CXCR7 RECEPTOR MODULATORS
20170327493 · 2017-11-16
Inventors
- Philippe Guerry (Allschwil, CH)
- Francois Lehembre (Allschwil, CH)
- Julien Pothier (Allschwil, CH)
- Hervé SIENDT (Allschwil, CH)
Cpc classification
A61P29/00
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61K31/553
HUMAN NECESSITIES
C07D243/14
CHEMISTRY; METALLURGY
A61P43/00
HUMAN NECESSITIES
C07D417/12
CHEMISTRY; METALLURGY
A61P37/06
HUMAN NECESSITIES
A61P1/16
HUMAN NECESSITIES
A61P19/04
HUMAN NECESSITIES
International classification
C07D417/12
CHEMISTRY; METALLURGY
A61K31/553
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
C07D405/12
CHEMISTRY; METALLURGY
Abstract
The present invention relates to derivatives of formula (I)
##STR00001##
wherein (R.sup.1).sub.n, ring (A), Y.sup.1, Y.sup.2, X, R.sup.4, L.sup.1, L.sup.2, and A.sup.1 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as CXCR7 receptor modulators.
Claims
1. A compound of formula (I) ##STR00034## wherein ring (A) represents a seven-membered ring, wherein Y.sup.1 and Y.sup.2 both represent CH.sub.2; and X represents —CH.sub.2—NR.sup.5—CH.sub.2—, or X represents *—CO—NR.sup.5—CH.sub.2—, or X represents *—CH.sub.2—NR.sup.5—CO—; or Y.sup.1 represents O, CH.sub.2, or NR.sup.Y1 wherein R.sup.Y1 represents hydrogen or (C.sub.1-3)alkyl; Y.sup.2 represents CH.sub.2 or CO; and X represents *—CH.sub.2—CH.sub.2—NR.sup.5—; or X represents *—CH.sub.2—CO—NR.sup.5—; or Y.sup.1 represents CH.sub.2 or CO; Y.sup.2 represents O, CH.sub.2, or NR.sup.Y2 wherein R.sup.Y2 represents hydrogen or (C.sub.1-3)alkyl; and X represents *—NR.sup.5—CH.sub.2—CH.sub.2—; or X represents *—NR.sup.5—CO—CH.sub.2—; wherein the asterisks indicate a bond which is attached to the group Y.sup.1; R.sup.5 represents (C.sub.1-6)alkyl; (C.sub.1-4)alkyl mono-substituted with (C.sub.1-3)alkoxy, cyano, vinyl; ethynyl, or (C.sub.1-3)alkoxy-carbonyl; —CO—R.sup.10 wherein R.sup.10 represents (C.sub.1-5)alkyl; (C.sub.1-5)alkoxy; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl; (C.sub.3-4)alkenoxy; (C.sub.3-4)alkynoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; (C.sub.1-3)alkoxy-(C.sub.2-3)alkoxy; hydroxy-(C.sub.1-5)alkyl, (C.sub.1-3)alkoxy-(C.sub.1-3)alkyl; (C.sub.3-6)cycloalkyl optionally comprising one ring oxygen atom, wherein said cycloalkyl is optionally mono- or di-substituted wherein the substituents independently are fluoro or (C.sub.1)fluoroalkyl; or —NR.sup.10aR.sup.10b wherein R.sup.10a and R.sup.10b independently represent hydrogen, (C.sub.1-4)alkyl or (C.sub.3-6)cycloalkyl, or R.sup.10a and R.sup.10b together with the nitrogen to which they are attached to form a 5- to 7-membered saturated ring; (C.sub.2-4)fluoroalkyl; (C.sub.3-6)cycloalkyl optionally comprises one ring oxygen atom; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl, wherein the (C.sub.3-6)cycloalkyl group optionally contains comprises one ring oxygen atom; wherein said cycloalkyl is optionally substituted with one or two methyl substituents; (R.sup.1).sub.n represents one or two optional substituents independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, (C.sub.1-3)fluoroalkoxy, or cyano; L.sup.1 represents a two-membered linker group selected from —NH—CH.sub.2—*; —O—CH.sub.2*; —CH.sub.2—CH.sub.2—; or —CH═CH—; wherein the asterisks indicate the bond with which the group L.sup.1 is attached to the carbonyl group; L.sup.2 represents —(C.sub.1-3)alkylene-; Ar.sup.1 represents phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl independently is unsubstituted, mono-, di- or tri-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; or cyano; and R.sup.4 represents (C.sub.2-6)alkyl; (C.sub.2-5)alkyl which is mono-substituted with (C.sub.1-4)alkoxy, cyano, or hydroxy; or di-substituted wherein the substituents are independently selected from (C.sub.1-3)alkoxy, or hydroxy; (C.sub.2-3)fluoroalkyl which is optionally further substituted with one hydroxy; —(C.sub.2-4)alkylene-NR.sup.6R.sup.7, wherein R.sup.6 and R.sup.7 independently represent hydrogen; (C.sub.1-4)alkyl; —CO—(C.sub.1-4)alkoxy; —SO.sub.2—(C.sub.1-3)alkyl; (C.sub.2-3)fluoroalkyl; (C.sub.3-6)cycloalkyl or (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl, wherein in the above groups the (C.sub.3-6)cycloalkyl group optionally contains comprises one ring oxygen atom, and wherein said (C.sub.3-6)cycloalkyl group is optionally substituted with methyl; —(C.sub.1-3)alkylene-CO—R.sup.8, wherein R.sup.8 represents (C.sub.1-4)alkoxy; or R.sup.8 represents NR.sup.81R.sup.82 wherein R.sup.81 and R.sup.82 independently represent hydrogen or (C.sub.1-4)alkyl, or R.sup.81 and R.sup.82 together with the nitrogen to which they are attached to form a 4- to 6-membered saturated ring optionally substituted with two fluoro substituents; (C.sub.3-6)cycloalkyl or (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl, wherein in the above groups the cycloalkyl group is optionally mono-substituted with hydroxy; (C.sub.4-7)heterocyclyl or (C.sub.4-7)heterocyclyl-(C.sub.1-3)alkyl, wherein in the above groups the (C.sub.4-7)heterocyclyl independently comprises one or two ring heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein in the above groups said (C.sub.4-7)heterocyclyl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from: one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen; and/or two oxo substituents at a ring sulfur ring atom (thus forming a —SO.sub.2-group); and/or (C.sub.1-4)alkyl attached to a ring nitrogen atom having a free valency; and/or two fluoro substituents attached to a ring carbon atom; and/or in case of a (C.sub.4-7)heterocyclyl-(C.sub.1-3)alkyl group, methyl attached to a ring carbon atom which is attached to the linking (C.sub.1-3)alkyl group; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1; wherein ring (A) represents a seven-membered ring, wherein Y.sup.1 and Y.sup.2 both represent CH.sub.2; and X represents —CH.sub.2—NR.sup.5—CH.sub.2—, or Y.sup.1 and Y.sup.2 both represent CH.sub.2; and X represents *—CO—NR.sup.5—CH.sub.2—, or Y.sup.1 and Y.sup.2 both represent CH.sub.2; and X represents *—CH.sub.2—NR.sup.5—CO—; or Y.sup.1 represents O, CH.sub.2, or NR.sup.Y1 wherein R.sup.Y1 represents hydrogen or (C.sub.1-3)alkyl; Y.sup.2 represents CH.sub.2; and X represents *—CH.sub.2—CH.sub.2—NR.sup.5—; or Y.sup.1 represents O, CH.sub.2, or NR.sup.Y1 wherein R.sup.Y1 represents hydrogen or (C.sub.1-3)alkyl; Y.sup.2 represents CH.sub.2; and X represents *—CH.sub.2—CO—NR.sup.5—; or Y.sup.1 represents O, CH.sub.2, or NR.sup.Y1 wherein R.sup.Y1 represents hydrogen or (C.sub.1-3)alkyl; Y.sup.2 represents CO; and X represents *—CH.sub.2—CH.sub.2—NR.sup.5—; or Y.sup.1 represents CH.sub.2; Y.sup.2 represents CH.sub.2, O, or NR.sup.Y2 wherein R.sup.Y2 represents hydrogen or (C.sub.1-3)alkyl; and X represents *—NR.sup.5—CH.sub.2—CH.sub.2—; or Y.sup.1 represents CH.sub.2; Y.sup.2 represents CH.sub.2; and X represents *—NR.sup.5—CO—CH.sub.2—; or Y.sup.1 represents CO; Y.sup.2 represents CH.sub.2, O, or NR.sup.Y2 wherein R.sup.Y2 represents hydrogen (C.sub.1-3)alkyl; and X represents *—NR.sup.5—CH.sub.2—CH.sub.2—; wherein the asterisks indicate the bond which is attached to the group Y.sup.1; or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1; wherein R.sup.5 represents (C.sub.1-6)alkyl; (C.sub.1-4)alkyl mono-substituted with (C.sub.1-3)alkoxy; —CO—R.sup.10 wherein R.sup.10 represents (C.sub.1-5)alkyl; (C.sub.1-5)alkoxy; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; (C.sub.1-3)alkoxy-(C.sub.2-3)alkoxy; hydroxy-(C.sub.1-3)alkyl; (C.sub.1-3)alkoxy-(C.sub.1-3)alkyl; or (C.sub.3-6)cycloalkyl optionally containing one ring oxygen atom, wherein said cycloalkyl is optionally mono- or di-substituted with fluoro; (C.sub.2-4)fluoroalkyl; (C.sub.3-6)cycloalkyl optionally containing one ring oxygen atom; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl, wherein the (C.sub.3-6)cycloalkyl group optionally comprises one ring oxygen atom; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1; wherein R.sup.5 represents (C.sub.1-6)alkyl; —CO—R.sup.10 wherein R.sup.10 represents (C.sub.1-5)alkyl; hydroxy-(C.sub.1-3)alkyl; (C.sub.1-3)alkoxy-(C.sub.1-3)alkyl; or (C.sub.3-6)cycloalkyl optionally comprising one ring oxygen atom, wherein said cycloalkyl is unsubstituted, or mono- or di-substituted with fluoro; (C.sub.2-4)fluoroalkyl; (C.sub.3-6)cycloalkyl optionally comprising one ring oxygen atom; or (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1; wherein (R.sup.1).sub.n is absent, or represents one substituent independently selected from (C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, halogen, (C.sub.1-3)fluoroalkyl, (C.sub.1-3)fluoroalkoxy, or cyano; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1; wherein L.sup.1 represents a two-membered linker group selected from —NH—CH.sub.2—*, —O—CH.sub.2—*, or —CH.sub.2CH.sub.2—; wherein the asterisks indicate the bond with which the group L.sup.1 is attached to the carbonyl group; or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1; wherein L.sup.2 represents —CH.sub.2—; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1; wherein Ar.sup.1 represents phenyl which is mono-, or di-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; or cyano; or 6-membered heteroaryl; which is mono-, or di-substituted, wherein the substituents are independently selected from (C.sub.1-4)alkyl; (C.sub.1-4)alkoxy; (C.sub.1-3)fluoroalkyl; (C.sub.1-3)fluoroalkoxy; halogen; or cyano; or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1; wherein R.sup.4 represents (C.sub.2-5)alkyl which is mono-substituted with hydroxy; or disubstituted wherein the substituents are independently methoxy or hydroxy; —(C.sub.2-4)alkylene-NR.sup.6R.sup.7, wherein R.sup.6 represents hydrogen or (C.sub.1-4)alkyl; and R.sup.7 represents (C.sub.1-4)alkyl; (C.sub.2-3)fluoroalkyl; (C.sub.3-6)cycloalkyl; or (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl; (C.sub.3-6)cycloalkyl-(C.sub.1-3)alkyl, wherein the cycloalkyl group is optionally mono-substituted with hydroxy; (C.sub.4-7)heterocyclyl or (C.sub.4-7)heterocyclyl-(C.sub.1-3)alkyl, wherein in the above groups the (C.sub.4-7)heterocyclyl independently comprises one or two ring heteroatoms independently selected from nitrogen or oxygen; wherein in the above groups said (C.sub.4-7)heterocyclyl independently is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from: one oxo substituent attached to a ring carbon atom in alpha position to a ring nitrogen; and/or (C.sub.1-4)alkyl attached to a ring nitrogen atom having a free Valency; or two fluoro substituents attached to a ring carbon atom; or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1; wherein R.sup.4 represents 2-hydroxy-ethyl, 2-hydroxy-propyl, 2-hydroxy-2-methyl-propyl, 3-hydroxy-3-methyl-butyl, or 2-methoxy-ethyl; 2-hydroxy-3-methoxy-propyl; —(C.sub.2-4)alkylene-NR.sup.6R.sup.7 selected from 2-amino-ethyl, 2-methylamino-ethyl, 2-dimethylamino-ethyl, 2-diethylamino-ethyl, 3-(dimethylamino)-propyl, 2-ethylamino-ethyl, 2-(ethyl-methylamino)-ethyl, 2-(isopropyl-amino)-ethyl, 2-(isopropyl-methylamino)-ethyl, 2-(diisopropylamino)-ethyl, 2-(tert-butylamino)-ethyl, 2-(butyl-methylamino)-ethyl, 2-[(2-fluoroethyl)-methylamino]-ethyl, 2-[(2,2,2-trifluoroethyl)-amino]-ethyl, 2-[methyl-(2,2,2-trifluoroethyl)-amino]-ethyl, 2-[(2-fluoro-1-methylethyl)-methylamino]-ethyl, 2-[(cyclopropyl)-methylamino]-ethyl, 2-[(cyclopropylmethyl)-methylamino]-ethyl, 2-[(cyclobutyl)-methylamino]-ethyl, or 2-[(cyclopentyl)-methylamino]-ethyl; (1-hydroxy-cyclopentyl)-methyl; (C.sub.4-7)heterocyclyl selected from pyrrolidin-3-yl, 1-methyl-pyrrolidin-3-yl, piperidin-3-yl, 1-methyl-piperidin-3-yl, piperidin-4-yl, 1-methyl-piperidin-4-yl, or tetrahydro-pyran-4-yl; (C.sub.4-7)heterocyclyl-(C.sub.1-3)alkyl selected from 2-(pyrrolidin-1-yl)-ethyl, 2-(1-methyl-pyrrolidin-2-yl)-ethyl, 2-(morpholin-4-yl)-ethyl, pyrrolidin-3-yl-methyl, 3-(pyrrolidin-1-yl)-propyl, 2-(piperazin-1-yl)-ethyl, 2-(piperidin-1-yl)-ethyl, 2-(azepan-1-yl)-ethyl, 2-(3,3-difluoroazetidin-1-yl)-ethyl, 2-(3,3-difluoropyrrolidin-1-yl)-ethyl, 2-(3,3-difluoropiperidin-1-yl)-ethyl, or 2-(4,4-difluoropiperidin-1-yl)-ethyl; or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1, wherein the compound is: N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4-propyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-propyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(3-Bromo-benzyl)-N-(2-dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(4-methoxy-pyridin-2-ylmethyl)-acetamide; N-[2-(Cyclopropyl-methyl-amino)-ethyl]-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2,4-Difluoro-benzyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-N-[2-(4,4-difluoro-piperidin-1-yl)-ethyl]-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(4-methyl-pyridin-2-ylmethyl)-acetamide; N-(2-Chloro-benzyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide; 2-(4-Isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-N-(4-fluoro-2-trifluoromethyl-benzyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-benzyl)-acetamide; N-(2,6-Difluoro-benzyl)-N-(2-dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; 2-(4-Acetyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(3-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-[3-(2-methoxy-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy]-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(3-Acetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino]-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(3-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(2-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2,3-dichloro-benzyl)-N-(2-dimethylamino-ethyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2,6-dichloro-benzyl)-N-(2-dimethylamino-ethyl)-acetamide; N-(2-Chloro-benzyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(6-methyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; {2-[[2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-methylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; {2-[[2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(1,4-Diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; 2-(1,4-Diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; {2-[[2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester; 2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-yl methyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; {2-[[2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester; N-(2-tert-Butylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-acetamide; N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-thiazol-5-ylmethyl)-acetamide; N-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide; (2-{(3-Chloro-pyridin-2-ylmethyl)-[2-(4-ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-amino}-ethyl)-methyl-carbamic acid tert-butyl ester; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; N-(2-Chloro-benzyl)-2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2,3-dichloro-benzyl)-N-(2-dimethylamino-ethyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide; N-(2-tert-Butylamino-ethyl)-N-(2-chloro-benzyl)-2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-acetamide; N-(2-tert-Butylamino-ethyl)-N-(3-chloro-pyridin-2-ylmethyl)-2-(4-cyclo propylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-acetamide; N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropyl methyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide; or N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide. or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising, as active principle, the compound according to claim 1, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
13. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, formulated as a medicament.
