Compounds useful as immunomodulators

Abstract

Disclosed are compounds of Formula (I): (I). Also disclosed are methods of using such compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of virological diseases or disorders and cancer. ##STR00001##

Claims

1. A compound of Formula (I): ##STR00394## or salts thereof, wherein: Ring B is phenyl or thienyl; Ring A is: ##STR00395## wherein A is CH or N, and wherein one of R.sup.1 and R.sup.2 is Q and the other of R.sup.1 and R.sup.2 is R.sup.b; R.sup.3 is H or CH.sub.2C(O)OH; R.sup.4 is NHCH.sub.2CH.sub.2NHC(O)CH.sub.3; Q is: (i) ##STR00396## wherein R.sup.y is OH, CH.sub.3, CH.sub.2OH, C(O)OH, CH.sub.2C(O)OH, or C(O)NHCH.sub.2CH.sub.2OH, C(O)NH.sub.2, NHC(O)CH.sub.3, and R.sup.z is OH, CH.sub.3, OCH.sub.3, OC(O)CH.sub.3, or CH.sub.2CHCH.sub.2 and R.sup.h is CH.sub.3 or C(O)CH.sub.3; (ii) CH.sub.2NHR.sup.x wherein R.sup.x is cyclobutyl, (CH.sub.2)cyclobutyl optionally substituted with two fluorine atoms, cyclopropyl, hydroxycyclopentyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxytetrahydrofuranyl, N-methyl piperidinyl, N-ethyl piperidinyl, hydroxytetrahydrothienyl, or ##STR00397## (iii) CH.sub.2NR.sup.aCR.sup.aR.sup.a(CH.sub.2).sub.nR.sup.x wherein R.sup.x is hydrogen, azetidinonyl, cyclohexyl, hydroxyphenyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinyl, imidazolyl, N-methylimidazolyl, C(O)(morpholinyl), piperazinyl optionally substituted with a methyl, phenyl, alkoxyphenyl, hydroxyphenyl, pyridinyl, pyrimidinyl, or C(O)OC(CH.sub.3).sub.3 group, pyrrolidinyl, pyridinyl, thiomorpholine dioxide, or methyl triazolyl; or (iv) CHR.sup.aNR.sup.aCR.sup.aR.sup.a(CHR.sup.a).sub.nR.sup.x wherein R.sup.x is OH, OCH.sub.3, C(O)OH, OPh, CH(CO.sub.2H)NHC(O)CH.sub.3, O(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CO.sub.2HO(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CO.sub.2H, C(O)CH.sub.3, C(O)NR.sup.aR.sup.a, C(O)NR.sup.qR.sup.q, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)Ph, C(O)NH(CH.sub.2).sub.2-imidazolyl, NHC(O)OCH.sub.2Ph, N(CH.sub.3)S(O).sub.2CH.sub.3, NHC(O)CHCH.sub.2, NHC(O)CHCHC(O)CH.sub.2CH.sub.3, NHS(O).sub.2CH.sub.3, or ##STR00398## each R.sup.a is independently H, CH(OH)CH.sub.3, OH, (CH.sub.2).sub.2OH, CH.sub.2OH, (CH.sub.2).sub.2NH.sub.2, CH.sub.2CH.sub.3, or CH.sub.3; or, two R.sup.a groups on the same carbon atom can form a four, five-, or six-membered carbocyclic ring, an N-methylpiperidinyl ring, or a pyranyl ring; each R.sup.b is independently H, F, Cl, Br, CF.sub.3, CN, CH.sub.3, or OCH.sub.3; each R.sup.c is independently OCH.sub.3, OH, OCH.sub.2CH.sub.3, O(CH.sub.2)OCH.sub.3, OCH.sub.2CHCH.sub.2, O(CH.sub.2).sub.2CH.sub.3, O(CH.sub.2).sub.2-morpholinyl, or F; or two R.sup.c attached to adjacent carbon atoms form O(CH.sub.2).sub.vO, wherein v is 1 or 2; each R.sup.q is selected from hydrogen, CH.sub.2C(O)NHCH.sub.2CO.sub.2H, (CH.sub.2)C(O)NHCH(CO.sub.2H)CH.sub.2CH(CH.sub.3).sub.2, CH(Bn)-C(O)NHCH(CO.sub.2H)(CH.sub.2).sub.3NHC(NH)NH.sub.2; m is zero or 1; n is zero, 1, 2, or 3; each p is independently zero or 1; and q is zero, 1, or 2.

2. The compound according to claim 1 or salts thereof, wherein Ring A is: ##STR00399##

3. The compound according to claim 2 or salts thereof, wherein Q is: ##STR00400##

4. The compound according to claim 2 or salts thereof, wherein Q is: CH.sub.2NHR.sup.x wherein R.sup.x is cyclobutyl, (CH.sub.2)cyclobutyl optionally substituted with two fluorine atoms, cyclopropyl, hydroxycyclopentyl, cyclopentyl, cyclohexyl, hydroxycyclohexyl, hydroxytetrahydrofuranyl, N-methyl piperidinyl, N-ethyl piperidinyl, hydroxytetrahydrothienyl, or ##STR00401##

5. The compound according to claim 2 or salts thereof, wherein Q is: CH.sub.2NR.sup.aCR.sup.aR.sup.a(CH.sub.2).sub.nR.sup.x wherein R.sup.x is hydrogen, azetidinonyl, cyclohexyl, hydroxyphenyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinyl, imidazolyl, N-methylimidazolyl, C(O)(morpholinyl), piperazinyl optionally substituted with a methyl, phenyl, alkoxyphenyl, hydroxyphenyl, pyridinyl, pyrimidinyl, or C(O)OC(CH.sub.3).sub.3 group, pyrrolidinyl, pyridinyl, thiomorpholine dioxide, or methyl triazolyl.

6. The compound according to claim 2 or salts thereof, wherein Q is CHR.sup.aNR.sup.aCR.sup.aR.sup.a(CHR.sup.a).sub.nR.sup.x wherein R.sup.x is OH, OCH.sub.3, C(O)OH, OPh, CH(CO.sub.2H)NHC(O)CH.sub.3, O(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2OH, O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CO.sub.2HO(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2O(CH.sub.2).sub.2CO.sub.2H, C(O)CH.sub.3, C(O)NR.sup.aR.sup.a, C(O)NR.sup.qR.sup.q, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHC(O)Ph, C(O)NH(CH2)2-imidazolyl, NHC(O)OCH.sub.2Ph, N(CH.sub.3)S(O).sub.2CH.sub.3, NHC(O)CHCH.sub.2, NHC(O)CHCHC(O)CH.sub.2CH.sub.3, NHS(O).sub.2CH.sub.3, or ##STR00402##

7. The compound according to claim 1 selected from: (S)-1-(2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid (1); 1-(4-((2-fluoro-2-methylbiphenyl-3-yl)methoxy)benzyl)azetidine (3); N-{2-[({3-bromo-2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (4); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) [2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine (5); N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}-N-methylmethanesulfonamide (6); 1-({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (7); 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-(morpholin-4-yl)ethan-1-one (8); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[2-(4-methylpiperazin-1-yl)ethyl]amine (9); 1-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}piperidin-2-one (10); 1-{3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}pyrrolidin-2-one (11); 4-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}piperazin-2-one (12); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[2-(morpholin-4-yl)ethyl]amine (13); 1-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (14); 2-[methyl({3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetic acid (15); N-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1-ethylpiperidin-3-amine (16); 1-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}pyrrolidin-2-one (17); (2S,4R)-4-(acetyloxy)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (18); N-(2-hydroxyethyl)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) piperidine-4-carboxamide (19); ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[1-(5-methyl-4H-1,2,4-triazol-3-yl)ethyl]amine (20); N-{2-[({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (21); (2S,4R)-1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-4-methoxypyrrolidine-2-carboxylic acid (22); N-{3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}acetamide (23); (1R,2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol (24); N-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1-methylpiperidin-3-amine (25); (2S)-1-({2-methoxy-3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (26); (2S)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-2-(prop-2-en-1-yl)pyrrolidine-2-carboxylic acid (27); 3-[({3-bromo-4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino]propanamide (28); 3-[({3-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino]propanamide (29); 4-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)morpholine-3-carboxylic acid (30); 3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butanoic acid (31); 1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-4-carboxylic acid (32); (2R)-1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (33); (2S)-1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (34); 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-N,N-dimethylacetamide (35); N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (36); 1-({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (37); 1-({3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (38); (2S,4R)-4-methoxy-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) pyrrolidine-2-carboxylic acid (39); 1-({2,6-dimethyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (40); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azepane-2-carboxylic acid (41); 2-[1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidin-2-yl]acetic acid (42); 1-{3-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}pyrrolidin-2-one (43); N-{2-[(1-{3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}ethyl)amino]ethyl}acetamide (44); 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]acetic acid (45); 3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanamide (46); (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (47); 1-({3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) piperidine-2-carboxylic acid (48); 1-({3-fluoro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (49); (2R,4R)-4-hydroxy-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (50); (2R,4S)-4-hydroxy-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) pyrrolidine-2-carboxylic acid (51); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (52); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-3-carboxylic acid (53); (3R)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-3-carboxylic acid (54); (2R,4R)-4-methyl-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (55); (2S)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (56); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-4-carboxylic acid (57); (2R)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (58); (2S)-1-({4-methyl-3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (59); 1-{3-[({3-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino]propyl}pyrrolidin-2-one (60); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid (63); 2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-methylpropanoic acid (64); N-{2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (65); 1-({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (66); N-{2-[({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (67); N-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl) cyclobutanamine (68); N-{2-[({2,6-dimethyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (69); N-{2-[(1-{3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}ethyl)amino]ethyl}acetamide (70); (2S)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (71); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (72); (1R,2R)-2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol (73); 1-({4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)piperidine-2-carboxylic acid (74); (2R)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)pyrrolidine-2-carboxylic acid (75); 5-{[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}pyrrolidin-2-one (76); (2S)-2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (77); (2R)-2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (78); N-{2-[({3-fluoro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (79); (2S)-2-[({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (80); (2S)-2-[({3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (81); 3-[({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanamide (82); 1-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (83); 3-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butanoic acid (84); (2R)-2-[methyl({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (85); 3-[({2,6-dimethyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanamide (86); N-{2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (87); N-{2-[({4-methyl-3-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide (88); [(2S)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)pyrrolidin-2-yl]methanol (89); (2S)-1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine-2-carboxylic acid (90); 5-{[({4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}pyrrolidin-2-one (91); 5-{[({4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}pyrrolidin-2-one (92); (2S)-2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (93); 2-[methyl({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetic acid (94); 3-[({3-methyl-4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino]propanamide (95); (2R)-2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (96); 1-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (97); 1-({2-methoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (98); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (99); 1-({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)azetidine (100); 2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethan-1-ol (102); 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino]ethan-1-ol (103); (2S)-2-[({3-bromo-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (104); (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propanoic acid (105); (2R)-2-{[(2,6-dimethoxy-4-{[3-(3-methoxyphenyl)-2-methylphenyl]methoxy}phenyl)methyl]amino}propanoic acid (106); (2R)-2-{[(4-{[3-(3-fluoro-5-methoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid (107); (2R)-2-{[(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid (108); 2-(6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid (2); N-[2-({5-[(2-methyl-3-phenylphenyl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}amino)ethyl]acetamide (61); N-[2-({6-[(2-methyl-3-phenylphenyl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl}amino)ethyl]acetamide (62); or 6-[(2-methyl-3-phenylphenyl) methoxy]-1,2,3,4-tetrahydroisoquinoline (101); or salts thereof.

8. The compound according to claim 1 or salts thereof, selected from N-[2-({4-[(2-methyl-3-phenylphenyl)methoxy]-2,3-dihydro-1H-inden-1-yl}amino)ethyl]acetamide; 4-{[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}azetidin-2-one; (3S)-4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; (2S)-1-[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-3-(trifluoromethyl)phenyl)methyl]piperidine-2-carboxylic acid; N-(2-{[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-3-(trifluoromethyl)phenyl)methyl]amino}ethyl)acetamide; (3S)-4-{[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-3-(trifluoromethyl)phenyl)methyl]amino}-3-hydroxybutanoic acid; (2R,3S)-2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; (2R,3R)-2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; (2S,3S)-2-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; 2-[({5-[(2-methyl-3-phenylphenyl)methoxy]thiophen-2-yl}methyl)amino]ethan-1-ol; 2-[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]ethan-1-ol; {1-[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]cyclopentyl}methanol; methyl({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amine; 5-{[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]methyl}pyrrolidin-2-one; 2-(3,5-dimethoxy-4-{[(pyridin-2-ylmethyl)amino]methyl}phenoxymethyl)-6-phenylbenzonitrile; 2-{4-[(cyclopropylamino)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-{3,5-dimethoxy-4-[(3-methylpiperidin-1-yl)methyl]phenoxymethyl}-6-phenylbenzonitrile; 2-[3,5-dimethoxy-4-({[2-(pyrrolidin-1-yl)ethyl]amino}methyl)phenoxymethyl]-6-phenylbenzonitrile; 2-{4-[(4-hydroxypiperidin-1-yl)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-[3,5-dimethoxy-4-(morpholin-4-ylmethyl)phenoxymethyl]-6-phenylbenzonitrile; 2-(3,5-dimethoxy-4-{[(pyridin-3-ylmethyl)amino]methyl}phenoxymethyl)-6-phenylbenzonitrile; 2-(3,5-dimethoxy-4-{[(pyridin-4-ylmethyl)amino]methyl}phenoxymethyl)-6-phenylbenzonitrile; 2-[4-({[(3-hydroxyphenyl)methyl]amino}methyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-[4-({[(2-hydroxyphenyl)methyl]amino}methyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-[4-({[(4-hydroxyphenyl)methyl]amino}methyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-{4-[(cyclobutylamino)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-{4-[(cyclopentylamino)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-{4-[(cyclohexylamino)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-[3,5-dimethoxy-4-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}methyl)phenoxymethyl]-6-phenylbenzonitrile; 2-(3,5-dimethoxy-4-{[(propan-2-yl)amino]methyl}phenoxymethyl)-6-phenylbenzonitrile; N-{2-[({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethyl}acetamide; 2-[4-({[2-(dimethylamino)ethyl]amino}methyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-(3,5-dimethoxy-4-{[(2-methoxyethyl)amino]methyl}phenoxymethyl)-6-phenylbenzonitrile; 2-(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxymethyl)-6-phenylbenzonitrile; 2-[4-({[1-(hydroxymethyl)cyclopentyl]amino}methyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-(4-{[(4-hydroxycyclohexyl)amino]methyl}-3,5-dimethoxyphenoxymethyl)-6-phenylbenzonitrile; 3-[({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]propanamide; 2-{3,5-dimethoxy-4-[(methylamino)methyl]phenoxymethyl}-6-phenylbenzonitrile; 2-[3,5-dimethoxy-4-({[2-(pyridin-2-yl)ethyl]amino}methyl)phenoxymethyl]-6-phenylbenzonitrile; 2-{3,5-dimethoxy-4-[(2-methylpyrrolidin-1-yl)methyl]phenoxymethyl}-6-phenylbenzonitrile; 2-{4-[(4-acetylpiperazin-1-yl)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-[3,5-dimethoxy-4-(pyrrolidin-1-ylmethyl)phenoxymethyl]-6-phenylbenzonitrile; 2-(4-{[3-(hydroxymethyl)piperidin-1-yl]methyl}-3,5-dimethoxyphenoxymethyl)-6-phenylbenzonitrile; N-[(3S)-1-({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)pyrrolidin-3-yl]acetamide; 2-[4-(azetidin-1-ylmethyl)-3,5-dimethoxyphenoxymethyl]-6-phenylbenzonitrile; 2-{4-[(4-acetyl-1,4-diazepan-1-yl)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-(4-{[ethyl(pyridin-4-ylmethyl)amino]methyl}-3,5-dimethoxyphenoxymethyl)-6-phenylbenzonitrile; 2-(4-{[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl}-3,5-dimethoxyphenoxymethyl)-6-phenylbenzonitrile; 2-{4-[(2, 5-dimethylpyrrolidin-1-yl)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 2-{4-[(3-hydroxypiperidin-1-yl)methyl]-3,5-dimethoxyphenoxymethyl}-6-phenylbenzonitrile; 1-({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)piperidine-3-carboxylic acid; (2S)-1-({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)pyrrolidine-2-carboxamide; (2S)-1-({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)piperidine-2-carboxylic acid; (6 S)-5-({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1,2,5-triazaspiro[2.4]hept-1-ene-6-carboxylic acid; {2-[2-(2-aminoethoxy)ethoxy]ethyl}({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amine; 2-(2-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethoxy}ethoxy)ethan-1-ol; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)({2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl})amine; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)({2-[4-(pyridin-2-yl)piperazin-1-yl]ethyl})amine; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)({2-[4-(pyrimidin-2-yl)piperazin-1-yl]ethyl})amine; tert-butyl 4-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}piperazine-1-carboxylate; 4-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}-1.sup.6,4-thiomorpholine-1,1-dione; benzyl N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}carbamate; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[3-(4-methylpiperazin-1-yl)propyl]amine; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[3-(morpholin-4-yl)propyl]amine; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[3-(1H-imidazol-1-yl)propyl]amine; 4-{[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}azetidin-2-one; 3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-N-[2-(1H-imidazol-4-yl)ethyl]propanamide; 2-({3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}(2-hydroxyethyl)amino)ethan-1-ol; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(3-phenoxypropyl)amine; 4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-hydroxybutanoic acid; 3-(4-{3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propyl}piperazin-1-yl)phenol; [2-(benzyloxy)ethyl]({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amine; 1-{2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}-5,8,11-trioxa-2-azatridecan-13-ol; 1-{2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}-5,8,11,14,17,20-hexaoxa-2-azatricosan-23-oic acid; 1-{2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}-5,8,11,14-tetraoxa-2-azaheptadecan-17-oic acid; (2S)-5-carbamimidamido-2-[(2R)-2-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetamido}-3-phenylpropanamido]pentanoic acid; 2-(2-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetamido}acetamido)acetic acid; (2S)-5-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-acetamidopentanoic acid; [(3,3-difluorocyclobutyl)methyl]({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amine; (cyclobutylmethyl)({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amine; (2S)-2-(2-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]acetamido}acetamido)-4-methylpentanoic acid; (2-aminoethyl)({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)methylamine; 3-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}-1-phenylurea; N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}-2-oxo-2H-chromene-6-sulfonamide; N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}prop-2-enamide; ethyl (2E)-3-({2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}carbamoyl)prop-2-enoate; (6 S)-5-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-1,2,5-triazaspiro[2.4]hept-1-ene-6-carboxylic acid; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-(hydroxymethyl)propane-1,3-diol; (3S)-4-[({3-chloro-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; N-{2-[({3-cyano-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide; N-(2-{[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-2,5-difluorophenyl)methyl]amino}ethyl)acetamide; (3S)-4-{[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-2, 5-difluorophenyl)methyl]amino}-3-hydroxybutanoic acid; (2S)-1-[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-2, 5-difluorophenyl)methyl]piperidine-2-carboxylic acid; N-{2-[({2-methoxy-6-[(2-methyl-3-phenylphenyl) methoxy]pyridin-3-yl}methyl)amino]ethyl}acetamide; 5-(azetidin-1-ylmethyl)-2-[(2-methyl-3-phenylphenyl)methoxy]pyridine; N-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)cyclobutanamine; N-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)cyclopentanamine; 1-{3-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]propyl}pyrrolidin-2-one; ({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)[2-(pyridin-2-yl)ethyl]amine; 2-[(2-methyl-3-phenylphenyl)methoxy]-5-(pyrrolidin-1-ylmethyl)pyridine; [(2S)-1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)pyrrolidin-2-yl]methanol; (2S)-1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)piperidine-2-carboxylic acid; 1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)piperidine-3-carboxylic acid; [1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)piperidin-3-yl]methanol; 1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)piperidin-4-ol; 2-[(2-methyl-3-phenylphenyl)methoxy]-5-[(2-methylpyrrolidin-1-yl)methyl]pyridine; ({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)(propan-2-yl)amine; methyl({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amine; N-{2-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]ethyl}acetamide; [2-(dimethylamino)ethyl]({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amine; (2-methoxyethyl)({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amine; 2-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]ethan-1-ol; {1-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]cyclopentyl}methanol; 4-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]cyclohexan-1-ol; 3-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]propanamide; (2S)-2-[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]propanoic acid; 5-{[({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]methyl}pyrrolidin-2-one; N-[(3S)-1-({6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)pyrrolidin-3-yl]acetamide; (2R)-2-{[(4-{[3-(3-fluoro-5-methoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid; (2R)-2-{[(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid; 3-[3-(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxymethyl)-2-methylphenyl]phenol; 2-{[(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}ethan-1-ol; 2-{[(4-{[3-(3-ethoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}ethan-1-ol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-{3-[2-(piperidin-1-yl)ethoxy]phenyl}phenyl)methoxy]phenyl}methyl)amino]ethan-1-ol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-methylpropane-1,3-diol; (2S,3S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-methylpentan-1-ol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-4-methylpentan-1-ol; 1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propan-2-ol; {1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclopentyl}methanol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propane-1,3-diol; 1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butan-2-ol; (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-4-methylpentan-1-ol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-methylbutan-1-ol; (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-methylbutan-1-ol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propan-1-ol; (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butan-1-ol; 2-{[(2,6-dimethoxy-4-{[2-methyl-3-(3-propoxyphenyl)phenyl]methoxy}phenyl)methyl]amino}ethan-1-ol; (2S)-3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propane-1,2-diol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-methylbutanoic acid; 1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-methylpropan-2-ol; (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]pentan-1-ol; 3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butan-2-ol; (2R)-3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propane-1,2-diol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butan-1-ol; (2S)-1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]propan-2-ol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol; (1S,2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol; (3R,4S)-4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]oxolan-3-ol; 1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-methylbutan-2-ol; ({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)[3-(dimethylamino)-2-hydroxypropyl]amine; (2R)-2-cyclopropyl-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethan-1-ol; 3-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-methylbutan-2-ol; (2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-phenylethan-1-ol; 1-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2,3-dihydro-1H-inden-2-ol; (1S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-phenylethan-1-ol; (3S)-4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; 4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]thiolan-3-ol; (1R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-phenylethan-1-ol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-(pyridin-3-yl)ethan-1-ol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-(pyridin-4-yl)ethan-1-ol; (2S)-2-cyclohexyl-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethan-1-ol; {4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]oxan-4-yl}methanol; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-1-(1-methyl-1H-imidazol-2-yl)ethan-1-ol; 1-{[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}cyclohexan-1-ol; (1R,2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclopentan-1-ol; 4-{[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}-1-methylpiperidin-4-ol; (1R,2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclohexan-1-ol; (1S,2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclopentan-1-ol; (1R,2R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]cyclopentan-1-ol; (2R,3S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butane-1,3-diol; (2S,3R)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]butane-1,3-diol; 1-{[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]methyl}cyclobutan-1-ol; (3R)-4-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-3-hydroxybutanoic acid; 2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-ethylpropane-1,3-diol; (2S)-2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]-2-phenylethan-1-ol; 1-({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)-4-hydroxypiperidine-4-carboxamide; N-(2-{[(2,6-dimethoxy-4-{[3-(3-methoxyphenyl)-2-methylphenyl]methoxy}phenyl)methyl]amino}ethyl)acetamide; N-(2-{[(4-{[3-(3-ethoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}ethyl)acetamide; N-(2-{[(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}ethyl)acetamide; [(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl][2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; N-(2-{[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}ethyl)acetamide; [(4-{[3-(3-ethoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl][2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; [(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl][2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; {[2,6-dimethoxy-4-({3-[3-(methoxymethoxy)phenyl]-2-methylphenyl}methoxy)phenyl]methyl}[2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; {[2,6-dimethoxy-4-({2-methyl-3-[3-(prop-2-en-1-yloxy)phenyl]phenyl}methoxy)phenyl]methyl}[2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; {[4-({3-[2-fluoro-5-(2-methoxyethoxy)phenyl]-2-methylphenyl}methoxy)-2,6-dimethoxyphenyl]methyl}[2-methyl-1-(4-methylpiperazin-1-yl)propan-2-yl]amine; (3S)-4-[({4-[(2-cyano-3-phenylphenyl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]-3-hydroxybutanoic acid; (3S)-3-hydroxy-4-[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]butanoic acid; and N-(2-{[(3-chloro-4-{[2-methyl-3-(thiophen-3-yl)phenyl]methoxy}phenyl)methyl]amino}ethyl)acetamid.

