US2016207933A1PendingUtilityA1
Glucosylceramide synthase inhibitors
Est. expiryMar 18, 2031(~4.7 yrs left)· nominal 20-yr term from priority
Inventors:Elyse Marie Josee BourqueMario Cabrera-SalazarCassandra CelatkaSeng H. ChengMary A. CromwellAndrew C. GoodBradford H. HirthKatherine JancsicsJohn LeonardLingyun LiJames LillieHanlan LiuElina MakinoJohn MarshallPaul MasonMarkus MetzFazeela MorshedThomas O'SheaRonald K. ScheuleRenato SkerljBing WangYibin XiangZhong Zhao
A61P 7/00A61P 43/00A61P 3/10A61P 9/10A61P 35/00A61P 3/00A61P 3/04A61P 31/04A61P 25/16A61P 29/00A61P 25/28A61P 19/02A61P 25/00A61P 1/00A61P 13/12A61P 11/06A61K 38/47A61K 31/46C07D 487/08C12Y 302/01022C07D 453/02C07D 455/02A61K 31/439C07D 453/00A61K 31/506A61K 31/454A61K 31/551A61K 31/55
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Claims
Abstract
The invention relates to inhibitors of glucosylceramide synthase (GCS) useful for the treatment metabolic diseases, such as lysosomal storage diseases, either alone or in combination with enzyme replacement therapy, and for the treatment of cancer.
Claims
exact text as granted — not AI-modified1 . A compound represented by the following structural formula,
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
n is 1, 2 or 3;
m is 0 or 1;
p is 0 or 1;
t is 0, 1 or 2;
y is 1 or 2;
z is 0, 1 or 2;
E is S, O, NH, NOH, NNO 2 , NCN, NR, NOR or NSO 2 R;
X 1 is CR 1 when m is 1 or N when m is 0;
X 2 is O, —NH, —CH 2 —, SO 2 , NH—SO 2 ; CH(C 1 -C 6 ) alkyl or —NR 2 ;
X 3 is O, —NH, —CH 2 —, CO, —CH(C 1 -C 6 ) alkyl, SO 2 NH, —CO—NH— or —NR 3 ;
X 4 is CR 4 R 5 , CH 2 CR 4 R 5 or CH 2 —(C 1 -C 6 ) alkyl-CR 4 R 5 ;
X 5 is a direct bond, O, S, SO 2 , CR 4 R 5 ; (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyloxy, (C 1 -C 6 )alkenyl, (C 1 -C 6 )alkenyloxy;
R is (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl, (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl;
R 1 is H, CN, (C 1 -C 6 )alkylcarbonyl, or (C 1 -C 6 )alkyl;
R 2 and R 3 are each independently —H, (C 1 -C 6 )alkyl optionally substituted by one or more substituents selected from the group consisting of halogen, (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 6 -C 12 )aryl, halo(C 6 -C 12 )aryl, and halo(C 2 -C 9 )heteroaryl, or optionally when X 2 is —NR 2 and X 3 is —NR 3 , R 2 and R 3 may be taken together with the nitrogen atoms to which they are attached form a non-aromatic heterocyclic ring optionally substituted by with one or more substituents selected from halogen, (C 1 -C 6 )alkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 1 -C 6 )alkyl(C 6 -C 12 )aryl, halo(C 6 -C 12 )aryl, and halo(C 2 -C 9 )heteroaryl;
R 4 and R 5 are independently selected from H, (C 1 -C 6 )alkyl, or taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring;
R 6 is —H, halogen, —CN, (C 6 -C 12 )aryl, (C 6 -C 12 )aryloxy, (C 1 -C 6 )alkyloxy; (C 1 -C 6 )alkyl optionally substituted by one to four halo or (C 1 -C 6 )alkyl;
A 1 is (C 2 -C 6 )alkynyl; (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl optionally substituted by one to three halo; (C 1 -C 6 )alkenyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, nitro, CN, —OH, (C 1 -C 6 )alkyloxy optionally substituted by one to three halo; (C 1 -C 6 )alkoxycarbonyl, and (C 1 -C 6 ) alkylcarbonyl;
A 2 is H, (C 3 -C 10 )cycloalkyl, (C 6 -C 12 )aryl, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or benzo(C 2 -C 9 )heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of halo, (C 1 -C 6 )alkyl optionally substituted by one to three halo; (C 1 -C 6 )alkylenyl, amino, (C 1 -C 6 ) alkylamino, (C 1 -C 6 )dialkylamino, (C 1 -C 6 )alkoxy, O(C3-C6 cycloalkyl), (C 3 -C 6 ) cycloalkoxy, nitro, CN, OH, (C 1 -C 6 )alkyloxy optionally substituted by one to three halo; (C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkoxycarbonyl, (C 1 -C 6 ) alkylcarbonyl, (C 1 -C 6 ) haloalkyl;
with the proviso that the sum of n+t+y+z is not greater than 6;
with the proviso that when p is 0; X 2 is NH—SO 2 and X 3 is NH;
with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2 is NH; E is O; X 3 is NH; A 2 is H and X 5 is a direct bond; A 1 is not unsubstituted phenyl, halophenyl or isopropenyl phenyl;
with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2 is O; E is O; X 3 is NH; A 1 is (C 6 -C 12 )aryl and X 5 is a direct bond; A 2 is H and R 4 is H then R 5 is not cyclohexyl; and
with the proviso that when n is 1; t is 0; y is 1; z is 1; X 2 is NH; E is O; X 3 is CH 2 ;
R 4 and R 5 are both hydrogen; A 2 is H and X 5 is a direct bond; then A 1 is not unsubstituted phenyl.
