x is an integer 0, 1, 2 or 3;
5 is a 5-10 membered heteroaryl or 5 to 6 membered heterocycle, wherein 1 to 4 ring
atoms are independently selected from -N-, -0- or -S-, and wherein heteroaryl or
heterocycle is optionally substituted by 1 to 4 substituents selected from
halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyi-OH, -(CO)NReRf and -NReRf, wherein Re
and Rf are independently selected from H, (C1-C4)alkyl or -CO(C1-C4)alkyl; or
1 o wherein Re and Rf form together with the nitrogen atom to which they are attached a
4 to 6 membered ring, which is optionally substituted with oxo;
R3 is Halogen or (C1-C2)alkyl;
15 m is an integer 0, 1, 2, 3 or 4;
R4 is OH, CN, -(CO)OH, -(CO)NRgRh or -(CO)O(C1-C4)alkyl;
wherein Rg and Rh are independently selected from H or (C1-C4)alkyl;
20 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
2. A compound of the formula I according to claim 1, with a TPSA (topological polar
surface area) value of 90 A2 or more;
25 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
3. A compound of the formula I according to claim 1, with a TPSA (topological polar
surface area) value of 105 A2 or more;
30 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
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4. A compound of the formula I according to claims 1, 2 or 3, wherein
R1 represents a 5-6 membered heteroaryl in which 1 to 2 ringatoms are -N-atoms
and wherein R1 is optionally substituted by 1 to 3 substituents independently
5 selected from
halogen,
-(C1-C4)alkyl,
-O(C1-C4)alkyl,
-S(C1-C4)alkyl,
10 -S(O)(C1-C4)alkyl,
-S(0)2(C1-C4)alkyl,
-O(C1-C4)alkyi-R4,
-(CO)OH,
-CN,
15 -(CO)O(C1-C4)alkyl,
-NRaRb,
-(CO)NRaRb, and
-(CO)NRcRd;
wherein Ra, Rb are independently from each other H or (C1-C4)alkyl; and
20 wherein Rc isH or (C1-C4)alkyl; and
25
R2
wherein Rd is -(CH2)x-cycloalkyl or -(CH2)x-heterocyclyl, wherein cycloalkyl or
heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C1-
C4)alkyl, COOH or COO(C1-C4)alkyl;
x is an integer 0, 1, 2 or 3;
is a 5-10 membered heteroaryl or 5 to 6 membered heterocycle, wherein 1 to 3 ring
atoms are independently selected from -N-, -0- or -S-, and wherein heteroaryl or
heterocycle is optionally substituted by 1 to 2 substituents selected from halogen,
30 CN, -(C1-C4)alkyl, -(C1-C4)alkyi-OH, (CO)NReRf and -NReRf, wherein Re and Rf are
independently selected from H, (C1-C4)alkyl or -CO(C1-C4)alkyl; or wherein Re and
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Rf form together with the nitrogen atom to which they are attached a 4 to 6 membered
ring, which is optionally substituted with oxo;
R3 is F, Cl, methyl or ethyl;
5 m is an integer 0, 1 or 2.