9. The compound according to claim 1 or salts thereof, wherein Ring A is: ##STR00403##

10. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A method of treating a disease or disorder associated with the inhibition of the PD-1/PD-L1 interaction, wherein said disease or disorder is a cancer selected from the group consisting of melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, bladder cancer, ovarian cancer, brain cancer, kidney cancer, colon cancer, rectal cancer, stomach cancer, testicular cancer, Hodgkin's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, myeloma, small intestine cancer, squamous cell cancer; or a virological infection selected from the group consisting of HPV, HBV, HCV, KHSV and HIV infections, the method comprising administering to a mammalian patient a compound according to claim 1 or a pharmaceutically acceptable salt.

Description

EXAMPLES

(1) The disclosure is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the disclosure, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the disclosure to various uses and conditions. As a result, the disclosure is not limited by the illustrative examples set forth hereinbelow, but rather is defined by the claims appended hereto.

ABBREVIATIONS

(2) Ac acetyl

(3) anhyd. anhydrous

(4) aq. aqueous

(5) Bn benzyl

(6) Bu butyl

(7) CV Column Volumes

(8) Et ethyl

(9) h, hr or hrs hour(s)

(10) HPLC high pressure liquid chromatography

(11) LC liquid chromatography

(12) M molar

(13) mM millimolar

(14) Me methyl

(15) MHz megahertz

(16) min. minute(s)

(17) mins minute(s)

(18) M.sup.+1 (M+H).sup.+

(19) MS mass spectrometry

(20) n or N normal

(21) nM nanomolar

(22) Ph phenyl

(23) Ret Time or RT retention time

(24) sat. saturated

(25) SFC supercritical fluid chromatography

Example 1

(S)-1-(2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzyl)piperidine-2-carboxylic acid

(26) ##STR00049##

Intermediate 1A: (2-methylbiphenyl-3-yl)methanol

(27) ##STR00050##

(28) A mixture of (3-bromo-2-methylphenyl)methanol (2.071 g, 10.3 mmol), phenylboronic acid (2.51 g, 20.60 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (0.084 g, 0.103 mmol) in toluene (15.45 ml) and ethanol (5.15 ml) was placed under argon. To this solution was added sodium bicarbonate, 2M (15.45 ml, 30.9 mmol) and the mixture was heated at 80 C. for 30 min. The reaction mixture was diluted with 20 mL ethyl acetate and 5 mL water. The organic portion was concentrated by rotatory evaporation. The crude product was chromatographed on silica gel eluting with 0-40% ethyl acetate in hexane to afford 2 g of an off-white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.47-7.29 (m, 7H), 7.23 (s, 1H), 4.80 (d, J=5.6 Hz, 2H), 2.27 (s, 3H), 1.63-1.59 (m, 1H).

Intermediate 1B: 2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzaldehyde

(29) ##STR00051##

(30) Diisopropyl azodicarboxylate (2.158 mL, 11.10 mmol) in THF (50 mL) was added dropwise to a cooled (0 C.) solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.838 g, 10.09 mmol), triphenylphosphine (2.91 g, 11.10 mmol) and 2-methyl-[1,1-biphenyl]-3-yl)methanol (2 g, 10.09 mmol) in dry THF (50 mL). The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. 1H NMR (500 MHz, CHLOROFORM-d) 10.40 (s, 1H), 7.48-7.42 (m, 3H), 7.40 (d, J=7.6 Hz, 1H), 7.36-7.30 (m, 4H), 6.23 (s, 2H), 5.19 (s, 2H), 3.94-3.89 (m, 6H), 2.30 (s, 3H). Rf=0.55 1:1 ethyl acetate:hexanes.

Example 1

(31) A solution of 2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzaldehyde (20 mg, 0.055 mmol), (S)-piperidine-2-carboxylic acid and sodium triacetoxy borohydride (35.1 mg, 0.166 mmol) in dichloromethane (4 mL) was stirred at 85 C. for 45 min. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 20.3 mg, and its estimated purity by LCMS analysis was 99%. LC/MS Method A: 2.8 min., M.sup.+1: 476.3, M.sup.1: 474.4, Exact Mass: 475.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.55-7.15 (m, 8H), 6.43 (s, 2H), 5.20 (s, 2H), 4.12 (s, 2H), 3.80 (s, 6H), 3.20-3.04 (m, 3H), 3.22-3.02 (m, 3H), 2.65 (br. s., 1H), 2.22 (s, 3H), 1.82 (br. s., 2H), 1.57 (br. s., 2H), 1.40 (d, J=6.7 Hz, 2H).

(32) Examples 6, 7, 9-15, 17, 18, 21, 24-26, 32, 36, 37, 46-48, 69, 84, 103, 105, 111, 163-190, 195, 196, 233-244 and 246-284 in the table were prepared from Intermediate 1B, 2,6-dimethoxy-4-((2-methylbiphenyl-3-yl)methoxy)benzaldehyde, and an appropriate amine according to the general synthetic process described for Example 1.

Example 2

2-(6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid

(33) ##STR00052##

Intermediate 2A: tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

(34) ##STR00053##

(35) A solution of 1,2,3,4-tetrahydroisoquinolin-6-ol HCl (1 g, 5.39 mmol) and BOC.sub.2O (2.251 ml, 9.70 mmol) in saturated aqueous sodium bicarbonate solution (10 mL) and chloroform (10 mL) was stirred at room temperature overnight. The aqueous portion was neutralized with concentrated HCl and extracted with ethyl acetate. The combined organic portions were washed with 0.1 N HCl, dried over MgSO.sub.4, filtered and concentrated to give 1.6 g of a yellow oil. The oil was chromatographed on silica gel with 0-60% ethyl acetate in hexanes to provide 0.58 g of product. .sup.1H NMR (400 MHz, CHLOROFORM-d) 6.99 (d, J=8.3 Hz, 1H), 6.70 (dd, J=8.3, 2.5 Hz, 1H), 6.64 (d, J=2.5 Hz, 1H), 4.52 (s, 2H), 3.64 (t, J=5.9 Hz, 2H), 2.80 (t, J=5.9 Hz, 2H), 1.62-1.46 (m, 13H).

Intermediate 2B: tert-butyl 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

(36) ##STR00054##

(37) A solution of diisopropyl azodicarboxylate (0.503 mL, 2.59 mmol) in THF (11.800 mL) was added dropwise to a cooled (0 C.) solution of tert-butyl 6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (586 mg, 2.351 mmol), triphenylphosphine (678 mg, 2.59 mmol) and (2-methyl-[1,1-biphenyl]-3-yl)methanol (513 mg, 2.59 mmol) in dry THF (11.800 mL). The resulting yellow solution was allowed to slowly warm to room temperature and stirred overnight. Excess solvent was removed and the residue purified via chromatography with 0-35% ethyl acetate in hexane on a silica gel column. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.48-7.42 (m, 3H), 7.41-7.33 (m, 3H), 7.30-7.26 (m, 2H), 7.07 (d, J=8.3 Hz, 1H), 6.90 (dd, J=8.3, 2.7 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H), 5.09 (s, 2H), 4.55 (s, 2H), 3.66 (t, J=5.6 Hz, 2H), 2.85 (t, J=5.7 Hz, 2H), 2.69 (br. s., 2H), 2.27 (s, 3H), 1.52 (s, 9H).

Intermediate 2C: 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline HCl

(38) ##STR00055##

(39) The compound, tert-butyl 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate (580 mg, 1.350 mmol), was dissolved in excess 2N HCl in diethyl ether, 3 mL, at room temperature. The solution was allowed to sit overnight. A yellow precipitate was collected, washed once with ether and dried under house vacuum overnight to afford a yellow solid (425 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.49-7.42 (m, 3H), 7.41-7.36 (m, 1H), 7.32 (d, J=7.6 Hz, 2H), 7.28 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.88-6.77 (m, 2H), 5.10 (s, 2H), 3.04-2.98 (m, 2H), 2.74 (t, J=5.6 Hz, 2H), 2.19 (s, 3H), 1.90 (s, 2H). Intermediate 2C is Example 101.

Example 2

(40) A mixture was prepared by combining potassium carbonate (0.055 g, 0.400 mmol) and 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)-1,2,3,4-tetrahydroisoquinoline (0.066 g, 0.2 mmol) in acetonitrile (2.000 ml). Methyl 2-bromoacetate was filtered through a small plug of potassium carbonate to remove any hydrogen bromide. The methyl 2-bromoacetate (0.034 g, 0.220 mmol) was added to the mixture. The resulting mixture was stirred for 3 hours. The extent of reaction was determined to be about 20%. The mixture was heated to 35 C. for 1 hour. The remaining starting material was consumed. The material was used without further purification.

(41) Half of the unpurified material was diluted with 2 mL methanol and 1 mL 1N sodium hydroxide. The mixture was stirred at room temperature overnight. LCMS showed that the starting material was consumed and product was present. The solvents were removed using a rotovap. The solid material was dissolved in DMF. An insoluble portion remained. The resulting mixture was filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters Xbridge C18, 19200 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.7 mg, and its estimated purity by LCMS analysis was 97%. LC/MS Method M: 2.8 min., M.sup.+1: 388.2, M.sup.1: 386.1, Exact Mass: 387.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.49-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.32 (d, J=7.3 Hz, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.3 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 6.85 (s, 2H), 5.11 (s, 2H), 3.72 (s, 2H), 3.30 (s, 2H), 2.85 (dd, J=10.8, 4.4 Hz, 4H), 2.19 (s, 3H).

Example 3

2-[({3-methyl-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethan-1-ol

(42) ##STR00056##

Intermediate 3A: 3-chloro-4-((2-methylbiphenyl-3-yl)methoxy)benzaldehyde

(43) ##STR00057##

(44) Diisopropyl azodicarboxylate (1.01 g, 5 mmol) in THF (30 mL) was added dropwise to a cooled (0 C.) solution of 4-hydroxy-3-chlorobenzaldehyde (0.782 g, 5 mmol), triphenylphosphine (1.3 g, 4.99 mmol) and intermediate 1A, 2-methyl-[1,1-biphenyl]-3-yl)methanol (0.90 g, 4.54 mmol) in dry THF (30 mL). The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Solvent was removed by rotary evaporator. The residue was purified on a 40 g silica gel column with 10:1 Hexane:Ethyl acetate. Isolated 0.97 g of the desired product as white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.90 (s, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.6, 2.0 Hz, 1H), 7.53-7.49 (m, 1H), 7.49-7.43 (m, 2H), 7.39 (d, J=7.1 Hz, 1H), 7.36-7.29 (m, 4H), 7.20 (d, J=8.3 Hz, 1H), 5.30 (s, 2H), 2.30 (s, 3H).

Example 3

(45) The solution of 3-chloro-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzaldehyde (20 mg, 0.059 mmol) and 2-aminoethanol (3.99 mg, 0.065 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 hour. The solvent was removed and toluene (3 mL) was added and removed with rotary evaporator. To the residue was added dichloromethane (5 mL) and sodium triacetoxyborohydride (37.8 mg, 0.178 mmol). The resulting light yellow mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in methanol for purification. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 10.7 mg, and its estimated purity by LCMS analysis was 100%. LC/MS Method A: 2.7 min., M.sup.+1: 382.4 Exact Mass: 381.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51 (d, J=7.6 Hz, 1H), 7.49-7.44 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 1H), 7.34-7.28 (m, 3H), 7.27 (s, 2H), 7.21 (d, J=7.6 Hz, 1H), 5.23 (s, 2H), 3.65 (s, 2H), 3.46 (t, J=5.8 Hz, 2H), 2.55 (t, J=5.8 Hz, 2H), 2.23 (s, 3H), 1.90 (s, 1H, acetate).

(46) Examples 23, 31, 33-35, 65, 66, 78, 79, 98, 115, 116, 117 and 197 were prepared according to the general procedure described in Example 3 except an appropriate, commercially available amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(47) Examples 162 was prepared according to the general procedure described in Example 3 except (S)-5-(tert-butoxycarbonyl)-1,2,5-triazaspiro[2.4]hept-1-ene-6-carboxylic acid (Van Der Meijden, B. Robinson, J. A. ARKIVOC, 2011, vi, 130-136) was used for reductive amination instead of piperidine-2-carboxylic acid.

(48) Examples 102 was prepared according to the general process described in Example 3 except that 4-hydroxy-3-methylbenzaldehyde was use in the first step instead of 4-hydroxy-3-chlorobenzaldehyde.

Example 4

1-(4-((3-methoxy-2-methylbiphenyl-3-yl)methoxy)benzyl)azetidine

(49) ##STR00058##

Intermediate 4A: 4-(3-bromo-2-methylbenzyloxy)benzaldehyde

(50) ##STR00059##

(51) A solution of diisopropyl azodicarboxylate (4.25 mL, 21.88 mmol) in THF (100 mL) was added to a cooled (0 C.) solution of 4-hydroxybenzaldehyde (2.67 g, 21.88 mmol), triphenylphosphine (5.74 g, 21.88 mmol) and (3-bromo-2-methylphenyl) methanol (4.0 g, 19.89 mmol) in dry THF (100 mL). The resulting yellow solution was allowed to slowly warm to room temperature and stirred overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexanes to give 4.9 grams of the title compound (81%). .sup.1H NMR (500 MHz, CHLOROFORM-d) 9.93 (s, 1H), 7.92-7.85 (m, 2H), 7.61 (dd, J=8.0, 0.9 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.15-7.07 (m, 3H), 5.17 (s, 2H), 2.48 (s, 3H).

Intermediate 4B: 1-(4-(3-bromo-2-methylbenzyloxy)benzyl)azetidine

(52) ##STR00060##

(53) A solution of tetramethyl ammonium triacetoxyborohydride (345 mg, 1.311 mmol) and azetidine hydrochloride salt (123 mg, 1.311 mmol) in dichloromethane (12 mL) was added to a solution of 4-((3-bromo-2-methylbenzyl)oxy)benzaldehyde (200 mg, 0.655 mmol) in dichloromethane (12 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated sodium bicarbonate. The organic layer, was washed with saturated, aqueous sodium chloride and dried (Na.sub.2SO.sub.4). The crude residue was then purified by preparative HPLC using a methanol-H.sub.2O-TFA buffer system. Fractions were collected and concentrated using a speed-vac overnight to give 102 mg of a white solid. Analytical LC/MS was used to determine the final purity: Column: Phenomenex Luna 2.030 mm, Mobile Phase A: 10:90 methanol:water with 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 methanol:water with 10.1% trifluoroacetic acid; Gradient: 0% B, 0-100% B over 2 minutes; Flow: 1.0 mL/min. Retention time: 1.8 minutes, M.sup.+1: 348.

Example 4

(54) A solution of 1-(4-((3-bromo-2-methylbenzyl)oxy)benzyl)azetidine (330 mg, 880 mol) in dioxane (22 mL) was prepared. Next, a solution of cesium carbonate (568 mg, 1.8 mmol) in water (4.4 mL) was prepared. To 3-methoxyphenylboronic acid in a 2 mL microwave vials was added 1 mL of the (S)-2-((4-((3-bromo-2-methylbenzyl)oxy)benzyl)amino)propanoic acid solution, 200 L of the cesium carbonate solution and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, dichloromethane (3.56 mg, 4.33 mol). The vial was capped and heated on a Biotage Initiator (400 W) microwave for 10 min at 140 C. with 20 seconds of stirring and using a fixed hold time. The contents were transferred to 6-mL PL-Thiol SPE cartridges (conditioned with methanol). The reaction vial was rinsed with 500 L methanol each and the rinses were transferred to SPE cartridges. The product eluted with 4 mL methanol each collecting into 16100 mm culture tubes. Sample was dried in a Zymark tabletop dryer at 35 C. for 3 hours. Next, 1 mL DMF was added to each vial and purified by reverse phase HPLC: Column: Waters Xbridge C18, 19200 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. LC/MS Method M: 3.9 min., M.sup.+1: 374.4, Exact Mass: 373.2. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.44 (d, J=7.0 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.20 (d, J=5.5 Hz, 3H), 6.99 (d, J=8.2 Hz, 2H), 6.95 (d, J=8.5 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.84 (br. s., 1H), 5.11 (s, 2H), 3.79 (s, 3H), 3.49 (br. s., 2H), 3.14 (t, J=6.9 Hz, 4H), 2.19 (s, 3H), 2.02-1.95 (m, 2H).

(55) Examples 75, 92, and 93 were prepared according to the general procedure described in Example 4 except the appropriate amine was substituted for azetidine in the reductive amination step and an appropriate boronic acid was used in the palladium catalyzed coupling step.