2 . A compound according to claim 1 , wherein n is 1; t is 0; y is 1 and z is 1.
3 . A compound according to claim 1 , wherein n is 1; t is 1; y is 1 and z is 1.
4 . A compound according to claim 1 , wherein n is 2; t is 0; y is 1 and z is 1.
5 . A compound according to claim 1 , wherein n is 2; t is 1; y is 1 and z is 1.
6 . A compound according to claim 1 , wherein n is 3; t is 0; y is 1 and z is 1.
7 . A compound according to claim 1 , wherein n is 1; t is 2; y is 1 and z is 1.
8 . A compound according to claim 1 , wherein n is 1; t is 0; y is 1 and z is 0.
9 . A compound according to claim 1 , wherein n is 1; t is 1; y is 1 and z is 0.
10 . A compound according to claim 1 , wherein n is 2; t is 0; y is 1 and z is 0.
11 . A compound according to claim 1 , wherein n is 2; t is 1; y is 1 and z is 0.
12 . A compound according to claim 1 , wherein n is 3; t is 0; y is 1 and z is 0.
13 . A compound according to claim 1 , wherein n is 1; t is 2; y is 1 and z is 0.
14 . A compound according to claim 1 , wherein n is 1; t is 1; y is 2 and z is 0.
15 . A compound according to claim 1 , wherein n is 2; t is 0; y is 2 and z is 0.
16 . A compound according to claim 1 , wherein m is 1 and X 1 is CR 1 .
17 . A compound according to claim 1 , wherein m is 0 and X 1 is N.
18 . A compound according to claim 1 , wherein m is 1; E is O; X 2 is O and X 3 is NH.
19 . A compound according to claim 1 , wherein m is 1; E is O; X 2 is NH and X 3 is NH.
20 . A compound according to claim 1 , wherein m is 1; E is O; X 2 is CH 2 and X 3 is NH.
21 . A compound according to claim 1 , wherein m is 1; E is O; X 2 is NH and X 3 is CH 2 .
22 . A compound according to claim 1 , wherein m is 1; E is S; X 2 is NH and X 3 is NH.
23 . A compound according to claim 1 , wherein m is 0; E is O; X 1 is NH and X 3 is NH.
24 . A compound according to claim 1 , wherein m is 1; E is O; X 2 is NH and X 3 is CO—NH.
25 . A compound according to claim 1 , wherein m is 1; p is 0; X 2 is NH—SO 2 and X 3 is NH.
26 . A compound according to claim 1 , wherein R 4 and R 5 are each (C 1 -C 6 )alkyl or taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or a spiro (C 3 -C 10 )cycloalkoxy ring.
27 . A compound according to claim 26 , wherein R 4 and R 5 are each methyl.
28 . A compound according to claim 26 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring.
29 . A compound according to claim 28 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro cyclopropyl ring.
30 . A compound according to claim 26 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkoxy ring.
31 . A compound according to claim 1 , wherein A 1 is (C 2 -C 6 )alkynyl or (C 6 -C 12 )aryl.