10
R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3 or -(CO)O(C1-C4)alkyl;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
5. A compound of the formula I as claimed in any of claims 1 to 4, wherein
R1 is pyridyl, pyrazinyl or pyrimidinyl and wherein R1 is optionally substituted by 1
to 2 substituents independently selected from
15 halogen,
-(C1-C4)alkyl,
-O(C1-C4)alkyl,
-S(C1-C4)alkyl,
-S(O)(C1-C4)alkyl,
20 -S(0)2(C1-C4)alkyl,
-O(C1-C4)alkyi-R4,
-(CO)OH,
-CN,
-(CO)O(C1-C4)alkyl,
25 -NRaRb,
-(CO)NRaRb, and
-(CO)NRcRd;
wherein Ra, Rb are independently from each other H or (C1-C4)alkyl; and
wherein Rc isH or (C1-C4)alkyl; and
30 wherein Rd is -(CH2)x-cycloalkyl or -(CH2)x-heterocyclyl, wherein cycloalkyl or
heterocyclyl is optionally substituted with 1 to 3 substituents selected from (C 1-
R2
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357
C4)alkyl, (CO)OH or (CO)O(C1-C4)alkyl;
x is an integer 0, 1, 2 or 3;
PCT/EP2021/064657
5 is a 5-10 membered heteroaryl wherein 1 to 3 ring atoms are independently selected
from -N-, or -S-, or a 5 to 6 membered heterocycle, wherein 1 to 2 ring atoms are
independently selected from -N-, -0- or -S-,
and wherein heteroaryl or heterocycle is optionally substituted by 1 to 2 substituents
selected from
10 halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyi-OH, (CO)NReRf and -NReRf, wherein Re
and Rf are independently selected from H, (C1-C4)alkyl or -CO(C1-C4)alkyl; or
wherein Re and Rf form together with the nitrogen atom to which they are attached a
4 to 6 membered ring, which is optionally substituted with oxo at the position adjacent
to the nitrogen atom;
15
R3 is F or methyl;
m is an integer 0 or 1;
R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3 or -(CO)O(C1-C4)alkyl;
20 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
6. A compound of the formula I as claimed in any one of claims 1 to 5, wherein
25 R1 is pyridyl, pyrazinyl or pyrimidinyl and wherein R1 is optionally substituted by 1
to 2 substituents independently selected from
F, Cl,
methyl,
-0-methyl,
30 -S methyl,
-S(O) methyl,
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358
-S(0)2 methyl,
-O-CH2-R4,
-(CO)OH,
-CN,
5 -(CO)O-CH3, -(CO)O-CH2-CH3,
-NH2,
-(CO)NH2, (CO)NHCH3,and
-(CO)NRcRd;
wherein Rc isH or methyl; and
10 wherein Rd is -(CH2)-cycloalkyl or -(CH2)-heterocyclyl, wherein cycloalkyl or
heterocyclyl is optionally substituted with methyl, ethyl, (CO)OH or (CO)O(C1-
C4)alkyl;
R2
15 is a 5-10 membered heteroaryl, wherein 1 to 2 ring atoms are -N-, and additionally up
to 1 ring atom is -S-; or
a 5 to 6 membered heterocycle, wherein 1 to 2 ring atoms are -0-,
and wherein heteroaryl or heterocycle is optionally substituted by 1 to 2 substituents
selected from
20 halogen, CN, -(C1-C4)alkyl, -(C1-C4)alkyi-OH, (CO)NReRf and -NReRf, wherein Re
and Rf are independently selected from H, (C1-C4)alkyl or -CO(C1-C4)alkyl; or
wherein Re and Rf form together with the nitrogen atom to which they are attached a
4 to 6 membered ring, which is optionally substituted with oxo at the position adjacent
to the nitrogen atom;
25
R3 is F or methyl;
m is an integer 0 or 1;
R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3 or -(CO)O(C1-C4)alkyl;
30 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
R1
5
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7. A compound of the formula I as claimed in any one of claims 1 to 5, wherein
is pyridyl, pyrazinyl or pyrimidinyl and wherein R1 is substituted by
-(CO)NRcRd;
wherein Rc isH or methyl; and
wherein Rd is -(CH2)-cycloalkyl or -(CH2)-heterocyclyl,
wherein cycloalkyl is selected from cycloprpopyl, cyclobutyl, cyclopentyl and
cyclohexyl,
10 and wherein heterocyclyl is selected from azirine, azetidine, pyrrolidine and