14. A method of treating a disease comprising administering to a subject in need thereof an amount of the compound of formula (I) according to claim 1, wherein the disease is cancer, autoimmune disorders, inflammatory diseases, transplant rejection, or fibrosis.
15. A method of treating a disease comprising administering to a subject in need thereof an amount of a pharmaceutical composition according to claim 12, wherein the disease is cancer, autoimmune disorders, inflammatory diseases, transplant rejection, or fibrosis.
16. A method of treating a tumor comprising administering an effective amount of the compound of formula (I) according to claim 1, or of a pharmaceutically acceptable salt thereof, wherein said effective amount leads to a change of tumor properties, said change being is achieved by modulating a CXCL12 receptor pathway.
17. A method of modulating an immune response comprising administering an effective amount of the compound of formula (I) according to claim 1, or of a pharmaceutically acceptable salt thereof, wherein said effective amount modulates an inflammatory disease, said modulation being mediated by a CXCL12 receptor pathway.
18. A method of treatment of a cancer, an autoimmune disorder, inflammatory disease, transplant rejection, or fibrosis comprising administering to a patient a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
19. A method of treating cancer comprising administering to a subject in need thereof an effective amount of the compound according to formula (I); wherein said compound is optionally administered in combination with one or more chemotherapy agents, radiotherapy, or targeted therapy.
Description
EXPERIMENTAL PART
I. Chemistry
[0458] All temperatures are stated in ° C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen. All compounds were purified by a method described below: flash column chromatography on silica-gel or preparative HPLC. Compounds described in the invention are characterized by LC-MS data (retention time t.sub.R is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given.
[0459] In case an Example compound's or Precursor's name is preceded with the mention rac- this means this Example compound or Precursor is obtained as a racemic mixture of two enantiomers.
NMR Spectroscopy:
[0460] Bruker Avance II spectrometer equipped with a 400 MHz Ultrashield™ Magnet and a BBO 5 mm probehead or a PAXTI 1 mm probehead. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimethylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm. The abbreviations s, d, t, q and m refer to singlet, doublet, triplet, quartet, multiplet and br to broad, respectively. Coupling constants J are reported in Hz. In case NMR spectra are measured using 1 mm Microprobe® tubes and a PAXTI 1 mm probehead, the compounds are dissolved in non-deuterated DMSO. The spectra are then measured with double irradiation for suppression of the DMSO and H.sub.2O peaks. In that case only a selection of representative NMR peaks of the compound is given.
LC-MS Equipment and Conditions
[0461] Method LC-A:
[0462] Agilent 1100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax SB-aq (3.5 m, 4.6×50 mm). Conditions: MeCN [eluent A]; water+0.04% TFA [eluent B]. Gradient: 95% B.fwdarw.5% B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.
[0463] Method LC-B:
[0464] Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Acquity UPLC BEH C18 1.7 um 2.1×50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60° C. Conditions: MeCN+0.045% TFA [eluent A]; water+0.05% TFA [eluent B]. Method: Gradient: 98% B.fwdarw.2% B over 2.0 min. Flow: 1.2 mL/min.
[0465] Detection: UV 214 nm and ELSD, and MS, t.sub.R is given in min.
Preparative HPLC Equipment:
[0466] Gilson 333/334 HPLC pump equipped with Gilson LH215, Dionex SRD-3200 degasser, Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector, Single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ Plus, MRA100-000 flow splitter, Polymer Laboratories PL-ELS1000 ELS detector
Preparative HPLC with Basic Conditions
[0467] Method LC-C:
[0468] Column: Waters XBridge (10 m, 75×30 mm). Conditions: MeCN [eluent A]; water+0.5% NH.sub.4OH (25% aq.) [eluent B]; Gradient see Table 1 (flow: 75 mL/min), the starting percentage of Eluent A (x) is determined depending on the polarity of the compound to purify. Detection: UV/Vis+MS
TABLE-US-00001 TABLE 1 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x Eluent B (%) 100 − x 100 − x 5 5 100 − x 100 − x
Preparative HPLC with Acidic Conditions
[0469] Method LC-D:
[0470] Column: Waters Atlantis T3 (10 μm, 75×30 mm). Conditions: MeCN [eluent A]; water+0.5% HCO.sub.2H [eluent B]; Gradient see Table 1 (flow: 75 mL/min), the starting percentage of Eluent A (x) is determined depending on the polarity of the compound to purify. Detection: UV/Vis+MS
TABLE-US-00002 TABLE 1 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x Eluent B (%) 100 − x 100 − x 5 5 100 − x 100 − x
Abbreviations (as Used Hereinbefore or Hereinafter)
[0471] AcOH acetic acid [0472] aq. aqueous [0473] Ar argon [0474] BINAP racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [0475] Brettphos® 2-(Dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl [0476] BSA bovine serum albumin [0477] DABCO 1,4-diazabicyclo[2.2.2]octane [0478] DCC N,N′-dicyclohexylcarbodiimide [0479] DCE 1,2-dichloroethane [0480] DCM dichloromethane [0481] DEAD diethylazadicarboxylate [0482] deion. deionized [0483] DIPEA diisopropyl-ethylamine, Hünig's base, ethyl-diisopropylamine [0484] dioxane 1,4-dioxane [0485] DMAP 4-dimethylaminopyridine [0486] DMF dimethylformamide [0487] DMSO dimethylsulfoxide [0488] eq. equivalent(s) [0489] Ether diethyl ether [0490] EtOAc ethyl acetate [0491] EtOH ethanol [0492] g gram(s) [0493] h hour(s) [0494] HATU 2-(7-aza-1H-benzotriazole-1-yl)-, 1,3,3-tetramethyluronium hexafluorophosphate [0495] HBTU N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate [0496] HCl hydrogen chloride [0497] HPLC high performance liquid chromatography [0498] HV high vacuum conditions [0499] Josiphos (R)-1-[(S.sub.P)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine palladium(II) dichloride [0500] LC-MS liquid chromatography-mass spectrometry [0501] MeCN acetonitrile [0502] MeI methyl iodide [0503] MeOH methanol [0504] mg milligram(s) [0505] mL milliliter(s) [0506] mmol millimole(s) [0507] min minute(s) [0508] N normality of a solution [0509] MS mass spectroscopy [0510] NaBH(OAc).sub.3 sodium triacetoxyborohydride [0511] NaBH.sub.3CN sodium cyanoborohydride [0512] NaOAc sodium acetate [0513] NH.sub.3 ammonia [0514] NMR nuclear magnetic resonance spectroscopy [0515] OAc acetate [0516] Pd/C 10% Palladium on activated charcoal (10%) [0517] Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0) [0518] Pd(PPh.sub.3).sub.4 Palladium tetrakistriphenylphosphine [0519] PMB para-methoxybenzyl [0520] PPh.sub.3 Triphenyphosphine [0521] prep. preparative [0522] rac racemic [0523] RT room temperature [0524] s second(s) [0525] sat. saturated [0526] soln. solution [0527] T temperature [0528] T.sub.3P n-propanephosphonic acid anhydride [0529] TBAF tetrabutylammonium fluoride [0530] TBME tert-butyl methyl ether [0531] TBDMS tert-butyldimethylsilyl [0532] TEA triethylamine [0533] Tf trifluoromethane-sulfonyl [0534] TFA trifluoroacetic acid [0535] TFAA trifluoroacetic acid anhydride [0536] THF tetrahydrofuran [0537] t.sub.R retention time [0538] X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
EXAMPLE 1
N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide
[0539] To a solution of Precursor 4A1 (200 mg, 0.503 mmol), Amine B1 (124 mg, 0.503 mmol) and HATU (229 mg, 0.604 mmol) in 5 mL DCM cooled to 0° C. is added DIPEA (0.129 mL, 0.754 mmol). The reaction mixture is allowed to stir at RT for 4 h. Water is added and the resulting organic phase is washed with sat. aq. NaHCO.sub.3 soln. and brine then dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.61 min; [M+H].sup.+=507.6; .sup.1H-NMR (DMSO-d.sup.6), 2:1 mixture of two rotamers:
[0540] Major rotamer spectrum δ: 7.75 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H), 6.84 (t, J=7.8 Hz, 1H), 6.58 (d, J=7.7 Hz, 1H), 6.44 (d, J=7.4 Hz, 1H), 5.37 (m, 1H), 4.79 (s, 2H), 4.18 (d, J=4.6 Hz, 2H), 3.91-3.97 (m, 2H), 3.55-3.63 (m, 1H), 3.45-3.51 (m, 1H), 2.96-3.03 (m, 2H), 2.40-2.45 (m, 2H), 2.06-2.22 (m, 10H), 1.70-1.79 (m, 1H), 0.80-0.89 (m, 6H)
[0541] Minor rotamer spectrum δ: 7.81 (d, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 6.74 (t, J=7.8 Hz, 1H), 6.39 (d, J=7.7 Hz, 1H), 6.32 (d, J=7.4 Hz, 1H), 5.37 (m, 1H), 4.86 (s, 2H), 3.88-3.92 (m, 2H), 3.85 (d, J=4.6 Hz, 2H), 3.65-3.71 (m, 1H), 3.39-3.45 (m, 1H), 2.96-3.03 (m, 2H), 2.35-2.41 (m, 2H), 2.06-2.22 (m, 10H), 1.70-1.79 (m, 1H), 0.80-0.89 (m, 6H)
[0542] Examples 2-19 listed in Table 1 are prepared applying the method described for Example 1 using the corresponding Precursor and Amine respectively.
TABLE-US-00003 TABLE 1 Examples 2-19 MS Data t.sub.R [min] m/z Example Compound (LC-B) [M + H].sup.+ 2 N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.43 508.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2- ylmethyl)-acetamide 3 N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4- 0.39 474.2 isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- acetamide 4 N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4- 0.33 446.2 ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- acetamide 5 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.43 479.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)- acetamide 6 N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4- 0.36 460.2 propyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- acetamide 7 N-(2-Dimethylamino-ethyl)-2-(4-propyl-2,3,4,5-tetrahydro- 0.46 493.2 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)- acetamide 8 N-(3-Bromo-benzyl)-N-(2-dimethylamino-ethyl)-2-(4-isobutyl- 0.49 517.2 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide 9 N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.34 470.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(4-methoxy-pyridin-2- ylmethyl)-acetamide 10 N-[2-(Cyclopropyl-methyl-amino)-ethyl]-2-(4-isobutyl-2,3,4,5- 0.54 533.3 tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl- benzyl)-acetamide 11 2-(4-Isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- 0.72 547.3 N-[2-(2-oxo-pyrrolidin-1-yl)-ethyl]-N-(2-trifluoromethyl-benzyl)- acetamide 12 N-(2,4-Difluoro-benzyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.46 501.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)- acetamide 13 N-(3-Chloro-pyridin-2-ylmethyl)-N-[2-(4,4-difluoro-piperidin-1-yl)- 0.47 550.3 ethyl]-2-(4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9- ylamino)-acetamide 14 N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.37 454.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(4-methyl-pyridin-2-ylmethyl)- acetamide 15 N-(2-Chloro-benzyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.47 499.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)- acetamide 16 2-(4-Isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- 0.52 549.3 N-(2-morpholin-4-yl-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide 17 N-(2-Dimethylamino-ethyl)-N-(4-fluoro-2-trifluoromethyl-benzyl)-2- 0.51 525.2 (4-isobutyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- acetamide 18 N-(2-Dimethylamino-ethyl)-2-(4-isobutyl-2,3,4,5-tetrahydro- 0.51 507.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-benzyl)- acetamide 19 N-(2,6-Difluoro-benzyl)-N-(2-dimethylamino-ethyl)-2-(4-isobutyl- 0.43 475.3 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetamide 69 {2-[[2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9- 0.95 593.3 ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl- carbamic acid tert-butyl ester 70 N-(2-tert-Butylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.47 507.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)- acetamide 72 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.37 480.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2- ylmethyl)-acetamide 73 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.32 426.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(3-methyl-pyridin-2-ylmethyl)- acetamide 74 2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N- 0.38 506.3 (2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)- acetamide 75 N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.35 472.2 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)- acetamide 76 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- 0.37 486.2 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-thiazol-5- ylmethyl)-acetamide 77 N-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-N- 0.38 517.2 (2-dimethylamino-ethyl)-2-(4-ethyl-2,3,4,5-tetrahydro- benzo[f][1,4]oxazepin-9-ylamino)-acetamide 82 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin- 0.42 532.3 9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin- 2-ylmethyl)-acetamide 83 N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-2,3,4,5- 0.51 533.3 tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl- benzyl)-acetamide 84 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin- 0.48 505.3 9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl- benzyl)-acetamide
EXAMPLE 71
2-(4-Ethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0543] To a solution of Example 69 (90 mg, 0.15 mmol) in 3 mL DCM is added TFA (69.8.4 μL, 0.911 mmol) at RT. The mixture is stirred for 2 h at RT. After evaporation of the volatiles the crude is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-B: t.sub.R=0.46 min; [M+H].sup.+=493.3
EXAMPLE 85
2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) {2-[[2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0544] In analogy to Example 1, condensation of Precursor 4A5 with amine B21 yields {2-[[2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester as a yellow foam. LC-A: t.sub.R=0.87 min; [M+H].sup.+=619.31
Step 2)
[0545] The title compound is obtained by treatment of {2-[[2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester with TFA in analogy to Example 71 as a yellowish oil; LC-A: t.sub.R=0.50 min; [M+H].sup.+=519.3
EXAMPLE 20
2-(4-Acetyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
a) N-(2-(dimethylamino)ethyl)-2-((4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]-oxazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide
[0546] To a solution of (4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine Precursor 4A4 (430 mg, 0.879 mmol), N-(2-(trifluoromethyl)benzyl)-N′,N′-dimethylethane-1,2-diamine Amine B1 (217 mg, 0.879 mmol) and HATU (401 mg, 1.05 mmol) in 8 mL DCM cooled to 0° C. is added DIPEA (0.226 mL, 1.32 mmol). The reaction mixture is allowed to stir at RT for 2 h. Water is added and the recovered organic phase is washed with sat. aq. NaHCO.sub.3 soln. and brine then dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 24 g of silica gel with DCM/MeOH system (1:0 to 4:1 gradient) as eluent to yield the title compound as a dark yellow oil. LC-A: t.sub.R=0.63 min; [M+H].sup.+=571.2;