Example 5

N-{2-[({3-bromo-2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide

(56) ##STR00061##

(57) Example 5 was prepared by bromination of Example 37: To a solution of potassium bromide (26.5 mg, 0.223 mmol) and bromine (14.25 mg, 0.089 mmol) in water was added N-(2-((2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)amino)ethyl)acetamide (20 mg, 0.045 mmol) at 0 C. The mixture was stirred at 0 C. for 2 hr and a yellow precipitate was formed. Water was added and the yellow precipitate was collected (19 mg). The crude material was purified via preparative LC/MS with the following conditions: Column: Waters Xbridge C18, 19200 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 30-70% B over 10 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 7.0 mg, and its estimated purity by LCMS analysis was 100%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.81 (br. s., 1H), 7.58 (d, J=7.6 Hz, 1H), 7.51-7.44 (m, 2H), 7.40 (d, J=7.0 Hz, 1H), 7.34-7.29 (m, 3H), 7.23 (d, J=7.6 Hz, 1H), 6.83 (s, 1H), 5.29 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71 (s, 2H), 3.14 (d, J=6.1 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.26 (s, 3H), 1.79 (s, 3H).

(58) Examples 8, 22, 29, 67 and 104 were prepared according to the general procedure described in Example 1 except 3-bromo-4-hydroxybenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(59) Examples 16, 30, 39, 49, 61 and 82 were prepared according to the general procedure described in Example 1 except 3-hydroxybenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(60) Examples 60 and 89 were prepared according to the general procedure described in Example 1 except 3-hydroxy-4-methylbenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(61) Examples 19, 20, 28, 40, 42-44, 51-59, 64, 72-74, 76, 77, 85, 86, 88, 90, 91, 94-97, 100 and 110 were prepared according to the general procedure described in Example 1 except 4-hydroxy-3-methylbenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(62) Example 27 was prepared according to the general procedure described in Example 1 except 4-hydroxy-2-methoxy-3-methylbenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde.

(63) Examples 38, 68, 81, 83 and 99 were prepared according to the general procedure described in Example 1 except 4-hydroxy-2-methoxybenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(64) Examples 41, 70 and 87 were prepared according to the general procedure described in Example 1 except 4-hydroxy-2,6-dimethylbenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(65) Examples 50 and 80 were prepared according to the general procedure described in Example 1 except 3-fluoro-4-hydroxybenzaldehyde was used instead of 4-hydroxy-2,6-dimethoxybenzaldehyde and an appropriate amine was used for reductive amination instead of piperidine-2-carboxylic acid.

(66) Examples 106, 107, and 108 were prepared according to the general procedure described in Example 4 except 4-hydroxy-2,6-dimethoxybenzaldehyde was used instead of 4-hydroxybenzaldehyde, alanine was substituted for azetidine in the reductive amination step and an appropriate boronic acid was used in the palladium catalyzed coupling step.

Example 45

N-{2-[(1-{3-chloro-4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}ethyl)amino]ethyl}acetamide

(67) ##STR00062##

Intermediate 45A: 1-(3-chloro-4-((2-methylbiphenyl-3-yl)methoxy)phenyl)ethanone

(68) ##STR00063##

(69) Intermediate 45A was prepared from 1-(3-chloro-4-hydroxyphenyl)ethanone and Intermediate 1A according to the general procedure described to prepare Intermediate 1B.

Example 45

(70) To a solution of 1-(3-chloro-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)phenyl) ethanone (20 mg, 0.057 mmol) in THF (2 mL) was added N-acetylethylenediamine (12.94 mg, 0.114 mmol) and tetra-tert-butyl orthotitanate (0.050 mL, 0.143 mmol). The resulting white mixture was heated at 85 C. in a microwave for 1 hour. Additional tetra-tert-butyl orthotitanate (0.050 mL, 0.143 mmol) was added and heated at 100 C. for 1 hour. Sodium borohydride (6.47 mg, 0.171 mmol) was added followed by ethanol (2 mL). The mixture was stirred at room temperature for 2 hrs. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters Xbridge C18, 19200 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 10-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.6 mg, and its estimated purity by LCMS analysis was 98%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.77 (br. s., 1H), 7.51 (d, J=7.3 Hz, 1H), 7.49-7.43 (m, 2H), 7.43-7.35 (m, 2H), 7.35-7.24 (m, 5H), 7.21 (d, J=7.6 Hz, 1H), 5.22 (s, 2H), 3.66 (d, J=6.4 Hz, 1H), 3.14-2.99 (m, 2H), 2.42-2.28 (m, 2H), 2.23 (s, 3H), 1.77 (s, 3H), 1.26-1.18 (m, 3H).

(71) Example 71 was prepared according to the general procedure described in Example 45 except 1-(4-hydroxy-3-methylphenyl)ethanone was used instead of 1-(3-chloro-4-hydroxyphenyl)ethanone.

(72) Example 62 was prepared according to the general procedure described in Example 45 except 5-hydroxy-3,4-dihydronaphthalen-1(2H)-one was used instead of 1-(3-chloro-4-hydroxyphenyl)ethanone.

(73) Example 63 was prepared according to the general procedure described in Example 45 except 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one was used instead of 1-(3-chloro-4-hydroxyphenyl)ethanone.

(74) Example 109 was prepared according to the general procedure described in Example 45 except 1-amino-2,3-dihydro-1H-inden-4-ol was used instead of 1-(3-chloro-4-hydroxyphenyl)ethanone.

Example 112

(2S)-1-[(4-{[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy}-3-(trifluoromethyl)phenyl)methyl]piperidine-2-carboxylic acid

(75) ##STR00064##

(76) Intermediate 112A: (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol

(77) ##STR00065##

(78) (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid (0.537 g, 2.98 mmol), (3-bromo-2-methylphenyl)methanol (0.5 g, 2.487 mmol) and 2nd Generation XPhos precatalyst (0.059 g, 0.075 mmol) was covered with THF (24 ml) and degassed. Potassium phosphate, tribasic (12.43 ml, 6.22 mmol) added as an 0.5 M aqueous solution. The reaction was stirred at room temperature sealed under argon overnight. The solvent was removed by rotary evaporation. The residue was purified using 3:1 hexanes:ethyl acetate on a 24 g silica gel column. The fractions containing the desired product provided 0.59 g of the title compound as a colorless oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.39 (d, J=7.3 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.22-7.18 (m, 1H), 6.92 (d, J=8.1 Hz, 1H), 6.83 (d, J=1.7 Hz, 1H), 6.78 (dd, J=8.2, 1.8 Hz, 1H), 4.79 (d, J=5.9 Hz, 2H), 4.33 (s, 4H), 2.28 (s, 3H).

Intermediate 112B: 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-3-(trifluoromethyl)benzaldehyde

(79) ##STR00066##

(80) Combined 4-hydroxy-3-(trifluoromethyl)benzaldehyde (35.9 mg, 0.189 mmol), triphenylphosphine (49.5 mg, 0.189 mmol) and (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (44 mg, 0.172 mmol) in dry THF (1 ml). Cooled to 0 C. Diisopropyl azodicarboxylate (0.037 ml, 0.189 mmol) in THF (1 ml) was added dropwise. The resulting yellow solution was allowed to slowly warm to room temperature while stirring overnight. Solvent was removed by rotary evaporator. The crude residue was purified with 5:1 hexanes:ethyl acetate on a 24 g silica gel column. Combined fractions to afford 0.046 g of the desired product as light yellow solid.

Example 112

(81) A DMF (1.5 mL) solution of 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-3-(trifluoromethyl)benzaldehyde (15 mg, 0.035 mmol) was stirred (S)-piperidine-2-carboxylic acid (13.57 mg, 0.105 mmol) at room temperature for 1 hour. Sodium cyanoborohydride (6.60 mg, 0.105 mmol) and 3 drops of acetic acid (2.004 l, 0.035 mmol) were added. The reaction was stirred at room temperature overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 14.3 mg, and its estimated purity by LCMS analysis was 100%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.67-7.55 (m, 2H), 7.52-7.37 (m, 2H), 7.27 (t, J=7.5 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.79-6.73 (m, 2H), 5.28 (s, 2H), 4.29 (s, 4H), 3.87 (d, J=13.2 Hz, 1H), 3.51 (d, J=13.6 Hz, 3H), 2.86 (br. s., 1H), 2.26-2.22 (m, 1H), 2.21 (s, 3H), 1.80 (br. s., 1H), 1.70 (d, J=9.2 Hz, 1H), 1.50 (d, J=18.7 Hz, 3H), 1.37 (br. s., 1H).

(82) Example 113 were prepared according to the general procedure described in Example 112 except N-(2-aminoethyl)acetamide was used for reductive amination instead of piperidine-2-carboxylic acid.

(83) Example 114 were prepared according to the general procedure described in Example 112 except (S)-4-amino-3-hydroxybutanoic acid was used for reductive amination instead of piperidine-2-carboxylic acid.

Example 118

2-[({5-[(2-methyl-3-phenylphenyl)methoxy]thiophen-2-yl}methyl)amino]ethan-1-ol

(84) ##STR00067##

(85) In a 8 mL clear vial, (2-methyl-[1,1-biphenyl]-3-yl)methanol (50 mg, 0.252 mmol), cesium carbonate (123 mg, 0.378 mmol), 2-(Di-t-butylphosphino)-3-methoxy-6-methyl-2-4-6-tri-i-propyl-1,1-biphenyl (7.09 mg, 0.015 mmol), 4A molecular sieves (50 mg) and toluene (0.4 mL) were combined. The reaction mixture was degassed with argon gas. 5-chlorothiophene-2-carbaldehyde (55.5 mg, 0.378 mmol, Cole, Andrew G.; Letourneau, Jeffrey John; Ho, Koc-Kan WO 2010059922 A1) and allylpalladium(ii) chloride dimer (2.77 mg, 7.57 mol) were added. Then reaction mixture was heated at 90 C. for 24 hrs. The reaction mixture was diluted with ethylacetate, filtered through celite and concentrated. The residue was purified using a gradient of 0 to 15% ethylacetate in petroleum ether on a 4 gm silica gel column. The fractions containing the product were combined and concentration to give the desired aldehyde (0.039 g). Example 118 was prepared from this aldehyde and 2-amino ethanol according to the reductive amination conditions as described for Example 1.

Example 119

2-[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]ethan-1-ol

(86) ##STR00068##

Intermediate 119A: 2-methyl-5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine

(87) ##STR00069##

(88) To a solution of 6-methylpyridin-3-ol (0.209 g, 1.915 mmol) and cesium carbonate (1.248 g, 3.83 mmol) in DMF (5 mL) was added 3-(bromomethyl)-2-methyl-1,1-biphenyl (0.5 g, 1.915 mmol) and the reaction mixture was stirred at room temperature for 3 hours. TLC analysis with 40% ethyl acetate in petroleum ether showed that the starting material was consumed. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (250 ml). The combined organic extracts were washed with water (50 ml), saturated, aqueous sodium chloride (50 ml), dried over sodium sulphate and concentrated to give a crude residue (500 mg). The crude residue was purified with a gradient of 25-30% ethyl acetate in petroleum ether on a 12 gram silica gel column to proved the desired compound (0.365 g, 65%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.25 (s, 1H), 7.50-7.30 (m, 5H), 7.30-7.25 (m, 3H), 7.18 (d, J=7.6 Hz, 2H), 5.19 (s, 2H), 2.40 (s, 3H), 2.19 (s, 3H).

Intermediate 119B: 2-methyl-5-((2-methyl-[1,1-biphenyl]3-yl)methoxy)pyridine 1-oxide

(89) ##STR00070##

(90) To a solution of 2-methyl-5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine (365 mg, 1.261 mmol) and sodium bicarbonate (318 mg, 3.78 mmol) in chloroform (8 mL) at 0 C. was added m-chloroperbenzoic acid (435 mg, 2.52 mmol). The reaction was allowed to warm to room temperature and then stirred at room temperature for 3 h during which time the reaction became a thick emulsion. TLC analysis with 50% ethyl acetate in petroleum ether showed that the starting material was consumed. To the reaction mixture water (20 ml) was added and extracted with dichloromethane (330 ml). The combined organic portions were washed with 10% sodium bicarbonate (40 ml), water (40 ml), saturated, aqueous sodium chloride (30 ml), dried over sodium sulphate and concentrated to get the crude which was used without purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (s, 1H), 7.45 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 7.29 (m, 3H), 7.20 (d, J=7.2 Hz, 1H), 7.20 (dd, J=8.8, 2.4 Hz, 1H), 5.20 (s, 2H), 2.28 (s, 3H), 2.19 (s, 3H).

Intermediate 119C: (5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridin-2-yl)methanol

(91) ##STR00071##

(92) A solution of 2-methyl-5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine 1-oxide (0.38 g, 1.244 mmol) in acetic anhydride (3 ml, 31.8 mmol) was heated to 100 C. for 30 minutes. TLC analysis with 50% Ethyl acetate in petroleum ether showed that the starting material was consumed to provide a higher rf compound consistent with the intermediate acetate. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (30 ml), water (30 ml), saturated, aqueous sodium chloride (30 ml), dried over sodium sulphate and concentrated to give the crude acetate (380 mg). The crude acetate (380 mg) was dissolved in methanol (20 mL) and potassium carbonate (0.602 g, 4.36 mmol) was added. The reaction mixture was stirred at room temperature overnight. TLC analysis with 50% ethyl acetate in petroleum ether showed that the acetate was consumed to provide a lower rf compound. The solvent was concentrated and the residue was dissolved in EtOAc (30 ml), washed with water (20 ml), saturated, aqueous sodium chloride (20 ml), dried over sodium sulphate and concentrated. The crude residue was purified with a gradient of 30% EtOAc in petroleum ether on a 4 gram silica gel column to isolate the desired product. .sup.1H NMR (300 MHz, DMSO-d.sub.6) 8.30 (s, 1H), 7.15-7.60 (m, 10H), 5.30 (t, J=7.6 Hz, 1H), 5.22 (s, 2H), 4.50 (d, J=7.6 Hz, 2H), 2.20 (s, 3H).

Intermediate 119D: 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)picolinaldehyde

(93) ##STR00072##

(94) To a solution of (5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridin-2-yl)methanol (190 mg, 0.622 mmol) in methanol (5 mL) at RT was added manganese dioxide (541 mg, 6.22 mmol) and the reaction mixture was stirred at room temperature for 4 hours. TLC analysis with 30% ethyl acetate in petroleum ether showed that the starting material was consumed. The reaction mixture was filtered through celite and the bed was washed with dichloromethane (50 ml). The filtrate was concentrated to give the crude product. The product (0.13 g, 67%) was isolated chromatography on a 4 gram silica gel column using 10-12% ethyl acetate in petroleum ether. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.90 (s, 1H, CHO), 8.6 (s, 1H), 7.97 (d, J=8.8 Hz, 1H), 7.74 (dd, J=8.4, 2.8 Hz, 1H), 7.50-7.40 (m, 3H), 7.39 (m, 1H), 7.36 (m, 3H), 7.23 (dd, J=7.6, 1.2 Hz, 1H), 5.38 (s, 2H), 2.21 (s, 3H).

(95) Example 119 was prepared from intermediate 119D, 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy) picolinaldehyde, and 2-amino ethanol according to the reductive amination conditions as described for Example 1.

(96) Example 120 was prepared from intermediate 119D, 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy) picolinaldehyde, and (1-aminocyclopentyl)methanol according to the reductive amination conditions as described for Example 1.

(97) Example 121 was prepared from intermediate 119D, 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy) picolinaldehyde, and methyl amine according to the reductive amination conditions as described for Example 1.

(98) Example 122 was prepared from intermediate 119D, 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy) picolinaldehyde, and 5-(aminomethyl)pyrrolidin-2-one according to the reductive amination conditions as described for Example 1.

Examples 123-161 and 295

(99) ##STR00073##

Intermediate 123A: 2-chloro-6-(hydroxymethyl)benzonitrile

(100) ##STR00074##

(101) To a 1000 ml single neck round-bottom flask was charged ethyl 3-chloro-2-cyanobenzoate (8.0 g, 38.2 mmol, Dean, David Kenneth; Munoz-Muriedas, Jorge; Sime, Mairi; Steadman, Jon Graham Anthony; Thewlis, Rachel Elizabeth Anne; Trani, Giancarlo; Walter, Daryl Simon WO 2010125102 A1) and tetrahydrofuran (390 mL). The mixture was stirred until a clear solution was obtained. The solution was cooled to 40 C. and lithium borohydride (1.663 g, 76 mmol) was added portion wise over 15 minutes. After all the lithium borohydride was added, the reaction was slowly brought to room temperature and stirred overnight. TLC analysis with 4:6 ethyl acetate:petroleum ether showed that the starting material was consumed. Saturated aqueous ammonium chloride was charged to a 2000 ml multineck round-bottom flask and cooled to 5 C. (inner temperature). Added crude reaction slowly over 15 minutes. After addition was complete the temperature was maintained at 5 C. for 20 minutes. The reaction was diluted with dichloromethane (500 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (1300 ml) and the combined organic portions were washed with 1.5 N aqueous hydrochloric acid (150 ml), saturated, aqueous sodium chloride (150 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow solid (7.0 g). The crude material was dissolved in minimum amount of dichloromethane and cooled in ice bath. Petroleum ether was added until white solid formed. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give the title compound (3.5 g). .sup.1H NMR (300 MHz, CDCl.sub.3) 7.55 (m, J=2.6 Hz, 2H), 4.99 (s, 2H), 2.14 (bs, 1H, OH).

Intermediate 123B: 3-(hydroxymethyl)-[1,1-biphenyl]-2-carbonitrile

(102) ##STR00075##

(103) To the solution of 2-chloro-6-(hydroxymethyl)benzonitrile, 123A, (2 g, 11.93 mmol) in THF (80 mL), was added phenylboronic acid (2.183 g, 17.90 mmol) and 2nd generation Xphos precatalyst (0.263 g, 0.334 mmol, CAS Number 1310584-14-5). Nitrogen was bubbled into the reaction for 5 minutes to purge oxygen. The reaction mixture was cooled to 0 C. and cold 0.5M potassium phosphate tribasic (47.9 mL, 23.94 mmol) in water was added into the reaction mixture and nitrogen purging was continued for 5 minutes. The reaction was stirred overnight at room temperature. TLC analysis with 1:1 ethyl acetate:petroleum ether showed that starting material was consumed. The reaction was diluted with 75 mL dichloromethane and the layers separated. The aqueous layer was extracted with 15 mL dichloromethane. The combined organic portions were washed with 20 mL saturated, aqueous sodium chloride solution, dried over sodium sulfate and evaporated under vacuum at 40 C. to give the crude product. The residue was purified on a 120 gram silica gel column using petroleum ether and ethyl acetate as eluent. The product was eluted at 10% ethyl acetate in petroleum ether. The collected fractions were evaporated to get the product as an off-white solid (1.82 g)

(104) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.60-7.70 (m, 2H), 7.40-7.55 (m, 6H), 4.99 (d, J=6.0 Hz, 2H), 2.13 (t, J=6.0, 1H, OH).

Intermediate 123C: 3-((4-formyl-3,5-dimethoxyphenoxy)methyl)-[1,1-biphenyl]-2-carbonitrile

(105) ##STR00076##

(106) To a solution of 3-(hydroxymethyl)-[1,1-biphenyl]-2-carbonitrile, 123B, (300 mg, 1.434 mmol) in tetrahydrofuran (10 mL) was added 4-hydroxy-2,6-dimethoxybenzaldehyde (261 mg, 1.434 mmol) and triphenylphosphine (489 mg, 1.864 mmol) under a nitrogen atmosphere. The reaction mixture appeared brown and cloudy. Cooled to 0 C. and then added a solution of diisopropyl azodicarboxylate (0.367 mL, 1.864 mmol) in 1 ml THF. Stirred the reaction overnight at room temperature. TLC analysis showed no product formation. Added tetrahydrofuran (10 mL), triphenylphosphine (489 mg, 1.864 mmol) and diisopropyl azodicarboxylate (0.367 mL, 1.864 mmol) at room temperature. The reaction mixture became clear solution. Stirred for 3 hours at room temperature. The solvent was evaporated under vacuum and the residue was purified by on a 40 gram silica gel column using petroleum ether and ethyl acetate as eluent. The product was eluted at 40%-45% ethyl acetate. The product was eluted as mixture along with the polar triphenyl phosphine oxide impurity. The collected fractions were evaporated to get the compound as an off white solid (500 mg). The 500 mg compound was slurried in 5 ml isopropyl alcohol and stirred for 30 minutes. The solids were collected by filtration, washed with 2.5 ml isopropyl alcohol and dried for 2 hours under vacuum to give the title compound (180 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.23 (s, 1H, CHO), 7.80 (m, 2H), 7.65 (dd, J=1.2, 7.6 Hz, 1H), 7.60 (m, 5H), 6.44 (s, 2H), 5.45 (s, 2H), 3.84 (s, 6H).