15
20
piperidine, and
wherein cycloalkyl or heterocyclyl, is optionally substituted with methyl, ethyl,
(CO)OH or (CO)O(C1-C4)alkyl;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
8. A compound of the formula I as claimed in any one of claims 1 to 6, wherein
R1 is pyrimidinyl and wherein R1 is substituted by
-(CO)NH2 and optionally additionally by F;
R2
is selected from pyridyl and pyrazinyl, and is optionally substituted by-methyl,
m is an integer 0;
25 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
9. A compound of the formula I as claimed in any one of claims 1 to 6, wherein
R1 is pyridyl, pyrazinyl or pyrimidinyl and wherein R1 is substituted by
30 -(CO)NRcRd
wherein Rc isH; and
5
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wherein Rd is -(CH2)-cyclopropyl, -(CH2)-azetidine or -(CH2)-piperidine,
wherein trhe cyclic group, is optionally substituted with methyl,ethyl, (CO)OH or
(CO)O(C1-C4)alkyl;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
10. A compound of the formula I as claimed in any one of claims 1 to 9, wherein
R2
is selected from pyrazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl,
10 imidazo[1 ,2a]pyridinyl or tetrahydropyranyl, and is optionally substituted by 1 to 2
substituents selected from
15
F, Cl, Br, CN, -methyl, -(CH2)-0H , NH2, NH(C1-C4)alkyl, NH(CO)-(C1-C4)alkyl,
(CO)NH2, -(CO)NH(C1-C4)alkyl, -(CO)NH(CO)-(C1-C4)alkyl, 1-oxo-azirinyl, 1-oxoazetidinyl,
1-oxo-pyrrolidinyl and 1-oxo-piperidinyl;
R3 is F or methyl;
m is an integer 0 or 1;
R4 is OH, CN, -(CO)OH, -(CO)NH2, -(CO)NHCH3, -(CO)O-CH3 or-(CO)O-CH2-CH3;
20 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
11. A compound of the formula I as claimed in any of claim 1, 2 or 3 wherein the
compound of formula I is selected from
25 6-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyrim idi ne-
4-carboxamide
2-[4-[(38)-3-Pyrimidin-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-
carboxamide
2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyri midi ne-
30 4-carboxamide
6-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidinewo
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4-carbonitrile
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxylic acid
Methyl 2 -[ 4-[ (38)-3-( 5-cyano-3-pyridyl) isoxazol id ine-2-carbonyl]-1-
5 piperidyl]pyrimidine-4-carboxylate
2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyrim idi ne-
4-carbon itri le
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-
carbonitrile
10 5-[(38)-2-[1-[4-(Cyanomethoxy)-5-fluoro-2-pyridyl]-4-methyl-piperidine-4-
carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-
piperidyl]pyrimidine-4-carboxamide
Methyl 2-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-
15 piperidyl]pyrimidine-4-carboxylate
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-
piperidyl]pyrimidine-4-carboxylic acid
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-
carboxamide
20 Ethyl 2-[2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-methyl-1-
piperidyl]-5-fluoro-pyrimidin-4-yl]oxyacetate
5-[(38)-2-[1-[4-(Cyanomethoxy)-5-fluoro-pyrimidin-2-yl]piperidine-4-
carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
2-[2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoro-
25 pyrimidin-4-yl]oxyacetic acid
2-[2-[4-[(38)-3-(5-Carbamoyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-
fluoro-pyrimidin-4-yl]oxyacetic acid
2-[2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyri
midi n-4-yl]oxyacetam ide
30 5-[(38)-2-[1-(4-Amino-5-fluoro-pyrimidin-2-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
2-[4-[(38)-3-(5-Acetamido-3-pyridyl)isoxazolidine-2-carbonyl]-1-
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piperidyl]pyrimidine-4-carboxamide