b) N-(2-(dimethylamino)ethyl)-2-((2,3,45-tetrahydrobenzo[f][1,4]oxazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide
[0547] To a degassed solution of N-(2-(dimethylamino)ethyl)-2-((4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]-oxazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide (143 mg, 0.15 mmol, 1 eq) and AcOH (0.3 mL) in 3 mL of MeOH (3 mL) at RT is added Palladium, 10 wt. % on activated carbon (16 mg, 0.015 mmol) and the well stirred suspension is put under an atmospheric pressure of H.sub.2 for the night. The mixture is filtered over Celite and washed three times with MeOH. The solvent is removed under reduced pressure. The crude residue is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.54 min; [M+H].sup.+=451.1
c) 2-(4-Acetyl-2,3,4,5-tetrahydro-benzo[f][1, 4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide (Example 20)
[0548] To a solution of N-(2-(dimethylamino)ethyl)-2-((2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide (7 mg, 0.016 mmol) in 0.5 mL DMF is added acetic anhydride (0.0022 mL, 0.023 mmol) followed by DIPEA (0.0054 mL, 0.031 mmol) and DMAP (1 mg, 0.0078 mmol). The reaction mixture is allowed to stir at RT overnight. Water is added and the mixture is extracted with EtOAc. The resulting organic phase is washed with sat. aq. NH.sub.4Cl soln. and brine then dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by prep. HPLC (Method C) to yield the title compound as a colorless oil. LC-A: t.sub.R=0.68 min; [M+H].sup.+=493.1
Precursor 4A1
(4-isobutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine
a) 2-((Isobutylamino)methyl)-6-nitrophenol (Precursor 4A1-2)
[0549] To a solution of 2-hydroxy-3-nitrobenzaldehyde (2600 mg, 15.6 mmol) in 60 mL of MeOH at RT under Ar is added isobutylamine (1.55 mL, 15.6 mmol). The resulting mixture is stirred at RT for 30 min at which time the reacting mixture is cooled down to 5° C. and NaBH.sub.4 (677 mg, 17.9 mmol) is added portionwise. After the end of the addition, the reacting mixture is stirred at 0° C. for 90 minutes. Water (60 ml) is added and a part of MeOH is distilled off under reduced pressure. The resulting aqueous phase is extracted with EtOAc; the combined organic layers are dried over Mg.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as a crude yellow solid of appropriate purity for the next step. LC-A: t.sub.R=0.54 min; [M+H].sup.+=225; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 8.04 (dd, J.sub.1=1.7 Hz, J.sub.2=8.6 Hz, 1H), 7.28 (m, 1H), 6.50 (t, J=7.9 Hz, 1H), 4.18 (s, 2H), 2.70 (d, J=6.8 Hz, 2H), 1.90 (m, 1H), 0.93 (d, J=6.7 Hz, 6H)
b) 2-Hydroxy-N-(2-hydroxy-3-nitrobenzyl)-N-isobutylacetamide (Precursor 4A1-3)
[0550] To a solution of Precursor 4A1-2 (2.880 g, 10.3 mmol) in 75 mL of DCM at RT are added 0.89 mL of a glycolic acid solution, 70 wt. % in H.sub.2O (10.3 mmol) and DIPEA (2.64 mL, 15.4 mmol) followed by HBTU (4.29 mg, 11.3 mmol). The reaction mixture is stirred at RT overnight. As some starting material is still present, 0.45 mL of glycolic acid solution (5.14 mmol), 1.32 ml of DIPEA (7.71 mmol) and finally HBTU (2.34 g, 6.16 mmol) are added and the mixture is stirred at RT for 2 h to reach completion. Water is added and the reaction mixture is extracted with DCM/NaHCO.sub.3; the combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound with a fair purity compatible with the next step without requiring further purification. LC-A: t.sub.R=0.77 min; [M+H].sup.+=283.3
c) 4-Isobutyl-9-nitro-4,5-dihydrobenzo[f][1,4]oxazepin-3(2H)-one (Precursor 4A1-5)
[0551] To a solution of Precursor 4A1-3 (3.09 g, 10.9 mmol) in 100 mL anhydrous THF at 0° C. is added PPh.sub.3 (3.48 g, 13.1 mmol) followed by DEAD solution 40% in toluene (8.97 mL, 19.7 mmol). The reaction mixture is stirred at 0° C. for 2 h. Saturated NH.sub.4Cl aq (100 mL) is added and the mixture is extracted with EtOAc. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with heptane/EtOAc system (4:1 to 1:1 gradient) as eluent to yield the title compound as a yellow solid. LC-A: t.sub.R=0.79 min; [M+H+MeCN].sup.+=306.0; .sup.1H-NMR (500 MHz, CDCl.sub.3) δ: 7.84 (dd, J.sub.1=1.5 Hz, J.sub.2=8.2 Hz, 1H), 7.48 (m, 1H), 7.22 (m, 1H), 4.89 (s, 2H), 4.55 (s, 2H), 3.40 (d, J=7.5 Hz, 2H), 2.03 (m, 1H), 0.92 (d, J=6.7 Hz, 6H)
d) 4-Isobutyl-9-nitro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Precursor 4A1-6)
[0552] To a solution of Precursor 4A1-5 (2.93 g, 11.1 mmol) in 40 mL of THF at RT is added a (1M) solution of BH.sub.3.THF complex in THF (22.1 mL, 22.1 mmol). The reaction mixture is refluxed overnight. As starting material is still present in major proportions, more (1M) solution of BH.sub.3.THF complex in THF has to be added at RT regularly and the mixture is further refluxed between check times. After an overall addition of 88.4 mL of (1M) solution of BH.sub.3.THF complex in THF (88.4 mmol) and total refluxing time of 44 h, starting material is not noticeable anymore and the reaction is complete. The mixture is cooled to RT and evaporated under reduced pressure. The residue is dissolved in 40 mL of MeOH and is treated with 5.5 mL of a (4.0M) solution of HCl in 1,4-dioxane (22.1 mmol). The mixture is stirred vigorously at RT overnight and then evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with heptane/EtOAc system (4:1 to 0:1 gradient) and then EtOAc/(MeOH+1.5% (7.0M) NH.sub.3 solution in MeOH) system (1:0 to 4:1 gradient) as eluents to yield the title compound as an orange oil. LC-A: t.sub.R=0.54 min; [M+H].sup.+=251.2
e) 4-Isobutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-amine (Precursor 4A1-7)
[0553] To a solution of Precursor 4A1-6 (2.38 g, 9.51 mmol) in 50 mL of acetone at RT is added 19 mL of a sat. ammonium chloride solution (19 mL, 9.51 mmol). The reaction mixture is cooled to 0° C. then zinc dust (6.54 g, 100.0 mmol) is added portionwise. The reaction mixture is warmed up to RT and the suspension is stirred vigorously at RT for 24 h. EtOAc (25 ml) is added followed by Na.sub.2SO.sub.4 (10 g). The suspension is stirred for 15 min then filtered through a Celite pad and washed with EtOAc then EtOAc/MeOH (9:1). The combined organic phases are evaporated under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.39 min; [M+H].sup.+=221.2; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 6.82 (t, J=7.6 Hz, 1H), 6.69 (d, J=7.8 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 4.09 (t, J=4.1 Hz, 2H), 3.88 (s, 2H), 3.19 (t, J=4.1 Hz), 2.28 (d, J=7.2 Hz, 2H), 1.81 (m, 1H), 0.92 (d, J=6.6 Hz, 6H)
f) (4-Isobutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine (Precursor 4A1)
[0554] To a solution of 4-isobutyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-amine (2.61 g, 9.48 mmol) in 100 mL of anhydrous MeOH is added glyoxylic acid monohydrate (1.05 g, 11.4 mmol). The reaction mixture is degassed and purged with Argon then Pearlman's catalyst Pd(OH).sub.2 (20% Pd/C) is added (50.4 mg, 0.095 mmol). The well stirred suspension is put under an atmospheric pressure of H.sub.2 and left reacting at RT for 48 h. As substantial amount of starting material can still be observed, the reaction kinetic is boosted up by adding more Pearlman's catalyst (252 mg, 0.474 mmol). The reaction mixture is put back under atmospheric pressure of H.sub.2 and stirred further at RT for 5 h. The mixture is purged with Ar and filtered over Celite and washed three times with MeOH. The solvent is removed under reduced pressure. The crude residue is purified by flash chromatography over 40 g of silica gel with EtOAc/(MeOH+1% TEA) system (1:0 to 4:1 gradient) as eluent to yield the title compound as an orange solid. LC-A: t.sub.R=0.51 min; [M+H].sup.+=279.4
Precursor 4A2
(4-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine
a) N-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-ethyl-2-fluoro-3-nitrobenzamide (Precursor 4A2-9)
[0555] A solution of 2-fluoro-3-nitrobenzoic acid (520 mg, 2.81 mmol) in thionyl chloride (6 mL, 82.3 mmol) is refluxed for 2 h. The mixture is cooled to RT and extensively evaporated under reduced pressure. The residue is dissolved back in 1 mL of anhydrous DCM and is slowly added to a solution of 2-((tert-butyldimethylsilyl)oxy)-N-ethylethan-1-amine (571 mg, 2.81 mmol) in 10% NaOH (3 mL) and DCM (2 mL) at 0° C. The mixture is left returning to RT and stirred at RT for 3 h. The mixture is extracted with DCM/H.sub.2O and the combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as yellow oil which is used in the next step without further purification. LC-A: t.sub.R=1.00 min; [M+H].sup.+=371.2
b) 4-Ethyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Precursor 4A2-10)
[0556] To a solution of Precursor 4A2-9 (900 mg, 2.43 mmol) in 5 mL of anhydrous THF at 0° C. is added 3.04 mL of a (1M) solution of TBAF in THF (3.04 mL, 3.04 mmol). The reaction mixture is left returning to RT and stirred at RT for 20 h. Water (5 mL) is added to the mixture and THF is partially distilled off under reduced pressure. The resulting aqueous phase is extracted with EtOAc. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and extensively evaporated under reduced pressure. The crude residue is purified by flash chromatography over 24 g of silica gel with Heptane/EtOAc system (3:2 to 2:3 gradient) as eluent to yield the title compound as yellow oil. LC-A: t.sub.R=0.68 min; [M+H].sup.+=237.2; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 8.01 (dd, J.sub.1=1.6 Hz, J.sub.2=7.8 Hz, 1H), 7.90 (dd, J.sub.1=1.5 Hz, J.sub.2=8.0 Hz), 7.30 (t, J=7.9 Hz, 1H), 4.59 (t, J=5.2 Hz, 2H), 3.71 (q, J=7.1 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H), 1.30 (t, J=7.1 Hz)
c) 4-Ethyl-9-nitro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Precursor 4A2-6)
[0557] To a solution of Precursor 4A2-10 (440 mg, 1.86 mmol) in 6.5 mL of THF at RT is added 7.45 mL of (1M) solution of BH.sub.3.THF complex in THF (7.45 mL, 7.45 mmol). The reaction mixture is refluxed overnight. The mixture is cooled down to 0° C. and MeOH (18 mL) and sodium hydroxide (1.67 g, 41 mmol) are added and the mixture is vigorously stirred at RT for 24 h. The mixture is concentrated and the residue is extracted with EtOAc/H.sub.2O. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as yellow oil with a purity compatible with the next chemical step. LC-A: t.sub.R=0.42 min; [M+H].sup.+=223.1
c2) 4-Ethyl-9-nitro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Precursor 4A2-6)
[0558] To a 2M solution of LiALH.sub.4 in THF (9.1 mL, 18.2 mmol) in 30 mL of dry THF is added sulfuric acid 98% (0.484 mL, 9.08 mmol) at 0° C. under Ar. The mixture is stirred at RT for 2 h then a solution of 4-ethyl-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (715 mg, 3.03 mmol) in 5 mL THF is added dropwise at RT. The resulting mixture is stirred overnight at RT. Water (20 mL) is carefully added at 0° C. Salts are removed by filtration and DCM (100 mL) is added. The mixture is stirred for 15 min, the organic phase is separated and the aqueous phase is extracted twice with DCM (2×40 mL). The combined organic phases are dried over MgSO.sub.4, filtered and evaporated to yield the title compound as a yellow oil with a purity compatible with the next chemical step. LC-A: t.sub.R=0.44 min; [M+H].sup.+=223.1
d) & e) (4-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine (Precursor 4A2)
[0559] These transformations are achieved according to the methodology described for Precursor 4A1, starting from Precursor 4A2-6 instead of Precursor 4A1-6, to yield the title compound as a brownish oil. LC-A: t.sub.R=0.42 min; [M+H].sup.+=251.2. Intermediate analytical details can be found in Table 2.
[0560] Precursor 4A3 ((4-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine) LC-A: t.sub.R=0.47 min; [M+H].sup.+=265.3 and Precursor 4A4 ((4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine) LC-A: t.sub.R=0.58 min; [M+H].sup.+=343.3 are prepared applying the method described for Precursor 4A1 using n-propylamine and 4-methoxybenzylamine in the first sequence step instead of isobutylamine respectively. Intermediate analytical details can be found in Table 2.
TABLE-US-00004 TABLE 2 Analytical data of the precursor synthesis intermediates MS Data t.sub.R [min] m/z Alias Name Aspect (LC-A) [M + H].sup.+ .sup.1H-NMR 4A2-7 4-Ethyl-2,3,4,5- Brown 0.23 193.3 tetrahydro- oil benzo[f][1,4]oxazepin- 9-amine 4A3-2 2-Nitro-6-((propyl- Yellow 0.48 211.2 (500 MHz, DMSO) amino)methyl)phenol solid δ: 7.69 (dd, J.sub.1 = 1.9 Hz, J.sub.2 = 8.5 Hz, 1 H), 7.16 (dd, J.sub.1 = 1.8 Hz, J.sub.2 = 6.9 Hz, 1 H), 6.13 (dd, J.sub.1 = 6.9 Hz, J.sub.2 = 8.4 Hz, 1 H), 3.97 (s, 2 H), 2.78 (t, J = 7.4 Hz, 2 H), 1.61 (h, J = 7.5 Hz, 2 H), 0.91 (t, J = 7.4 Hz, 3 H) 4A3-3 2-Hydroxy-N-(2- Red 0.71 269.2 hydroxy-3-nitrobenzyl)- oil N-propylacetamide 4A3-5 9-Nitro-4-propyl-4,5- Yellow 0.75 251.2 (400 MHz, CDCl.sub.3) dihydro- oil δ: 7.85 (dd, J1 = 1.5 Hz, J2 = 8.2 benzo[f][1,4]oxazepin- Hz, 1 H), 7.49 (dd, J1 = 1.4 Hz, J2 = 3(2H)-one 7.5 Hz, 1 H), 7.24 (dd, J1 = 7.5 Hz, J2 = 8.3 Hz, 1 H), 4.88 (s, 2 H), 4.55 (s, 2 H), 3.55 (dd, J1 = 7.4 Hz, J2 = 8.6 Hz, 2 H), 1.64 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3 H) 4A3-6 9-Nitro-4-propyl- Brown 0.50 237.3 2,3,4,5- oil tetrahydro- benzo[f][1,4]oxazepine 4A3-7 4-Propyl-2,3,4,5- Brown 0.33 207.2 tetrahydro- oil benzo[f][1,4]oxazepin- 9-amine 4A4-2 2-(((4-Methoxy- Yellow 0.61 289.1 (400 MHz, DMSO) benzyl)amino)methyl)-6- solid δ: 7.70 (m, 1 H), 7.37 (d, J = 8.5 nitrophenol Hz, 2 H), 7.17 (d, J = 6.9 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.27 (t, J = 7.7 Hz, 1 H), 3.93 (s, 2 H), 3.92 (s, 2 H), 3.77 (s, 3 H) 4A4-3 2-Hydroxy-N-(2- Orange 0.79 347.1 hydroxy-3-nitrobenzyl)- oil N-(4-methoxy- benzyl)acetamide 4A4-5 4-(4-Methoxybenzyl)-9- Yellow 0.83 329.1 nitro-4,5-dihydro- solid benzo[f][1,4]oxazepin- 3(2H)-one 4A4-6 4-(4-Methoxybenzyl)-9- Yellow 0.60 315.2 (400 MHz, CDCl.sub.3) nitro-2,3,4,5- oil δ: 7.64 (dd, J.sub.1 = 1.6 Hz, J.sub.2 = 8.1 tetrahydro- Hz, 1 H), 7.23 (m, 3 H), 7.09 (t, J = benzo[f][1,4]oxazepine 7.8 Hz, 1 H), 6.90 (d, J = 8.6 Hz, 2 H), 4.24 (m, 2 H), 3.88 (s, 2 H), 3.84 (s, 3 H), 3.62 (s, 2 H), 3.17 (m, 2 H) 4A4-7 4-(4-Methoxybenzyl)- Orange 0.51 285.2 S2,3,4,5- oil tetrahydro- benzo[f][1,4]oxazepin- 9-amine
Precursor 4A5 (4-(Cyclopropylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine
[0561] a) In analogy to the preparation of precursor 4A2 step c2) above, 4-cyclopropylmethyl-9-nitro-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine 4A5-6 is obtained from 4-cyclopropylmethyl-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one 4A5-10 by treatment with borane THF complex; LC-A: t.sub.R=0.51 min; [M+H].sup.+=249.24.
