2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONES USEFUL AS INHIBITORS OF DHODH

The present invention provides triazolone compounds of general formula (I):

2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONES USEFUL AS INHIBITORS OF DHODH

The present invention provides triazolone compounds of general formula (I): in which R, R, R, Rand Rare as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients. 2. The compound of formula (I)in which{'sup': '1', 'claim-text': [{'sub': 5', '8, 'a C-C-alkyl group,'}, {'sub': 2', '8, 'a C-C-haloalkyl group,'}, {'sub': 4', '8, 'claim-text': {'sup': 7', '8, 'claim-text': wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from', {'sub': 1', '3', '1', '4', '1', '3, 'C-C-alkyl, C-C-haloalkyl, C-C-alkoxy and hydroxy,'}], 'wherein said cycloalkyl groups are optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R)(R),'}, 'a C-C-cycloalkyl group,'}, {'sub': 1', '6', '3', '8, 'a C-C-alkyl group which is substituted with a C-C-cycloalkyl group,'}, {'sub': 2', '6, 'a C-C-alkyl group which is substituted with a cyano group, a hydroxy group or a phenyl group,'}, {'sub': 3', '6, 'a C-C-alkyl group which is substituted with a monocyclic- or bicyclic heteroaryl group,'}, {'sub': 2', '6', '2', '6, 'a (C-C-hydroxyalkyl)-O—(C-C-alky)- group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-N(R)(R) group,'}, {'sub': 3', '8, 'sup': 7', '8, 'a —(C-C-cycloalkyl)-N(R)(R) group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-C(═O)N(R)(R) group,'}, which is optionally substituted one or two times, each substituent independently selected from a group selected from', {'sub': 1', '3', '1', '4', '1', '6', '3', '6', '2', '1', '6, ' ...

2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONES USEFUL AS INHIBITORS OF DHODH

The present invention provides triazolone compounds of general formula (I): 2. The method according to in which{'sup': '1', 'claim-text': [{'sub': 5', '8, 'a C-C-alkyl group,'}, {'sub': 2', '5, 'a C-C-haloalkyl group,'}, {'sub': 4', '5, 'claim-text': {'sup': 7', '8, 'claim-text': {'sub': 1', '3', '1', '4', '1', '3, 'wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C-C-alkyl, C-C-haloalkyl, C-C-alkoxy and hydroxy,'}, 'wherein said cycloalkyl groups are optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R)(R),'}, 'a C-C-cycloalkyl group,'}, {'sub': 1', '6', '3', '5, 'a C-C-alkyl group which is substituted with a C-C-cycloalkyl group,'}, {'sub': 2', '6, 'a C-C-alkyl group which is substituted with a cyano group, a hydroxy group or a phenyl group,'}, {'sub': 3', '6, 'a C-C-alkyl group which is substituted with a monocyclic- or bicyclic heteroaryl group,'}, {'sub': 2', '6', '2', '6, 'a (C-C-hydroxyalkyl)-O—(C-C-alky)-group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-N(R)(R) group,'}, {'sub': 3', '5, 'sup': 7', '8, 'a —(C-C-cycloalkyl)-N(R)(R) group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-C(═O)N(R)(R) group,'}, [{'sub': 1', '3', '1', '4', '1', '6', '3', '6', '2', '1', '6, 'claim-text': 'wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from', 'which is optionally substituted one or two times, each substituent independently selected from a group selected from C-C-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C-C-alkyl), —C(═O)(C-C-alkyl), —C(═O)(C-C-cycloalkyl), —S(═O)(C-C-alkyl) and oxo (═O),'}, {'sub': 1', '3', '1', '4', '1', '3, 'C-C-alkyl, C-C-haloalkyl, C-C-alkoxy and hydroxy,'}, 'and wherein said- to 7- ...

4,5-annulated 1,2,4-triazolones

The present invention provides triazolone compounds of general formula (I):in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Methods for generating universal and custom mhc/hla-compatible hematopoietic progenitor cells

Disclosed herein are methods for generating universal MHC/HLA-compatible hematopoietic progenitor cells and methods for generating custom patient-specific MHC/HLA-compatible hematopoietic progenitor cells. Compositions comprising the universal and custom hematopoietic progenitor cells and therapeutic applications thereof are also disclosed.

COMPOUNDS AND METHODS USEFUL FOR TREATING OR PREVENTING HEMATOLOGICAL CANCERS

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid). 1. A method of treating or preventing a hematological cancer in a subject in need thereof , the method comprising administering to the subject a therapeutically effective amount of a dihydroorotate dehydrogenase (DHODH) inhibitor , wherein the dihydroorotate inhibitor is selected from the group consisting of 6-fluoro-2-(2′-fluoro-[1 ,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid); 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide); and (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide); or any combinations salts , or solvates thereof; wherein said DHODH inhibitor is administered to the subject with a frequency less than or equal to once every 72 hours.2. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1 claim 1 ,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid) or a salt or solvate thereof is administered to the subject with a frequency less than or equal to once every 72 hours.3. The method according to claim 1 , wherein 6-fluoro-2-(2′-fluoro-[1 claim 1 ,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid) or a salt or solvate thereof is administered to the subject with a frequency less than or equal to once every 48 hours.4. The method according to claim 1 , wherein the hematological cancer comprises acute myeloid leukemia (AML) claim 1 , acute promyelocytic leukemia (APL) claim 1 , mixed-lineage leukemia (MLL) claim 1 , myelodysplastic syndrome (MDS) claim 1 , and/or chronic myeloid leukemia (CML).5. The method according to claim 4 , wherein the hematological cancer comprises AML.6. The method according to claim 1 , wherein the subject has been treated or is being treated for a hematological cancer characterized by differentiation arrest.7. The method according to ...

