US 12,011,460 B2
Expansion of NK and DC cells in vivo mediating immune response
Guy Sauvageau, Montréal (CA); Sandra Cohen, Montréal (CA); Jean Roy, Ville Mont-Royal (CA); Silvy Lachance, Westmount (CA); Jean-Sébastien Delisle, Saint-Lambert (CA); and Jalila Chagraoui, Montreal (CA)
Assigned to UNIVERSITE DE MONTREAL, Montréal (CA)
Appl. No. 16/970,473
Filed by UNIVERSITE DE MONTREAL, Montréal (CA)
PCT Filed Feb. 20, 2019, PCT No. PCT/CA2019/050208
§ 371(c)(1), (2) Date Aug. 17, 2020,
PCT Pub. No. WO2019/161494, PCT Pub. Date Aug. 29, 2019.
Claims priority of provisional application 62/632,733, filed on Feb. 20, 2018.
Prior Publication US 2021/0085714 A1, Mar. 25, 2021
Int. Cl. C07D 471/14 (2006.01); A61K 35/15 (2015.01); A61K 35/17 (2015.01); A61K 35/28 (2015.01); A61P 37/04 (2006.01); C12N 5/0783 (2010.01)
CPC A61K 35/17 (2013.01) [A61K 35/15 (2013.01); A61K 35/28 (2013.01); A61P 37/04 (2018.01); C07D 471/14 (2013.01); C12N 5/0646 (2013.01); C12N 2501/999 (2013.01); C12N 2506/1315 (2013.01)] 15 Claims
 
1. A method for reducing severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections in a patient comprising the steps of:
a) culturing a starting population of hematopoietic stem and/or progenitor cells (HSC) with at least one compound of formula I:

OG Complex Work Unit Chemistry
or a salt or a prodrug thereof,
wherein:
each Y is independently selected from N and CH;
Z is
—CN
—C(O)OR1,
—C(O)N(R1)R3,
—C(O)R1, or
heteroaryl optionally substituted with one or more RA or R4 substituents,
wherein, when (R1) and R3 are attached to a nitrogen atom, optionally they join together with the nitrogen atom to form a 3 to 7-membered ring which optionally includes one or more other heteroatom selected from N, O and S, optionally the ring is substituted with one or more RA or R4;
W is
—CN,
—N(R1)R3,
—C(O)OR1,
—C(O)N(R1)R3,
—NR1C(O)R1,
—NR1C(O)OR1,
—OC(O)N(R1)R3,
—OC(O)R1,
—C(O)R1,
—NR1C(O)N(R1)R3,
—NR1S(O)2R1,
benzyl optionally substituted with 1, 2 or 3 RA or R1 substituents,
—X-L-(X-L)n-N(R1)R3,
—X-L-(X-L)n-heteroaryl optionally substituted with one or more RA or R4 substituents attached on either or both the L and heteroaryl groups,
—X-L-(X-L)n-heterocyclyl optionally substituted with one or more RA or R4 substituents attached on either or both the L and heterocyclyl groups,
—X-L-(X-L)n-aryl optionally substituted with one or more RA or R4 substituents,
—X-L-(X-L)n-NR1RA or
—(N(R1)-L)n-N+R1R3R5 R6−
wherein n is an integer equal to either 0, 1, 2, 3, 4, or 5,
and wherein, when R1 and R3 are attached to a nitrogen atom, optionally they join together with the nitrogen atom to form a 3 to 7-membered ring which optionally includes one or more other heteroatom selected from N, O and S, optionally the ring is substituted with one or more RA or R4;
each X is independently selected from C, O, S, and NR1;
each L is independently
—C1-6 alkylene,
—C2-6 alkenylene,
—C2-6 alkynylene,
—C3-7cycloalkylene, which optionally includes one or more other heteroatom selected from N, O and S or
—C3-7 cycloalkenylene, which optionally includes one or more other heteroatom selected from N, O and S