(107) Examples 123-161 and 295 were prepared from intermediate 123C 3-((4-formyl-3,5-dimethoxyphenoxy)methyl)-[1,1-biphenyl]-2-carbonitrile according to the reductive amination conditions as described for Example 1 using the appropriate amine to obtain the desired product.

Example 190

N1-(2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)-N1-methylethane-1,2-diamine

(108) ##STR00077##

Intermediate 190A: tert-butyl (2-((2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)(methyl)amino)ethyl)carbamate

(109) ##STR00078##

(110) Combined tert-butyl (2-(methylamino)ethyl)carbamate (0.348 g, 2.000 mmol), sodium triacetoxyborohydride (0.636 g, 3.00 mmol) and 2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzaldehyde (0.362 g, 1 mmol) in DMF (5 ml). Stirred at room temperature overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 600 mg, and its estimated purity by LCMS analysis was 100%. LC\MS Method A: 2.2 minutes, M.sup.+1=521.6, EM=520.3. LC\MS Method M: 3.1 minutes, M.sup.+1=521.6, EM=520.3. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.44 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.28 (m, 3H), 7.21 (d, J=7.0 Hz, 1H), 6.45-6.25 (m, 3H), 5.17 (s, 2H), 3.82-3.73 (m, 6H), 3.41 (br. s., 2H), 3.06 (d, J=5.8 Hz, 2H), 2.38 (br. s., 2H), 2.28-2.18 (m, 3H), 2.07 (s, 3H), 1.43-1.34 (m, 9H).

Example 191

(111) Dissolved Intermediate 191A tert-butyl (2-((2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)(methyl)amino)ethyl)carbamate (0.6 g, 1.15 mmol) in 5 mL of 0.5N hydrochloric acid in diethyl ether. Stirred at room temperature for 1 hour. Diluted with ether and bubbled nitrogen through reaction for 10 minutes. The solvent was removed by rotary evaporation. The residue was place under vacuum overnight.

(112) Chromatographed by reverse phase HPLC using the following conditions. Start % B=5 to Final % B=100, Gradient time=10 minutes, Flow Rate=40 mL/minute, Wavelength=220 nm, Solvent A=10% methanol, 90% water with 0.1% TFA, Solvent B=90% methanol, 10% water with 0.1% TFA, Column=Phenomenex-Luna 3050 mm S10.

(113) The major peak at 8.6 minutes was consistent with desired product. Fractions containing the desired product were combined and dried via centrifugal evaporation to the title compound as the bis trifluoro acetic acid salt (0.61 g, 82%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.47-7.41 (m, 3H), 7.38 (d, J=7.1 Hz, 1H), 7.33 (d, J=6.8 Hz, 2H), 7.30 (d, J=3.2 Hz, 1H), 6.28 (s, 2H), 5.48 (br. s., 4H), 5.12 (s, 2H), 4.29 (q, J=13.0 Hz, 2H), 3.92-3.77 (m, 6H), 3.70-3.39 (m, 5H), 2.86-2.73 (m, 3H), 2.29 (s, 3H). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.44 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.22 (d, J=7.6 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.77 (s, 6H), 3.40 (s, 2H), 2.74 (br. s., 2H), 2.45-2.38 (m, 2H), 2.25-2.19 (m, 3H), 2.07 (s, 3H).

Example 191

1-(2-((2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)(methyl)amino)ethyl)-3-phenylurea

(114) ##STR00079##

(115) Charged isocyanatobenzene (0.012 g, 0.100 mmol) in dichloromethane (0.5 mL) to a 5 mL reaction vial. Added a solution of Example 190, N1-(2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)-N1-methylethane-1,2-diamine, 2 TFA (0.032 g, 0.05 mmol) and Hunig's Base (0.027 mL, 0.155 mmol) in dichloromethane (0.5 mL). Stirred at room temperature overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over 25 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 5.9 mg, and its estimated purity by LCMS analysis was 99%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.82 (br. s., 1H), 7.55-7.45 (m, 3H), 7.39 (d, J=7.3 Hz, 3H), 7.37-7.28 (m, 3H), 7.25-7.16 (m, 3H), 6.88 (t, J=7.2 Hz, 1H), 6.38 (s, 2H), 6.05 (br. s., 1H), 5.18 (s, 2H), 3.76 (s, 6H), 3.47 (br. s., 2H), 3.23 (d, J=5.2 Hz, 2H), 2.48-2.42 (m, 2H), 2.24 (s, 3H), 2.13 (s, 3H).

Example 192

N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}-2-oxo-2H-chromene-6-sulfonamide

(116) ##STR00080##

(117) Charged 2-oxo-2H-chromene-6-sulfonyl chloride (0.024 g, 0.100 mmol) to a 5 mL reaction vial. Added a solution of Example 190, N1-(2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)-N1-methylethane-1,2-diamine, 2 TFA (0.032 g, 0.05 mmol) and Hunig's Base (0.027 mL, 0.155 mmol) in dichloromethane (0.5 mL). Stirred at room temperature 30 minutes. Reaction check by LCMS showed mostly desired product. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.3 mg, and its estimated purity by LCMS analysis was 97%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.25 (s, 1H), 8.20 (d, J=9.8 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.53-7.45 (m, 3H), 7.43-7.37 (m, 1H), 7.36-7.27 (m, 3H), 7.22 (d, J=7.3 Hz, 1H), 6.63 (d, J=9.8 Hz, 1H), 6.36 (s, 2H), 5.17 (s, 2H), 3.73 (s, 6H), 3.36 (s, 2H), 2.91 (t, J=6.7 Hz, 2H), 2.35 (t, J=6.9 Hz, 2H), 2.23 (s, 3H), 1.99 (s, 3H).

Example 193

N-{2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}prop-2-enamide

(118) ##STR00081##

(119) Example 190, N1-(2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)-N1-methylethane-1,2-diamine (0.021 g, 0.05 mmol), was combined with Hunig's Base (0.026 mL, 0.150 mmol) and acryloyl chloride (0.014 g, 0.150 mmol) in Dichloromethane (1 mL). After 1 hour, LC/MS showed desired product. Added methanol and removed solvent under a stream of air. Redissolved in methanol and filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-70% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 19.2 mg, and its estimated purity by LCMS analysis was 98%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.91-7.86 (m, 1H), 7.47 (s, 3H), 7.42-7.37 (m, 1H), 7.33 (d, J=7.9 Hz, 3H), 7.24-7.19 (m, 1H), 6.37 (s, 2H), 6.27-6.16 (m, 1H), 6.13-5.97 (m, 1H), 5.61-5.52 (m, 1H), 5.17 (s, 2H), 3.75 (s, 6H), 3.30-3.22 (m, 2H), 2.44-2.37 (m, 2H), 2.23 (s, 3H), 2.10 (s, 3H).

Example 194

Ethyl (2E)-3-({2-[({2,6-dimethoxy-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)(methyl)amino]ethyl}carbamoyl)prop-2-enoate

(120) ##STR00082##

(121) Combined Example 190 N1-(2,6-dimethoxy-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzyl)-N1-methylethane-1,2-diamine (0.021 g, 0.05 mmol), Hunig's Base (0.026 mL, 0.150 mmol) and (E)-ethyl 4-chloro-4-oxobut-2-enoate (0.024 g, 0.150 mmol) in dichloromethane (1 mL). After 30 minutes, reaction check by LC/MS showed desired product. Added methanol and removed solvent under a stream of air. Redissolved in methanol and filtered. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 17.8 mg, and its estimated purity by LCMS analysis was 97%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.40 (br. s., 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J=7.3 Hz, 1H), 7.02 (d, J=15.3 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.37 (s, 2H), 5.16 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.75 (s, 6H), 3.30 (d, J=5.8 Hz, 2H), 2.43 (t, J=6.6 Hz, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).

Example 198

N-{2-[({3-cyano-4-[(2-methyl-3-phenylphenyl)methoxy]phenyl}methyl)amino]ethyl}acetamide

(122) ##STR00083##

Intermediate 198A: 3-bromo-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzaldehyde

(123) ##STR00084##

(124) To a cooled (0 C.) solution of 3-bromo-4-hydroxybenzaldehyde (101 mg, 0.5 mmol), triphenylphosphine (146 mg, 0.555 mmol) and (2-methyl-[1,1-biphenyl]-3-yl)methanol (100 mg, 0.504 mmol) in dry THF (3 mL) was added dropwise of diisopropyl azodicarboxylate (0.108 mL, 0.555 mmol) in THF (3 mL). The resulting yellow solution was allowed to slowly warm to room temperature while stirring overnight. Excess solvent was evaporated by rotary evaporation. The crude residue was dissolved in methanol and purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19200 mm, 5-m particles; Guard Column: Waters XBridge C18, 1910 mm, 5-m particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 20-mM ammonium acetate; Gradient: 30-100% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 106.9 mg, and its estimated purity by LCMS analysis was 100%. LC/MS Method A: 3.1 minutes, M.sup.+1=381.0, EM=380.0.

Example 198

(125) Combined copper(i) cyanide (18 mg, 0.201 mmol) and 3-bromo-4-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)benzaldehyde (50 mg, 0.131 mmol) in DMF (1311 l) under argon. Sealed and heated at 120 C. for 72 hours. Filtered and combined the solution directly with sodium triacetoxyhydroborate (84 mg, 0.394 mmol) and N-(2-aminoethyl)acetamide (26.8 mg, 0.263 mmol) in DMF (657 l). Stirred at room temperature overnight and filtered through a 0.45 m PVDF Whatman syringe filter. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 16.1 mg, and its estimated purity by LCMS analysis was 91%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.80 (br. s., 1H), 7.69 (s, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.53-7.44 (m, 3H), 7.42-7.36 (m, 2H), 7.34-7.28 (m, 3H), 7.23 (d, J=7.7 Hz, 1H), 5.33 (s, 2H), 3.66 (s, 2H), 3.38 (d, J=11.7 Hz, 2H), 3.18-3.06 (m, 2H), 2.23 (s, 3H), 1.79 (s, 3H).

Example 199

N-(2-((4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2,5-difluorobenzyl)amino)ethyl)acetamide

(126) ##STR00085##

Intermediate 199A 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2,5-difluorobenzaldehyde

(127) ##STR00086##

(128) Combined 2,5-difluoro-4-hydroxybenzaldehyde (204 mg, 1.288 mmol), triphenylphosphine (338 mg, 1.288 mmol) and (3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)methanol (300 mg, 1.171 mmol) in dry THF (5853 l) and cooled on an ice/water bath. Added diisopropyl azodicarboxylate (250 l, 1.288 mmol) in THF (5853 l) dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring over the weekend. The major peak did not have the product mass by LCMS. Excess solvent was evaporated by rotary evaporator. Chromatographed on a 40 g silica gel column with 0-30% ethyl acetate in hexanes over 20 column volumes to give 340 mg of a white solid. In CDCl.sub.3 some of the aromatic peaks were missing and most likely hidden by residual chloroform. NMR in DMSO confirmed the structure. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.09 (d, J=2.2 Hz, 1H), 7.66 (dd, J=10.9, 6.5 Hz, 1H), 7.57 (dd, J=12.2, 6.6 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.32-7.25 (m, 1H), 7.24-7.19 (m, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.79 (s, 1H), 6.78-6.74 (m, 1H), 5.37 (s, 2H), 4.29 (s, 4H), 2.22 (s, 3H).

Example 199

(129) A mixture of N-(2-aminoethyl)acetamide (12.37 mg, 0.121 mmol) and 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2,5-difluorobenzaldehyde (40 mg, 0.101 mmol) were combined in dichloroethane (505 l). The solids did not dissolve. Sodium triacetoxyborohydride (42.8 mg, 0.202 mmol) was added and the mixture stirred at room temperature overnight. Most solids had dissolved. LCMS suggested 1:1:5:2 mixture of product:imine:starting material:dialkylation. Added 10 equivalents of N-(2-aminoethyl)acetamide (100 mg, 1 mmol) and sodium cyano borohydride and stirred for 2 hours. LCMS showed only desired product: The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 30-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 29.6 mg, and its estimated purity by LCMS analysis was 96%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.79 (br. s., 1H), 7.42 (d, J=7.7 Hz, 1H), 7.36-7.23 (m, 3H), 7.19 (d, J=7.0 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.78 (s, 1H), 6.76 (d, J=8.1 Hz, 1H), 5.21 (s, 2H), 4.29 (s, 4H), 3.12 (q, J=6.1 Hz, 2H), 2.21 (s, 3H), 1.92 (br. s., 2H), 1.82-1.74 (m, 3H). 2 missing hydrogens are assumed to be under the DMSO or water peaks.

(130) Example 200 was prepared from intermediate 199A, 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2,5-difluorobenzaldehyde, and (S)-4-amino-3-hydroxybutanoic acid according to the reductive amination conditions as described for Example 1.

(131) Example 201 was prepared from intermediate 199A, 4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)-2,5-difluorobenzaldehyde, and (S)-piperidine-2-carboxylic acid according to the reductive amination conditions as described for Example 1.

Example 202

N-{2-[({2-methoxy-6-[(2-methyl-3-phenylphenyl)methoxy]pyridin-3-yl}methyl)amino]ethyl}acetamide

(132) ##STR00087##

Intermediate 202A: 2-methoxy-6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy) nicotinaldehyde

(133) ##STR00088##

(134) Cesium carbonate (223 mg, 0.683 mmol), palladium(ii) acetate (7.67 mg, 0.034 mmol), 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl(t-butyl Xphos) (29 mg, 0.068 mmol), 6-chloro-2-methoxynicotinaldehyde (58.6 mg, 0.341 mmol), and (2-methyl-[1,1-biphenyl]-3-yl)methanol (88 mg, 0.444 mmol) were combined in a 25 mL round-bottom flask equipped with a stir bar. Toluene (2 mL) was added and the mixture purged with a stream of argon for 5 minutes. The reaction was sealed and heated at 80 C. overnight. LC/MS showed 11 peaks of similar intensities. Peaks at 4 minutes had an M+1 of 334 consistent with desired product. The soluble portion of the crude reaction was charged to a 25 g silica gel column with dichloromethane. Chromatographed with 0-60% ethyl acetate in hexanes. A fraction containing at least 2 compounds tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction was isolated and used without further purification.

Example 202

(135) Combined sodium cyanoborohydride (20 mg, 0.318 mmol), N-(2-aminoethyl)acetamide (25 mg, 0.245 mmol), and crude 2-methoxy-6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)nicotinaldehyde (20 mg, 0.060 mmol) in DMF (2 mL) and acetic acid (0.100 mL) at 1:00 pm. Stirred at room temperature overnight. LC/MS showed product: 3.5 minutes, M+1=420.3, EM=419.2. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 35-75% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 11.0 mg, and its estimated purity by LCMS analysis was 96%. .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.80 (br. s., 1H), 7.62 (d, J=8.1 Hz, 1H), 7.48-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.31 (d, J=7.3 Hz, 2H), 7.26 (t, J=7.5 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H), 6.42 (d, J=7.7 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.58 (s, 1H), 3.18-3.05 (m, 2H), 2.22 (s, 3H), 1.82-1.72 (m, 3H). The methylenes of the diamino acetamide were assumed to be under the DMSO peak at 2.5 ppm.

Examples 203 Through 226

(136) ##STR00089##

Intermediate 203A: 5-bromo-2-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine

(137) ##STR00090##

(138) A mixture of 2,5-dibromopyridine (5 g, 21.11 mmol), (2-methyl-[1,1-biphenyl]-3-yl)methanol (5.44 g, 27.4 mmol), dibenzo-18-crown-6 (0.380 g, 1.055 mmol), potassium hydroxide (2.84 g, 50.7 mmol) and toluene (50 mL) was stirred at reflux with a Dean-Stark trap (pre-filled with toluene). After 1.5 hours, the heat was removed. TLC analysis showed that starting material was consumed. LC/MS consistent with crude desired product. The solvents were removed under reduced pressure by rotary evaporation. Water (50 mL) was added and the product extracted into dichloroethane (350 mL). The combined organic portion was dried over magnesium sulfate and filtered. The solvents were removed under reduced pressure by rotary evaporation to give 9.7 grams of a yellow oil. LC/MS was consistent with crude desired product. The yellow oil became an off-white solid on standing. Chromatographed on a 330 g silica gel column with 0-20% ethyl acetate in hexanes to give the product (6.3 g, 84%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.34 (dd, J=2.8, 0.5 Hz, 1H), 7.95 (dd, J=8.8, 2.5 Hz, 1H), 7.50-7.43 (m, 3H), 7.42-7.37 (m, 1H), 7.34-7.31 (m, 2H), 7.28 (t, J=7.5 Hz, 1H), 7.23-7.18 (m, 1H), 6.95 (dd, J=8.8, 0.5 Hz, 1H), 5.41 (s, 2H), 2.20 (s, 3H).

Intermediate 203B: 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)nicotinaldehyde

(139) ##STR00091##

(140) N-butyllithium (1.140 mL, 2.96 mmol) (2.6M in toluene) was added to a THF (10 mL) solution of 5-bromo-2-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine (1.0 g, 2.82 mmol) at 78 C. The reaction was stirred for 1 hr before adding DMF (0.437 mL, 5.65 mmol). After 30 minutes, the reaction was warmed to room temperature. LC/MS was consistent with the presence of the desired product. The reaction was poured into 20 mL of 5% aqueous sodium bicarbonate and extracted with diethyl ether (320 mL). The combined organics were dried over magnesium sulphate and filtered. The solvents were removed under reduced pressure by rotary evaporation to provide 840 mg of a yellow solid. This compound was used without further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.99 (s, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.16 (dd, J=8.6, 2.4 Hz, 1H), 7.53-7.16 (m, 8H), 7.09 (d, J=8.6 Hz, 1H), 5.55 (s, 2H), 2.24-2.16 (m, 3H).

(141) Examples 203-226 were prepared from Intermediate 203B 6-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)nicotinaldehyde according to the reductive amination conditions as described for Example 1 using the appropriate amine to obtain the desired product.

Example 227

(2R)-2-{[(4-{[3-(3-fluoro-5-methoxyphenyl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid

(142) ##STR00092##

Intermediate 227A: (R)-methyl 2-((4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzyl)amino)propanoate

(143) ##STR00093##

(144) A solution of 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde (1.15 g, 3.15 mmol) in dichloroethane (50 mL) was combined with D-alanine methyl ester hydrochloride (1.319 g, 9.45 mmol) and sodium triacetoxyborohydride (2.002 g, 9.45 mmol). The reaction was heated at 85 C. for 3 hours. The crude was concentrated, redissolved in ethyl acetate and washed with water, brine and dried over magnesium sulfate. The solvent was removed and the crude product was used directly in the next step without purification.

Intermediate 227B: 5-bromo-2-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)pyridine

(145) ##STR00094##

(146) Aqueous sodium hydroxide (1N) (3.15 mL, 3.15 mmol) was added to a THF (20 mL) and methanol (20 mL) solution of intermediate 227A (R)-methyl 2-((4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzyl)amino)propanoate (1.425 g, 3.15 mmol). The mixture was stirred at room temperature overnight. The solvent was removed to afford a light yellow solid. Purified by preparative HPLC to afford reddish, light-brown solid (1.2 g).