2-[4-[(38)-3-(6-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
2-[4-[(38)-3-(6-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
5 piperidyl]pyrimidine-4-carbonitrile
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-
4-carboxamide
2-[4-[(38)-3-[5-(2-0xoazetidin-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
1 o 2-[4-[(38)-3-[5-(2-0xoazetidin-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carbonitrile
Ethyl 6-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-
fl uoro-pyri midi ne-4-carboxy late
6-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoro-
15 pyrimidine-4-carboxylic acid
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-4-fluoro-1-piperidyl]-5-
fl uoro-pyri midi ne-4-carboxam ide
2-[4-[(38)-3-[5-(2-0xopyrrolidin-1-yl)-3-pyridyl]isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
20 2-[4-Methyl-4-[(38)-3-pyrimidin-5-ylisoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
2-[5-Fiuoro-2-[4-methyl-4-[(38)-3-pyrimidin-5-ylisoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidin-4-yl]oxyacetonitrile
2-[5-Fiuoro-2-[4-[(38)-3-pyrimidin-5-ylisoxazolidine-2-carbonyl]-1-
25 piperidyl]pyrimidin-4-yl]oxyacetonitrile
[1-(5-Fiuoro-4-methoxy-pyrimidin-2-yl)-4-piperidyl]-[(38)-3-pyrimidin-5-
yl isoxazol id i n-2 -yl] methanone
2-[4-[(38)-3-Pyrimidin-5-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyridine-4-
carbonitrile
30 5-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-
carbonitrile
6-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-
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carbonitrile
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide
2-[ 4-[ (38)-3-( 5-Fiuoro-3-pyridyl)isoxazol idi ne-2 -carbonyl]-1-piperidyl]pyri midi ne-4-
5 carboxamide
6-[ 4-[ (38 )-3-( 5-Cyano-3-pyri dyl) i soxazol id i ne-2 -carbonyl ]-1-pi peri dyl ]pyrazi ne-2-
carboxamide
5-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrazine-2-
carboxamide
1 o 6-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl)isoxazol idi ne-2 -carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide
2-[4-[(38)-3-Pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-
carboxamide
5-Fiuoro-2-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
15 4-carboxamide
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyi]-N-(1-
methylazetidin-3-yl)pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Cyano-3-pyridyl) isoxazolidine-2-carbonyl]-1-piperidyi]-N-[2-(1-
methylcyclo-propyl)ethyl]pyrimidine-4-carboxamide
20 Tert-butyl 3-[[2-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]
pyrimidine-4-carbonyl]amino] azetidine-1-carboxylate
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyi]-N-[(1-ethyl-
4-piperidyl)methyl]pyrimidine-4-carboxamide
5-Fiuoro-2-[ 4-[ (38)-3-( 5-fl uoro-3-pyridyl)isoxazol idi ne-2 -carbonyl]-1-
25 piperidyl]pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
5-Fiuoro-2-[4-[(38)-3-(6-methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
30 2-[4-[(38)-3-(5-Chloro-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxam ide
2-[4-[(38)-3-(5-Chloro-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluorowo
2021/245070 PCT/EP2021/064657
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pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Cyano-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-
fl uoro-pyri midi ne-4-carboxam ide
N-(Azetidin-3-yl)-2-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-
5 piperidyl]pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
Ethyl 3-[[2-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl ]pyri midi ne-4-carbonyl]am i no ]azetidine-1-carboxylate
1 o 5-Fiuoro-2-[ 4-[(38)-3-( 5-methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