[0562] b) In analogy to the preparation of precursor 4A1 step e) above, 4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamine 4A5-7 is obtained from 4-cyclopropylmethyl-9-nitro-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine 4A5-6 by treatment with Pd/C 10%; LC-A: t.sub.R=0.35 min; [M+H].sup.+=219.28
[0563] c) in analogy to the preparation of precursor 4A1 step f) above, (4-(cyclopropylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine 4A5 is obtained from 4-cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamine 4A5-7 by treatment with glyoxylic acid monohydrate and Pd/C 10% LC-A: t.sub.R=0.48 min; [M+H].sup.+=277.24
EXAMPLE 67
2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
a) 2-[(Cyclopropylmethyl-amino)-methyl]-6-nitro-phenol
[0564] (Precursor 4A5-2) is obtained according to the reaction a) described above for the preparation of Precursor 4A1-2 using 2-hydroxy-3-nitrobenzaldehyde and cyclopropylmethanamine. LC-A: t.sub.R=0.50 min; [M+H].sup.+=223.24.
b) N-Cyclopropylmethyl-2-hydroxy-N-(2-hydroxy-3-nitro-benzyl)-acetamide
[0565] (Precursor 4A5-3) is obtained according to the reaction b) described above for the preparation of Precursor 4A1-3 using 2-[(cyclopropylmethyl-amino)-methyl]-6-nitro-phenol and glycolic acid. LC-A: t.sub.R=0.72 min; [M+H].sup.+=281.19.
c) 4-Cyclopropylmethyl-9-nitro-4,5-dihydro-benzo[f][1,4]oxazepin-3-one
[0566] (Precursor 4A5-5): is obtained according to the reaction c) described above for the preparation of Precursor 4A1-5 by treating N-cyclopropylmethyl-2-hydroxy-N-(2-hydroxy-3-nitro-benzyl)-acetamide with DEAD and PPh.sub.3. LC-A: t.sub.R=0.77 min; [M+H+MeCN].sup.+=304.2.
d) 9-Amino-4-cyclopropylmethyl-4,5-dihydro-benzo[f][1,4]oxazepin-3-one
[0567] (Precursor 4E1-1): A flask is charged with Pd/C 10% wet (223 mg, 2.1 mmol). 10 mL MeOH are added under Ar. 4-Cyclopropylmethyl-9-nitro-4,5-dihydro-benzo[f][1,4]oxazepin-3-one (1100 mg, 4.19 mmol) is suspended in 10 mL MeOH, the resulting suspension is purged with argon and then added to the Pd suspension. The dark mixture is stirred under H.sub.2 at RT overnight. The mixture is filtered and evaporated until dryness under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.54 min; [M+MeCN].sup.+=274.14.
e) (4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetic acid
[0568] (Precursor 4E1) is obtained according to the reaction f) described above for the preparation of Precursor 4A1 by treating 9-amino-4-cyclopropylmethyl-4,5-dihydro-benzo[f][1,4]oxazepin-3-one with glyoxilic acid monohydrate and Pd/C 10% under H.sub.2. LC-A: t.sub.R=0.67 min; [M+H].sup.+=297.16.
EXAMPLE 65
[0569] In analogy to Example 1, condensation of Precursor 4E1 with amine B24 yields 2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide. LC-B: t.sub.R=0.72 min; [M+H].sup.+=546.3.
EXAMPLE 66
[0570] In analogy to Example 1, condensation of Precursor 4E1 with amine B16 yields N-(2-tert-butylamino-ethyl)-2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide. LC-B: t.sub.R=0.80 min; [M+H].sup.+=547.3.
EXAMPLE 67
[0571] In analogy to Example 1, condensation of Precursor 4E1 with amine B1 yields 2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide. LC-B: t.sub.R=0.76 min; [M+H].sup.+=519.3.
EXAMPLE 68
2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) {2-[[2-(4-Cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0572] In analogy to Example 1, condensation of Precursor 4E1 with amine B21 yields {2-[[2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester as a light yellow solid. LC-A: t.sub.R=1.06 min; [M+H].sup.+=633.28.
Step 2)
[0573] The title compound is obtained by treatment of {2-[[2-(4-cyclopropylmethyl-3-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester with TFA in analogy to Example 71 as a yellowish oil; LC-B: t.sub.R=0.79 min; [M+H].sup.+=533.3.
EXAMPLE 21
N-(2-(dimethylamino)ethyl)-2-((4-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide
a) N-(2-(dimethylamino)ethyl)-2-((4-ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl) acetamide
[0574] To a solution of (4-ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)glycine Precursor 4B1 (135 mg, 0.347 mmol) and N-(2-(trifluoromethyl)benzyl)-N′,N′-dimethylethane-1,2-diamine Amine B1 (85.5 mg, 0.347 mmol) in 3 mL of DCM at RT are added HATU (158 mg, 0.417 mmol) and DIPEA (0.0891 mL, 0.521 mmol). The reaction mixture is allowed to stir at RT for 4 h. Water is added and the resulting organic phase is washed with sat. aq. NaHCO.sub.3 soln. and brine then dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as a yellow oil. The crude is directly used in the next step without further purification. LC-A: t.sub.R=0.66 min; [M+H].sup.+=598.1
b) N-(2-(dimethylamino)ethyl)-2-((4-ethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide (Example 21)
[0575] N-(2-(dimethylamino)ethyl)-2-((4-ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide (320 mg, 0.268 mmol) is dissolved in 4 mL TFA and stirred at 50° C. for 1 h. The mixture is cooled down to 0-5° C. and is carefully quenched with sat. NaHCO.sub.3 solution. The resulting aq. phase is extracted with DCM. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.56 min; [M+H].sup.+=478.1; .sup.1H-NMR (400 MHz, CDCl.sub.3), 55:45 mixture of two rotamers:
[0576] Major rotamer spectrum δ: 7.74 (d, J=7.8 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.75 (t, J=7.5 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H), 6.46 (d, J=7.6 Hz, 1H), 4.82 (s, 2H), 4.62 (t, J=4.7 Hz, 1H), 3.82 (s, 2H), 3.79 (d, J=4.8 Hz, 2H), 3.60 (t, J=6.6 Hz, 2H), 3.13 (m, 2H), 2.98 (m, 2H), 2.53 (q, J=7.3 Hz, 2H), 2.45 (t, J=6.9 Hz, 2H), 2.26 (s, 6H), 1.11 (t, J=7.3 Hz, 3H)
[0577] Minor rotamer spectrum δ: 7.68 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.84 (t, J=7.7 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H), 4.93 (s, 2H), 4.68 (t, J=4.8 Hz, 1H), 4.07 (d, J=4.8 Hz, 2H), 3.86 (s, 2H), 3.36 (t, J=6.9 Hz, 2H), 3.18 (m, 2H), 2.98 (m, 2H), 2.56 (q, J=7.3 Hz, 2H), 2.53 (m, 2H), 2.24 (s, 6H), 1.14 (t, J=7.3 Hz, 3H)
Precursor 4B1
(4-Ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)glycine
a) tert-Butyl (4-methoxybenzyl)(2-oxoethyl)carbamate (Precursor 4B-2)
[0578] To a suspension of Dess-Martin periodinane (1.36 g, 3.19 mmol) in 20 mL of anhydrous DCM is added a solution of tert-butyl (2-hydroxyethyl)(4-methoxybenzyl)carbamate (749 mg, 2.66 mmol) in DCM (15 mL). The reaction mixture is stirred at RT for 150 minutes. Sodium thiosulfate (1M aq) (26.6 mL, 26.6 mmol) is added and the biphasic system is vigorously stirred for 10 minutes. The organic phase is collected and aqueous phase is further extracted with DCM. The combined organic layers are dried over Mg.sub.2SO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 40 g of silica gel with Heptane/EtOAc system (9:1 to 1:1 gradient) as eluent to yield the title compound as a clear yellows oil. LC-A: t.sub.R=0.86 min; [M+H].sup.+=280.1 & [M+H+MeCN-.sup.tBu].sup.+=265.2
b) tert-Butyl (2-(ethylamino)ethyl)(4-methoxybenzyl)carbamate (Precursor 4B1-4)
[0579] To a solution of Precursor 4B-2 (565 mg, 1.42 mmol) in 20 mL of MeOH at RT is added 1.42 mL of a (2.0M) solution of ethylamine in MeOH (1.42 mL, 2.83 mmol). The reaction mixture is refluxed for 4 h then cooled to 0° C. Sodium borohydride (107 mg, 2.83 mmol) is added portionwise then the mixture is allowed to return slowly to RT and is stirred at RT for 90 min. The mixture is concentrated under reduced pressure and the residue is extracted with DCM/H.sub.2O. The combined organic layers are dried over MgSO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as yellow oil with a purity acceptable for the next step. LC-A: t.sub.R=0.65 min; [M+H].sup.+=309.4; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.19 (d, J=8.4 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.41 (s, 2H), 3.82 (s, 3H), 3.31 (m, 2H), 2.73 (m, 2H), 2.62 (q, J=7.2 Hz, 2H), 1.49 (m, 9H), 1.08 (t, J=7.1 Hz, 3H)
c) tert-Butyl (2-(N-ethyl-2-fluoro-3-nitrobenzamido)ethyl) (4-methoxybenzyl) carbamate (Precursor 4B1-5)
[0580] A solution of 2-fluoro-3-nitrobenzoic acid (285 mg, 1.54 mmol) in thionyl chloride (3.29 mL, 45.1 mmol) is refluxed for 2 h. The mixture is cooled to RT and extensively evaporated under reduced pressure. The residue is dissolved back in 0.6 mL of anhydrous DCM and the resulting solution is slowly added to a solution of Precursor 4B-4 (540 mg, 1.54 mmol) in 10% NaOH (1.6 mL) and DCM (1 mL) at 0° C. The mixture is left returning to RT and stirred at RT for 2 h. The mixture is extracted with DCM/H.sub.2O and the combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as yellow oil which is used in the next step without further purification. LC-A: t.sub.R=0.96 min; [M+H].sup.+=476.3
d) 4-Ethyl-1-(4-methoxybenzyl)-9-nitro-1, 2,3, 4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Precursor 4B1-6)
[0581] To a solution of Precursor 4B1-5 (843 mg, 1.56 mmol) in 25 mL of 1,4-dioxane at RT is added 10.1 mL of a (4.0M) HCl soln. in dioxane (10.1 mL, 40.4 mmol). The reaction mixture is stirred at RT for 40 h until completion. The mixture is extensively evaporated under reduced pressure. The residue is dissolved back in 25 mL of DMF and DIPEA (0.54 mL, 3.12 mmol) is added at RT. The reaction mixture is then stirred at RT overnight. The mixture is extracted with EtOAc/NH.sub.4Cl sat. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as an orange oil. The crude is directly used in the next step without further purification. LC-A: t.sub.R=0.88 min; [M+H].sup.+=356.2; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.92 (dd, J.sub.1=1.6 Hz, J.sub.2=7.6 Hz, 1H), 7.86 (dd, J.sub.1=1.5 Hz, J.sub.2=8.1 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 3.94 (s, 2H), 3.80 (s, 3H), 3.58 (q, J=7.2 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.29 (t, J=5.6 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H)
e) 4-Ethyl-1-(4-methoxybenz yl)-9-nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (Precursor 4B1-7)
[0582] To a solution of Precursor 4B1-6 (616 mg, 1.39 mmol) in 5 mL of THF at RT is added 5.55 mL of (1M) solution of BH.sub.3.THF complex in THF (5.55 mL, 5.55 mmol).
[0583] The reaction mixture is refluxed for 64 h. The desired compound is obtained but contaminated by some deprotected starting material, 4-ethyl-9-nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine. The mixture is cooled down to 0° C. and MeOH (15 mL) and sodium hydroxide (1.25 g, 31 mmol) are added and the mixture is vigorously stirred at RT for 24 h. The mixture is concentrated and the residue is extracted with EtOAc/H.sub.2O. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as a crude yellow oil. This crude is directly used in the next step. LC-A: t.sub.R=0.68 min; [M+H].sup.+=342.2
f) 4-Ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-amine (Precursor 4B1-8)
[0584] To a solution of Precursor 4B1-7 (521 mg, 0.763 mmol) in 10 mL of acetone at RT is added 2 mL of a sat. NH.sub.4Cl soln. The reaction mixture is cooled down to 0° C. then zinc dust (524 mg, 8.01 mmol) is added portionwise. The reaction mixture is warmed up to RT and the suspension is stirred vigorously at RT for 16 h. EtOAc (5 ml) is added followed by 2 g Na.sub.2SO.sub.4. The suspension is stirred for 15 min then filtered through a Celite pad and washed with EtOAc then EtOAc/MeOH (9:1). The combined organic phase is evaporated under reduced pressure. The crude residue is purified by flash chromatography over 24 g of silica gel with Heptane/EtOAc system (4:1 to 0:1 gradient) as eluent and then a second time by prep. HPLC (Method C) to yield the title compound as a colorless solid. LC-A: t.sub.R=0.57 min; [M+H].sup.+=312.2
g) (4-Ethyl-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-yl)glycine (Precursor 4B1)
[0585] To a solution of Precursor 4B1-8 (115 mg, 0.369 mmol) in 2.5 mL of MeOH is added glyoxylic acid monohydrate (40.8 mg, 0.443 mmol). The reaction mixture is degassed and purged with Argon then Pearlman's catalyst Pd(OH).sub.2 (20% Pd/C) is added (77.8 mg, 0.554 mmol). The well stirred suspension is put under an atmospheric pressure of H.sub.2 and left reacting at RT for 24 h. The mixture is purged with Ar and filtered over Celite and washed three times with MeOH. The solvent is removed under reduced pressure to yield the title compound as an orange oil of purity compatible with the next step. LC-A: t.sub.R=0.62 min; [M+H].sup.+=370.2; .sup.1H-NMR (400 MHz, CDCl.sub.3) δ: 7.42 (d, J=8.1 Hz), 7.06 (dd, J.sub.1=7.5 Hz, J.sub.2=8.3 Hz), 6.82 (d, J=8.2 Hz, 2H), 6.63 (d, J=8.1 Hz, 1H), 6.47 (d, J=7.4 Hz, 1H), 4.33-4.49 (m, 1H), 4.23 (d, J=13.3 Hz, 1H), 4.01 (d, J=13.3 Hz, 1H), 3.75-3.91 (m, 2H), 3.71 (s, 3H), 3.51 (s, 2H), 3.14-3.37 (m, 2H), 2.75-2.99 (m, 4H), 1.29 (t, J=7.2 Hz, 3H)
EXAMPLE 42
2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0586] To a solution of (4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid Precursor 4F1 (55 mg, 0.16 mmol) and N-(2-(trifluoromethyl)benzyl)-N′,N′-dimethylethane-1,2-diamine Amine B1 (40 mg, 0.16 mmol) in 3 mL of DCM at RT are added HATU (75 mg, 0.2 mmol) and DIPEA (0.056 mL, 0.33 mmol). The reaction mixture is allowed to stir at RT for 4 h. Water is added and the resulting organic phase is washed with sat. aq. NaHCO.sub.3 soln. and brine then dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure The crude is purified by prep. HPLC (Method C) to yield the title compound as a beige foam. LC-B: t.sub.R=0.74 min; [M+H].sup.+=532.3
Precursor 4F1
(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid
a) [2-(Cyclopropylmethyl-amino)-ethyl]-methyl-carbamic acid tert-butyl ester (Precursor 4B2-4)
[0587] Cyclopropanecarboxaldehyde (3.43 mL, 45.9 mmol) is added to a solution of N-Boc-N-methylethylenediamine (8.21 mL, 44.5 mmol) in MeOH (100 mL). The reaction mixture is stirred at RT for 1 h and then cooled at 0° C. NaBH.sub.4 (1911 mg, 50.5 mmol, 1.1 eq) is then added in 5 portions and the reaction is stirred at rt for 4 h. The mixture is concentrated under reduced pressure and the residue is extracted with DCM/H.sub.2O. The combined organic layers are dried over MgSO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as yellow oil with a purity acceptable for the next step. LC-A: t.sub.R=0.53 min; [M+H].sup.+=229.25
b) {2-[Cyclopropylmethyl-(2-fluoro-3-nitro-benzoyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (Precursor 4B2-5)
[0588] A solution of 2-fluoro-3-nitrobenzoic acid (1 g, 5.4 mmol) in thionyl chloride (10 mL, 137 mmol) is refluxed for 5 h. The mixture is cooled to RT and extensively evaporated under reduced pressure. The residue is dissolved back in 5 mL of anhydrous DCM and is slowly treated successively with DIPEA (1.4 mL, 8.1 mmol) and Precursor 4B2-4 (1.393 g, 3.78 mmol) at 0° C. The mixture is left returning to RT and stirred at RT for 1 h. The mixture is extracted with DCM/H.sub.2O and the combined organic layers are dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with Heptane/EtOAc system (1:0 to 1:4 gradient) as eluent to yield the title compound as a yellow oil. LC-A: t.sub.R=0.90 min; [M+H].sup.+=396.13
c) 4-Cyclopropylmethyl-1-methyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Precursor 4B2-6)
[0589] To a solution of Precursor 4B2-5 (1.28 g, 2.78 mmol) in 5 mL of DCM at RT is added 1.28 mL TFA (16.7 mmol) The reaction mixture is stirred at RT for 6 h until completion. The mixture is evaporated under reduced pressure. The residue is dissolved back in 15 mL of AcOEt and aq NaOH 1M is added until the solution has a pH of 14. The mixture is strongly stirred for 10 min. during this time cyclisation occurs. The reaction mixture is extracted three times with 15 mL EtOAc The combined organic layers are washed three times with 15 mL HCl 0.1N, once with 15 mL brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to yield the title compound as an orange oil. The crude is directly used in the next step without further purification. LC-A: t.sub.R=0.82 min; [M+H].sup.+=276.18
d) 9-Amino-4-cyclopropylmethyl-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Precursor 4F1-1)