wherein the alkylene, the alkenylene, the alkynylene the cycloalkylene and the cycloalkenylene groups are each independently optionally substituted with one or two R4 or RA substituent;
R1 is each independently
—H,
—C1-6 alkyl,
—C2-6 alkenyl,
—C2-6 alkynyl,
—C3-7 cycloalkyl,
—C3-7 cycloalkenyl,
—C1-5 perfluorinated,
heterocyclyl,
aryl,
heteroaryl, or
benzyl,
wherein the alkyl, the alkenyl, the alkynyl, the cycloalkenyl, the perfluorinated alkyl, the heterocyclyl, the aryl, the heteroaryl and the benzyl groups are each independently optionally substituted with 1, 2 or 3 RA or Rd substituents;
R2 is
—H,
—C1-6 alkyl, optionally substituted with one more RA substituents
—C(O)R4,
-L-heteroaryl optionally substituted with one or more RA or R4 substituents
-L-heterocyclyl optionally substituted with one or more RA or R4, or
-L-aryl optionally substituted with one or more RA or R4 substituents;
R3 is each independently
—H,
—C1-6 alkyl,
—C2-6 alkenyl,
—C2-6 alkynyl,
—C3-7 cycloalkyl,
—C3-7 cycloalkenyl,
—C1-5 perfluorinated,
-heterocyclyl,
-aryl,
-heteroaryl, or
-benzyl,
wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the cycloalkenyl, the perfluorinated alkyl, the heterocyclyl, the aryl, the heteroaryl and the benzyl groups are each independently optionally substituted with 1, 2 or 3 RA or Rd substituents;
R4 is each independently
—H,
—C1-6 alkyl,
—C2-6 alkenyl,
—C2-6 alkynyl,
—C3-7 cycloalkyl,
—C3-7 cycloalkenyl,
—C1-5 perfluorinated,
-heterocyclyl,
-aryl,
-heteroaryl, or
-benzyl,
wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the cycloalkenyl, the perfluorinated alkyl, the heterocyclyl, the aryl, the heteroaryl and the benzyl groups are each independently optionally substituted with 1, 2 or 3 RA or Rd substituents;
R5 is each independently
—C1-6 alkyl,
—C1-6 alkylene-C2-6 alkenyl which optionally includes one or more other heteroatom selected from N, O and S
—C1-6 alkylene-C2-6 alkynyl which optionally includes one or more other heteroatom selected from N, O and S
-L-aryl which optionally includes one or more RA or R4 substituents
-L-heteroaryl which optionally includes one or more RA or R4 substituents
—C1-6 alkylene-C(O)O—
—C1-6 alkylene-C(O)OR1
—C1-6 alkylene-CN
—C1-6 alkylene-C(O)NR1 R3, wherein R1 and R3 optionally they join together with the nitrogen atom to form a 3 to 7-membered ring which optionally includes one or more other heteroatom selected from N, O and S; or
—C1-6 alkylene-OH;
R6 is
Halogen
—OC(O)CF3 or
—OC(O)R1;
RA is each independently
-halogen,
—CF3,
—OR1,
-L-OR1,
—OCF3,
—SR1,
—CN,
—NO2,
—NR1 R3,
-L-NR1R1,
—C(O)OR1,
—S(O)2R4
—C(O)N(R1)R3,
—NR1C(O)R1,
—NR1C(O)OR1,
—OC(O)N(R1)R3,
—OC(O)R1,
—C(O)R4,
—NHC(O)N(R1)R3,
—NR1C(O)N(R1)R3, or
—N3; and
Rd is each independently
—H,
—C1-6 alkyl,
—C2-6 alkenyl,
—C2-6 alkynyl,
—C3-7 cycloalkyl,
—C3-7 cycloalkenyl,
—C1-5 perfluorinated
-benzyl or
-heterocyclyl;
optionally together with at least one cell expanding factor,
b) expanding said cultured population of hematopoietic stem and/or progenitor cells (HSC) producing a graft; and
c) transplanting said graft in said patient thereby reducing severe graft-versus-host disease (GVHD), relapse, and/or severe viral infections in said patient.