Compounds that expand hematopoietic stem cells

Patent metadata

Field	Value
Publication number	US-9580426-B2
Application number	US-201313857939-A
Country	US
Kind code	B2
Filing date	Apr 5, 2013
Priority date	Oct 30, 2008
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

The present invention relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. The invention further relates to a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficient and autoimmune diseases and diverse hematopoietic disorders to reconstitute the hematopoietic cell lineages and immune system defense.

First claim

We claim:

1. A compound of Formula Ia:

in which:
L is selected from —NR 5a (CH 2 ) 2-3 , —NR 5a (CH 2 ) 2 NR 5b —, —NR 5a (CH 2 ) 2 S—, —NR 5a CH 2 CH(OH)— and —NR 5a CH(CH 3 )CH 2 —; wherein R 5a and R 5b are independently selected from hydrogen and C 1-4 alkyl;
R 1 is selected from thiophenyl, 1H-benzoimidazolyl, isoquinolinyl, 1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, and thiazolyl; wherein
said thiophenyl, 1H-benzoimidazolyl, isoquinolinyl, 1H-imidazopyridinyl, benzothiophenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, or thiazolyl of R 1 can be optionally substituted by 1 to 3 radicals independently selected from cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo, halo-substituted-C 1-4 alkyl, halo-substituted-C 1-4 alkoxy, amino, —C(O)R 8a , —S(O) 0-2 R 8a , —C(O)OR 8a and —C(O)NR 8a R 8b ; wherein R 8a and R 8b are independently selected from hydrogen and C 1-4 alkyl;

R 2 is selected from —S(O) 2 NR 6a R 6b , —NR 6a C(O)R 6b —, —NR 6a C(O)NR 6b R 6c , phenyl, 1H-pyrrolopyridin-3-yl, 1H-pyrrolopyridin-5-yl, 1H-indolyl thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl and 1H-indazolyl; wherein
R 6a , R 6b and R 6c are independently selected from hydrogen and C 1-4 alkyl; and
said phenyl, 1H-pyrrolopyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-indolyl, thiophenyl, pyridinyl, 1H-1,2,4-triazolyl, 2-oxoimidazolidinyl, 1H-pyrazolyl, 2-oxo-2,3-dihydro-1H-benzoimidazolyl or 1H-indazolyl of R 2 is optionally substituted with 1 to 3 radicals independently selected from hydroxy, halo, methyl, methoxy, amino, —O(CH 2 ) 2 NR 7a R 7b , —S(O) 2 NR 7a R 7b , —OS(O) 2 NR 7a R 7b and —NR 7a S(O) 2 R 7b ; wherein R 7a and R 7b are independently selected from hydrogen and C 1-4 alkyl;

R 3 is selected from hydrogen, C 1-4 alkyl and biphenyl; and
R 4 is selected from C 1-10 alkyl, prop-1-en-2-yl, cyclohexyl, cyclopropyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-2-yl, oxetan-3-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, and benzyl, (4-pentylphenyl)(phenyl)methyl and 1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl wherein
said alkyl, cyclopropyl, cyclohexyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, phenyl, tetrahydrofuran-3-yl, benzyl, (4-pentylphenyl)(phenyl)methyl or 1-(1-(2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)ethyl can be optionally substituted with 1 to 3 radicals independently selected from hydroxy, C 1-4 alkyl and halo-substituted-C 1-4 alkyl;

or a salt thereof.

2. The compound of claim 1 :
R 1 is selected from thiophen-2-yl, thiophen-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-4-yl, pyrazin-2-yl, pyridin-3-yl, pyridazin-4-yl and thiazol-5-yl; wherein
said thiophen-2-yl, thiophen-3-yl, 1H-benzo[d]imidazol-1-yl, isoquinolin-4-yl, 1H-imidazo[4,5-b]pyridin-1-yl, benzo[b]thiophen-3-yl, pyrimidin-5-yl, pyridiny-2-yl, pyridin-4-yl, pyrazin-2-yl, pyridiny-3-yl, pyridazin-4-yl or thiazol-5-yl of R 1 can be optionally substituted by 1 to 3 radicals independently selected from cyano, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, halo, halo-substituted-C 1-4 alkyl, —S(O) 0-2 R 8a and —C(O)OR 8a ; wherein R 8a is selected from hydrogen and C 1-4 alkyl;