6-[4-[(38)-3-(5-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carbonitrile
2-[ (3R, 4R)-4-[ (38)-3-( 5-Cyano-3-pyridyl)isoxazolidi ne-2-carbonyl]-3-fl uoro-1-
15 piperidyl]pyrimidine-4-carboxamide
2-[(3R,4R)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-
piperidyl]pyrimidine-4-carboxamide
2-[(38,48)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-
piperidyl]pyrimidine-4-carboxamide
20 2-[(3R,48)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-
piperidyl]pyrimidine-4-carboxamide
2-[(38,4R)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-fluoro-1-
piperidyl]pyrimidine-4-carboxamide
5-Methyl-2-[4-[(38)-3-(6-methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
25 piperidyl]pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Fiuoro-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-methylpyrimidine-
4-carboxamide
5-Methyl-2-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxam ide
30 Methyl 2-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxylate
2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyri midi newo
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4-carboxylic acid
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxylic acid
5-[(38)-2-[1-(5-Fiuoro-4-methylsulfanyl-pyrimidin-2-yl)piperidine-4-
5 carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(5-Fiuoro-4-methylsulfinyl-pyrimidin-2-yl)piperidine-4-
carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(5-Fiuoro-4-methylsulfonyl-pyrimidin-2-yl)piperidine-4-
carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
1 o 2-[ 4-[ (38)-3-( 5-Cyano-2-pyridyl)isoxazol idi ne-2 -carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide
6-[ 4-[ (38)-3-( 5-Cyano-2 -pyridyl) isoxazol idi ne-2 -carbonyl]-1-piperidyl]pyrim idi ne-
4-carboxamide
2-[ 4-[ (38)-3-( 5-Cyano-2 -pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyri midi ne-
15 4-carboxamide
(8)-6-(4-(3-(5-Methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carboxam ide
(8)-2-(4-(3-(5-Methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carboxamide
20 2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carbonitrile
2-[4-[(38)-3-(5-Cyano-2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carbonitrile
5-[(38)-2-[1-(3-Methyl-1 ,2,4-thiadiazol-5-yl)piperidine-4-carbonyl]isoxazolidin-3-
25 yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(5-Fiuoro-4-methoxy-pyrimidin-2-yl)piperidine-4-
carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl)isoxazol idi ne-2 -carbonyl]-3, 3,4-trifluoro-1-
piperidyl]pyrimidine-4-carboxamide
30 [1-(5-Fiuoro-4-methoxy-pyrimidin-2-yl)-4-piperidyl]-[(38)-3-(6-methylpyrazin-2-
yl)isoxazolidin-2-yl]methanone
6-[(38)-2-[1-(5-Fiuoro-4-methoxy-pyrimidin-2-yl)piperidine-4-
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carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
2-[4-[(38)-3-(6-Cyanopyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
6-[(38)-2-[1-(5-Fiuoro-4-methoxy-pyrimidin-2-yl)piperidine-4-
5 carbonyl]isoxazolidin-3-yl]pyridine-3-carbonitrile
5-Fiuoro-2-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carbonitrile
2-Chloro-5-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxylic acid
1 o 2-[3, 3,4-Trifluoro-4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl)isoxazol id ine-2 -carbonyl]-3, 3, 4-trifluoro-1-
piperidyl]pyrimidine-4-carbonitrile
2-[3, 3,4-Trifluoro-4-[ (38)-3-pyrazi n-2-yl isoxazol idi ne-2 -carbonyl]-1-
15 piperidyl]pyrimidine-4-carbonitrile
5-[(38)-2-[1-(5-Fiuoro-4-hydroxy-pyrimidin-2-yl)piperidine-4-carbonyl]isoxazolidin-
3-yl]pyridine-3-carbonitrile
(8)-5-Fiuoro-2-(4-fluoro-4-(3-(5-fluoropyridin-3-yl)isoxazolidine-2-
carbonyl)piperidin-1-yl)pyrimidine-4-carboxamide