32 . A compound according to claim 1 , wherein A 1 is (C 2 -C 9 )heteroaryl.
33 . A compound according to claim 32 , wherein A 1 is thiophene, thiazole, isothiazole, furane, oxazole, isoxazole, pyrrole, imidazole, pyrazole, triazole, pyridine, pymiridine, pyridazine, indole, benzotiazole, benzoisoxazole, benzopyrazole, benzoimidazole, benzofuran, benzooxazole or benzoisoxazole.
34 . A compound according to claim 1 , wherein A 1 is (C 2 -C 9 )heterocycloalkyl.
35 . A compound according to claim 34 , wherein A 1 is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or octahydro-1H-indolyl.
36 . A compound according to claim 1 , wherein A 1 is benzo(C 2 -C 9 )heterocycloalkyl.
37 . A compound according to claim 36 , wherein A 1 is 2,3-dihydrobenzo[b][1,4]dioxine or 2,2-difluorobenzo[d][1,3]dioxole.
38 . A compound according to claim 1 , wherein R 6 is H.
39 . A compound according to claim 1 , X 5 is a direct bond.
40 . A compound according to claim 1 , X 5 is a CR 4 R 5 .
41 . A compound according to claim 40 , wherein R 4 and R 5 are each methyl.
42 . A compound according to claim 40 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring.
43 . A compound according to claim 42 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro cyclopropyl ring.
44 . A compound according to claim 40 , wherein R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkoxy ring.
45 . A compound according to claim 1 , wherein A 2 is (C 6 -C 12 )aryl.
46 . A compound according to claim 1 , wherein A 2 is (C 2 -C 9 )heteroaryl.
47 . A compound according to claim 46 , wherein A 2 is pyridine.
48 . A compound according to claim 1 , wherein A 2 is (C 2 -C 9 )heterocycloalkyl.
49 . A compound according to claim 48 , wherein A 2 is pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, azetidinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, piperizin-2-onyl, piperizin-3-onyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, imidazolidinyl, 2-imidazolidinyl, 1,4-dioxanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.1.0]hexanyl 2-azaspiro[4.4]nonanyl, 7-oxa-1-aza-spiro[4.4]nonanyl, 7-azabicyclo[2.2.2]heptanyl or octahydro-1H-indolyl.
50 . A compound according to claim 1 , wherein A 2 is benzo(C 2 -C 9 )heterocycloalkyl.
51 . A compound according to claim 50 , wherein A 2 is 2,3-dihydrobenzo[b][1,4]dioxine or 2,2-difluorobenzo[d][1,3]dioxole.
52 . A compound according to claim 1 , where R 1 is hydrogen or methyl.
53 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
54 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
55 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
56 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
57 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
58 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
59 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
60 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
61 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
62 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
63 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
64 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
65 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
66 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
67 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
68 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
69 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
70 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
71 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
72 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
73 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
74 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
75 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
76 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
77 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
78 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
79 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
80 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
81 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
82 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
83 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
84 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
85 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
86 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
87 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
88 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
89 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
90 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
91 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
92 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
93 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
94 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
95 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
96 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
97 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
98 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
99 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
100 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
101 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
102 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
103 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
104 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl;
X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
105 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
106 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
107 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
108 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
109 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
110 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
111 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
112 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
113 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
114 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
115 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
116 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
117 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
118 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
119 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
120 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
121 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
122 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
123 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
124 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
125 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
126 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
127 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
128 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, 0 or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
129 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
130 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
131 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
132 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
133 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
134 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
135 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
136 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
137 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
138 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
139 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
140 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
141 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
142 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
143 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
144 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
145 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
146 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
147 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
148 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
149 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
150 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
151 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
152 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
153 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
154 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
155 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
156 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
157 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
158 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
159 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
160 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, 0 or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
161 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
162 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heterocycloalkyl.
163 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
164 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heterocycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
165 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
166 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
167 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
168 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
169 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
170 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
171 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
172 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
173 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
174 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
175 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
176 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
177 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
178 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
179 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
180 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
181 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
182 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
183 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
184 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
185 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
186 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
187 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
188 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
189 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
190 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
191 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
192 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
193 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
194 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
195 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
196 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
197 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
198 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
199 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
200 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
201 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
202 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
203 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
204 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
205 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
206 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
207 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
208 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
209 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
210 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 6 -C 12 )aryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
211 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
212 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 6 -C 12 )aryl.
