Substituted boronic acids and boronate esters as immunoproteasome inhibitors

Patent metadata

Field	Value
Publication number	US-10294246-B2
Application number	US-201515516424-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Oct 1, 2014
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

Compounds of formula (I) are inhibitors of LMP7 and can be employed, inter alia, for the treatment of an autoimmune disorder or hematological malignancies.

First claim

The invention claimed is:

1. A compound of formula (I):

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
wherein:
LX denotes —CH 2 —, —O(CH 2 ) n —, —S(CH 2 ) p — or —(CH 2 ) p S—, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, N 3 , R 3a , OR 4a , (CH 2 ) r A2, (CH 2 ) r Ar2 or (CH 2 ) r Het2;
LY denotes —CH 2 —;
X denotes an aromatic 6-membered carbocyclyl or aromatic 6-membered heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N 3 , CN, OH, NR 4a R 4b , Ar1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR 4a R 4b , NR 4a C(O)R 3a , NR 4a S(O) 2 R 3a , S(O) 2 R 3a , S(O)R 3a , NR 4a C(O) 2 R 3a , OC(O)NR 3a R 4a , O(CH 2 ) q A1, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A2;
Y denotes Cyc;
R 1 and R 2 each independently denote H or C1-C6 alkyl; or
R 1 and R 2 , together with the oxygen atoms to which they are attached, form a residue according to formula (CE):

R 3a and R 3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
R 4a and R 4b each independently denote H or R 3a ; or
R 4a and R 4b , together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
A1 denotes linear or branched C1-C6 alkyl or C3-C6 cycloalkyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R 3a , SR 3a , OR 4a or (CH 2 ) r A2, where 1, 2 or 3 CH 2 groups of C3-C6 cycloalkyl may be independently replaced by O, C(O) or N;
A2 denotes OR 4a ;
Alk denotes linear or branched C1-C6 alkyl;
Ar1 denotes phenyl, optionally substituted by 1, 2 or 3 substituents selected from Hal, NO 2 , CN, R 3a , OR 4a , C(O)NR 4a R 4b , NR 4a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2 or (CH 2 ) r A2;
Het1 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, where each heterocyclyl may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, NO 2 , CN, R 3a , OR 4a , C(O)NR 4a R 4b , NR 4a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2 or (CH 2 ) r A2;
Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R 3a , OR 4a , C(O)NR 4a R 4b , NR 4a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b or (CH 2 ) q A2;
Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R 3a , OR 4a , C(O)NHR 3a , NR 3a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b or (CH 2 ) q A2;
Cyc denotes a monocyclic or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclyl or heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R 3a , OR 3a , C(O)NR 4a R 4b , NR 3a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A2, where the monocyclic carbocyclyl is aromatic and at least one ring of the bicyclic carbocyclyl or heterocyclyl is aromatic, and further where the heterocyclyl comprises 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
n denotes 1, 2, 3, 4, 5 or 6;
p denotes 1, 2, 3, 4, 5 or 6;
q denotes 0, 1, 2, 3 or 4;
r denotes 0, 1, 2, 3 or 4; and
Hal denotes F, Cl, Br or I;
with the proviso that when LX denotes —O(CH 2 ) n —, the oxygen atom of LX is bonded to X.

2. The compound according to claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
X denotes phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N 3 , CN, OH, NR 4a R 4b , Ar1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR 4a R 4b , NR 4a C(O)R 3a , NR 4a S(O) 2 R 3a , S(O) 2 R 3a , S(O)R 3a , NR 4a C(O) 2 R 3a , OC(O)NR 3a R 4a , O(CH 2 ) q A1, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A2;
R 1 and R 2 each independently denote H or C1-C4 alkyl; or
R 1 and R 2 , together with the oxygen atoms to which they are attached, form a residue according to formula (CE):

n denotes 1, 2, 3 or 4;
p denotes 1, 2, 3 or 4;
q denotes 1, 2, 3 or 4; and
r denotes 1, 2, 3 or 4.

3. The compound according to claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
LX denotes —CH 2 —, —OCH 2 —, —O(CH 2 ) 2 —, —SCH 2 — or —S(CH 2 ) 2 —, where 1, 2, 3 or 4 H atoms may be independently replaced by Hal, R 3a , OR 4a , (CH 2 ) r A2, Ar2 or Het2; and
Cyc denotes phenyl, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R 3a , OR 3a , C(O)NR 4a R 4b , NR 3a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A2, where disubstitution occurs in a 2,4-, 2,5- or 3,4-pattern and trisubstitution occurs in a 2,3,4-pattern; or
Cyc denotes 1-naphthalenyl, 2-naphthalenyl, 4-indanyl, 5-indanyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 1-azulenyl, 2-azulenyl, 3-azulenyl, 4-azulenyl, 5-azulenyl, 6-azulenyl, 1-tetrahydronaphthalen-5-yl, 2-tetrahydronaphthalen-5-yl, 1-tetrahydronaphthalen-6-yl, 2-tetrahydronaphthalen-6-yl, 2-furanyl, 3-furanyl, 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, 2-benzothiophenyl, 3-benzothiophenyl, 4-benzothiophenyl, 5-benzothiophenyl, 6-benzothiophenyl, 7-benzothiophenyl, methylenedioxyphenyl, 6-benzodioxanyl, 7-benzodioxanyl, 3,4-dihydro-1,5-benzodioxepin-6-yl or 3,4-dihydro-1,5-benzodioxepin-7-yl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R 3a , OR 3a , C(O)NR 4a R 4b , NR 3a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A2.

4. The compound according to claim 1 , or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
LX denotes —CH 2 —, —OCH 2 —, —O(CH 2 ) 2 —, —SCH 2 — or —S(CH 2 ) 2 —, where 1, 2, 3 or 4 H atoms may be independently replaced by Hal, R 3a , OR 4a , (CH 2 ) r A2, phenyl, methylphenyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, aminophenyl, furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, morpholinyl or piperidinyl;
Cyc denotes 1-naphthalenyl, 2-naphthalenyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-benzofuranyl, 3-benzofuranyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, 2-benzothiophenyl or 3-benzothiophenyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R 3a , OR 3a , C(O)NR 4a R 4b , NR 3a C(O)R 3b , S(O) 2 R 3a , S(O)R 3a , NR 4a R 4b , Ar2, Het2, (CH 2 ) r SR 3a , (CH 2 ) r N(R 4a ) 2 or (CH 2 ) r A

Assignees

• Merck Patent Gmbh

Inventors

• Klein Markus
• Schadt Oliver
• Haselmayer Philipp
• Busch Michael

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61P35/02

  specific for leukemia · CPC title