[0590] To a solution of Precursor 4B2-6 (792 mg, 2.82 mmol) in 10 mL of acetone at RT is added 4.4 mL of a sat. ammonium chloride solution (2.2 mmol). The reaction mixture is cooled to 0° C. then zinc dust (1933 mg, 29.6 mmol) is added portionwise. The reaction mixture is warmed up to RT and the suspension is stirred vigorously at RT for 24 h. EtOAc (10 ml) is added followed by Na.sub.2SO.sub.4 (3 g). The suspension is stirred for 15 min then filtered through a Celite pad and washed with EtOAc then EtOAc/MeOH (9:1). The combined organic phases are evaporated under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.51 min; [M+H].sup.+=246.21
e) (4-Cyclopropylmethyl-1-methy-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid benzyl ester (Precursor 4F1-2)
[0591] To a solution of Precursor 4F1-1 (286 mg, 1.17 mmol) in 3 mL MeCN is added benzyl bromoacetate (267 mg, 1.17 mmol). The reaction mixture is stirred at RT for 24 h. Benzyl bromoacetate (53 mg, 0.23 mmol) is added again and the mixture is stirred for 72 h. The mixture is evaporated under reduced pressure and the residue is taken up in 20 mL DCM and washed with 20 mL NaOH. The aqueous phase is extracted twice with 20 mL DCM. The combined organic phases are dried over MgSO.sub.4, filtered and evaporated. The crude is purified by prep. HPLC (Method C) to yield the title compound as an orange gum. LC-A: t.sub.R=0.92 min; [M+H].sup.+=394.19
f) (4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid (Precursor 4F1)
[0592] To a suspension of Pd/C 10% (44.6 mg, 0.42 mmol, 50% wet) in MeOH (5 mL) is added a solution of Precursor 4F1-2 (330 mg, 0.84 mmol) in 5 mL MeOH. The reaction mixture is degassed and is put under an atmospheric pressure of H.sub.2 and left reacting at RT for 4 h. The mixture is purged with Ar and filtered over Celite® and washed three times with MeOH. The solvent is removed under reduced pressure to yield the title compound as an orange oil of purity compatible with the next step. LC-A: t.sub.R=0.66 min; [M+H].sup.+=304.19
EXAMPLE 43
N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide
[0593] In analogy to Example 1, condensation of Precursor 4F1 with N-tert-butyl-N′-(2-trifluoromethyl-benzyl)-ethane-1,2-diamine (amine B16) yields N-(2-tert-butylamino-ethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide. LC-B: t.sub.R=0.79 min; [M+H].sup.+=560.3
EXAMPLE 44
2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide
[0594] In analogy to Example 1, condensation of Precursor 4F1 with N,N-dimethyl-N′-(6-methyl-pyridin-2-ylmethyl)-ethane-1,2-diamine (amine B20) yields 2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide. LC-B: t.sub.R=0.61 min; [M+H].sup.+=479.3
EXAMPLE 45
N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-acetamide
[0595] In analogy to Example 1, condensation of Precursor 4F1 with N′-(3-chloro-pyridin-2-ylmethyl)-N,N-dimethyl-ethane-1,2-diamine (amine B2) yields N-(3-chloro-pyridin-2-ylmethyl)-2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-acetamide LC-B: t.sub.R=0.64 min; [M+H].sup.+=499.3
EXAMPLE 46
2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) {2-[[2-(4-Cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0596] In analogy to Example 1, condensation of Precursor 4F1 with amine B21 yields {2-[[2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester as a yellow solid. LC-A: t.sub.R=1.06 min; [M+H].sup.+=646.33
Step 2)
[0597] The title compound is obtained by treatment of {2-[[2-(4-cyclopropylmethyl-1-methyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester with TFA in analogy to Example 71 as a yellowish oil; LC-B: t.sub.R=0.77 min; [M+H].sup.+=546.3
EXAMPLE 47
2-(1,4-Diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide
[0598] In analogy to Example 1, condensation of Precursor 4F2 with (2-morpholin-4-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine (amine B27) yields 2-(1,4-diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide. LC-B: t.sub.R=0.65 min; [M+H].sup.+=563.3
Precursor 4F2
(1,4-Diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acetate sodium salt
a) 1,4-Diethyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Precursor 4B3-6)
[0599] To a solution of methyl 2-fluoro-3-nitrobenzoate (6 g, 28.6 mmol) in n-butanol (25 mL) are added Na.sub.2CO.sub.3 (3034 mg, 28.6 mmol) and N,N′-diethylethylenediamine (4.32 mL, 28.6 mmol). The reaction is heated at 80° C. for 18 h. The reaction mixture is cooled and diluted with water (100 mL). The resulting mixture is extracted with EtOAc (3×150 mL) dried over MgSO.sub.4, and concentrated. The crude product is purified by flash chromatography over 80 g of silica gel with Heptane/EtOAc (9:1 to 0:10 gradient) as eluent to yield the title compound as a yellow oil. LC-A: t.sub.R=0.79 min; [M+H].sup.+=264.25
b) 9-Amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (Precursor 4F2-1)
[0600] In analogy to reaction d) to precursor 4F1-1, 9-amino-1,4-diethyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one is obtained from precursor 4B3-6 by treatment with Zn and ammonium chloride. LC-A: t.sub.R=0.46 min; [M+H].sup.+=234.27
c) (1,4-Diethyl-5-oxo-2,3, 4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid methyl ester (Precursor 4F2-2)
[0601] In analogy to reaction e) to precursor 4F1-2, (1,4-diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid methyl ester is obtained from precursor 4F1-1 by treatment with methyl bromoacetate. LC-A: t.sub.R=0.74 min; [M+H].sup.+=306.11
d) ((1,4-diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetate sodium salt (Precursor 4F2)
[0602] In analogy to reaction f) to precursor 4F1, the title compound is obtained from precursor 4F2-2 by treatment with sodium hydroxide in water/THF. LC-A: t.sub.R=0.62 min; [M+H].sup.+=292.25
EXAMPLE 48
2-(1,4-Diethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide
[0603] In analogy to Example 1, condensation of Precursor 4F2 with (2-pyrrolidin-1-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine (amine B24) yields the title compound. LC-B: t.sub.R=0.66 min; [M+H].sup.+=547.3
EXAMPLE 49
2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0604] In analogy to Example 1, condensation of Precursor 4B2 with N,N-dimethyl-N′-(3-trifluoromethyl-benzyl)-ethane-1,2-diamine (amine B1) yields the title compound as a yellow gum. LC-B: t.sub.R=0.51 min; [M+H].sup.+=518.3
Precursor 4B2
(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid
a) 4-Cyclopropylmethyl-1-methyl-9-nitro-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine (Precursor 4B2-7)
[0605] In analogy to the synthesis of Precursor 4B1-7 described above, the title compound is obtained by treatment of Precursor 4B2-6 with borane THF complex. LC-A: t.sub.R=0.57 min; [M+H].sup.+=262.26
b) 4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamine (Precursor 4B2-8)
[0606] In analogy to reaction f) of the synthesis to precursor 4B1-8 described above the title compound is obtained from precursor 4B2-7 by treatment with Zn and ammonium chloride. LC-A: t.sub.R=0.37 min; [M+H].sup.+=232.32
c) (4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetic acid (Precursor 4B2)
[0607] In analogy to reaction g) of the synthesis to precursor 4B1 described above the title compound is obtained from precursor 4B2-8 by treatment with glyoxylic acid monohydrate under hydrogen atmosphere. LC-A: t.sub.R=0.53 min; [M+H].sup.+=290.13
EXAMPLE 50
{2-[[2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0608] In analogy to Example 1, condensation of Precursor 4B2 with isopropyl-[2-(2-trifluoromethyl-benzylamino)-ethyl]-carbamic acid tert-butyl ester (amine B21) yields the title compound as a yellow gum. LC-B: t.sub.R=1.01 min; [M+H].sup.+=632.4
EXAMPLE 51
2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide
[0609] In analogy to Example 1, condensation of Precursor 4B2 with (2-pyrrolidin-1-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine (amine B24) yields the title compound as a yellow gum. LC-B: t.sub.R=0.46 min; [M+H].sup.+=545.3
EXAMPLE 52
2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0610] In analogy to Example 71, treatment of Example 50 with TFA in DCM yields the title compound as a yellowish oil. LC-B: t.sub.R=0.53 min; [M+H].sup.+=532.3
EXAMPLE 55
2-(4-Cyclopropylmethyl-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-9-ylamino)-N-(2-morpholin-4-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide
[0611] In analogy to Example 1, condensation of Precursor 4B2 with (2-morpholin-4-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine (amine B27) yields the title compound as a yellow gum. LC-B: t.sub.R=0.46 min; [M+H].sup.+=560.3
EXAMPLE 22
2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) N-Cyclopropylmethyl-2-fluoro-N-(2-hydroxy-ethyl)-6-nitro-benzamide (Precursor 5A1-7)
[0612] A mixture of 2-bromo-6-fluorobenzoic acid (1000 mg, 5.4 mmol) and thionyl chloride (5.92 mL, 15.11 eq) is refluxed for 2 h. The mixture is cooled down to RT then concentrated. The residue is dissolved in toluene and concentrated again to remove the remaining any excess thionyl chloride. The residue is dissolved in 10 mL THF and the resulting solution is cooled to 0° C. then a solution of 2-[(cyclopropylmethyl)amino]ethan-1-ol (622 mg, 1 eq) and TEA (1.13 mL, 1.5 eq) dissolved in 10 mL THF is added. The mixture is then allowed to warm up to RT and is further stirred at this temperature for 72 h. The mixture is then poured into water and the resulting aq. phase is extracted twice with EtOAc. The combined organic layers are dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford the sub-title compound as a light grey oil. This compound is a mixture of rotamers which are separable by LC-MS but equilibrate slowly on standing. LC-A: t.sub.R=0.63 and 0.65 min; [M+H].sup.+=283.3
Step 2) 4-Cyclopropylmethyl-6-nitro-3, 4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (Precursor 5A1-8)
[0613] To a solution of Precursor 5A1-7 (1200 mg, 4.25 mmol) in 100 mL THF stirred at 0° C. in an ice bath is added in small portions NaH (187 mg, 1.1 eq). The light brown suspension is stirred at RT for 2 h. Then more NaH (200 mg, 1.2 eq). is added and the stirring is continued at RT overnight. The brown solution is poured onto water and the resulting aq. solution is extracted twice with EtOAc. The combined organic layers are washed with sat. aq. NaHCO.sub.3 soln., with brine, dried over MgSO4, filtered then evaporated under reduced pressure to afford after silica gel flash chromatography (Biotage, SNAP 50 g, gradient Hept/EtOAc 100:0 to 60:40) yields the sub title compound as a yellow oil. LC-A: t.sub.R=0.75 min; [M+H].sup.+=263.2; .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 7.73 (m, 1H), 7.65 (t, J=8.1 Hz, 1H), 7.41 (dd, J.sub.1=0.9 Hz, J.sub.2=8.1 Hz, 1H), 4.40 (t, J=5.4 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.43 (d, J=7.0 Hz, 2H), 1.09 (m, 1H), 0.52 (m, 2H), 0.32 (m, 2H)
Step 3) 4-Cyclopropylmethyl-6-nitro-2,3, 4,5-tetrahydro-benzo[f][1,4]oxazepine (Precursor 5A1-9)
[0614] To a solution of Precursor 5A1-8 (291 mg, 0.821 mmol) in 10 mL THF stirred at RT is added 1M BH.sub.3.THF complex soln. in THF (3.92 mL, 4.7 eq). The mixture is refluxed overnight, then 1M BH.sub.3.THF complex soln. in THF (1 mL, 1.2 eq) is added and the reflux is continued for 8 h, then 1M BH.sub.3.THF complex soln. in THF (2 mL, 2.4 eq) is added again and the resulting mixture is refluxed overnight. The mixture is then cooled to 0° C. and 10 mL MeOH and solid NaOH (996 mg, 22 eq) are added and the mixture is stirred at RT for 4 h. The MeOH is then concentrated under reduced pressure and the residue is dissolved in EtOAc. After addition of water the resulting aq. phase is extracted twice with EtOAc. The combined organic phase is washed with water and brine, then dried over MgSO.sub.4. Filtration and evaporation of the solvent under reduced pressure followed by purification of the crude residue by silica gel flash chromatography (Biotage, SNAP 25 g, gradient Hept/EtOAc 95:5 to 50:50) yields the sub title compound as a yellow oil. LC-A: t.sub.R=0.49 min; [M+H].sup.+=249.2; .sup.1H NMR (400 MHz, DMSO) δ: 7.54 (dd, J.sub.1=1.0 Hz, J.sub.2=8.0 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.29 (dd, J.sub.1=1.0 Hz, J.sub.2=8.0 Hz, 1H), 4.14 (m, 2H), 3.89 (s, 2H), 3.07 (m, 2H), 2.39 (d, J=6.5 Hz, 2H), 0.81 (m, 1H), 0.44 (m, 2H), 0.04 (m, 2H)
Step 4) 4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamine (Precursor 5A1-10)
[0615] To a solution of Precursor 5A1-9 (165 mg, 0.545 mmol) in 10 mL acetone stirred at RT are added 2 mL sat. aq. NH.sub.4Cl soln. and Zn dust (558 mg, 15.6 eq). The reaction mixture is stirred at RT for 2 h. Then EtOAc is added and the resulting organic phase is dried over Na.sub.2SO.sub.4. After filtration through celite and rinsing of the filter cake with EtOAc, the mixture is concentrated in vacuo and dried under high vacuum to yield the sub title compound as a yellow oil which is used as such in the next step. LC-A: t.sub.R=0.45 min; [M+H].sup.+=219.3
Step 5): (4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-acetic acid (Precursor 5A1-11)
[0616] To a solution of Precursor 5A1-10 (115 mg, 0.5 mmol) in 3 mL MeOH are added successively 50% aq. glyoxylic acid soln. (0.0755 mL, 1.1 eq) and TEA (0.0766 mL, 1.1 eq). The reaction mixture is stirred for 20 min then NaBH.sub.3CN (34.6 mg, 1.1 eq) is added and the resulting mixture is stirred for 1 h. The mixture is then poured into water (pH 6-7) and the resulting aq phase is extracted twice with DCM. The organics are washed with brine, dried over MgSO.sub.4 and filtered. Evaporation of the solvents under reduced pressure afford a small amount of crude product which is dissolved in the aqueous. The aq. phase is then evaporated under reduced pressure and the crude solid obtained is suspended in MeOH/DCM. After filtration and drying under high vacuum, this affords the sub title compound as a white solid. LC-A: t.sub.R=0.50 min; [M+H].sup.+=277.3
Step 6)
[0617] To a solution of Precursor 5A1-11 (79 mg, 0.14 mmol) in 2 mL DMF stirred at RT are added Amine B1 (42.2 mg, 1.1 eq), HATU (63.9 mg, 1.2 eq) and DIPEA (48 μL, 2 eq). The yellow suspension is stirred for 1 h at rt. The organic phase is washed with sat. aq. NaHCO.sub.3 soln. and with brine. The organic layer is dried over MgSO.sub.4 then filtered and the solvent is evaporated under reduced pressure. The crude is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.61 min; [M+H].sup.+=505.2
[0618] Examples 86-88 and 91-94 listed in Table 3 are prepared applying the method described for Example 22 using Precursor 5A1-11 and Amine respectively.
TABLE-US-00005 TABLE 3 Examples 86-88 and 91-94 MS Data t.sub.R [min] m/z Example Compound (LC-B) [M + H].sup.+ 86 N-(2-Chloro-benzyl)-2-(4-cyclopropylmethyl-2,3,4,5-tetrahydro- 0.46 471.2 benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)- acetamide 87 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin- 0.38 452.3 6-ylamino)-N-(2-dimethylamino-ethyl)-N-(3-methyl-pyridin-2- ylmethyl)-acetamide 88 2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin- 0.51 505.2 6-ylamino)-N-(2,3-dichloro-benzyl)-N-(2-dimethylamino-ethyl)- acetamide 91 N-(2-tert-Butylamino-ethyl)-N-(2-chloro-benzyl)-2-(4- 0.49 499.3 cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6- ylamino)-acetamide 92 N-(2-tert-Butylamino-ethyl)-N-(3-chloro-pyridin-2-ylmethyl)-2-(4- 0.43 500.3 cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6- ylamino)-acetamide 93 N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-2,3,4,5- 0.52 533.3 tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-trifluoromethyl- benzyl)-acetamide 94 N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-2,3,4,5- 0.46 534.3 tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(3-trifluoromethyl- pyridin-2-ylmethyl)-acetamide
EXAMPLE 89
2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step a): tert-butyl (2-(2-((4-(cyclopropylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamido)ethyl) (isopropyl)carbamate
[0619] As described for the synthesis of Example 22, Precursor 5A1-11 is reacted with amine B21 to yield the subtitle compound as a white solid after purification by preparative HPLC. LC-A: t.sub.R=1.23 min; [M+H].sup.+=633.2.