Example 227

(147) Intermediate 227B, (S)-2-(((3-bromo-3,5-dimethoxy-2-methyl-[1,1-biphenyl]-4-yl)methyl)amino)propanoic acid (714 mg, 1.8 mmol) was dissolved in dioxane (35 mL). Cesium carbonate (1.7 gm, 5.3 mmol) was dissolved in water (3.5 mL). (3-Fluoro-5-methoxyphenyl)boronic acid (18 mg, 0.1 mmol) was weighed into 0.5-2 mL microwave vial. (S)-2-(((3-bromo-3,5-dimethoxy-2-methyl-[1,1-biphenyl]-4-yl)methyl)amino)propanoic acid solution (1 mL, 0.052 mmol), 100 L of the cesium carbonate solution and 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.25 mg, 0.0052 mmol). The reaction was heated in a Biotage Initiator (400 W) microwave for 15 minutes at 150 C. with 20 seconds of prestirring and using a fixed hold time. Transferred contents to 6 mL MP-Thiol SPE cartridges (conditioned with methanol). Rinsed reaction vials 2500 L methanol, transferring rinses to the SPE cartridge. Eluted products with 4 mL methanol. Samples were blown down in the Zymark tabletop dryer at 40 C. for 1 hour. Added 1 mL DMF to each vial. Transferred contents to 1648 mm threaded vials. Rinsed culture tubes with 500 L DMF each. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 10-100% B over 18 minutes, then a 7-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 8.1 mg, and its estimated purity by LCMS analysis was 100%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.24 (d, J=7.9 Hz, 1H), 6.86 (d, J=11.3 Hz, 1H), 6.76-6.68 (m, 2H), 6.44 (s, 2H), 5.20 (s, 2H), 3.97 (br. s., 2H), 3.82 (d, J=3.7 Hz, 9H), 3.05 (d, J=6.7 Hz, 1H), 2.23 (s, 3H), 1.27 (d, J=6.7 Hz, 3H).

(148) Example 228, (2R)-2-{[(4-{[3-(2H-1,3-benzodioxol-5-yl)-2-methylphenyl]methoxy}-2,6-dimethoxyphenyl)methyl]amino}propanoic acid, was prepared from Intermediate 227B, (S)-2-(((3-bromo-3,5-dimethoxy-2-methyl-[1,1-biphenyl]-4-yl)methyl)amino)propanoic acid and benzo[d][1,3]dioxol-5-ylboronic acid using the same reaction conditions employed for the synthesis of Example 227.

Example 229

3-[3-(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxymethyl)-2-methylphenyl]phenol

(149) ##STR00095##

Intermediate 229A: 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde

(150) ##STR00096##

(151) A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (3.99 g, 21.88 mmol), triphenylphosphine (6 g, 22.88 mmol) and (3-bromo-2-methylphenyl)methanol (4 g, 19.89 mmol) in dry THF (50 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate (4.25 mL, 21.88 mmol) in THF (50 mL) was added dropwise. The resulting yellow solution was allowed to slowly warm to room temperature with stirring overnight. Excess solvent was removed by rotary evaporator. The crude product was purified by chromatography on a 360 g silica gel cartridge eluting with ethyl acetate in hexanes. Fractions containing the desired product were combined and the solvent removed under vacuum to give the title compound (4.0 g, 55%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 10.39 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.18 (s, 2H), 5.13 (s, 2H), 3.91 (s, 6H), 2.49 (s, 3H).

Example 229

(152) A solution of 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde (310 mg, 850 mol) in DCE (8.5 mL) was prepared. Separately, a solution of 2-aminoethanol (77 uL, 1.3 mmol) in DCE (7.5 mL) was prepared. A 0.5 mL aliquot of each solution was charged to a reaction vial. Acetic acid (2.86 l, 50.0 mol) was added to the vial, capped and allowed to shake at 40 C. for 1 hr. The solvent was removed in a Zymark tabletop dryer at 40 C. for 1 hour. Toluene (0.5 mL) was added and the solvent was removed in a Zymark tabletop dryer at 40 C. for 1 hour. A solution of tetramethylammonium triacetoxyborohydride (672 mg, 2.6 mmol) in DCE (17 mL) was prepared and 1 mL was added to the reaction. The reaction was capped and allowed to shake at room temperature overnight. The contents were transferred to a 6-mL PL-SO3H SPE cartridge (conditioned with methanol). The reaction vial was rinsed with 500 L methanol and the rinse transferred to the SPE cartridge. The cartridge was washed with 4 mL methanol. The product was eluted with 4 mL 1N ammonia in methanol The solvent was removed in a Zymark tabletop dryer at 35 C. for 1 hour. The residue was dissolved in dioxane (1 mL) and transferred to a vial containing (3-hydroxyphenyl)boronic acid (13.8 mg, 0.1 mmol). A solution (0.1 mL) of the cesium carbonate (831 mg, 2.6 mmol) in water (1.7 mL) and solid 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.08 mg, 0.005 mmol) were added. The reaction was heated overnight at 100 C. with stirring. The reaction contents were transferred to a 6-mL PL-Thiol SPE cartridges (conditioned with methanol). The reaction vial was rinsed with methanol (0.5 mL) and the rinse added to the SPE cartridges. The product was eluted with 4 mL methanol. The solvent was removed in a Zymark tabletop dryer at 35 C. for 2 hour. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19mm, 5-m particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-90% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 2.4 mg, and its estimated purity by LCMS analysis was 96%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.47 (d, J=7.3 Hz, 1H), 7.30-7.22 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.68 (br. s., 1H), 6.38 (s, 2H), 5.16 (s, 2H), 3.91 (s, 1H), 3.78 (s, 6H), 3.67 (br. s., 2H), 3.47-3.43 (m, 2H), 2.56-2.53 (m, 2H), 2.22 (s, 3H).

(153) Examples 230, 231, 232 and 245 were prepared from 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde and 2-aminoethanol using the same procedure outlined for Example 229 except the appropriate boronic acid was substituted for (3-hydroxyphenyl)boronic acid to obtain the desired product.

(154) Examples 285, 286, 287 and 289 were prepared from 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde and N-(2-aminoethyl)acetamide using the same procedure outlined for Example 229 except the appropriate boronic acid was substituted for (3-hydroxyphenyl)boronic acid to obtain the desired product.

(155) Examples 288, 290, 291, 292, 293 and 294 were prepared from 4-((3-bromo-2-methylbenzyl)oxy)-2,6-dimethoxybenzaldehyde and 2-methyl-1-(4-methylpiperazin-1-yl)propan-2-amine using the same procedure outlined for Example 229 except the appropriate boronic acid was substituted for (3-hydroxyphenyl)boronic acid to obtain the desired product.

Example 296

(3S)-3-hydroxy-4-[({5-[(2-methyl-3-phenylphenyl)methoxy]pyridin-2-yl}methyl)amino]butanoic acid

(156) ##STR00097##

(157) (S)-4-amino-3-hydroxybutanoic acid (35.7 mg, 300 mol) and 5-((2-methyl-[1,1-biphenyl]-3-yl)methoxy)picolinaldehyde (30.3 mg, 100 mol) were dissolved in a mixture of DMF (0.5 mL) and acetic acid (5.72 l, 100 mol). The reaction was stirred at 40 C. for 1 hour and a solution of sodium cyanoborohydride (18.85 mg, 300 mol) in DMF (0.5 mL) was added. Stirred at room temperature overnight. The reaction was diluted with 500 L MeOH. The solvent was removed in a Zymark tabletop dryer at 35 C. for 1 hour. The residue was redissolved in 1 mL DMF and filtered using syringe filter. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.1 mg, and its estimated purity by LCMS analysis was 94%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.33 (d, J=2.6 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.46 (t, J=7.5 Hz, 3H), 7.41-7.36 (m, 2H), 7.32 (d, J=7.3 Hz, 2H), 7.29 (t, J=7.7 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 5.22 (s, 2H), 3.89-3.83 (m, 1H), 3.78 (br. s., 2H), 3.45 (br. s., 3H), 2.28 (dd, J=15.0, 5.1 Hz, 1H), 2.21 (s, 3H), 2.17-2.09 (m, 1H).

Example 297

N-(2-{[(3-chloro-4-{[2-methyl-3-(thiophen-3-yl)phenyl]methoxy}phenyl)methyl]amino}ethyl)acetamide

(158) ##STR00098##

Intermediate 297A: (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

(159) ##STR00099##

(160) Dioxane (200 mL) was charged to a 500 mL round-bottom flask and nitrogen was bubbled through for 10 minutes. (3-bromo-2-methylphenyl)methanol (9.0 g, 44.8 mmol) was added and nitrogen was bubbled through for 10 minutes. Potassium acetate (13.18 g, 134 mmol) was added and nitrogen was bubbled through for 10 minutes. Bis(pinacolato)diboron (18.19 g, 71.6 mmol) was added and nitrogen was bubbled through for 10 minutes. PdCl.sub.2(dppf)-CH.sub.2Cl.sub.2 (4.75 g, 5.82 mmol) was added and nitrogen was bubbled through for 10 minutes. The reaction was heated at 80 C. overnight.

(161) The reaction was diluted with ethyl acetate (200 ml), filtered through a celite bed and the bed washed with ethyl acetate. The combined organic portions were concentrated under vacuum to provide a black pasty residue. This crude residue was adsorbed onto silica gel and chromatographed on a 120 g silica gel column using acetone in petroleum ether. The product eluted at 5.0% acetone. Fractions containing the product were combined and the solvent was removed under vacuum. An off-white solid was obtained. The solid was stirred with petroleum ether and filtered under vacuum to remove boron impurities. The title compound (8.7 g, 77%) was pure by NMR analysis. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.33 (dd, J=0.9, 7.5 Hz, 1H), 7.45 (d, J=6.9 Hz, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.73 (d, J=3.0 Hz, 2H), 2.58 (s, 3H), 1.58 (br. s., 1H, OH), 1.37 (s, 12H).

Intermediate 297B: 3-chloro-4-((2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde

(162) ##STR00100##

(163) A solution of 3-chloro-4-hydroxybenzaldehyde (126 mg, 0.806 mmol), triphenylphosphine (233 mg, 0.887 mmol) and (2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (200 mg, 0.806 mmol) in dry THF (5 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate (0.172 mL, 0.887 mmol) in THF (5 mL) was added dropwise. The resulting yellow solution was allowed to slowly warm to room temperature while stirring overnight. The solvent was removed and the residue was purified on a 24 g silica column with 2:1 hexanes:ethyl acetate. Collected fractions to afford the desired product (0.305 g, 98%). .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.86 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.81 (dd, J=7.5, 1.1 Hz, 1H), 7.75 (dd, J=8.4, 2.1 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 5.24 (s, 2H), 2.61 (s, 3H), 1.39 (s, 12H).

Example 297

(164) A solution of (3-((2-chloro-4-formylphenoxy)methyl)-2-methylphenyl)boronic acid (352 mg, 1.2 mmol) in dioxane (16 mL) was degassed with nitrogen. Tripotassium phosphate (613 mg, 2.9 mmol) was dissolved in water (4 mL) and degassed with nitrogen. A reaction vial was charged with 2-bromothiophene (23.6 mg, 0.144 mmol), 1 mL of the (3-((2-chloro-4-formylphenoxy)methyl)-2-methylphenyl)boronic acid solution, 250 L of the tripotassium phosphate solution and solid 2nd generation Xphos precatalyst (2.84 mg, 3.61 mol, CAS Number 1310584-14-5). The vial was sealed and allowed to shake at room temperature overnight. The reaction mixture was transferred to 6 mL PL-Thiol SPE cartridge (conditioned with methanol). The reaction vial was rinsed with 500 L methanol and the rinse transferred to the SPE cartridges. The intermediate product was eluted with 4 mL methanol and solvent removed in a Zymark tabletop dryer at 40 C. for 3 hours. The intermediate was used without further purification.

(165) A solution of N-(2-aminoethyl)acetamide (336 L, 3.5 mmol) in DCE (8.0 mL) was prepared and 500 L of the N-(2-aminoethyl)acetamide solution was added to the dried aldehyde intermediate. Acetic acid (4.14 l, 0.072 mmol) was added and the sealed reaction was allowed to stir at 40 C. for 1 hour. The solvent was removed in a Zymark tabletop dryer at 40 C. for 2 hours. Toluene (500 L) was added and solvent removed in a Zymark tabletop dryer at 40 C. for 1 hour. Tetramethylammonium triacetoxyborohydride (1.4 gm, 5.2 mmol) was dissolved in DCE (16 mL) and 1.0 mL of this solution was added to the reaction. The reaction was sealed allowed to shake at room temperature overnight. LCMS consistent mostly with imine intermediate. The solvent was removed in a Zymark tabletop dryer at 40 C. for 3 hours. A solution of N-(2-aminoethyl)acetamide (336 L, 3.5 mmol) in DMF (8.0 mL) was prepared and 500 L was added to the reaction. Acetic acid (4.14 l, 0.072 mmol) was added. The sealed reaction was allowed to shake at room temp for 1 hr. Sodium cyanoborohydride (327 mg, 5.2 mmol) was dissolved in DMF (8.0 mL) and 500 L was added to the reaction. The sealed reaction was allowed to shake at room temperature overnight. The reaction contents were transferred to 6-mL PL-SO3H SPE cartridge conditioned with methanol. The reaction vial was rinsed with 500 L methanol and the rinse was transferred to the SPE cartridge. The cartridge was rinsed with 4 mL methanol. The product was eluted with 4 mL 1N ammonia in methanol. The solvent was removed in a Zymark tabletop dryer at 40 C. for 2 hours and the residue dissolved in DMF (1 mL). The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19200 mm, 5-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 40-80% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 6.3 mg, and its estimated purity by LCMS analysis was 97%. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.64 (d, J=5.1 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.40-7.34 (m, 3H), 7.33-7.27 (m, 1H), 7.20-7.16 (m, 1H), 7.14 (d, J=3.3 Hz, 1H), 5.28 (s, 2H), 3.92 (br. s., 2H), 3.25 (d, J=6.2 Hz, 2H), 2.77 (br. s., 2H), 2.36 (s, 3H), 1.82 (s, 3H).

HPLC Methods

(166) Method A: Column: Waters BEH C18, 2.050 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min.
Method M: Column: Waters BEH C18, 2.050 mm, 1.7-m particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 40 C.; Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min.
Method AA: Ascentis Express C18, 4.650 mm, 2.7 m column; 4 ml/min flow; 4 min gradient from 0% B to 100% B; A=5% ACN-95% H2O 10 mM NH4OAc, B=95% ACN-5% H2O 10 mM NH4OAc UV detection at 220 nm; and a column heater set at 45 C.
Method AT: Ascentis Express C18, 2.150 mm, 2.7 m column; 1.1 ml/min flow; 3 min gradient from 0% B to 100% B; A=5% ACN-95% H2O 0.1% TFA, B=95% ACN-5% H2O 0.1% TFA UV detection at 220 nm; and a column heater set at 50 C.
Method A50: Column: Waters BEH C18, 2.050 mm, 1.7-m particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B, 0-100% B over 3 minutes, then a 0.5-minute hold at 100% B; Flow: 1 mL/min; Detection: UV at 220 nm.
Method M50: Column: Waters BEH C18, 2.050 mm, 1.7-m particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10 mM ammonium acetate; Temperature: 50 C.; Gradient: 0% B, 0-100% B over 3 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm.