20 (8)-2-(4-(3-(6-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carbonitrile
(8)-6-(4-(3-(6-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carbonitrile
(8)-2-(4-(3-(6-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
25 yl)pyrimidine-4-carboxamide
5-[(38)-2-[1-(2-Chloro-5-fluoro-pyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
(8)-2-(4-(3-(5-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carbonitrile
30 (8)-2-(4-(3-(5-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carboxamide
(8)-6-(4-(3-(5-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
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yl)pyrimidine-4-carbonitrile
(8)-6-(4-(3-(5-Methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carboxamide
(8)-6-( 4-(3-(6-Methylpyridi n-3-yl)isoxazolidi ne-2-carbonyl)pi peridi n-1-
5 yl)pyrimidine-4-carboxamide
(8)-2-(4-(3-(5-Fiuoro-6-methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carbonitrile
2-[4-[(38)-3-(5-Fiuoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
1 o (8)-6-( 4-(3-( 5-FI uoro-6-methylpyridi n-3-yl)isoxazol idi ne-2-carbonyl)pi peridi n-1-
yl)pyrimidine-4-carbonitrile
6-[4-[(38)-3-(5-Fiuoro-6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
(8)-2 -( 4-(3-( 5-FI uoro-4-methylpyridi n-3-yl)isoxazol idi ne-2-carbonyl)pi peridi n-1-
15 yl)pyrimidine-4-carbonitrile
(8)-2 -( 4-(3-( 5-FI uoro-4-methylpyridi n-3-yl)isoxazol idi ne-2-carbonyl)pi peridi n-1-
yl)pyrimidine-4-carboxamide
(8)-6-( 4-(3-( 5-FI uoro-4-methylpyridi n-3-yl)isoxazol idi ne-2-carbonyl)pi peridi n-1-
yl)pyrimidine-4-carboxamide
20 (8)-6-(4-(3-(5-Fiuoro-4-methylpyridin-3-yl)isoxazolidine-2-carbonyl)piperidin-1-
yl)pyrimidine-4-carbonitrile
5-[(38)-2-[1-(2-Methoxypyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
4-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
25 2-carbonitrile
5-[(38)-2-[1-(2-Methylsulfanylpyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(2-Chloropyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
30 5-[(38)-2-[1-(2-Aminopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
Ethyl 4-[4-[(38)-3-(5-cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-
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piperidyl]pyrimidine-2-carboxylate
(8)-2-(4-(3-(4-Methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carbonitrile
(8)-2-(4-(3-(4-Methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
5 4-carboxamide
(8)-6-(4-(3-(4-Methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carbonitrile
(8)-6-(4-(3-(4-Methylfuran-2-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carboxamide
1 o 2-[(3R,4R or 38,48)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-
fluoro-1-piperidyl]-5-fluoro-pyrimidine-4-carboxamide
2-[(38,48 or 3R,4R)-4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-3-
fluoro-1-piperidyl]-5-fluoro-pyrimidine-4-carboxamide
4-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
15 2-carboxamide
5-[(38)-2-[1-(2-Bromopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(4-Chloropyrimidin-2-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
20 5-[(38)-2-[1-(6-Chloropyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
5-[(38)-2-[1-(4-Bromopyrimidin-2-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
(8)-2-(4-(3-(5-Methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
25 4-carbonitrile
(8)-6-(4-(3-(5-Methylfuran-3-yl)isoxazolidine-2-carbonyl)piperidin-1-yl)pyrimidine-
4-carbonitrile
2-Chloro-5-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxylic acid
30 5-[(38)-2-[1-(6-Bromopyrimidin-4-yl)piperidine-4-carbonyl]isoxazolidin-3-
yl]pyridine-3-carbonitrile
2-[4-[(38)-3-(5-Cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluorowo
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pyrimidine-4-carboxamide
2-[4-[(38)-3-(5-Cyano-3-furyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide
2-[4-[(38)-3-(5-Cyano-3-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
5 4-carboxamide
(8)-5-(2-(1-(6-Fiuoropyrimidin-4-yl)piperidine-4-carbonyl)isoxazolidin-3-
yl)nicotinonitrile
5-Fiuoro-2-[4-[(38)-3-(2-methylthiazol-4-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
1 o 2 -[ 4-[ (38)-3-( 5-Cyano-3-furyl)isoxazol idi ne-2-carbonyl]-1-piperidyl]pyri midi ne-4-
carboxamide
[1-(4-Chloro-1 ,3,5-triazin-2-yl)-4-piperidyl]-[(38)-3-pyrazin-2-ylisoxazolidin-2-
yl]methanone
5-Fiuoro-2-[4-[(38)-3-(2-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-4-
15 carboxamide
6-[4-[(38)-3-(5-Methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxam ide
2-[4-[(38)-3-(6-Cyanopyridazin-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-
fl uoro-pyri midi ne-4-carboxam ide
20 2-[4-[(38)-3-(6-Cyanopyridazin-4-yl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
[1-( 4-Chloro-6-methyl-1, 3,5-triazin-2-yl)-4-piperidyl]-[ (38)-3-pyrazin-2-
yl isoxazol id i n-2 -yl ]m ethanone
[1-(4-Chloro-6-methoxy-1 ,3,5-triazin-2-yl)-4-piperidyl]-[(38)-3-pyrazin-2-
25 ylisoxazolidin-2-yl]methanone
5-Methyl-2-[4-[(38)-3-(5-methyl-2-thienyl)isoxazolidine-2-carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
5-FI uoro-2-[ 4-[ (38)-3-( 5-methyl-2-thienyl)isoxazol id ine-2 -carbonyl]-1-
piperidyl]pyrimidine-4-carboxamide
30 [1-(4-Amino-6-chloro-1 ,3,5-triazin-2-yl)-4-piperidyl]-[(38)-3-pyrazin-2-
yl isoxazol id i n-2 -yl ]m ethanone
2-[(3R,4R or 38,48)-3-Fiuoro-4-[(38)-3-(6-methyl-3-pyridyl)isoxazolidine-2-
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carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide
2-[(38,48 or 3R,4R)-3-Fiuoro-4-[(38)-3-(6-methyl-3-pyridyl)isoxazolidine-2-
carbonyl]-1-piperidyl]-5-methyl-pyrimidine-4-carboxamide
5-Fiuoro-6-[4-[(38)-3-(6-methyl-3-pyridyl)isoxazolidine-2-carbonyl]-1-
5 piperidyl]pyrimidine-4-carboxamide; trifluoroacetic acid
2-[4-[(38)-3-(2-Cyanothiazol-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxamide and
2-[4-[(38)-3-(2-Cyanothiazol-4-yl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide
10 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
12. A compound of the formula I as claimed in claim 1, wherein the compound of
formula I is selected from
15 2-[ 4-[ (38)-3-( 5-Cyano-3-pyridyl) isoxazol idi ne-2-carbonyl]-1-piperidyl]pyrim idi ne-
4-carboxamide,
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide,
2-[4-[(38)-3-(6-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
20 piperidyl]pyrimidine-4-carboxamide and
5-Fiuoro-2-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxamide;
25
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
13. A compound of the formula I as claimed in claim 1, wherein the compound of
formula I is selected from
2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxamide,
30 2-[4-[(38)-3-(5-Cyano-3-pyridyl)isoxazolidine-2-carbonyl]-1-piperidyl]-5-fluoropyrimidine-
4-carboxamide,
2-[4-[(38)-3-(6-Methylpyrazin-2-yl)isoxazolidine-2-carbonyl]-1-
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piperidyl]pyrimidine-4-carboxamide and
5-Fiuoro-2-[4-[(38)-3-pyrazin-2-ylisoxazolidine-2-carbonyl]-1-piperidyl]pyrimidine-
4-carboxam ide
with a TPSA (topological polar surface area) value of >120 A2 or more;
5 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
10
15
14. The compound of any one of claims 1 to 13 for use in human medicine.
15. The compound for use according to claim 14 which is present as an active agent
in a pharmaceutical composition together with at least one pharmaceutically
acceptable carrier.