Step b)
[0620] The product of Step a) is dissolved in DCM and 2 eq. TFA are added. The resulting solution is allowed to stir at rt for 2 h. Evaporation of the solvent in vacuo followed by thorough crying under high vacuum yields the pure title compound as a yellow oil. LC-B: t.sub.R=0.51 min; [M+H].sup.+=519.3
EXAMPLE 90
2-(4-Cyclopropylmethyl-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(3-trifluoromethyl-pyridin-2-ylmethyl)-acetamide
[0621] Is obtained as described above for Example 89 using in the first step amine B28 instead of amine B21 to yield tert-butyl (2-(2-((4-(cyclopropylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-yl)amino)-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)acetamido)ethyl)(isopropyl)carbamate as a yellow oil LC-A: t.sub.R=1.01 min; [M+H].sup.+=620.2 and then in a second step the title compound as a yellow oil LC-B: t.sub.R=0.44 min; [M+H].sup.+=520.3
EXAMPLE 23
2-(3-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): 2,2,2-Trifluoro-1-(6-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone
[0622] 6-Methoxy-2,3,4,5-1H-benzoazepine (1 g, 5.64 mmol) is dissolved in 10 mL DCM. The solution is cooled to 0° C. then TEA (2.36 mL, 3 eq) and TFAA (0.877 mL, 1.1 eq) are added. The reaction mixture is stirred at 0° C. for 3 h then allowed to warm to rt. The mixture is washed with water then brine. The organic layer is dried over MgSO.sub.4, filtered and evaporated, then dried under high vacuum to yield the subtitle compound as a yellow oil which is used as such in the next step. LC-A: t.sub.R=0.89 min; [M+H].sup.+=nd; .sup.1H-NMR (400 MHz, d.sub.6-DMSO) δ: 7.14 (td, J.sub.1=1.8 Hz, J.sub.2=8.1 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.80 (t, J=6.6 Hz, 1H), 3.78 (m, 3H), 3.67 (m, 4H), 3.01 (m, 4H).
Step 2): 2,2,2-Trifluoro-1-(6-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (Precursor 3A1-1)
[0623] To a solution of 1M BBr.sub.3 soln. in DCM (9.25 mL, 9.25 mol, 1.6 eq), cooled at 0° C., is added dropwise a solution of 2,2,2-trifluoro-1-(6-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone from Step 1) (1.58 g, 5.78 mol) in 5 mL DCM while maintaining the temperature between 0° C. and 10° C. in an ice water bath. The brown solution is then allowed to warmed up to RT and is further stirred for 2 h 30 at this temperature. The crude is poured into ice water and the resulting aq. phase is then extracted thrice with EtOAc. The organic layer is washed with sat. aq. NaHCO.sub.3 soln. and brine, dried over MgSO.sub.4. After filtration, the solvent is evaporated under reduced pressure to yield the sub-title compound as yellow solid which is used as such in the next step. LC-A: t.sub.R=0.78 min; [M+H].sup.+=nd
Step 3):) [3-(2, 2, 2-Trifluoro-acetyl)-2,3, 4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy]-acetic acid methyl ester (Precursor 3A1-2)
[0624] To a solution of Precursor 3A1-1 (700 mg, 2.7 mmol) in 8 mL acetone stirred at RT are added K.sub.2CO.sub.3 (560 mg, 1.5 eq) and methylbromoacetate (0.256 mL, 1 eq). The reaction is stirred for 5 h 30 at 80° C. After filtration of the white solid formed, the filtrate is evaporated under reduced pressure, dried with HV to yield the expected crude sub-title compound as a yellow oil which is used as such in the next step. LC-A: t.sub.R=0.87 min; [M+H].sup.+=332.2; .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 7.10 (td, J.sub.1=2.9 Hz, J.sub.2=7.9 Hz, 1H), 6.83 (m, 2H), 4.80 (m, 2H), 3.69 (m, 7H), 3.10 (m, 2H), 2.99 (m, 2H)
Step 4): (2,3,4,5-Tetrahydro-1H-benzo[d]azepin-6-yloxy)-acetic acid
[0625] To a solution of Precursor 3A1-2 (960 mg, 2.9 mmol) in 10 mL MeOH stirred at RT is added 1M NaOH aq. soln. (5.8 mL, 2 eq). The yellow mixture is stirred at RT for 2 h, then 1N aq. HCl soln. is added until pH>7. The aq. phase is then evaporated under reduced pressure and then dried under high vacuum to yield the subtitle compound as yellow solid containing 2 eq NaCl. LC-A: t.sub.R=0.43 min; [M+H].sup.+=222.6
Step 5): (3-(tert-Butoxycarbonyl)-2,3, 4,5-tetrahydro-1H-benzo[d]azepin-6-yl)glycine (Precursor 3A1-3)
[0626] To a stirring solution of (2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-acetic acid from Step 4) (990 mg, 3.08 mmol) in 6 mL THF and 10 mL water stirred at RT are added NaOH (246 mg, 2 eq) and Boc.sub.2O (739 mg, 1.1 eq). The reaction mixture is stirred overnight at rt. The mixture is diluted with EtOAc and water. The layers are separated and the aq. layer is extracted twice with EtOAc. The aq. layer is then acidified with HCl 1M (pH 6) then evaporated to give the title compound mixed with 2 eq NaCl as a yellow solid which is used as such in the next step. LC-A: t.sub.R=0.82 min; [M+H].sup.+=322.1
Step 6): tert-Butyl 6-{[(2-dimethylamino-ethyl)-(2-trifluoromethyl-benzyl)-carbamoyl]-methoxy}-1,2,4,5-tetrahydro-benzo[d]azepine-3-acetate (Precursor 3A1-4)
[0627] To a solution of Precursor 3A1-3 (1.41 g, 3.49 mmol) and Amine B1 (953 mg, 1.05 eq) in 20 mL DCM is added HATU (1682 mg, 1.2 eq) and DIPEA (1.26 mL, 2 eq). The yellow suspension is stirred for 2 h at rt. The organic phase is washed with sat. aq. NaHCO.sub.3 soln. then with brine. The organic layer is dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude is purified by silica gel flash chromatography (Biotage, SNAP 25 g, gradient Hept/EtOAc 30:70 to 80:20 to 0:100). The obtained product is dissolved in EtOAc and washed with sat. aq. NaHCO.sub.3 soln. then water and brine, dried over MgSO.sub.4, filtered and the solvent evaporated. This yields the sub title compound as a yellow oil. LC-A: t.sub.R=0.81 min; [M+H].sup.+=550.2
Step 7): N-(2-Dimethylamino-ethyl)-2-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-N-(2-trifluoromethyl-benzyl)-acetamide (Precursor 3A1)
[0628] To a solution of Precursor 3A1-4 (750 mg, 1.19 mmol) dissolved in 10 mL DCM is added 4N HCl in dioxane soln. (1.18 mL, 4 eq) and the resulting mixture is allowed to stir at RT for 2 h, then 4N HCl in dioxane soln. (0.59 mL, 2 eq) is added again and the resulting mixture is allowed to stir at RT for 4 h. Then sat. aq. NaHCO.sub.3 soln. is added until pH>9 and the phases are separated. The organic phase is washed with water and brine then dried over MgSO.sub.4 and evaporated under reduced pressure to afford the sub-title compound as a yellow oil which is used as such in the next step. LC-A: t.sub.R=0.54 min; [M+H].sup.+=449.9
Step 8)
[0629] To a solution of Precursor 3A1 (100 mg, 0.206 mmol) in 2 mL DCM is added at RT cyclopropanecarboxaldehyde (31 μL, 2.331 eq) and DIPEA (70.5 μL, 2.314 eq). The yellow suspension is stirred for 10 mn at RT then NaBH(OAc).sub.3 (75.4 mg, 2 eq) is added and the resulting mixture is stirred for overnight at rt. Cyclopropanecarboxaldehyde (31 μL, 2.331 eq) and NaBH(OAc).sub.3 (75.4 mg, 2 eq) are added again and the stirring is continued for 2 h. Water is added and the resulting aq. phase extracted thrice with DCM. The combined organic phase is washed with sat. aq. NaHCO.sub.3 soln. then brine and dried with MgSO.sub.4. The organic phase is filtered and evaporated under reduced pressure. The crude is purified by two successive prep. HPLC (Method C, then Method D) to yield the title compound as a colorless oil. LC-B: t.sub.R=0.59 min; [M+H].sup.+=504.1; .sup.1H NMR (d.sub.6-DMSO) 64:36 mixture of rotamers δ: 7.79 (d, J=7.8 Hz, 0.36H), 7.72 (d, J=7.8 Hz, 0.64H), 7.67 (m, 0.36H), 7.62 (t, J=7.7 Hz, 0.64H), 7.53 (t, J=7.7 Hz, 0.36H), 7.47 (t, J=7.5 Hz, 0.64H), 7.32 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.9 Hz, 0.64H), 7.05 (t, J=7.9 Hz, 0.36H), 6.92 (d, J=8.3 Hz, 0.64H), 6.80 (m, 1H), 6.70 (d, J=8.4 Hz, 0.36H), 5.10 (s, 1.28H), 4.84 (s, 0.72H), 4.74 (m, 2H), 3.49 (t, J=6.3 Hz, 2H), 3.27-2.90 (m, 8H), 2.85 (d, J=6.9 Hz, 1.28H), 2.79 (d, J=6.9 Hz, 0.72H), 2.70 (t, J=6.2 Hz, 0.72H), 2.57 (t, J=6.1 Hz, 1.28H), 2.35 (s, 2.16H), 2.25 (s, 3.84H), 1.01 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
EXAMPLE 24
N-(2-Dimethylamino-ethyl)-2-[3-(2-methoxy-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy]-N-(2-trifluoromethyl-benzyl)-acetamide
[0630] To a solution of Precursor 3A1 (100 mg, 0.146 mmol) in 2 mL DCM is added at RT methoxyacetic acid (13.4 μL, 1.2 eq), HATU (66.5 mg, 1.2 eq) and DIPEA (49.9 μL, 2 eq). The mixture is stirred overnight at rt, then water is added and the resulting aq. phase extracted three times with DCM using phase separator cartridges. The organic phase is evaporated under reduced pressure and the crude product is purified by prep. HPLC (Method D). After purification the obtained solid is dissolved in DCM and sat. aq. NaHCO.sub.3 soln. is added, the two layers are separated and the organic layer is dried over MgSO.sub.4 and evaporated under reduced pressure to yield the title compound as a yellow oil. LC-A: t.sub.R=0.69 min; [M+H].sup.+=522.2
EXAMPLE 25
2-(3-Acetyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yloxy)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0631] Is obtained from Precursor 3A1 using the same procedure as described for Example 24 with acetic acid instead of methoxyacetic acid yielding the title compound as a yellow oil. LC-A: t.sub.R=0.70 min; [M+H].sup.+=492.2
EXAMPLE 26
N-(2-Dimethylamino-ethyl)-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino]-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): Trifluoro-methanesulfonic acid 3-(2, 2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-yl ester (Precursor 3B1-1)
[0632] To a solution of Precursor 3A1-1 (500 mg, 1.93 mmol) in 5 mL DCM cooled to 0° C. in an ice bath are added TEA (0.591 mL, 2.2 eq) and trifluoromethanesulfonic anhydride (0.409 mL, 1.26 eq). The ice bath is removed and the reaction is stirred overnight at rt. The mixture is then poured into water and extracted twice with DCM. The organic extracts are washed with brine, dried over MgSO.sub.4, filtered, and evaporated. The crude is purified by silica gel flash chromatography (Biotage, SNAP 15 g, gradient Hept/EtOAc 90:10 to 70:30). This yields the sub title compound as a yellow oil. LC-A: t.sub.R=0.97 min; [M+H].sup.+=nd; .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 7.36 (m, 3H), 3.73 (m, 4H), 3.12 (m, 4H).
Step 2): {[(2-Dimethylamino-ethyl)-(2-trifluoromethyl-benzyl)-carbamoyl]-methyl}-carbamic acid tert-butyl ester (Precursor 5A1-1)
[0633] To a solution of Amine B1 (1 g, 4.06 mmol) and BOC-Glycine (0.782 g, 1.1 eq) in 10 mL DCM at RT is added HATU (2.32 g, 1.5 eq) followed by DIPEA (2.09 mL, 3 eq). The yellow solution is stirred at RT for 1 h 30. Then sat. aq. NaHCO.sub.3 is added and the mixture is extracted with DCM. The combined organic layer is dried over MgSO.sub.4, filtered and concentrated. The crude is purified by silica gel flash chromatography (Biotage, SNAP 15 g, gradient Hept/EtOAc 80:20 to 0:100). This yields the subtitle compound as a yellow oil. LC-A: t.sub.R=0.67 min; [M+H].sup.+=404.3
Step 3): 2-Amino-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide (Precursor 5A1-2)
[0634] To a solution of Precursor 5A1-1 (2.24 g, 3.61 mmol) in 10 mL DCM at RT is added 4M HCl soln. in dioxane (6.6 mL, 3 eq) and the resulting mixture is stirred overnight at rt. The mixture is concentrated, co-evaporated with DCM and dried under high vacuum to yield the sub title compound as light yellow foam which is used as such in the next step. LC-A: t.sub.R=0.40 min; [M+H].sup.+=304.2
Step 4)
[0635] To a microwave tube containing Precursor 5A1-2 (375 mg, 2 eq), Cs.sub.2CO.sub.3 (386 mg, 3.4 eq), Pd.sub.2(dba.sub.2).sub.3 (63.9 mg, 0.2 eq), Brettphos (74.9 mg, 0.4 eq) is added a solution of Precursor 3B1-1 (150 mg, 0.349 mmol) in 2 mL degassed toluene. The brown mixture is stirred for 20 mn at 140° C. under microwave irradiation. It is then cooled to RT and poured into water/DCM (1:1) mixture, the layers are separated and the resulting aq. phase is extracted twice with DCM. The combined organic layers are washed with sat. aq. NaHCO.sub.3 soln., with brine, dried over MgSO.sub.4, filtered and the volatiles are removed under reduced pressure. The crude is purified by silica gel flash chromatography (Biotage, SNAP 15 g, gradient Hept/EtOAc/MeOH 50:50:0 to 0:100:0 to 0:90:10). This yields the title compound as a yellow oil. LC-A: t.sub.R=0.77 min; [M+H].sup.+=545.1
EXAMPLE 27
2-(3-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): N-(2-Dimethylamino-ethyl)-2-(2,3, 4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide (Precursor 3B1)
[0636] To a solution of Example 26 (80 mg, 0.141 mmol) in 2 mL MeOH and 1 mL water stirred at RT is added K.sub.2CO.sub.3 (117 mg, 6 eq). The yellow solution is stirred at 60° C. for 1 h. After cooling, water is added and extracted thrice with DCM. The combined organic phase is washed with NaHCO.sub.3, with brine, dried over MgSO.sub.4. Filtration and evaporation under reduced pressure yield the sub-title compound as a yellow oil which is used as such in the next step. LC-A: t.sub.R=0.55 min; [M+H].sup.+=449.1
Step 2)
[0637] Example 2 is obtained from Precursor 3B1 as described in the synthesis of Example 23 (Step 8). This yields the title compound as colorless oil. LC-A: t.sub.R=0.60 min; [M+H].sup.+=503.2; .sup.1H-NMR (400 MHz, d.sub.6-DMSO) 66:34 mixture of rotamers δ: 7.78 (d, J=7.5 Hz, 0.34H), 7.72 (d, J=7.8 Hz, 0.66H), 7.67 (s, 0.34H), 7.60 (t, J=7.5 Hz, 1H), 7.52 (d, J=0.3 Hz, 0.34H), 7.46 (t, J=7.7 Hz, 0.66H), 7.37 (d, J=7.7 Hz, 0.34H), 7.33 (d, J=7.7 Hz, 0.66H), 6.91 (t, J=7.7 Hz, 0.66H), 6.82 (t, J=7.7 Hz, 0.34H), 6.48 (d, J=8.1 Hz, 0.66H), 6.44 (d, J=7.4 Hz, 0.66H), 6.41 (d, J=7.6 Hz, 0.34H), 6.24 (d, J=8.1 Hz, 0.34H), 5.22 (bs, 0.66H), 5.17 (bs, 0.34H), 4.88 (s, 0.68H), 4.77 (s, 1.32H), 4.13 (bs, 1.32H), 3.81 (bs, 0.68H), 2.86-2.54 (m, 8H), 2.41 (t, J=5.9 Hz, 1.32H), 2.36 (m, 0.68H), 2.29 (m, 2H), 2.16 (s, 3.96H), 2.10 (s, 2.04H), 0.83 (m, 1H), 0.44 (d, J=7.8 Hz, 2H), 0.05 (m, 2H).