213 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
214 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
215 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
216 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; p is 1; E is O; X 2 is O; X 3 is NH; R 1 is H; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
217 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
218 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
219 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
220 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
221 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
222 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
223 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
224 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CH 2 ; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
225 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
226 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
227 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
228 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is CH 2 ; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
229 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
230 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
231 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
232 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is S; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
233 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
234 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
235 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
236 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is SO 2 ; X 2 is NH; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
237 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
238 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
239 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
240 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is N; m is 0; E is O; X 3 is NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
241 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
242 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 2 -C 9 )heteroaryl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 3 -C 10 )cycloalkyl.
243 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are taken together with the carbon to which they are attached to form a spiro (C 3 -C 10 )cycloalkyl ring or Spiro (C 3 -C 10 )cycloalkoxy ring; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
244 . A compound according to claim 1 , wherein n is 1; 2 or 3; t is 0, 1 or 2; y is 0 or 1; z is 0, 1 or 2; X 1 is CR 1 ; m is 1; E is O; X 2 is NH; X 3 is CO—NH; R 4 and R 5 are each independently methyl; R 6 is a hydrogen or methyl; A 1 is (C 3 -C 10 )cycloalkyl; X 5 is a direct bond, O or CR 4 R 5 and A 2 is (C 2 -C 9 )heteroaryl.
245 . A compound according to claim 1 , wherein A 1 is (C 3 -C 10 )cycloalkyl.
246 . A compound according to claim 1 , wherein A 2 is (C 3 -C 10 )cycloalkyl.
247 . A compound according to claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of:
1-azabicyclo[2.2.2]oct-3-yl [2-(2,4′-difluorobiphenyl-4-yl)propan-2-yl]carbamate; 1-azabicyclo[2.2.2]oct-3-yl {2-[4-(1,3-benzothiazol-6-yl)phenyl]propan-2-yl}carbamate; 1-azabicyclo[3.2.2]non-4-yl {1-[5-(4-fluorophenyl)pyridin-2-yl]cyclopropyl}carbamate; 1-azabicyclo[2.2.2]oct-3-yl {1-[3-(4-fluorophenoxy)phenyl]cyclopropyl}carbamate; 1-azabicyclo[2.2.2]oct-3-yl {1-[4-(1,3-benzothiazol-5-yl)phenyl]cyclopropyl}carbamate; 1-azabicyclo[2.2.2]oct-3-yl [1-(4′-fluoro-3′-methoxybiphenyl-4yl)cyclopropyl]carbamate; 1-azabicyclo[2.2.2]oct-3-yl [3-(4′-fluorobiphenyl-4-yl)oxetan-3-yl]carbamate; 1-azabicyclo[2.2.2]oct-3-yl {1-[6-(4-fluorophenoxy)pyridin-2-yl]cyclopropyl}carbamate; 1-azabicyclo[2.2.2]oct-3-yl [3-(4′-fluorobiphenyl-4-yl)pentan-3-yl]carbamate; 1-azabicyclo[2.2.2]oct-3-yl {2-[2-(4-fluorophenyl)-2H-indazol-6-yl]propan-2 yl}carbamate; 1-azabicyclo[2.2.2]oct-3-yl {2-[2-(1H-pyrrol-1-yl)pyridin-4-yl]propan-2-yl}carbamate; 1-(3-ethyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]urea; N-(1-azabicyclo[2.2.2]oct-3-yl)-N-[1-(4′-fluorobiphenyl-4yl)cyclopropyl]ethanediamide; 1-azabicyclo[2.2.2]oct-3-yl (1-{4 [(4,4difluorocyclohexyl)oxy]phenyl}cyclopropyl) carbamate; 1-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)-3-[1-(5-phenylpyridin-2-yl)cyclopropyl]urea; 1-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea; 1-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1-methyl-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea; 1-{2-[4′-(2-methoxyethoxy)biphenyl-4-yl]propan-2-yl}-3-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)urea; 2-(1-azabicyclo[3.2.2]non-4-yl)-N-[1-(5-phenylpyridin-2-yl)cyclopropyl]acetamide; 3-(4′-fluorobiphenyl-4-yl)-3-methyl-N-(4-methyl-1-azabicyclo[3.2.2]non-4-yl)butanamide; N-[2-(biphenyl-4-yl)propan-2-yl]-N′-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide; N-[2-(4′-fluorobiphenyl-4-yl)propan-2-yl]-N′-(3-methyl-1-azabicyclo[2.2.2]oct-3-yl)sulfuric diamide; 1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-{2-[1-(4-fluorophenyl)-1H-pyrazol-4-yl]propan-2-yl}urea; 1-azabicyclo[2.2.2]oct-3-yl [4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]carbamate; 1-(3-butyl-1-azabicyclo[2.2.2]oct-3-yl)-3-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]urea; N-[1-(4′-fluorobiphenyl-4-yl)cyclopropyl]-1,4-diazabicyclo[3.2.2]nonane-4-carboxamide; 1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicyclo[3.2.2]nonan-3-yl)urea; 1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(4-methyl-1-azabicyclo[4.2.2]decan-4-yl)urea; 1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(3-methyl-1-azabicyclo[4.2.2]decan-3-yl)urea; and 1-(2-(4′-fluoro-[1,1′-biphenyl]-4-yl)propan-2-yl)-3-(5-methyl-1-azabicyclo[4.2.2]decan-5-yl)urea.