16. The compound for use according to claim 14 which is present as an active agent
in a pharmaceutical composition together with at least one pharmaceutically
acceptable carrier and/or one or more additional active pharmaceutical agent
selected from a thrombolytic agent, a tissue plasminogen activator, an
20 anticoagulant, a platelet aggregation inhibitor, an antimicrobial agent (an
antibiotic, a broad-spectrum antibiotic, a lactam, an antimycobacterial agent, a
bactericidal antibiotic, anti-MRSA therapy), a long acting beta agonist, a
combination of an inhaled corticosteroid and a long acting beta agonist, a short
acting beta agonist, a leukotriene modifier, an anti-lgE, a methylxanthine
25 bronchodilator, a mast cell inhibitor, a protein tyrosine kinase inhibitor, a
CRTH2/D prostanoid receptor antagonist, an epinephrine inhalation aerosol, a
phosphodiesterase inhibitor, a combination of a phosphodiesterase-3 inhibitor
and a phosphodiesterase-4 inhibitor, a long-acting inhaled anticholinergic, a
muscarinic antagonist, a long-acting muscarinic antagonist, a low dose steroid,
30 an inhaled corticosteroid, an oral corticosteroid, a topical corticosteroid, antithymocyte
globulin, thalidomide, chlorambucil, a calcium channel blocker, a
topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1
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receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor, a cystic fibrosis
transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic
enzymes, a bronchodilator, an opthalmalic intravitreal injection, an anti-vascular
endothelial growth factor inhibitor, a ciliary neurotrophic growth factor agent, a
5 trivalent (IIV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated
influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live
attenuated influenza vaccine, an antiviral agent, inactivated influenza vaccine, a
ciliary neurotrophic growth factor, a gene transfer agent, a topical
immunomodulator, calcineurin inhibitor, an interferon gamma, an antihistamine, a
10 monoclonal antibody, a polyclonal anti-Tcell antibody, an anti-thymocyte gamma
globulin-equine antibody, an antithymocyte globulin- rabbit antibody, an antiCD40
antagonist, a JAK inhibitor, and an anti-TCR murine mAb.
15 17. The compound for use according to any one of claims 1 to 16 for the treatment of
a RIP kinase 1 mediated disease or disorder.
18. The compound for use according to any one of the claims 1 to 16 for the
20 treatment of necrotizing enterocolitis, tuberous sclerosis, Tangier's Disease,
Wohlman's Syndrome, inflammatory bowel disease, Crohn's disease, ulcerative
colitis, psoriasis, retinal detachment, retinitis pigmentosa, macular degeneration,
pancreatitis (e.g., acute pancreatitis), atopic dermatitis, rheumatoid arthritis (RA),
spondyloarthritis, gout, SoJIA, systemic lupus erythematosus, Sjogren's
25 syndrome, systemic scleroderma, anti phospholipid syndrome, vasculitis,
osteoarthritis, non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune
hepatitis autoimmune hepatobiliary diseases, primary sclerosing cholangitis,
nephritis, Celiac disease, autoimmune ITP, transplant rejection, ischemia
reperfusion injury of solid organs, sepsis, systemic inflammatory response
30 syndrome, cerebrovascular accident, myocardial infarction, Huntington's disease,
Alzheimer's disease, Parkinson's disease, allergic diseases, asthma, atopic
dermatitis, multiple sclerosis, type I diabetes, Wegener's granulomatosis,
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pulmonary sarcoidosis, 8ehget's disease, interleukin-1 converting enzyme
associated fever syndrome, chronic obstructive pulmonary disease, tumor
necrosis factor receptor-associated periodic syndrome, periodontitis, bacterial
infection, staphylococcus infection, mycobacterium infection, retinitis pigmentosa,
5 influenza, transplant rejection, burns, or hypoxia.
19. The compound for use according to any one of the claims 1 to 16 for the
treatment of rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease
10 (180), Crohn's disease or ulcerative colitis.
20. The compound for use according to any one of the claims 1 to 16 for the
treatment of cutaneous lupus erythematosus (CLE), Lichen planus (LP), toxic
15 epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS).
21. The compound for use according to claim 18 for the treatment of rheumatoid
arthritis (RA), psoriasis, inflammatory bowel disease (180), Crohn's disease or
20 ulcerative colitis.
22. The compound for use according to any one of the claims 1 to 16 for the
treatment of acute respiratory distress syndrome (AROS), systemic inflammatory
25 response syndrome (SIRS).
23. The compound for use according to any one of the claims 1 to 16 for the
treatment of Influenza (e.g. swine flu, H7N9), severe acute respiratory syndrome
30 (SARS), Middle East Respiratory Syndrome (MERS), Respiratory-Syncytial-Virus
(RSV) or bronchiolitis.
5
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24. A pharmaceutical composition comprising at least one compound according to
any one of claims 1 to 13 or a physiological acceptable salt or solvate of any of
them, for use as a pharmaceutical.