(167) TABLE-US-00001 HPLC Retention ESI- ESI- Time MS MS Ex. (minutes) m/z m/z No. Structure Name (Method) MH.sup.+ MH.sup. 5 01 N-{2-[({3-bromo-2,6-dimethoxy-4- [(2-methyl-3-phenylphenyl) methoxy]phenyl[methyl)amino] ethyl}acetamide 2.8 A 529.2 6 02 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)[2-methyl-1-(4- methylpiperazin-1-yl) propan-2-yl] amine 4.16 M 518.5 7 03 N-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}-N-methylmethanesulfon- amide 2.91 A 499.3 8 04 1-({3-bromo-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.15 M 494.4 9 05 2-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino]- 1-(morpholin-4-yl)ethan-1-one 2.9 A 491.4 10 06 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)[2-(4- methylpiperazin-1-yl)ethyl] amine 4.1 M 490.5 11 07 1-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}piperidin-2-one 4.1 M 489.4 12 08 1-{3-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl) amino]propyl}pyrrolidin-2-one 4.0 M 489.4 13 09 4-{2-[({2,6-dimethoxy-4-[(2- 3-phenylphenyl) methyl-methoxy]phenyl}methyl) amino]ethyl}piperazin-2-one 4.0 M 489.4 14 0 1-({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)(2-(morpholin-4- yl)ethyl]amine 4.0 M 477.3 15 1-({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)piperidine-2- carboxylic acid 4.2 M 476.5 16 2-[methyl({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]acetic acid 4.2 M 476.5 17 N-({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl) methoxy]phenyl}methyl)-1- ethylpiperidin-3-amine 4.3 M 475.5 18 1-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}pyrrolidin-2-one 4.1 M 475.4 19 (2S,4R)-4-(acetyloxy)-1-({3- methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)pyrrolidine-2-carboxylic acid 4.1 M 474.3 20 N-(2-hydroxyethyl)-1-({3-methyl- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-4-carboxamide 4.2 M 473.5 21 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)[1-(5-methyl-4H- 1,2,4-triazol-3-yl)ethyl] amine 2.7 A 473.4 22 N-{2-[({3-bromo-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]ethyl} acetamide 2.8 A 467.4 23 (2S,4R)-1-({3-chloro-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)-4- methoxypyrrolidine-2-carboxylic acid 2.7 A 466.4 464.4 24 0 N-{3-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] propyl}acetamide 4.0 M 463.5 25 (1R,2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] cyclohexan-1-ol 4.2 M 462.4 26 N-({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl) methoxy]phenyl}methyl)-1- methylpiperidin-3-amine 4.1 M 461.6 27 (2S)-1-({2-methoxy-3-methyl-4- [(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl) piperidine-2-carboxylic acid 2.7 A 460.3 458.4 28 (2S)-1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)-2-(prop-2-en-1- yl)pyrrolidine-2-carboxylic acid 4.3 M 456.4 29 3-[({3-bromo-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propanamide 2.7 A 453.4 30 3-[({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propanamide 4.1 M 452.4 31 4-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)morpholinc-3-carboxylic acid 4.2 M 452.7 450.6 32 3-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] butanoic acid 4.0 M 450.2 33 l-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-4-carboxylic acid 4.1 M 450.3 448.3 34 0 (2R)-1-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)piperidine-2- carboxylic acid 4.1 M 450.4 448.5 35 (2S)-1-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)piperidine-2- carboxylic acid 4.1 M 450.4 448.5 36 2-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino]- N,N-dimethylacetamidc 4.1 M 449.4 37 N-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}acetamide 2.7 A 449.0 38 1-({2-methoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.1 M 446.5 39 1-({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)azetidine 4.1 M 446.5 40 (2S,4R)-4-methoxy-1-({3-methyl- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)pyrrolidinc-2-carboxylic acid 2.7 A 446.4 444.5 41 1-({2,6-dimethyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.2 M 444.6 42 l-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)azepane-2-carboxylic acid 4.2 M 444.4 43 2-[1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidin-2-yl]acetic acid 4.1 M 444.4 44 0 1-{3-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]propyl} pyrrolidin-2-one 4.1 M 443.3 45 N-{2-[(1-{3-chloro-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}ethyl)amino] ethyl}acetamide 2.7 A 427.2 46 2-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl) (methyl)amino]acetic acid 2.6 A 436.4 47 3-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] propanamide 2.7 A 435.4 48 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] propanoic acid 4.1 M 434.5 49 1-({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.1 M 434.5 50 1-({3-fluoro-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.0 M 434.4 51 (2R,4R)-4-hydroxy-1-({3-methyl- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)pyrrolidine-2-carboxylic acid 4.0 M 432.3 52 (2R,4S)-4-hydroxy-1-({3-methyl- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)pyrrolidine-2-carboxylic acid 4.0 M 432.3 53 1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.2 M 430.4 54 0 1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-3-carboxylic acid 4.1 M 430.4 55 (3R)-1-({3-methyl-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl[methyl)piperidine-3- carboxylic acid 4.1 M 430.4 56 (2R,4R)-4-methyl-1-({3-methyl- 4-[(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl) pyrrolidine-2-carboxylic acid 4.2 M 430.4 57 (2S)-1-({3-methyl-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl}methyl)piperidine-2- carboxylic acid 2.7 A 430.4 428.5 58 1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-4-carboxylic acid 2.7 A 430.4 428.5 59 (2R)-1-({3-methyl-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl}methyl)piperidine-2- carboxylic acid 2.7 A 430.4 428.5 60 (2S)-1-({4-methyl-3-[(2-methyl- 3-phenylphenyl)methoxy) phenyl}methyl)piperidine-2- carboxylic acid 2.7 A 430.4 428.5 61 l-{3-[({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propyl}pyrrolidin- 2-one 4.1 M 429.5 62 N-[2-({5-[(2-methyl-3- phenylphenyl)methoxy]-1,2,3,4- tetrahydronaphthalen-1-yl} amino)ethyl]acetamide 2.9 A 429.4 63 N-[2-({6-[(2-methyl-3- phenylphenyl)methoxy]-1,2,3,4- tetrahydronaphthalen-1-yl} amino)ethyl]acetamide 2.9 A 429.4 64 0 l-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy)phenyl} methyl)-1,2,5,6-tetrahydro- pyridine-3-carboxylic acid 4.1 M 428.4 65 2-[({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-methylpropanoic acid 2.7 A 424.3 422.3 66 N-{2-[({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]ethyl} acetamide 4.2 M 423.4 421.0 67 l-({3-bromo-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)azetidine 4.4 M 422.4 68 N-{2-[({2-methoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}acetamide 4.0 M 419.5 69 N-({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl) cyclobutanamine 4.1 M 418.2 70 N-{2-[({2,6-dimethyl-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] ethyl}acetamide 2.8 A 417.5 71 N-{2-[(1-{3-methyl-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}ethyl)amino] ethyl}acetamide 2.7 A 417.3 72 (2S)-1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)pyrrolidine-2- carboxylic acid 4.0 M 416.4 73 1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy)phenyl} methyl)pyrrolidine-2-carboxylic acid 4.0 M 416.4 74 0 (1R,2R)-2-[({3-methyl-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] cyclohexan-1-ol 4.2 M 416.4 75 l-({4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)piperidine-2-carboxylic acid 4.2 M 416.4 76 (2R)-1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl) pyrrolidine-2- carboxylic acid 4.1 M 416.3 77 5-{[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]methyl[pyrrolidin-2- one 4.3 M 415.3 78 (2S)-2-[({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]propanoic acid 4.1 M 410.2 79 (2R)-2-[({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]propanoic acid 2.6 410.3 408.4 80 N-{2-[({3-fluoro-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]ethyl} acetamide 3.68 M 407.5 81 (2S)-2-[({2-methoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] propanoic acid 4.0 M 406.4 82 (2S)-2-[({3-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propanoic acid 4.0 M 406.4 83 3-[({2-methoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propanamide 2.6 A 405.5 84 0 l-({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl) azetidine 2.8 A 404.5 85 3-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]butanoic acid 4.0 M 404.3 86 (2R)-2-[methyl({3-methyl-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl) amino]propanoic acid 4.1 M 404.3 87 3-[({2,6-dimethyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino] propanamide 2.7 A 403.5 88 N-{2-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]ethyl} acetamide 2.7 A 403.5 89 N-{2-[({4-methyl-3-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]ethyl} acetamide 2.8 A 403.4 90 [(2S)-1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl) pyrrolidin-2- yl]methanol 4.2 M 402.4 91 (2S)-1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)azetidine-2- carboxylic acid 4.0 M 402.3 92 5-{[({4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]methyl} pyrrolidin-2-one 4.1 M 401.5 93 5-{[({4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]methyl} pyrrolidin-2-one 4.1 M 401.5 399.5 94 0 (2S)-2-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy) phenyl}methyl)amino] propanoic acid 4.1 M 390.4 95 2-[methyl({3-methyl-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] acetic acid 4.0 M 390.3 96 3-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino] propanamide 4.1 M 389.4 97 (2R)-2-[({3-methyl-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] propanoic acid 4.1 M 390.4 98 1-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy)phenyl} methyl)azetidine 4.3 M 378.3 99 l-({2-methoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)azetidine 2.7 A 374.5 100 1-({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)azetidine 2.8 A 358.4 101 6-[(2-methyl-3-phenylphenyl) methoxy]-1,2,3,4- tetrahydroisoquinoline 2.6 A 330.0 328 102 2-[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy)phenyl} methyl)amino]ethan-1-ol 2.8 A 362.2 360.2 103 2-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl) methoxy]phenyl}methyl)amino] ethan-1-ol 2.7 A 408.2 406.2 104 00 (2S)-2-[({3-bromo-4-[(2-methyl-3- phenylphenyl)methoxy] phenyl}methyl)amino]propanoic acid 4.1 M 452.4 105 01 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] propanoic acid 2.7 A 436.2 434.2 106 02 (2R)-2-{[(2,6-dimethoxy-4-{[3-(3- methoxyphenyl)-2- methylphenyl]methoxy}phenyl) methyl]amino}propanoic acid 2.7 A 931.4 107 03 (2R)-2-{[(4-{[3-(3-fluoro-5- methoxyphenyl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl] amino}propanoic acid 2.5 A 484.5 108 04 (2R)-2-{[(4-{[3-(2H-1,3- benzodioxol-5-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} propanoic acid 2.4 A 502.4 109 05 N-[2-({4-[(2-methyl-3- phenylphenyl)methoxy]-2,3- dihydro-1H-inden-1- yl}amino)ethyl]acetamide 2.6 A 415.3 110 06 4-{[({3-methyl-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino)methyl}azetidin- 2-one 3.0 A 399.4 111 07 (3S)-4-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl) amino]-3-hydroxybutanoic acid 2.0 A 466.4 464.4 112 08 (2S)-1-[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-3- (trifluoromethyl)phenyl)methyl] piperidine-2-carboxylic acid 1.8 A 542.4 540.4 113 09 N-(2-{[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-3- (trifluoromethyl)phenyl)methyl] amino}ethyl)acetamide 1.9 A 515.3 114 0 (3S)-4-{[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-3- (trifluoromethyl)phenyl)methyl] amino}-3-hydroxybutanoic acid 2.0 A 532.3 530.3 115 (2R,3S)-2-[({3-chloro-4-[(2- methyl-3-phenylphenyl)methoxy] phenyl}methyl)amino]-3- hydroxybutanoic acid 1.8 A 440.3 438.3 116 (2R,3R)-2-[({3-chloro-4-[(2- methyl-3-phenylphenyl)methoxy] phenyl}methyl)amino]-3- hydroxybutanoic acid 1.7 A 440.2 438.2 117 (2S,3S)-2-[({3-chloro-4-[(2- methyl-3-phenylphenyl)methoxy] phenyl}methyl)amino]-3- hydroxybutanoic acid 1.8 A 440.2 438.3 118 2-[({5-[(2-methyl-3- phenylphenyl)methoxy]thiophen-2- yl}methyl)amino]ethan-1-ol 2.4 AA 354.2 119 2-[({5-[(2-methyl-3- phenylphenyl)methoxy]pyridin-2- yl}methyl)amino]ethan-1-ol 1.5 AA 349.0 120 {1-[({5-[(2-methyl-3-phenyl phenyl)methoxy]pyridin-2-yl} methyl)amino]cyclopentyl} methanol 1.7 AA 403.2 121 methyl({5-[(2-methyl-3- phenylphenyl)methoxy]pyridin-2- yl}methyl)amine 1.5 AA 319.0 122 5-{[({5-[(2-methyl-3- phenylphenyl)methoxy]pyridin-2- yl}methyl)amino]methyl} pyrrolidin-2-one 1.6 AA 402.2 123 2-(3,5-dimethoxy-4-{[(pyridin-2- ylmethyl)amino]methyl} phenoxymethyl)-6- phenylbenzonitrile 1.5 AT 466.0 124 0 2-{4-[(cyclopropylamino)methyl]- 3,5-dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.5 AT 415.0 125 2-(3,5-dimethoxy-4-[(3- methylpiperidin-1- yl)methyl]phenoxymethyl}-6- phenylbenzonitrile 1.7 AT 457.2 126 2-[3,5-dimethoxy-4-({[2- (pyrrolidin-1-yl)ethyl]amino} methyl)phenoxymethyl]-6- phenylbenzonitrile 1.2 AT 472.2 127 2-{4-[(4-hydroxypiperidin-1- yl)methyl]-3,5- dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.4 AT 459.2 128 2-[3,5-dimethoxy-4-(morpholin- 4-ylmethyl)phenoxymethyl]-6- phenylbenzonitrile 1.4 AT 445.2 129 2-(3,5-dimethoxy-4-{[(pyridin-3- ylmethyl)amino]methyl} phenoxymethyl)-6- phenylbenzonitrile 1.3 AT 466.0 130 2-(3,5-dimethoxy-4-{[(pyridin-4- ylmethyl)amino]methyl} phenoxymethyl)- 6-phenylbenzonitrile 1.2 AT 466.0 131 2-[4-({[(3- hydroxyphenyl)methyl]amino} methyl)-3,5-dimethoxyphenoxy methyl]-6- phenylbenzonitrile 1.5 AT 481.0 132 2-[4-({[(2- hydroxyphenyl)methyl]amino} methyl)-3,5- dimethoxyphenoxymethyl]-6- phenylbenzonitrile 1.6 AT 481.0 133 2-[4-({[(4- hydroxyphenyl)methyl]amino} methyl)-3,5- dimethoxyphenoxymethyl]-6- phenylbenzonitrile 1.5 AT 481.0 134 0 2-{4-[(cyclobutylamino)methyl]- 3,5-dimethoxyphenoxymethyl}- 6-phenylbenzonitrile 1.6 AT 429.0 135 2-{4-[(cyclopentylamino)methyl]- 3,5-dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.6 AT 443.2 136 2-{4-[(cyclohexylamino)methyl]- 3,5-dimethoxyphenoxymethyl}- 6-phenylbenzonitrile 1.7 457.2 137 2-[3,5-dimethoxy-4-({[3-(2- oxopyrrolidin-1- yl)propyl]amino}methyl) phenoxymethyl]-6- phenylbenzonitrile 1.4 AT 500.2 138 2-(3,5-dimethoxy-4-({[(propan-2- yl)amino]methyl}phenoxymethyl)- 6-phenylbenzonitrile 1.5 417.0 139 N-{2-[({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl)amino] ethyl}acetamide 140 2-[4-({[2- (dimethylamino)ethyl]amino} methyl)-3,5- dimethoxyphenoxymethyl]-6- phenylbenzonitrile 1.2 AT 446.2 141 2-(3,5-dimethoxy-4-{[(2- methoxyethyl)amino]methyl} phenoxymethyl)-6- phenylbenzonitrile 1.5 AT 433.0 142 2-(4-{[(2- hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxymethyl)-6- phenylbenzonitrile 1.4 AT 419.0 143 2-[4-({[1- (hydroxymethyl)cyclopentyl] amino}methyl)-3,5- dimethoxyphenoxymethyl]-6- phenylbenzonitrile 1.5 AT 473.2 144 0 2-(4-{[(4- hydroxycyclohcxyl)amino] methyl}-3,5- dimethoxyphenoxymethyl)-6- phenylbenzonitrile 1.4 AT 473.2 145 3-[({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl)amino] propanamide 1.4 AT 446.0 146 2-{3,5-dimethoxy-4- [(methylamino)methyl] phenoxymethyl}- 6-phenylbenzonitrile 1.4 AT 389.0 147 2-[3,5-dimethoxy-4-({[2- (pyridin-2-yl)ethyl]amino} methyl)phenoxymethyl]- 6-phenylbenzonitrile 1.4 AT 480.0 148 2-{3,5-dimethoxy-4-[(2- methylpyrrolidin-1- yl)methyl]phenoxymethyl}-6- phenylbenzonitrile 1.6 AT 443.2 149 2-{4-[(4-acetylpiperazin-1- yl)methyl]-3,5- dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.4 AT 486.2 150 2-[3,5-dimethoxy-4-(pyrrolidin-1- ylmethyl)phenoxymethyl]-6- phenylbenzonitrile 1.5 AT 429.0 151 2-(4-{[3-(hydroxymethyl) piperidin-1-yl]methyl}-3,5- dimethoxyphenoxymethyl)-6- phenylbenzonitrile 1.5 AT 473.2 152 N-[(3S)-1-({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl) pyrrolidin-3-yl]acetamide 1.4 AT 486.2 153 2-[4-(azetidin-1-ylmethyl)-3,5- dimethoxyphenoxymethyl]-6- phenylbenzonitrile 1.5 AT 415.0 154 0 2-{4-[(4-acetyl-1,4-diazepan-1- yl)methyl]-3,5- dimethoxyphenoxymethyl}-6- phenylbenzonitrilc 1.4 AT 500.2 155 2-(4-{[ethyl(pyridin-4- ylmethyl)amino]methyl}-3,5- dimethoxyphenoxymethyl)-6- phenylbenzonitrile 1.3 AT 494.2 156 2-(4-{[(2S)-2- (hydroxymethyl)pyrrolidin-1- yl]methyl}-3,5- dimethoxyphenoxymethyl)-6- phenylbenzonitrile 1.5 AT 459.0 157 2-{4-[(2,5-dimethylpyrrolidin-1- yl)methyl]-3,5- dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.6 AT 457.2 158 2-{4-[(3-hydroxypiperidin-1- yl)methyl]-3,5- dimethoxyphenoxymethyl}-6- phenylbenzonitrile 1.4 AT 459.2 159 1-({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl) piperidine-3-carboxylic acid 1.5 487.0 160 (2S)-1-({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl) pyrrolidine-2-carboxamide 1.5 AT 472.0 161 (2S)-1-({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl) piperidine-2-carboxylic acid 1.5 AT 487.0 162 (6S)-5-({3-chloro-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)-1,2,5-triazaspiro[2.4] hept-1-ene-6-carboxylic acid 2.9 A 462.2 460.2 163 {2-[2-(2- aminoethoxy)ethoxy]ethyl}({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amine 2.8 A 495.3 164 0 2-(2-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl)methoxy] phenyl}methyl)amino]ethoxy} ethoxy)ethan-1-ol 2.9 A 497.3 165 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)({2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl})amine 3.2 A 582.4 166 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)({2-[4-(pyridin-2-yl) piperazin-1-yl]ethyl})amine 3.2 A 553.4 167 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)({2-[4-(pyrimidin-2-yl) piperazin-1-yl]ethyl})amine 3.0 A 554.4 168 tert-butyl 4-{2-[({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]ethyl} piperazine-1-carboxylate 3.3 A 576.4 169 4-{2-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl)methoxy] phenyl}methyl)amino] ethyl}-1.sup.6,4-thiomorpholine- 1,1-dione 2.8 A 525.3 170 benzyl N-{2-[({2,6-dimethoxy-4- [(2-methyl-3-phenylphenyl} methoxy]phenyl}methyl) amino]ethyl}carbamate 3.2 A 541.4 171 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)[3-(4-methylpiperazin-1- yl)propyl]amine 2.6 A 504.5 172 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)[3-(morpholin-4-yl) propyl]amine 3.0 A 491.5 173 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)[3-(1H-imidazol-1- yl)propyl]amine 2.7 A 472.4 174 0 4-{[({2,6-dimethoxy-4- [(2-methyl-3-phenylphenyl) methoxy]phenyl}methyl)amino] methyl}azetidin-2-one 2.5 A 347.3 175 3-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl) amino]-N-[2-(1H-imidazol-4- yl)ethyl]propanamide 2.9 A 529.2 527.3 176 2-({3-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propyl}(2- hydroxyethyl)amino)ethan-1-ol 3.0 A 509.4 177 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)(3-phenoxypropyl)amine 4.2 M 498.5 178 4-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl)methoxy(phenyl} methyl)amino]-2-hydroxybutanoic acid 2.9 A 466.3 179 3-(4-{3-[2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propyl} piperazin-1-yl)phenol 4.4 M 582.5 180 [2-(benzyloxy)ethyl]({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amine 3.6 A 498.3 181 1-{2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl}-5,8,11-trioxa-2- azatridecan-13-ol 3.1 A 541.4 182 1-{2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl}-5,8,11,14,17,20- hexaoxa-2-azatricosan-23- oic acid 3.8 M 700.4 183 1-{2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl)methoxy] phenyl}-5,8,11,14-tetraoxa-2- azaheptadecan-17-oic acid 2.4 A 612.4 610.5 184 0 (2S)-5-carbamimidamido-2- [(2R)-2-{2-[({2,6-dimethoxy-4- [(2-methyl-3-phenylphenyl) methoxy]phenyl} methyl)amino]acetamido}-3- phenylpropanamido]pentanoic acid 2.9 A 725.5 185 2-(2-{2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]acetamido} acetamido)acetic acid 2.4 A 536.2 186 (2S)-5-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]pheny} methyl)amino]-2- acetamidopentanoic acid 2.8 A 521.3 519.3 187 [(3,3- difluorocyclobutyl)methyl]({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amine 3.1 A 468.4 188 (cyclobutylmethyl)({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amine 2.2 A 432.4 189 (2S)-2-(2-{2-[({2,6-dimethoxy- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]acetamido} acetamido)-4- methylpentanoic acid 3.1 M 592.5 590.5 190 (2-aminoethyl)({2,6-dimethoxy- 4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)methylamine 1.9 A 421.4 191 3-{2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)(methyl)amino]ethyl}-1- phenylurea 2.1 A 540.4 538.4 192 N-{2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]pheny} methyl)(methyl)amino]ethyl}-2- oxo-2H-chromene-6- sulfonamide 2.2 A 629.5 627.4 193 N-{2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)(methyl)amino]ethyl} prop-2-enamide 2.0 A 475.4 194 0 ethyl (2E)-3-({2-[({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)(methyl)amino]ethyl} carbamoyl)prop-2-enoate 2.2 A 547.5 195 (6S)-5-({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)-1,2,5-triazaspiro[2.4] hept-1-ene-6-carboxylic acid 1.8 A 486.6 196 2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2- (hydroxymethyl)propane-1,3- diol 1.9 A 468.4 197 (3S)-4-[({3-chloro-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3- hydroxybutanoic acid 1.6 A 440.3 438.4 198 N-{2-[({3-cyano-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]ethyl}acetamide 1.8 A 414.4 199 N-(2-{[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-2,5- difluorophenyl)methyl]amino} ethyl)acetamide 1.8 A 483.5 481.5 200 (3S)-4-{[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-2,5- difluorophenyl)methyl]amino}-3- hydroxybutanoic acid 1.6 A 500.3 498.3 201 (2S)-1-[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-2,5- difluorophenyl)methyl] piperidine-2-carboxylic acid 1.7 A 510.3 202 N-{2-[({2-methoxy-6-[(2- methyl-3- phenylphenyl)methoxy] pyridin-3-yl} methyl)amino] ethyl}acetamide 1.9 A 420.3 478.4 (+HOAc) 203 5-(azetidin-1-ylmethyl)-2- [(2-methyl-3-phenylphenyl) methoxy]pyridine 4.1 M50 345.3 204 00 N-({6-[(2-methyl-3- phenylphenyl)methoxy] pyridin-3-yl}methyl) cyclobutanaminc 4.2 M50 359.2 205 01 N-({6-[(2-methyl-3- phenylphenyl)methoxy] pyridin-3-yl}methyl) cyclopentanamine 2.8 A50 373.3 206 02 1-{3-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl[methyl)amino]propyl} pyrrolidin-2-one 2.5 A50 430.4 207 03 ({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)[2-(pyridin-2- yl)ethyl]amine 2.8 A50 410.3 208 04 2-[(2-methyl-3- phenylphenyl)methoxy]-5- (pyrrolidin-1-ylmethyl)pyridine 3.2 M50 359.3 209 05 [(2S)-1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)pyrrolidin-2-yl] methanol 2.7 A50 389.3 210 06 (2S)-1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)piperidine-2-carboxylic acid 2.5 A50 417.3 211 07 1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)piperidine-3-carboxylic acid 2.5 A50 417.3 212 08 [1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)piperidin-3-yl] methanol 4.4 M50 403.3 213 09 1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)piperidin-4-ol 2.6 A50 389.3 214 0 2-[(2-methyl-3- phenylphenyl)methoxy]-5-[(2- methylpyrrolidin-1- yl)methyl]pyridine 2.8 A50 373.3 215 ({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)(propan-2-yl)amine 2.6 A50 347.3 216 methyl({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amine 3.9 M50 319.3 217 N-{2-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]ethyl}acetamide 4.0 M50 390.3 218 [2-(dimethylamino)ethyl]({6-[(2- methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amine 4.0 M50 376.4 219 (2-methoxyethyl)({6-[(2-methyl- 3-phenylphenyl)methoxy] pyridin-3-yl[methyl)amine 2.7 A50 363.3 220 2-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]ethan-1-ol 2.4 A50 349.3 221 {1-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]cyclopentyl} methanol 4.1 M50 403.4 222 4-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]cyclohexan-1-ol 3.9 M50 403.4 223 3-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]propanamide 2.4 A50 376.3 224 0 (2S)-2-[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl[methyl)amino]propanoic acid 2.2 A50 377.3 225 5-{[({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)amino]methyl} pyrrolidin-2-one 2.7 A50 402.3 226 N-[(3S)-1-({6-[(2-methyl-3- phenylphenyl)methoxy]pyridin-3- yl}methyl)pyrrolidin-3-yl] acetamide 4.3 M50 416.2 227 (2R)-2-{[(4-{[3-(3-fluoro-5- methoxyphenyl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} propanoic acid 2.5 A50 484.5 228 (2R)-2-{[(4-{[3-(2H-1,3- benzodioxol-5-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} propanoic acid 2.4 A50 502.4 229 3-[3-(4-{[(2- hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxymethyl)-2- methylphenyl]phenol 2.6 A50 424.3 230 2-{[(4-{[3-(2H-1,3-benzodioxol-5- yl)-2-methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} ethan-1-ol 3.0 A50 452.2 231 2-{[(4-{[3-(3-ethoxyphenyl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} ethan-1-ol 4.3 M50 452.2 232 2-[({2,6-dimethoxy-4-[(2-methyl-3- {3-[2-(piperidin-1- yl)ethoxy]phenyl}phenyl)methoxy] phenyl}methyl)amino]ethan-1-ol 2.6 A50 535.3 233 2-[({2,6-dimethoxy-4-[(2-methyl- 3-phenylphenyl)methoxy]phenyl} methyl)amino]-2-methylpropane- 1,3-diol 2.9 A50 452.3 234 0 (2S,3S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3-methylpentan- 1-ol 3.3 A50 464.4 235 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-4-methylpentan- 1-ol 3.3 A50 464.4 236 1-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propan-2-ol 3.0 A50 422.3 237 {1-[({2,6-dimethoxy-4-[(2- methyl-3-phenylphenyl) methoxy]phenyl}methyl) amino]cyclopentyl}methanol 3.2 A50 462.3 238 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propane-1,3-diol 4.2 M50 438.3 239 1-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butan-2-ol 3.1 A50 436.3 240 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-4-methylpentan- 1-ol 3.2 A50 465.3 241 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3-methylbutan- 1-ol 4.0 M50 450.5 242 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3-methylbutan- 1-ol 2.8 A50 450.5 243 (2R)2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propan-1-ol 3.8 M50 422.4 244 0 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butan-1-ol 3.9 M50 436.4 245 2-{[(2,6-dimethoxy-4- {[2-methyl-3-(3-propoxyphenyl) phenyl]methoxy}phenyl) methyl]amino}ethan-1-ol 4.2 M50 466.4 246 (2S)-3-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propane-1,2-diol 2.9 A50 438.3 247 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-methylbutanoic acid 3.0 A50 464.3 248 1-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-methylpropan- 2-ol 3.1 A50 436.3 249 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]pentan-1-ol 4.4 M50 450.4 250 3-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butan-2-ol 4.3 M50 436.3 251 (2R)-3-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propane-1,2-diol 2.9 A50 438.3 252 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butan-1-ol 2.8 A50 436.4 253 (2S)-1-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]propan-2-ol 2.7 A50 422.4 254 0 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclohexan-1-ol 2.8 A50 462.5 255 (1S,2R)-2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclohexan-1-ol 2.89 A50 462.4 256 (3R,4S)-4-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]oxolan-3-ol 2.7 A50 450.3 257 1-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3-methylbutan- 2-ol 2.9 A50 450.4 258 ({2,6-dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)[3-(dimethylamino)-2- hydroxypropyl]amine 3.9 M50 465.5 259 (2R)-2-cyclopropyl-2-[({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]ethan-1-ol 2.8 A50 448.4 260 3-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-methylbutan- 2-ol 2.8 A50 450.4 261 (2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-phenylethan- 1-ol 3.0 A50 484.5 262 1-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2.3-dihydro-1H- inden-2-ol 3.1 A50 496.5 263 (1S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-1-phenylethan- 1-ol 3.0 A50 484.5 264 0 (3S)-4-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3-hydroxybutanoic acid 2.4 A50 466.4 265 4-[((2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]thiolan-3-ol 2.9 A50 466.4 266 (1R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-1-phenylethan- 1-ol 3.0 A50 484.5 267 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-1-(pyridin-3-yl) ethan-1-ol 3.9 M50 485.4 268 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-1-(pyridin-4-yl) ethan-1-ol 2.7 A50 485.5 269 (2S)-2-cyclohexyl-2-[({2,6- dimethoxy-4-[(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]ethan-1-ol 3.1 A50 490.5 270 {4-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]oxan-4-yl} methanol 2.7 A50 478.4 271 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-1-(1-methyl-1H- imidazol-2-yl)ethan-1-ol 2.8 A50 488.4 272 1-{[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]methyl} cyclohexan-1-ol 4.1 M50 476.5 273 (1R,2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclopentan-1-ol 2.8 A50 448.4 274 0 4-{[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]methyl}-1- methylpiperidin-4-ol 3.9 M50 491.5 275 (1R,2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclohexan-1-ol 2.9 A50 462.4 276 (1S,2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclopentan-1-ol 2.7 A50 448.4 277 (1R,2R)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]cyclopentan-1-ol 2.7 A50 448.4 278 (2R,3S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butane-1,3-diol 3.0 A50 452.3 279 (2S,3R)-2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]butane-1,3-diol 4.3 M50 452.3 280 1-{[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]methyl} cyclobutan-1-ol 2.9 A50 448.4 281 (3R)-4-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-3- hydroxybutanoic acid 3.8 M50 466.4 282 2-[({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-ethylpropane- 1,3-diol 3.0 A50 466.4 283 (2S)-2-[({2,6-dimethoxy-4-[(2- methyl-3- phenylphenyl)methoxy]phenyl} methyl)amino]-2-phenylethan- 1-ol 3.0 A50 484.4 284 0 1-({2,6-dimethoxy-4- [(2-methyl-3- phenylphenyl)methoxy]phenyl} methyl)-4-hydroxypiperidine-4- carboxamide 2.6 A50 491.6 285 N-(2-{[(2,6-dimethoxy-4-{[3-(3- methoxyphenyl)-2- methylphenyl]methoxy}phenyl) methyl]amino}ethyl)acetamide 2.9 M50 479.4 286 N-(2-{[(4-{[3- (3-ethoxyphenyl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl] amino}ethyl)acetamide 1.9 A50 493.3 287 N-(2-{[(4-{[3-(2H-1,3- benzodioxol-5-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} ethyl)acetamide 1.7 A50 493.5 288 [(4-{[3-(2H-1,3- benzodioxol-5-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl] [2-methyl-1-(4-methylpiperazin- 1-yl)propan-2-yl]amine 1.9 A50 562.4 289 N-(2-{[(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl]amino} ethyl)acetamide 1.7 A50 507.3 290 [(4-{[3-(3-ethoxyphenyl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl][2- methyl-1-(4-methylpiperazin- 2-yl)propan-2-yl]amine 2.1 A50 562.5 291 [(4-{[3-(2,3-dihydro-1,4- benzodioxin-6-yl)-2- methylphenyl]methoxy}-2,6- dimethoxyphenyl)methyl] [2-methyl-1-(4-methylpiperazin- 1-yl)propan-2-yl]amine 1.8 A50 576.5 292 {[2,6-dimethoxy-4-({3-[3- (methoxymethoxy)phenyl]-2- methylphenyl}methoxy)phenyl] methyl}[2-methyl-1- (4-methylpiperazin-1-yl) propan-2-yl]amine 2.8 M50 578.6 293 {[2,6-dimethoxy-4-({2-methyl- 3-[3-(prop-2-en-1- yloxy)phenyl]phenyl}methoxy) phenyl]methyl}[2-methyl-1-(4- methylpiperazin-1-yl)propan-2- yl]amine 3.0 M50 574.6 294 0 {[4-({3-[2-fluoro-5-(2- methoxyethoxy)phenyl]-2- methylphenyl}methoxy)-2,6- dimethoxyphenyl]methyl} [2-methyl-1-(4- methylpiperazin-1-yl)propan-2- yl]amine 2.9 M50 610.4 295 (3S)-4-[({4-[(2-cyano-3- phenylphenyl)methoxy]-2,6- dimethoxyphenyl}methyl) amino]-3-hydroxybutanoic acid 2.5 M50 477.5 296 (3S)-3-hydroxy-4-[({5-[(2- methyl-3- phenylphenyl)methoxy]pyridin-2- yl}methyl)amino]butanoic acid 1.7 A50 407.3 297 N-(2-{[(3-chloro-4-{[2-methyl-3- (thiophen-3- yl)phenyl]methoxy}phenyl) methyl]amino}ethyl)acetamidc 2.9 M50 429