248 . A pharmaceutical composition for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 1 .
249 . A method for treating a disease or disorder mediated by glucosylceramide synthase (GCS) or a disease or disorder in which GCS is implicated in a subject in need of such treatment comprising administering to the subject an effective amount of a compound according to claim 1 .
250 . The method of claim 249 , wherein the disease or disorder is cancer.
251 . The method of claim 249 , wherein the disease or disorder is a metabolic disorder.
252 . The method of claim 249 , wherein the disease or disorder is a neuropathic disease.
253 . The method of claim 252 , wherein the neuropathic disease is Alzheimers disease.
254 . The method of claim 252 , wherein the neuropathic disease is Parkinsons disease.
255 . The method for inducing decreased glucosylceramide synthase catalytic activity in a cell, in vitro, comprising contacting the cell with an effect amount of a compound according to claim 1 .
256 . A compound according to claim 1 , represented by the following structural formula,
or a pharmaceutically acceptable salt or prodrug thereof.
257 . A compound according to claim 1 , represented by the following structural formula,
or a pharmaceutically acceptable salt or prodrug thereof.
258 . A method of treating a subject diagnosed as having a lysosomal storage disease, comprising administering to the subject an effective amount of the compound according to claim 1 .
259 . The method of claim 258 , wherein the lysosomal storage disease results from a defect in the glycosphingolipid pathway.
260 . The method of claim 259 , wherein the lysosomal storage disease is selected from the group consisting of Gaucher, Fabry, G M1 -gangliosidosis, G M2 Activator deficiency, Tay-Sachs and Sandhoff.
261 . The method of claim 260 , wherein the lysosomal storage disease is Fabry.
262 . The method of claim 258 , further comprising the step of administering to the subject a therapeutically effective amount of a lysosomal enzyme.
263 . The method of claim 262 , wherein the lysosomal enzyme is selected from the group consisting of glucocerebrosidase, alpha-galactosidase A, Hexosaminidase A, Hexosaminidase B and G M1 -ganglioside-β-galactosidase.
264 . The method of claim 262 , wherein the lysosomal enzyme is alpha-galactosidase A.
265 . The method of claim 262 , wherein prior to treatment the subject has elevated levels of a lysosomal substrate.
266 . The method of claim 265 , wherein the subject undergoing treatment has lower combined amounts of the lysosomal substrate in the urine and plasma than a subject treated with either the lysosomal enzyme or compound alone.
267 . The method of claim 266 , wherein the substrate is selected from the group consisting of globotriaosylceramide and lyso-globotriaosylceramide, and combinations thereof.
268 . The method of claim 258 , wherein the compound is represented by the following structural formula,
or a pharmaceutically acceptable salt or prodrug thereof.
269 . The method of claim 258 , wherein the compound is represented by the following structural formula,
or a pharmaceutically acceptable salt or prodrug thereof.
270 . A method of reducing glucosylceramide synthase (GCS) activity in a subject diagnosed as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to claim 1 , either alone or as a combination therapy with an enzyme replacement therapy.
271 . A method of reducing accumulation of a GCS-derived material in a subject diagnosed as having a lysosomal storage disease, comprising administering to the patient an effective amount of the compound according to claim 1 , either alone or as a combination therapy with an enzyme replacement therapy.Cited by (0)
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