2,4,5-TRISUBSTITUTED 1,2,4-TRIAZOLONES USEFUL AS INHIBITORS OF DHODH

The present invention provides triazolone compounds of general formula (I): 2. The method according to in which{'sup': '1', 'claim-text': [{'sub': 5', '8, 'a C-C-alkyl group,'}, {'sub': 2', '5, 'a C-C-haloalkyl group,'}, {'sub': 4', '5, 'claim-text': {'sup': 7', '8, 'claim-text': {'sub': 1', '3', '1', '4', '1', '3, 'wherein said phenyl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from C-C-alkyl, C-C-haloalkyl, C-C-alkoxy and hydroxy,'}, 'wherein said cycloalkyl groups are optionally substituted, one or two times, each substituent independently selected from a halogen atom or a group selected from hydroxy, phenyl and —N(R)(R),'}, 'a C-C-cycloalkyl group,'}, {'sub': 1', '6', '3', '5, 'a C-C-alkyl group which is substituted with a C-C-cycloalkyl group,'}, {'sub': 2', '6, 'a C-C-alkyl group which is substituted with a cyano group, a hydroxy group or a phenyl group,'}, {'sub': 3', '6, 'a C-C-alkyl group which is substituted with a monocyclic- or bicyclic heteroaryl group,'}, {'sub': 2', '6', '2', '6, 'a (C-C-hydroxyalkyl)-O—(C-C-alky)-group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-N(R)(R) group,'}, {'sub': 3', '5, 'sup': 7', '8, 'a —(C-C-cycloalkyl)-N(R)(R) group,'}, {'sub': 3', '6, 'sup': 7', '8, 'a —(C-C-alkyl)-C(═O)N(R)(R) group,'}, [{'sub': 1', '3', '1', '4', '1', '6', '3', '6', '2', '1', '6, 'claim-text': 'wherein said 5- to 6-membered heteroaryl substituent is optionally substituted, one, two or three times, each substituent independently selected from a halogen atom or a group selected from', 'which is optionally substituted one or two times, each substituent independently selected from a group selected from C-C-alkyl, 5- to 6-membered heteroaryl, —C(═O)O(C-C-alkyl), —C(═O)(C-C-alkyl), —C(═O)(C-C-cycloalkyl), —S(═O)(C-C-alkyl) and oxo (═O),'}, {'sub': 1', '3', '1', '4', '1', '3, 'C-C-alkyl, C-C-haloalkyl, C-C-alkoxy and hydroxy,'}, 'and wherein said- to 7- ...

4,5-annulated 1,2,4-triazolones

The present invention provides triazolone compounds compounds of general formula (I): in which R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Compounds and methods useful for treating or preventing hematological cancers

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2'-fluoro-[1,1'- biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).

Compounds and methods useful for treating or preventing hematological cancers

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2′-fluoro-[1,1′-biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).

4,5-annulated 1,2,4-triazolones

Compounds and methods useful for treating or preventing hematological cancers

The present invention includes methods of treating patients with acute myeloid leukemia across a range of genetic subtypes with DHODH inhibitors, such as 6-fluoro-2-(2'fluoro[1,1'- biphenyl]-4-yl)-3-methylquinoline-4-carboxylic acid).

4,5-annulated 1,2,4-triazolones

The present invention provides triazolone compounds of general formula (I):in which R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

2,4,5-trisubstituted 1,2,4-triazolones useful as inhibitors of dhodh

The present invention provides triazolone compounds of general formula (I): in which R 1 , R 2 , R 3 , R 4 , and R 5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment and prophylaxis of diseases, in particular hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Model for hematopoietic cell growth, differentiation and disease

Model for hematopoietic cell growth, differentiation and disease

The invention is a genetic construct comprising the coding sequence for a hormone dependent E2a-Pbx1 protein. The invention is the use of the construct to generate hematopoietic cell lines arrested in differentiation upon exposure to the appropriate hormone. Upon removal of the hormone, cells undergo normal, synchronous differentiation providing a system for the study of normal differentiation. Expression of a number of oncogenes in the cells maintains the cells in an undifferentiated state, providing a model for the study the mechanisms of leukemia, and for the testing of pharmacological agents for the treatment and amelioration of the disease.

Model for myeloid cell growth, differentiation and disease

The invention is a genetic construct comprising the coding sequence for a hormone dependent E2a-Pbx1 protein. The invention is the use of the construct to generate hematopoietic cell lines arrested in differentiation upon exposure to the appropriate hormone. Upon removal of the hormone, cells undergo normal, synchronous differentiation providing a system for the study of normal differentiation. Expression of a number of oncogenes in the cells maintains the cells in an undifferentiated state, providing a model for the study the mechanisms of leukemia, and for the testing of pharmacological agents for the treatment and amelioration of the disease.