EXAMPLE 28
2-(2-Cyclopropylmethyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): 2,2,2 Trifluoro-1-(6-methoxy-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl) ethan-1-one Precursor 4C1-1
[0638] To a solution of 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (293 mg, 1.59 mmol) in 5 mL DCM cooled to 0° C. are added TEA (0.442 mL, 3.17 mmol) and TFAA (0.243 mL, 1.75 mmol). The reaction mixture is stirred between 0-5° C. for 2 h. The organic phase is washed with water then brine. The organic layer is dried over MgSO.sub.4, filtered and evaporated under reduced pressure then dried with high vacuum. LC-A: t.sub.R=0.88 min; [M+MeCN+H].sup.+=315.1
Step 2): 2,2,2-Trifluoro-1-(6-hydroxy-1,3, 4,5-tetrahydro-2H-benzo[c]azepin-2-yl)ethan-1-one
[0639] Precursor 4C1-2 is obtained from Precursor 4C1-1 following the procedure described for the synthesis of Precursor 3A1-1 from 2,2,2-trifluoro-1-(6-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone. LC-A: t.sub.R=0.76 min; [M+H].sup.+=n.d.
Step 3): 2-(2,2,2-Trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl trifluoromethanesulfonate
[0640] Precursor 4C1-3 is obtained from Precursor 4C1-2 following the procedure described for the synthesis of Precursor 3B1-1 from Precursor 3A1-1. LC-A: t.sub.R=0.96 min; [M+H].sup.+=n.d.; .sup.1H NMR (500 MHz, d.sub.6-DMSO) δ: 7.48 (dd, J.sub.1=1.5 Hz, J.sub.2=7.1 Hz, 1H), 7.37 (m, 2H), 4.75 (bs, 2H), 3.90 (bs, 3H), 3.11 (dd, J.sub.1=5.0 Hz, J.sub.2=6.1 Hz, 2H), 1.85 (m, 2H)
Step 4): N-(2-(dimethylamino)ethyl)-2-((2-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide
[0641] Precursor 4C1-4 is made according to the procedure described in the formation of Example 26 Step 4) using Precursor 5A1-2 and Precursor 4C1-3 as starting materials. LC-A: t.sub.R=0.90 min; [M+H].sup.+=545.0
Step 5): N-(2-(dimethylamino)ethyl)-2-((2,3,4,5-tetrahydro-1H-benzo[c]azepin-6-yl)amino)-N-(2-(trifluoromethyl)benzyl)acetamide Precursor 4C1
[0642] To a solution of Precursor 4C1-4 (75 mg, 0.11 mmol) in 2 mL MeOH and 1 mL water at RT is added K.sub.2CO.sub.3 (43.5 mg, 0.22 mmol). The yellow suspension is stirred for 1 h at 60° C. After cooling the suspension is poured into a mixture of water and DCM, the layers are separated and the aqueous phase is extracted twice with DCM. The combined organic layers are washed with sat. aq. NaHCO.sub.3 sol. and brine then dried over MgSO.sub.4. Filtration and evaporation of the volatiles under reduced pressure yield the sub-title compound which is pure enough for further for the next step. LC-A: t.sub.R=0.63 min; [M+H].sup.+=449.0
Step 6)
[0643] To a solution of Precursor 4C1 (45 mg, 0.0831 mmol) in 2 mL DCM is added at RT cyclopropanecarboxaldehyde (12.4 μL, 0.166 mmol) and DIPEA (28.4 μL, 0.166 mmol). The yellow suspension is stirred for 10 min at RT then NaBH.sub.3CN (35.2 mg, 0.166 mmol) is added and the mixture is stirred for a further 2 h at this temperature. Water is added and the resulting aq. phase is extracted thrice with DCM. The combined organic phase is washed with sat. aq. NaHCO.sub.3 soln. and brine then dried over MgSO.sub.4. After filtration and evaporation under reduced pressure the crude is purified by 2 prep. HPLC (Method C then Method D) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.60 min; [M+H].sup.+=503.2
EXAMPLE 29
N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): 6-amino-4-(cyclopropylmethyl)-3, 4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Precursor 5A2-10)
[0644] To a solution of Precursor 5A1-8 (730 mg, 2.45 mmol) in 10 mL acetone are added at RT 2 mL sat. aq. NH.sub.4Cl soln. and Zn powder (2508 mg, 38.4 mmol). The reaction mixture is stirred at rt. EtOAc is added followed by solid Na.sub.2SO.sub.4. The mixture is filtered through celite and the filtrate is rinsed with EtOAc. The combined organic mixture is concentrated under reduced pressure to yield the sub-title compound as a yellow solid. LC-A: t.sub.R=0.64 min; [M+H].sup.+=233.2; .sup.1H NMR (400 MHz, d.sub.6-DMSO) δ: 7.07 (t, J=8.0 Hz, 1H), 6.51 (d, J=8.2 Hz, 1H), 6.21 (d, J=7.8 Hz, 1H), 5.75 (s, 2H), 4.20 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.40 (d, J=7.0 Hz, 2H), 1.06 (m, 1H), 0.49 (m, 2H), 0.31 (m, 2H)
Step 2): (4-(Cyclopropylmethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-6-yl)glycine (Precursor 5A2-11)
[0645] To a solution of Precursor 5A2-10 (670 mg, 2.17 mmol) in 10 mL MeOH are added glyoxylic acid solution in water (0.595 mL, 4.34 mmol) and TEA (0.453 mL, 3.25 mmol). The reaction mixture is stirred for 20 min then is added NaBH.sub.3CN (272 mg, 4.33 mmol) and stirred the resulting mixture is stirred for for 2 h. It is then poured into water and the resulting neutral aq. phase is then extracted twice with DCM. The organics are washed with brine, dried over MgSO.sub.4, filtered and evaporated to yield the sub-title compound as a yellow oil which is used as such in the next step without any purification. LC-A: t.sub.R=0.67 min; [M+H].sup.+=291.1
Step 3)
[0646] To a solution of Precursor 5A2-11 (82 mg, 0.261 mmol) in 1.4 mL DMF are added at RT Amine B16 (71.6 mg, 0.261 mmol), HATU (119 mg, 0.313 mmol) and DIPEA (89.4 μL, 0.522 mmol). The yellow suspension is stirred for 2 h at rt, poured into sat. aq. NaHCO.sub.3 solution. The resulting aq. phase is extracted twice with EtOAc, the combined organic phase is then washed with brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The resulting crude is purified by prep. HPLC (Method C) to yield the title compound as a yellow oil. LC-A: t.sub.R=0.93 min; [M+H].sup.+=547.1; .sup.1H NMR (400 MHz, d.sub.6-DMSO) 75:25 mixture of rotamers δ: 7.79 (d, J=7.7 Hz, 0.25H), 7.73 (d, J=7.8 Hz, 0.75H), 7.68 (d, J=7.5 Hz, 0.25H), 7.61 (t, J=7.5 Hz, 0.75H), 7.48 (m, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.23 (t, J=8.1 Hz, 0.75H), 7.14 (t, J=8.1 Hz, 0.25H), 6.97 (bs, 1H), 6.56 (d, J=8.3 Hz, 0.75H), 6.31 (m, 1H), 6.27 (d, J=7.9 Hz, 0.25H), 4.90 (s, 0.5H), 4.80 (s, 1.5H), 4.22 (s, 3.5H), 3.88 (d, J=3.4 Hz, 0.5H), 2.64 (d, J=4.3 Hz, 2H), 1.05 (m, 1H), 0.97 (m, 9H), 0.48 (m, 2H), 0.30 (d, J=4.3 Hz, 2H).
[0647] Example 30-33 and 35-38 from Table 4 below are made according in analogy to the procedure described for the synthesis of Example 29
TABLE-US-00006 TABLE 4 MS Data t.sub.R [min] m/z Example Compound (LC-A) [M + H].sup.+ 30 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 0.90 519.0 benzo[f][1,4]oxazepin-6-ylamino)-N-(2,3-dichloro-benzyl)-N-(2- dimethylamino-ethyl)-acetamide 31 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 0.89 519.0 benzo[f][1,4]oxazepin-6-ylamino)-N-(2,6-dichloro-benzyl)-N-(2- dimethylamino-ethyl)-acetamide 32 N-(2-Chloro-benzyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5- 0.85 485.1 tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino- ethyl)-acetamide 33 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 0.66 466.1 benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(6- methyl-pyridin-2-ylmethyl)-acetamide 35 {2-[[2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 1.23 633.2 benzo[f][1,4]oxazepin-6-ylamino)-acetyl]-(2-trifluoromethyl- benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester 37 {2-[[2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 1.17 605.1 benzo[f][1,4]oxazepin-6-ylamino)-acetyl]-(2-trifluoromethyl- benzyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester 38 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 0.75 519.4 benzo[f][1,4]oxazepin-6-ylamino)-N-(2-dimethylamino-ethyl)-N-(2- trifluoromethyl-benzyl)-acetamide
EXAMPLE 34
2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
[0648] To a solution Example 35 in 2 mL DCM is added TFA (46.4 μL, 0.606 mmol) at RT. The mixture is stirred for 2 h at RT. After evaporation of the volatiles the crude is purified by prep. HPLC (Method C) the yield the title compound as a yellow foam. LC-A: t.sub.R=0.91 min; [M+H].sup.+=533.1
[0649] Example 36 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-6-ylamino)-N-(2-methylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide is made from Example 37 as described in the synthesis of Example 34 from Example 35. LC-A: t.sub.R=0.88 min; [M+H].sup.+=505.1
EXAMPLE 39
N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(3-methyl-pyridin-2-ylmethyl)-acetamide
Step 1): N-ethyl-2-fluoro-N-(2-hydroxyethyl)-3-nitrobenzamide (Precursor 4A1-9)
[0650] To a solution of 2-fluoro-3-nitrobenzoic acid (2 g, 10.8 mmol) and COMU (5724 mg, 13 mmol) in 100 mL of DCM are added 2-(ethylamino)ethanol (1.08 mL, 10.8 mmol) and DIPEA (5.55 mL, 32.4 mmol) at RT under Ar. The resulting mixture is stirred at RT for 18 h. The reaction mixture is treated with 50 mL aq. sat. NaHCO.sub.3 solution. The organic phase is separated. The aqueous phase is extracted twice with 50 mL DCM. The combined organic phase is washed with 100 mL brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with heptane/EtOAc system (1:1 to 0:1 gradient) as eluent to yield the title compound as a brownish oil. LC-A: t.sub.R=0.59 min; [M+H].sup.+=257.2
Step 2): 4-Ethyl-9-nitro-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Precursor 4A1-10)
[0651] A solution of Precursor 4A1-9 (1238 mg, 4.83 mmol) in 20 mL DMF is treated at once with cesium carbonate (4723 mg, 14.5 mmol) at 0° C. under Ar. The mixture is stirred overnight at 60° C. The mixture is cooled to RT and filtered. The filter cake is washed with 20 mL ACN and the resulting solution is evaporated until dryness under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.68 min; [M+H].sup.+=237.1
Step 3): 9-Amino-4-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (Precursor 4D1-1)
[0652] To a solution of Precursor 4A2-10 (3.05 g, 12.9 mmol) in 40 mL of acetone at RT is added 20 mL of a sat. aq. NH.sub.4Cl solution. The reaction mixture is cooled to 0° C. then Zn dust (10.14 g, 155.0 mmol) is added portionwise. The reaction mixture is warmed up to RT and the suspension is stirred vigorously at RT for 24 h. EtOAc (30 ml) is added followed by MgSO.sub.4 (10 g). The suspension is stirred for 15 min then filtered through a Celite pad and washed with 80 mL EtOAc. The combined filtrates are evaporated under reduced pressure to afford the crude subtitle product with a purity level compatible with the next step. LC-A: t.sub.R=0.41 min; [M+H].sup.+=207.1
Step 4): (4-ethyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-9-yl)glycine) (Precursor 4D1)
[0653] To a solution of 9-amino-4-ethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one from Step 3) (200 mg, 0.97 mmol) and TEA (147 mg, 1.45 mmol) in 10 mL of anhydrous MeOH is added glyoxylic acid monohydrate (182 mg, 1.94 mmol). The reaction mixture is stirred at RT for 30 min then treated with NaBH.sub.3CN (122 mg, 1.94 mmol). The stirred reaction mixture is left reacting at RT for 2 h. The mixture is treated with 15 mL water and 20 mL 1N HCl aq. soln. then extracted three times with 25 mL EtOAc. The combined organic phase is washed with 25 mL brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure to afford the crude sub-title product with a purity level compatible with the next step. LC-A: t.sub.R=0.53 min; [M+H].sup.+=265.1
Step 5)
[0654] To a solution of Precursor 4D1 (150 mg, 0.568 mmol) in 5 mL DMF is added Amine B23 (110 mg, 0.568 mmol), HATU (259 mg, 0.681 mmol) and DIPEA (0.243 mL, 1.42 mmol). The resulting mixture is stirred overnight at RT then 5 mL sat. NaHCO.sub.3 sol. are added and the resulting aq. phase is extracted twice with DCM, dried over MgSO.sub.4, filtered and evaporated. The residue is purified by prep. HPLC (Method C) then by preparative TLC using as eluent DCM/MeOH 95:5 to yield the title compound. LC-A: t.sub.R=0.54 min; [M+H].sup.+=440.2
EXAMPLE 61
2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-dimethylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1): N-Cyclopropylmethyl-2-fluoro-N-(2-hydroxy-ethyl)-3-nitro-benzamide (Precursor 4A1-9)
[0655] A solution of 2-fluoro-3-nitrobenzoic acid (0.5 g, 2.7 mmol) in 1.6 mL of thionylchloride is heated under reflux for 5 h. The resulting solution is concentrated under reduced pressure The residue is dissolved in 5 mL toluene and concentrated again under reduced pressure. The crude 2-fluoro-3-nitro-benzoyl chloride is dissolved in 25 mL DCM, the resulting solution is cooled to 0° C. and treated with 0.7 mL DIPEA under argon. A solution of cyclopropylmethyl-[2-(4-methoxy-benzyloxy)-ethyl]-amine (636 mg, 2.7 mmol) in 10 mL DCM is added dropwise. The mixture is stirred at RT for 18 h. The reaction mixture is treated with 50 mL aq. sat. NaHCO.sub.3 solution. The organic phase is separated. The aqueous phase is extracted twice with 50 mL DCM. The combined organic phase is washed with 100 mL brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. The crude residue is purified by flash chromatography over 80 g of silica gel with heptane/EtOAc (4:1 to 1:1 gradient) as eluent to yield N-cyclopropylmethyl-2-fluoro-N-[2-(4-methoxy-benzyloxy)-ethyl]-3-nitro-benzamide as a yellowish oil. LC-A: t.sub.R=0.92 min; [M+H].sup.+=403.15.
[0656] A solution of N-cyclopropylmethyl-2-fluoro-N-[2-(4-methoxy-benzyloxy)-ethyl]-3-nitro-benzamide (609 mg, 1.51 mmol, 1 eq) in DCM (10 mL) at 0° C. is treated with a solution of boron tribromide solution 1M in DCM (1.55 mL, 9.08 mmol, 6 eq). The mixture is stirred at 0° C. for 45 min. Then 15 mL of saturated aqueous NaHCO.sub.3 solution are added and the aqueous phase is extracted with DCM (2×30 mL), dried over MgSO.sub.4, filtered and evaporated. The title compound is obtained as a yellowish oil. LC-A: t.sub.R=0.67 min; [M+H].sup.+=283.18.
Step 2): 4-Cyclopropylmethyl-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (Precursor 4A5-10)
[0657] A solution of N-cyclopropylmethyl-2-fluoro-N-(2-hydroxy-ethyl)-3-nitro-benzamide (804 mg, 2.85 mmol) in 15 mL DMF is treated at once with cesium carbonate (2784 mg, 8.55 mmol) at 0° C. under Ar. The mixture is stirred overnight at 60° C. The mixture is cooled to RT and filtered. The filter cake is washed with 20 mL ACN and the resulting solution is evaporated until dryness under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.77 min; [M+H].sup.+=263.21.