R 2 is selected from —NR 6a C(O)NR 6b R 6c , phenyl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl, and 1H-indazol-3-yl; wherein
R 6a , R 6b and R 6c are independently selected from hydrogen and C 1-4 alkyl;
said phenyl, 1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl or 1H-indazol-3-yl of R 2 is optionally substituted with 1 to 3 radicals independently selected from hydroxy, halo, methoxy, amino, —OS(O) 2 NR 7a R 7b and —NR 7a S(O) 2 R 7b ; wherein R 7a and R 7b are independently selected from hydrogen and C 1-4 alkyl; and

R 4 is selected from isopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, nonan-2-yl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, phenyl, tetrahydrofuran-3-yl and benzyl; wherein
said cyclohexyl, 2-(2-oxopyrrolidin-1-yl)ethyl, oxetan-3-yl, oxetan-2-yl, benzhydryl, tetrahydro-2H-pyran-2-yl, phenyl, tetrahydrofuran-3-yl or benzyl can be optionally substituted with 1 to 3 radicals independently selected from C 1-4 alkyl and halo-substituted-C 1-4 alkyl.

3. The compounds of claim 2 in which L is selected from —NH(CH 2 ) 2-3 —, —NH(CH 2 ) 2 NH—, —NH(CH 2 ) 2 S—, —NHCH(CH 3 )CH 2 — and —NHCH 2 CH(OH)—.

4. The compounds of claim 3 , in which L is —NH(CH 2 ) 2 —.

5. The compound of claim 4 , in which R 2 is selected from phenyl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl; wherein
said phenyl, 1H-indol-3-yl, thiophen-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 2-oxoimidazolidin-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl of R 2 is optionally substituted with hydroxy, methoxy, methyl, halo, amino and amino-sulfonyl.

6. The compound of claim 5 , in which
R 4 is selected from isopropyl, methyl, ethyl, prop-1-en-2-yl, isobutyl, cyclohexyl, sec-butyl, (S)-sec-butyl, (R)-sec-butyl, 1-hydroxypropan-2-yl, (S)-1-hydroxypropan-2-yl, (R)-1-hydroxypropan-2-yl, nonan-2-yl.

7. The compound of claim 1 selected from:
4-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-sec-butyl-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(9-benzhydryl-2-(benzo[b]thiophen-3-yl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-(tetrahydro-2H-pyran-3-yl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(9-isopropyl-2-(thiophen-2-yl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-(4-(trifluoromethyl)benzyl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-isobutyl-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-methyl-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(2-(benzo[b]thiophen-3-yl)-9-(4-methylbenzyl)-9H-purin-6-ylamino)ethyl)phenol;
N-(2-(1H-indol-3-yl)ethyl)-2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-amine;
2-(benzo[b]thiophen-3-yl)-9-isopropyl-N-(2-(thiophen-3-yl)ethyl)-9H-purin-6-amine;
3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol;
2-(benzo[b]thiophen-3-yl)-N-(4-fluorophenethyl)-9-isopropyl-9H-purin-6-amine;
N-(4-aminophenethyl)-2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-amine;
4-(2-(9-isopropyl-2-(pyrimidin-5-yl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(9-isopropyl-2-(pyridin-3-yl)-9H-purin-6-ylamino)ethyl)phenol;
4-(2-(9-isopropyl-2-(thiophen-3-yl)-9H-purin-6-ylamino)ethyl)phenol;
2-(benzo[b]thiophen-3-yl)-N-(4-fluorophenethyl)-9-phenyl-9

Assignees

• Boitano Anthony E
• Cooke Michael
• Pan Shifeng
• Schultz Peter G
• TELLEW John
• Wan Yongqin
• Wang Xing
• Novartis Ag
• Scripps Research Inst

Inventors

• Boitano Anthony E
• Cooke Michael
• Pan Shifeng
• Schultz Peter G
• TELLEW John
• Wan Yongqin
• Wang Xing

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title