(168) TABLE-US-00002 Ex. No. .sup.1H NMR (500 MHz) ppm 5 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.81 (br. s., 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.51-7.44 (m, 2H), 7.40 (d, J = 7.0 Hz, 1H), 7.34-7.29 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 6.83 (s, 1H), 5.29 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 3.71 (s, 2H), 3.14 (d, J = 6.1 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.26 (s, 3H), 1.79 (s, 3H) 6 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.45 (m, 3H), 7.43-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.22 (d, J = 7.0 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.79 (s, 6H), 3.61 (s, 2H), 2.31 (br. s., 3H), 2.23 (s, 5H), 2.15 (s, 3H), 1.89 (s, 5H, acetate), 1.04 (s, 6H) 23 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.57-7.13 (m, 11H), 5.23 (br. s., 2H), 3.89 (d, J = 12.5 Hz, 3H), 3.52 (d, J = 13.7 Hz, 1H), 3.36 (br. s., 1H), 3.17 (br. s., 3H), 2.39 (d, J = 7.9 Hz, 1H), 2.22 (br. s., 3H), 2.03 (br. s., 2H) 27 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.44 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.28 (m, 3H), 7.28-7.19 (m, 2H), 6.96 (d, J = 8.5 Hz, 1H), 5.15 (s, 2H), 3.93-3.88 (m, 1H), 3.70-3.64 (m, 4H), 3.19-3.14 (m, 2H), 2.94 (d, J = 11.3 Hz, 1H), 2.36 (d, J = 5.8 Hz, 1H), 2.12 (s, 3H), 1.91 (s, 3H), 1.86-1.70 (m, 2H), 1.56-1.32 (m, 3H) 31 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51 (d, J = 7.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.42-7.36 (m, 2H), 7.34-7.23 (m, 5H), 7.21 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 3.83 (d, J = 13.7 Hz, 1H), 3.75 (d, J = 3.4 Hz, 2H), 3.58-3.54 (m, 2H), 3.49 (d, J = 13.7 Hz, 1H), 3.19-3.15 (m, 1H), 2.90-2.85 (m, 1H), 2.22 (s, 4H) 33 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.57-7.13 (m, 11H), 5.23 (br. s., 2H), 2.72 (d, J = 10.7 Hz, 2H), 2.29-2.11 (m, 4H), 2.02-1.85 (m, 4H), 1.77 (d, J = 10.1 Hz, 2H), 1.53 (d, J = 9.2 Hz, 2H) 34 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.54-7.42 (m, 4H), 7.39 (d, J = 7.3 Hz, 1H), 7.34-7.25 (m, 5H), 7.21 (d, J = 7.3 Hz, 1H), 5.24 (br. s., 2H), 3.82 (d, J = 13.4 Hz, 1H), 3.45 (d, J = 12.2 Hz, 1H), 3.05 (br. s., 1H), 2.85 (br. s., 1H), 2.27-2.15 (m, 4H), 1.80 (br. s., 1H), 1.68 (br. s., 1H), 1.48 (br. s., 3H), 1.35 (br. s., 1H) 35 .sup.1H NMR (500 MHz, DMSO-d.sub.6) ppm 7.58-7.12 (m, 11H), 5.24 (br. s., 2H), 3.99-3.80 (m, 2H), 3.12-3.04 (m, 1H), 2.95-2.85 (m, 1H), 2.37-2.27 (m, 1H), 2.22 (s, 3H), 1.95-1.25 (m, 6H) 37 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.94 (br. s., 1H), 7.45 (t, J = 7.3 Hz, 3H), 7.41-7.33 (m, 1H), 7.33-7.25 (m, 3H), 7.19 (d, J = 7.6 Hz, 1H), 6.35 (s, 2H), 5.15 (s, 2H), 3.15 (d, J = 4.9 Hz, 2H), 2.56 (br. s., 2H), 2.51 (br. s., 6H), 2.20 (s, 3H), 1.83 (s, 3H), 1.79 (s, 3H) 40 1H NMR (500 MHz, DMSO-d.sub.6) 7.56-7.01 (m, 11H), 5.14 (br. s., 2H), 3.98-3.84 (m, 2H), 3.56 (d, J = 13.4 Hz, 1H), 3.41-3.35 (m, 1H), 3.17 (s, 4H), 2.20 (d, J = 11.3 Hz, 6H), 2.11-1.98 (m, 2H) 45 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.77 (br. s., 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.49-7.43 (m, 2H), 7.43-7.35 (m, 2H), 7.35-7.24 (m, 5H), 7.21 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 3.66 (d, J = 6.4 Hz, 1H), 3.14-2.99 (m, 2H), 2.42-2.28 (m, 2H), 2.23 (s, 3H), 1.77 (s, 3H), 1.26-1.18 (m, 3H) 57 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.56-7.04 (m, 11H), 5.15 (br. s., 2H) 3.67 (d, J = 13.7 Hz, 2H), 3.13-2.90 (m, 2H), 2.42 (br. s., 1H), 2.20 (d, J = 9.5 Hz, 6H), 1.95-1.27 (m, 6H) 58 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51-7.43 (m, 3H), 7.39 (d, J = 6.7 Hz, 1H), 7.35-7.26 (m, 3H), 7.19 (d, J = 6.7 Hz, 1H), 7.10-7.00 (m, 3H), 5.13 (br. s., 2H), 2.72 (br. s., 2H), 2.20 (s, 7H), 1.99-1.88 (m, 3H), 1.76 (d, J = 12.5 Hz, 2H), 1.52 (d, J = 10.7 Hz, 2H) 59 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.43 (m, 3H), 7.38 (br. s., 1H), 7.35-7.27 (m, 3H), 7.19 (br. s., 3H), 7.09 (d, J = 7.0 Hz, 1H), 5.15 (br. s., 2H), 3.97 (d, J = 13.1 Hz, 1H), 3.04 (br. s., 1H), 2.95 (br. s., 1H), 2.35 (br. s., 1H), 2.20 (d, J = 9.8 Hz, 6H), 1.85 (br. s., 1H), 1.68 (d, J = 8.9 Hz, 1H), 1.53 (br. s., 3H), 1.34 (br. s., 1H) 60 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.44 (m, 3H), 7.41-7.36 (m, 1H), 7.33 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.15-7.10 (m, 2H), 6.87 (d, J = 7.9 Hz, 1H), 5.16 (s, 2H), 3.96 (d, J = 13.1 Hz, 1H), 3.65 (d, J = 13.4 Hz, 1H), 3.08 (dd, J = 8.1, 3.8 Hz, 1H), 2.92 (br. s., 1H), 2.31 (br. s., 1H), 2.23 (s, 3H), 2.18 (s, 3H), 1.82 (br. s., 1H), 1.76-1.65 (m, 1H), 1.51 (br. s., 3H), 1.35 (br. s., 1H) 65 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.64-7.12 (m, 11H), 5.27 (br. s., 2H), 3.84 (br. s., 2H), 2.22 (br. s., 3H), 1.38-1.23 (m, 6H) 66 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.81 (br. s., 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.50-7.45 (m, 2H), 7.44 (s, 1H), 7.42-7.37 (m, 1H), 7.35-7.25 (m, 5H), 7.22 (d, J = 6.7 Hz, 1H), 5.24 (s, 2H), 3.66 (s, 2H), 3.14 (q, J = 6.2 Hz, 2H), 2.57-2.49 (m, 2H), 2.24 (s, 3H), 1.80 (s, 3H) 71 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.82 (br. s., 1H), 7.51-7.44 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.20 (d, J = 7.3 Hz, 1H), 7.18-7.12 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 5.14 (s, 2H), 3.75 (br. s., 1H), 3.16-3.05 (m, 2H), 2.48-2.36 (m, 2H), 2.21 (d, J = 9.2 Hz, 6H), 1.91 (s, 3H, acetate), 1.78 (s, 3H) 78 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.57 (br. s., 1H), 7.51-7.42 (m, 3H), 7.41-7.27 (m, 6H), 7.21 (d, J = 6.4 Hz, 1H), 5.26 (br. s., 2H), 3.99-3.82 (m, 2H), 3.15 (br. s., 1H), 2.22 (br. s., 3H), 1.27 (d, J = 6.4 Hz, 3H) 79 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.67-7.10 (m, 11H), 5.27 (s, 2H), 4.08-3.88 (m, 2H), 2.22 (s, 3H), 1.46-1.05 (m, 3H) 89 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.81 (br. s., 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.49-7.43 (m, 2H), 7.42-7.36 (m, 1H), 7.36-7.27 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 7.14-7.06 (m, 2H), 6.83 (d, J = 7.3 Hz, 1H), 5.14 (s, 2H), 3.68 (s, 2H), 3.18-3.10 (m, 2H), 2.54 (t, J = 6.4 Hz, 2H), 2.23 (s, 3H), 2.17 (s, 3H), 1.79 (s, 3H) 93 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.66 (br. s., 1H), 7.45 (d, J = 6.7 Hz, 3H), 7.39 (d, J = 7.3 Hz, 1H), 7.34-7.24 (m, 5H), 7.19 (d, J = 7.3 Hz, 1H), 7.01 (d, J = 7.6 Hz, 2H), 5.12 (br. s., 2H), 3.69-3.57 (m, 4H), 2.49-2.45 (m, 2H), 2.20 (br. s., 3H), 2.14-2.05 (m, 3H), 1.91 (br. s., 3H, acetate), 1.66 (br. s., 1H) 97 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52-7.42 (m, 3H), 7.39 (d, J = 7.3 Hz, 1H), 7.36-7.26 (m, 3H), 7.19 (d, J = 7.6 Hz, 1H), 7.14 (br. s., 2H), 7.03 (d, J = 7.9 Hz, 1H), 5.13 (br. s., 2H), 3.68-3.52 (m, 2H), 2.85 (br. s., 1H), 2.20 (d, J = 11.0 Hz, 6H), 1.10 (br. s., 3H) 101 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.49-7.42 (m, 3H), 7.41-7.36 (m, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.88-6.77 (m, 2H), 5.10 (s, 2H), 3.04-2.98 (m, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.19 (s, 3H), 1.90 (s, 2H). 102 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51-7.44 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 7.14-7.10 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 5.13 (s, 2H), 3.62 (s, 2H), 3.47 (t, J = 5.6 Hz, 2H), 2.56 (t, J = 5.6 Hz, 2H), 2.21 (s, 3H), 2.20 (s, 3H), 1.89 (s, 1H, acetate) 103 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.51-7.45 (m, 3H), 7.41-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.0 Hz, 1H), 6.41-6.33 (m, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.65 (s, 2H), 3.44 (t, J = 5.5 Hz, 2H), 2.55-2.51 (m, 2H), 2.23 (s, 3H), 1.87 (s, 2H, acetate) 105 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.48 (d, J = 8.2 Hz, 3H), 7.39 (br. s., 1H), 7.33 (d, J = 6.7 Hz, 3H), 7.23 (br. s., 1H), 6.45 (br. s., 2H), 5.21 (br. s., 2H), 3.97 (br. s., 2H), 3.83 (br. s., 6H), 3.06 (br. s., 1H), 2.22 (br. s., 3H), 1.27 (d, J = 5.8 Hz, 3H) 106 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.49 (d, J = 7.0 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.32-7.26 (m, 1H), 7.22 (d, J = 7.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 7.3 Hz, 1H), 6.85 (s, 1H), 6.44 (s, 2H), 5.20 (s, 2H), 3.97 (s, 2H), 3.83 (s, 6H), 3.80 (s, 3H), 3.05 (q, J = 7.2 Hz, 1H), 2.23 (s, 3H), 1.27 (d, J = 7.3 Hz, 3H) 107 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.52 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 11.3 Hz, 1H), 6.74 (d, J = 9.8 Hz, 1H), 6.70 (br. s., 1H), 6.44 (s, 2H), 5.20 (s, 2H), 3.97 (br. s., 2H), 3.82 (d, J = 3.7 Hz, 9H), 3.05 (d, J = 6.7 Hz, 1H), 2.23 (s, 3H), 1.91 (s, 1H), 1.27 (d, J = 6.7 Hz, 3H) 108 .sup.1H NMR (500 MHz, DMSO-d.sub.6) 7.46 (d, J = 7.6 Hz, 1H), 7.29-7.24 (m, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.44 (s, 2H), 6.07 (s, 2H), 5.18 (s, 2H), 3.99 (br. s., 2H), 3.83 (s, 6H), 3.11-3.05 (m, 1H), 2.23 (s, 3H), 1.29 (d, J = 6.7 Hz, 3H) 163 .sup.1H NMR (500 MHz, DMSO-d6) 7.52-7.44 (m, 3H), 7.42-7.36 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.63 (s, 2H), 3.53-3.40 (m, 8H), 2.73 (t, J = 5.2 Hz, 2H), 2.61-2.54 (m, 2H), 2.22 (s, 3H) methoxy peaks hidden by residual water 164 .sup.1H NMR (500 MHz, DMSO-d6) 7.51-7.44 (m, 3H), 7.41-7.36 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.77 (s, 6H), 3.63 (s, 2H), 3.50-3.37 (m, 10H), 2.58 (t, J = 5.3 Hz, 2H), 2.23 (s, 3H) 174 .sup.1H NMR (500 MHz, DMSO-d6) 7.94 (br. s., 1H), 7.52-7.44 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.65 (s, 2H), 3.52 (br. s., 1H), 2.84 (dd, J = 14.6, 3.4 Hz, 1H), 2.61-2.54 (m, 1H), 2.44 (d, J = 15.0 Hz, 1H), 2.23 (s, 3H). A peak a 2.5 was partially hidden by the DMSO peak. 175 .sup.1H NMR (500 MHz, DMSO-d6) 8.07 (br. s., 1H), 7.51-7.43 (m, 4H), 7.40 (d, J = 7.3 Hz, 1H), 7.35-7.26 (m, 3H), 7.21 (d, J = 7.0 Hz, 1H), 6.76 (s, 1H), 6.39 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.66 (s, 2H), 3.24 (d, J = 6.4 Hz, 2H), 2.67 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.22 (m, 5H). 176 .sup.1H NMR (500 MHz, DMSO-d6) 7.53-7.44 (m, 3H), 7.40 (d, J = 7.6 Hz, 1H), 7.36-7.27 (m, 3H), 7.22 (d, J = 6.4 Hz, 1H), 6.39 (s, 2H), 5.18 (br. s., 2H), 3.79 (s, 6H), 3.69 (br. s., 2H), 3.42 (t, J = 5.8 Hz, 4H), 2.56 (d, J = 9.8 Hz, 2H), 2.23 (s, 2H), 1.86 (s, 5H), 1.56 (br. s., 2H) NMR signals hidden under residual DMSO and integrals off due to poor phasing. 177 .sup.1H NMR (500 MHz, DMSO-d6) 7.54-7.17 (m, 10H), 6.91 (br. s., 3H), 6.37 (br. s., 2H), 5.16 (br. s., 2H), 3.99 (br. s., 2H), 3.76 (br. s., 6H), 3.65 (br. s., 2H), 2.60 (br. s., 2H), 2.22 (br. s., 3H), 1.84 (d, J = 5.5 Hz, 2H). 178 .sup.1H NMR (500 MHz, DMSO-d6) 7.47 (br. s., 3H), 7.39 (br. s., 1H), 7.33 (d, J = 7.0 Hz, 3H), 7.23 (br. s., 1H), 6.45 (br. s., 2H), 5.21 (br. s., 2H), 3.91 (br. s., 2H), 3.83 (br. s., 6H), 3.50 (br. s., 1H), 2.95 (br. s., 2H), 2.23 (br. s., 3H), 1.83-1.65 (m, 2H). 179 .sup.1H NMR (500 MHz, DMSO-d6) 7.52-7.43 (m, 3H), 7.40 (d, J = 7.0 Hz, 1H), 7.35-7.26 (m, 3H), 7.21 (d, J = 7.0 Hz, 1H), 6.96 (t, J = 7.9 Hz, 1H), 6.42-6.33 (m, 3H), 6.29 (br. s., 1H), 6.20 (d, J = 6.1 Hz, 1H), 5.16 (br. s., 2H), 3.81-3.74 (m, 8H), 3.66 (br. s., 2H), 3.03 (br. s., 4H), 2.44 (br. s., 4H), 2.33 (br. s., 2H), 2.25-2.17 (m, 3H), 1.60 (br. s., 2H) unable to integrate signal at 2.5 ppm because of partial overlap with DMSO. 180 .sup.1H NMR (500 MHz, DMSO-d6) 7.53-7.43 (m, 3H), 7.42-7.25 (m, 9H), 7.21 (d, J = 7.0 Hz, 1H), 6.37 (s, 2H), 5.16 (br. s., 2H), 4.42 (s, 2H), 3.76 (s, 6H), 3.63 (br. s., 2H), 3.48 (br. s., 2H? partially hidden by water), 2.62 (br. s., 2H), 2.22 (br. s, 3H). 181 .sup.1H NMR (500 MHz, DMSO-d6) 7.52-7.43 (m, 3H), 7.39 (d, J = 7.0 Hz, 1H), 7.36-7.26 (m, 3H), 7.21 (d, J = 6.7 Hz, 1H), 6.37 (s, 2H), 5.16 (s, 2H), 3.77 (s, 6H), 3.62 (br. s., 2H), 3.52-3.47 (m, impossible to integrate due to a large water signal), 2.57 (br. s., 1H), 2.22 (s, 3H) 182 .sup.1H NMR (500 MHz, DMSO-d6) 7.53-7.44 (m, 3H), 7.39 (d, J = 7.3 Hz, 1H), 7.36-7.25 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 6.39 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.68 (br. s., 2H), 3.59 (t, J = 6.0 Hz, 2H), 3.50 (br. s., 22H), 2.63 (br. s., 2H), 2.39 (t, J = 5.8 Hz, 2H), 2.22 (s, 3H). Integrals for the region 3.4-3.9 imprecise due to the presence of a broad water peak centered at 3.75. 183 .sup.1H NMR (500 MHz, DMSO-d6) 7.52-7.44 (m, 3H), 7.42-7.36 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 6.39 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.69 (s, 2H), 3.59 (t, J = 6.3 Hz, 2H), 3.52-3.44 (m, 14H), 2.63 (t, J = 5.5 Hz, 2H), 2.38 (t, J = 6.3 Hz, 2H), 2.23 (s, 3H). 184 .sup.1H NMR (500 MHz, DMSO-d6) 9.35-9.26 (m, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 6.7 Hz, 1H), 7.52-7.43 (m, 3H), 7.42-7.35 (m, 2H), 7.34-7.25 (m, 3H), 7.21 (d, J = 4.3 Hz, 5H), 7.16 (d, J = 4.6 Hz, 1H), 6.37 (s, 2H), 5.17 (s, 2H), 4.59 (d, J = 4.9 Hz, 1H), 3.93 (d, J = 6.4 Hz, 2H), 3.75 (s, 6H), 3.52 (br. s., 2H), 3.18 (s, 1H), 3.11-2.88 (m, 6H), 2.84 (d, J = 4.6 Hz, 1H), 2.22 (s, 3H), 1.71-1.32 (m, 4H). 185 .sup.1H NMR (400 MHz, METHANOL-d4) 7.44 (s, 3H), 7.40-7.34 (m, 1H), 7.32-7.25 (m, 3H), 7.24-7.19 (m, 1H), 6.42 (s, 2H), 5.22 (s, 2H), 4.20 (s, 2H), 3.96 (s, 2H), 3.90 (s, 6H), 3.78 (s, 2H), 3.69 (s, 2H), 2.26 (s, 3H) 186 .sup.1H NMR (500 MHz, DMSO-d6) 7.54-7.45 (m, 4H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 6.42 (s, 2H), 5.20 (s, 2H), 3.90 (br. s., 3H), 3.81 (s, 6H), 3.17 (s, 1H), 2.72 (br. s., 2H), 2.22 (s, 3H), 1.84 (s, 3H), 1.62 (br. s., 4H). 187 .sup.1H NMR (500 MHz, DMSO-d6) 7.51-7.44 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.62 (s, 2H), 2.61-2.53 (m, 2H(? partially obscured), 2.25-2.16 (m, 6H) 188 .sup.1H NMR (500 MHz, DMSO-d6) 7.51-7.44 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 6.37 (s, 2H), 5.17 (s, 2H), 3.77 (s, 6H), 3.60 (s, 2H), 2.46 (d, J = 7.0 Hz, 2H), 2.40-2.32 (m, 1H), 2.23 (s, 3H), 1.95 (d, J = 8.5 Hz, 2H), 1.86-1.73 (m, 2H), 1.62-1.52 (m, 2H) 189 .sup.1H NMR (500 MHz, DMSO-d6) 8.16-7.98 (m, 2H), 7.51-7.44 (m, 3H), 7.42-7.36 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 4.20 (q, J = 7.8 Hz, 1H), 3.77 (s, 8H), 3.64 (s, 2H), 3.09 (s, 2H), 2.22 (s, 3H), 1.67-1.57 (m, 1H), 1.50 (t, J = 7.2 Hz, 2H), 0.86 (dd, J = 18.0, 6.4 Hz, 6H). 190 .sup.1H NMR (400 MHz, CHLOROFORM-d) 7.47-7.41 (m, 3H), 7.38 (d, J = 7.1 Hz, 1H), 7.33 (d, J = 6.8 Hz, 2H), 7.30 (d, J = 3.2 Hz, 1H), 6.28 (s, 2H), 5.48 (br. s., 4H), 5.12 (s, 2H), 4.29 (q, J = 13.0 Hz, 2H), 3.92-3.77 (m, 6H), 3.70-3.39 (m, 5H), 2.86-2.73 (m, 3H), 2.29 (s, 3H). 191 .sup.1H NMR (500 MHz, DMSO-d6) 8.82 (br. s., 1H), 7.55-7.45 (m, 3H), 7.39 (d, J = 7.3 Hz, 3H), 7.37-7.28 (m, 3H), 7.25-7.16 (m, 3H), 6.88 (t, J = 7.2 Hz, 1H), 6.38 (s, 2H), 6.05 (br. s., 1H), 5.18 (s, 2H), 3.76 (s, 6H), 3.47 (br. s., 2H), 3.23 (d, J = 5.2 Hz, 2H), 2.48-2.42 (m, 2H), 2.24 (s, 3H), 2.13 (s, 3H). 192 .sup.1H NMR (500 MHz, DMSO-d6) 8.25 (s, 1H), 8.20 (d, J = 9.8 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.53-7.45 (m, 3H), 7.43-7.37 (m, 1H), 7.36-7.27 (m, 3H), 7.22 (d, J = 7.3 Hz, 1H), 6.63 (d, J = 9.8 Hz, 1H), 6.36 (s, 2H), 5.17 (s, 2H), 3.73 (s, 6H), 3.36 (s, 2H), 2.91 (t, J = 6.7 Hz, 2H), 2.35 (t, J = 6.9 Hz, 2H), 2.23 (s, 3H), 1.99 (s, 3H). 193 .sup.1H NMR (500 MHz, DMSO-d6) 7.91-7.86 (m, 1H), 7.47 (s, 3H), 7.42-7.37 (m, 1H), 7.33 (d, J = 7.9 Hz, 3H), 7.24-7.19 (m, 1H), 6.37 (s, 2H), 6.27-6.16 (m, 1H), 6.13-5.97 (m, 1H), 5.61-5.52 (m, 1H), 5.17 (s, 2H), 3.75 (s, 6H), 3.30-3.22 (m, 2H), 2.44-2.37 (m, 2H), 2.23 (s, 3H), 2.10 (s, 3H) 194 .sup.1H NMR (500 MHz, DMSO-d6) 8.40 (br. s., 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.21 (d, J = 7.3 Hz, 1H), 7.02 (d, J = 15.3 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 6.37 (s, 2H), 5.16 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.75 (s, 6H), 3.30 (d, J = 5.8 Hz, 2H), 2.43 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H). 195 .sup.1H NMR (500 MHz, DMSO-d6) 7.53-7.43 (m, 3H), 7.43-7.37 (m, 1H), 7.36-7.28 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 6.50-6.34 (m, 2H), 5.25-5.13 (m, 2H), 3.94-3.69 (m, 8H), 3.42 (t, J = 7.3 Hz, 2H), 2.46 (d, J = 11.3 Hz, 1H), 2.29 (d, J = 11.6 Hz, 1H), 2.24 (s, 3H), 1.76 (dd, J = 14.0, 7.9 Hz, 1H), 1.50 (dd, J = 14.0, 7.0 Hz, 1H) 196 .sup.1H NMR (500 MHz, DMSO-d6) 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.35-7.27 (m, 3H), 7.22 (d, J = 7.3 Hz, 1H), 6.38 (s, 2H), 5.17 (s, 2H), 3.78 (s, 6H), 3.69 (s, 2H), 3.42 (s, 6H), 2.23 (s, 3H) 198 .sup.1H NMR (500 MHz, DMSO-d6) 7.80 (br. s., 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.53-7.44 (m, 3H), 7.42-7.36 (m, 2H), 7.34-7.28 (m, 3H), 7.23 (d, J = 7.7 Hz, 1H), 5.33 (s, 2H), 3.66 (s, 2H), 3.38 (d, J = 11.7 Hz, 2H), 3.18-3.06 (m, 2H), 2.23 (s, 3H), 1.79 (s, 3H) 199 .sup.1H NMR (500 MHz, DMSO-d6) 7.79 (br. s., 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.36-7.23 (m, 3H), 7.19 (d, J = 7.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.78 (s, 1H), 6.76 (d, J = 8.1 Hz, 1H), 5.21 (s, 2H), 4.29 (s, 4H), 3.12 (q, J = 6.1 Hz, 2H), 2.21 (s, 3H), 1.92 (br. s., 2H), 1.82-1.74 (m, 3H). 2 missing hydrogens are assumed to be under the DMSO or water peaks. 200 .sup.1H NMR (500 MHz, DMSO-d6) 7.42 (d, J = 7.3 Hz, 1H), 7.34 (dd, J = 11.7, 7.0 Hz, 1H), 7.31-7.23 (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.78 (s, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.20 (s, 2H), 4.28 (s, 4H), 3.96-3.88 (m, 1H), 3.70 (br. s., 2H), 3.58 (br. s., 2H), 3.18 (s, 1H), 2.42 (dd, J = 15.2, 5.3 Hz, 1H), 2.27-2.22 (m, 1H), 2.21 (s, 3H). 201 .sup.1H NMR (500 MHz, DMSO-d6) 7.43 (d, J = 7.3 Hz, 1H), 7.32-7.24 (m, 3H), 7.19 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.79 (s, 1H), 6.76 (dd, J = 8.1, 1.8 Hz, 1H), 5.21 (s, 2H), 4.29 (s, 4H), 3.76-3.65 (m, 1H), 3.52 (s, 1H), 3.09 (d, J = 3.7 Hz, 1H), 2.92-2.81 (m, 1H), 2.21 (s, 4H), 1.83-1.63 (m, 2H), 1.47 (br. s., 3H), 1.35 (br. s., 1H) 202 .sup.1H NMR (600 MHz, DMSO-d6) 7.80 (br. s., 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.48-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.31 (d, J = 7.3 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 5.41 (s, 2H), 3.89 (s, 3H), 3.58 (s, 1H), 3.18-3.05 (m, 2H), 2.22 (s, 3H), 1.82-1.72 (m, 3H). The methylenes of the diamino acetamide were assumed to be under the DMSO peak at 2.5 ppm.