Step 3): 9-Amino-4-cyclopropylmethyl-3, 4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (Precursor 4D2-1)
[0658] A flask is charged with Pd/C 10% wet (50.7 mg, 0.477 mmol) then 25 mL MeOH are added under Ar. Then 4-cyclopropylmethyl-9-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (250 mg, 0.953 mmol, 1 eq) is suspended in 10 mL MeOH and the resulting suspension is purged with argon and then added to the Pd suspension. The dark mixture is stirred under H.sub.2 at RT overnight. The mixture is filtered and evaporated until dryness under reduced pressure to afford the crude product with a purity level compatible with the next step. LC-A: t.sub.R=0.50 min; [M+H].sup.+=233.24.
Step 4): (4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetic acid (Precursor 4D2)
[0659] To a solution of 9-amino-4-cyclopropylmethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one from Step 3) (209 mg, 0.9 mmol) in 10 mL of anhydrous MeOH is added glyoxylic acid monohydrate (166 mg, 1.8 mmol). The reaction mixture is stirred at RT for 30 min. The reaction mixture is degassed and purged with Ar then treated with Pd/C 10% (67 mg, 0.63 mmol). The well stirred suspension is put under an atmospheric pressure of H.sub.2 and left reacting at RT for 18 h. The mixture is purged with Ar, filtered and evaporated until dryness under reduced pressure. Purification of the crude by prep. HPLC (Method LC-C) affords the title compound as a light brownish oil. LC-A: t.sub.R=0.61 min; [M+H].sup.+=291.16
Step 5)
[0660] To a solution of Precursor 4D2 (80 mg, 0.276 mmol) in 2 mL DCM is added Amine B1 (68 mg, 0.276 mmol), T.sub.3P (351 mg of a 50% sol. In DCM, 0.55 mmol) in DCM and DIPEA (0.118 mL, 0.69 mmol). The resulting mixture is stirred overnight at RT then 5 mL sat. NaHCO.sub.3 sol. are added and the resulting aq. phase is extracted twice with DCM. The organic phase is dried over MgSO4, filtered and evaporated. The residue is purified by Prep (Method LC-C) to yield the title compound. LC-B: t.sub.R=0.70 min; [M+H].sup.+=519.3
[0661] Example 40, 41, 57, 58, 59, 60, 63 and 64 from Table 5 are made from Precursor 4D1 or 4D2 as described for the synthesis of Example 39
TABLE-US-00007 TABLE 5 MS Data t.sub.R [min] m/z Example Compound (LC-) [M + H].sup.+ 40 N-(2-tert-Butylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro- 0.71 521.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)- (LC-A) acetamide 41 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro- 0.67 493.2 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl-benzyl)- (LC-A) acetamide 57 2-(4-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9- 0.58 520.2 ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3-trifluoromethyl-pyridin-2- (LC-B) ylmethyl)-acetamide 58 N-(2-Dimethylamino-ethyl)-2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro- 0.56 494.2 benzo[f][1,4]oxazepin-9-ylamino)-N-(3-trifluoromethyl-pyridin-2- (LC-B) ylmethyl)-acetamide 59 N-(3-Chloro-pyridin-2-ylmethyl)-2-(4-ethyl-5-oxo-2,3,4,5- 0.54 486.2 tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl- (LC-B) ethyl)-acetamide 60 N-(3-Chloro-pyridin-2-ylmethyl)-N-(2-dimethylamino-ethyl)-2-(4- 0.52 460.2 ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)- (LC-B) acetamide 63 N-(2-tert-Butylamino-ethyl)-2-(4-cyclopropylmethyl-5-oxo-2,3,4,5- 0.74 547.3 tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-trifluoromethyl- (LC-B) benzyl)-acetamide 64 2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro- 0.65 546.3 benzo[f][1,4]oxazepin-9-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-N-(3- (LC-B) trifluoromethyl-pyridin-2-ylmethyl)-acetamide
EXAMPLE 56
2-(4-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) {2-[[2-(4-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0662] To a solution of Precursor 4D (200 mg, 0.76 mmol) in 5 mL DMF is added Amine B21 (273 mg, 0.76 mmol), HATU (345 mg, 0.91 mmol) and DIPEA (0.324 mL, 1.89 mmol). The resulting mixture is stirred overnight at RT then 5 mL sat. NaHCO.sub.3 sol. are added and the resulting aq. phase is extracted twice with 10 mL DCM, dried over MgSO4, filtered and evaporated. The residue is purified by prep. HPLC (Method C) then by prep. TLC using as eluent DCM/MeOH 95:5 to yield the title compound. LC-A: t.sub.R=1.01 min; [M+H].sup.+=607.2
Step 2)
[0663] To a solution of {2-[[2-(4-ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester (185 mg, 0.305 mmol) in 5 mL DCM is added TFA (0.14 mL, 1.83 mmol) at RT. The mixture is stirred for 2 h at RT. After evaporation of the volatiles the crude is purified by prep. HPLC (Method LC-C) to yield the title compound as a yellow foam. LC-B: t.sub.R=0.66 min; [M+H].sup.+=507.3
EXAMPLE 62
2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-N-(2-isopropylamino-ethyl)-N-(2-trifluoromethyl-benzyl)-acetamide
Step 1) {{2-[[2-(4-Cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester
[0664] To a solution of Precursor 4D2 (100 mg, 0.34 mmol) in 3 mL DCM is added Amine B21 (124 mg, 0.34 mmol), T.sub.3P (438 mg of a 30% solution in DCM, 0.7 mmol) and DIPEA (0.15 mL, 0.86 mmol). The resulting mixture is stirred overnight at RT then 5 mL sat. NaHCO.sub.3 sol. are added and the resulting aq. phase is extracted twice with 10 mL DCM, dried over MgSO.sub.4, filtered and evaporated. The residue is purified by prep. HPLC (Method C) then by prep. TLC using as eluent DCM/MeOH 95:5 to yield the title compound. LC-A: t.sub.R=1.04 min; [M+H].sup.+=633.28
Step 2)
[0665] To a solution of {{2-[[2-(4-cyclopropylmethyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-acetyl]-(2-trifluoromethyl-benzyl)-amino]-ethyl}-isopropyl-carbamic acid tert-butyl ester (54 mg, 0.085 mmol) in 3 mL DCM is added TFA (0.04 mL, 0.51 mmol) at RT. The mixture is stirred for 2 h at RT. After evaporation of the volatiles the crude is purified by prep. HPLC (Method LC-C) to yield the title compound as a yellow foam. LC-B: t.sub.R=0.73 min; [M+H].sup.+=533.3
Amine Building Blocks
[0666] Amines B1-B31 are either commercially available or are prepared following of the method A described below:
Amine B2
Method A
[0667] N′-(3-Chloro-pyridin-2-ylmethyl)-N,N-dimethyl-ethane-1,2-diamine
[0668] To a solution of 3-chloro-2-formylpyridine (1.5 g, 10.6 mmol) in 25 mL DCM are added 2-dimethylamino-ethylamine (1.27 mL, 11.7 mmol) and DIPEA (3.6 mL, 21.2 mmol). The resulting solution is treated portionwise with NaBH(OAc).sub.3 (3.37 g, 15.9 mmol) and allowed to stir for 18 h at RT. The reaction mixture is diluted with 10 mL DCM and washed with 25 mL aq. sat. NaHCO.sub.3 solution. The aqueous phase is extracted twice with 20 mL DCM. The combined organic phase is washed with 70 mL brine, dried over MgSO.sub.4, filtered and evaporated under reduced pressure. This yields the title compound (1.6 g, 71%) as a colourless liquid. LC-A: t.sub.R=0.20 min; [M+H].sup.+=214.17
[0669] Amines listed in Table 6 below are commercially available or are prepared by applying the above-mentioned methods A using commercially available starting materials. Prepared amines are characterized by their LC-MS data.
TABLE-US-00008 TABLE 6 Amine No Compound name B1 N,N-Dimethyl-N′-(2-trifluoromethyl-benzyl)-ethane-1,2-diamine B3 N,N-Dimethyl-N′-(3-trifluoromethyl-benzyl)-ethane-1,2-diamine B4 N′-(4-Fluoro-2-trifluoromethyl-benzyl)-N,N-dimethyl-ethane-1,2-diamine; LC-A: t.sub.R = 0.42 min; [M + H].sup.+ = 265.1 B5 (2-Morpholin-4-yl-ethyl)-(2-trifluoromethyl-benzyl)-amine B6 1-[2-(2-Trifluoromethyl-benzylamino)-ethyl]-pyrrolidin-2-one; LC-A: t.sub.R = 0.51 min; [M + H].sup.+ = 287.2 B7 (2-Chloro-benzyl)-(2-pyrrolidin-1-yl-ethyl)-amine B8 (2,4-Difluoro-benzyl)-(2-pyrrolidin-1-yl-ethyl)-amine B9 N,N-Dimethyl-N′-(3-trifluoromethyl-pyridin-2-ylmethyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.25 min; [M + H].sup.+ = 248.1 B10 N′-(2,6-Difluoro-benzyl)-N,N-dimethyl-ethane-1,2-diamine;: LC-G: t.sub.R = 1.12 min; [M + H].sup.+ = 215.2 B11 N-Cyclopropyl-N-methyl-N′-(2-trifluoromethyl-benzyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.42 min; [M + H].sup.+ = 273.2 B12 N′-(3-Bromo-benzyl)-N,N-dimethyl-ethane-1,2-diamine; LC-A: t.sub.R = 0.36 min; [M + H].sup.+ = 257.1 B13 (3-Chloro-pyridin-2-ylmethyl)-[2-(4,4-difluoro-piperidin-1-yl)-ethyl]-amine; LC-A: t.sub.R = 0.42 min; [M + H].sup.+ = 290.1 B14 N′-(4-Methoxy-pyridin-2-ylmethyl)-N,N-dimethyl-ethane-1,2-diamine; LC-A: t.sub.R = 0.19 min; [M + H].sup.+ = 210.2 B15 N,N-Dimethyl-N′-(4-methyl-pyridin-2-ylmethyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.19 min; [M + H].sup.+ = 194.2 B16 N-tert-Butyl-N′-(2-trifluoromethyl-benzyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.44 min; [M + H].sup.+ = 275.2 B17 N′-(2,3-Dichloro-benzyl)-N,N-dimethyl-ethane-1,2-diamine; LC-C: t.sub.R = 0.95 min; [M + H].sup.+ = 247.1 B18 N′-(2,6-Dichloro-benzyl)-N,N-dimethyl-ethane-1,2-diamine; LC-C: t.sub.R = 0.94 min; [M + H].sup.+ = 247.0 B19 N′-(2-Chloro-benzyl)-N,N-dimethyl-ethane-1,2-diamine; LC-A: t.sub.R = 0.30 min; [M + H].sup.+ = 212.1 B20 N,N-Dimethyl-N′-(6-methyl-pyridin-2-ylmethyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.20 min; [M + H].sup.+ = 194.4 B21 Isopropyl-[2-(2-trifluoromethyl-benzylamino)-ethyl]-carbamic acid tert-butyl ester; LC-A: t.sub.R = 0.74 min; [M + H].sup.+ = 361.3 B22 Methyl-[2-(2-trifluoromethyl-benzylamino)-ethyl]-carbamic acid tert-butyl ester; LC-A: t.sub.R = 0.65 min; [M + H].sup.+ = 333.1 B23 N,N-Dimethyl-N′-(3-methyl-pyridin-2-ylmethyl)-ethane-1,2-diamine; LC-A: t.sub.R = 0.20 min; [M + H].sup.+ = 194.3 B24 (2-Pyrrolidin-1-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine; LC-A: t.sub.R = 0.31 min; [M + H].sup.+ = 274.08 B25 N,N-Dimethyl-N′-(2-trifluoromethyl-thiazol-5-ylmethyl)-ethane- 1,2-diamine; LC-A: t.sub.R = 0.29 min; [M + H].sup.+ = 254.17 B26 N′-(5-Chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-N,N- dimethyl-ethane-1,2-diamine; LC-A: t.sub.R = 0.31 min; [M + H].sup.+ = 285.17 B27 (2-Morpholin-4-yl-ethyl)-(3-trifluoromethyl-pyridin-2-ylmethyl)-amine; LC-A: t.sub.R = 0.33 min; [M + H].sup.+ = 290.07 B28 Isopropyl-[2-(3-trifluoromethyl-pyridin-2-ylmethyl)amino-ethyl]-carbamic acid tert-butyl ester; LC-A: t.sub.R = 0.81 min; [M + H].sup.+ = 362.3 B29 N-tert-Butyl-N′-(2-chloro-benzyl)-ethane-1,2-diamine; t.sub.R = 0.41 min; [M + H].sup.+ = 241.1 B30 N-tert-Butyl-N′-(3-chloro-pyridin-2-ylmethyl)-ethane-1,2-diamine; t.sub.R = 0.31 min; [M + H].sup.+ = 242.1 B31 N-tert-Butyl-N′-(3-trifluoromethyl-pyridin-2-ylmethyl)-ethane-1,2-diamine; t.sub.R = 0.40 min; [M + H].sup.+ = 276.2
II. Biological Assays
In Vitro Assay
[0670] The CXCI12 receptor and CXCR7 agonistic activities of the compounds of formula (I) are determined in accordance with the following experimental method.
[0671] The assay is using the PathHunter™ CHO-K1 CXCR7 β-arrestin cell line from DiscoverX. The system is based on the Enzyme Fragment Complementation Technology. Two complementing fragments of the β-galactosidase enzyme are expressed within stably transfected cells. The larger portion of β-gal, termed EA for Enzyme Acceptor, is fused to the C-terminus of b-arrestin 2. The smaller fragment, termed ProLink™ tag, is fused to CXCR7 at the C-terminus. Upon activation, b-arrestin is recruited which forces the interaction of ProLink and EA, allowing complementation of the two fragments of b-gal and the formation of a functional enzyme which is capable of hydrolysing the substrate and generating a chemiluminescent signal.
[0672] CHO-K1 CXCR7 β-arrestin cells are detached from culture dishes with a cell dissociation buffer (Invitrogen, #13151-014) and collected in growing medium (F12 HAMS 90% (v/v)/FCS 10% (v/v), Penicillin/streptomycin 1% (v/v)). 5000 cells per well (in 20 μl) are seeded in a 384 well plate (white-walled, clear bottom; BD Falcon #353274). The plate is incubated at 37° C./5% CO.sub.2 for 24 hours. Medium is then replaced by 20 μl OPTIMEM (Invitrogen #31985) for 3 to 4 hours. Test compounds are dissolved at 10 mM in DMSO and serially diluted in DMSO to 200× of the final concentration for dose response curves. Compounds are then diluted 1:33.3 in HBSS1X. 5 μl/well of HBSS1X/20 mM HEPES/0.2% BSA are added to the assay plate followed by addition of 5 μl/well of diluted compounds. CXCL12 (Peprotech #300-28A) may be used as a reference agonist. The plate is incubated for 90 minutes at 37° C. 12 μl of detection reagent (Path Hunter Detection Kit, DiscoveRx, #93-0001) is transferred to the assay plate and to the plate is incubated for 1 hour at room temperature. Luminescent signal is read in a microplate reader (FLUOstar Optima, bmg). The calculated EC.sub.50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average EC.sub.50 values from several measurements are given as geometric mean values.
[0673] Agonistic activities of exemplified compounds are displayed in Table 7:
TABLE-US-00009 TABLE 7 Example CXCR7 Number EC.sub.50 (nM) 1 8 2 3 3 9 4 24 5 7 6 19 7 4 8 36 9 200 10 58 11 190 12 14 13 88 14 76 15 11 16 74 17 59 18 53 19 12 20 73 21 6 22 4 23 1 24 3 25 3 26 4 27 2 28 3 29 3 30 7.8 31 27 32 15 33 24 34 5 35 420 36 12 37 410 38 4 39 400 40 7 41 22 42 7 43 4 44 130 45 50 46 5 47 430 48 47 49 2 50 340 51 1 52 1 55 10 56 16 57 60 58 74 59 260 60 260 61 9 62 5 63 2 64 7 65 18 66 18 67 37 68 15 69 430 70 4 71 4 72 6 73 59 74 5 75 19 76 430 77 280 78 240 82 2 83 3 84 4 85 3 86 14 87 23 88 15 89 5 90 7 91 8 92 10 93 3 94 4