Biological Assay

(169) The ability of the compounds of Formula (I) to bind to PD-L1 was investigated using a PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay.

(170) Homogenous Time-Resolved Fluorescence (HTRF) Binding Assay.

(171) All binding studies were performed in an HTRF assay buffer consisting of dPBS supplemented with 0.1% (withv) bovine serum albumin and 0.05% (v/v) Tween-20. For the PD-1-Ig/PD-L1-His binding assay, inhibitors were pre-incubated with PD-L1-His (10 nM final) for 15 m in 4 l of assay buffer, followed by addition of PD-1-Ig (20 nM final) in 1 l of assay buffer and further incubation for 15 m. PD-L1 from either human, cyno, or mouse were used. HTRF detection was achieved using europium crypate-labeled anti-Ig (1 nM final) and allophycocyanin (APC) labeled anti-His (20 nM final). Antibodies were diluted in HTRF detection buffer and 5 l was dispensed on top of binding reaction. The reaction mixture was allowed to equilibrate for 30 minutes and signal (665 nm/620 nm ratio) was obtained using an EnVision fluorometer. Additional binding assays were established between PD-1-Ig/PD-L2-His (20 & 5 nM, respectively), CD80-His/PD-L1-Ig (100 & 10 nM, respectively) and CD80-His/CTLA4-Ig (10 & 5 nM, respectively). Competition studies between biotinylated SEQ ID NO:71 and human PD-L1-His were performed as follows. Inhibitors were pre-incubated with PD-L1-His (10 nM final) for 60 m in 4 l of assay buffer followed by addition of biotinylated SEQ ID NO:71 (0.5 nM final) in 1 l of assay buffer. Binding was allowed to equilibrate for 30 m followed by addition of europium crypated labeled Strepatavidin (2.5 pM final) and APC-labeled anti-His (20 nM final) in 5 l of HTRF buffer. The reaction was allowed to equilibrate for 30 m and signal (665 nm/620 nm ratio) was obtained using an EnVision fluorometer. The table below lists the IC.sub.50 values for Examples 1-108 of this disclosure measured in the PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay. The compounds of the present disclosure, as exemplified by Examples 1-297, showed IC.sub.50 values in the following ranges: A=0.006-0.10 M; B=0.11-1.00 M; C=1.01-10 M.

(172) TABLE-US-00003 PD1L1 HTRF Example IC.sub.50, (M) 1 A 2 B 3 A 4 C 5 B 6 A 7 B 8 0.146 9 B 10 B 11 B 12 B 13 B 14 B 15 B 16 1.945 17 B 18 B 19 B 20 B 21 B 22 B 23 B 24 B 25 B 26 B 27 B 28 B 29 B 30 C 31 B 32 B 33 B 34 B 35 A 36 B 37 A 38 B 39 4.184 40 A 41 B 42 B 43 B 44 B 45 B 46 B 47 B 48 B 49 9.492 50 B 51 B 52 B 53 A 54 B 55 B 56 B 57 A 58 B 59 B 60 B 61 C 62 B 63 C 64 C 65 A 66 B 67 B 68 B 69 B 70 B 71 B 72 B 73 B 74 B 75 0.953 76 B 77 B 78 A 79 A 80 C 81 B 82 3.186 83 B 84 C 85 B 86 B 87 B 88 B 89 B 90 B 91 B 92 C 93 B 94 B 95 B 96 B 97 B 98 B 99 B 100 B 101 1.076 102 A 103 A 104 B 105 A 106 B 107 0.329 108 B 109 B 110 A 111 A 112 A 113 A 114 0.043 115 A 116 A 117 B 118 B 119 B 120 B 121 B 122 B 123 A 124 A 125 A 126 B 127 A 128 A 129 B 130 B 131 B 132 B 133 B 134 A 135 A 136 A 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 A 147 A 148 A 149 A 150 A 151 A 152 A 153 A 154 A 155 B 156 A 157 B 158 A 159 B 160 B 161 A 162 B 163 0.093 164 A 165 B 166 B 167 B 168 B 169 B 170 B 171 B 172 0.107 173 A 174 0.022 175 B 176 B 177 B 178 A 179 B 180 B 181 A 182 B 183 B 184 B 185 A 186 A 187 B 188 B 189 B 190 B 191 B 192 B 193 B 194 B 195 B 196 A 197 A 198 A 199 B 200 0.080 201 B 202 0.018 203 B 204 B 205 B 206 B 207 B 208 B 209 B 210 B 211 B 212 B 213 B 214 B 215 B 216 B 217 B 218 B 219 B 220 A 221 B 222 B 223 B 224 B 225 B 226 B 227 B 228 B 229 B 230 A 231 B 232 B 233 A 234 A 235 B 236 A 237 A 238 A 239 A 240 A 241 A 242 A 243 A 244 A 245 B 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 A 254 A 255 A 256 A 257 A 258 A 259 A 260 B 261 B 262 B 263 B 264 A 265 A 266 B 267 A 268 A 269 A 270 A 271 A 272 B 273 A 274 A 275 A 276 A 277 A 278 A 279 A 280 B 281 A 282 A 283 A 284 A 285 B 286 B 287 B 288 B 289 A 290 B 291 A 292 B 293 B 294 B 295 A 296 B 297 B

(173) The compounds of Formula (I) possess activity as inhibitors of the PD-1/PD-L1 interaction, and therefore, may be used in the treatment of diseases associated with the PD-1/PD-L1 interaction. Via inhibition of the PD-1/PD-L1 interaction, the compounds of the present disclosure may be employed to treat infectious diseases such as Hepatitis C, and cancer.