WO2005113537B1

WO2005113537B1 - Urea antagonists of p2y1 receptor useful in the treatment of thrombotic conditions

Info

Publication number: WO2005113537B1
Application number: PCT/US2005/016525
Authority: WO
Filing date: 2005-05-11
Publication date: 2006-02-16
Anticipated expiration: 2006-11-12

Abstract

The present invention provides novel ureas containing N-aryl or N-heteroaryl substituted heterocycles and analogues thereof, which are selective inhibitors of the human P2Y1 receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y1 receptor activity.

Claims

[Received by the International Bureau on December 22, 2005 (22/12/2005); original claims 1, 10 and 11 have been amended. Other claims remain unchanged]

1. A compound of Formula (I):

(D or a stereoisomer or pharmaceutically acceptable salt, or solvate thereof, wherein: ring A is Cδ-io aryl substituted with 0-5 R¹ , or a 5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹ *, O, and S(O)_p, wherein said heterocycle is substituted with 0-5 R¹; ring B is phenyl or naphthyl substituted with 0-4 R?, or a 5- to 10-membered heteroaryl comprising: carbon atoms and 1-4 ring heteroatoms selected from N, NR¹¹, S(O )p, and O, wherein said heteroaryl is substituted with 0-4 R⁷; ring D is substituted with 0-5 R^6a and selected from:

wherein D₁ is a 5- to 7-raembered carbocycle or a 5-6-membered heterocycle comprising: carbon atoms and 0-3 ring heteroatoms selected from N, NR^{1 ]} , O, and S(O)p, and 0-2 carbonyl groups, and 0-3 double bonds;

W is O or S; X₂ is -(CRJ 6Rl 7)_s__{5 or} _(CR16R17)_tC(O)(CR^] ^Rl 7)_r;

R¹ is, independently at each occurrence, H, =0, F, Cl, Br, I₅ CF₃, -CF2CF3, OCF₃, -OCF₂CF₂H, -OCF₂CF₃, SiMe₃, -(CR^fR^f)_rOR^c, SR^C, CN₅ NO₂, -(CR^fR^f)_rNR¹²R¹³, -(CRfRfJr-C(O)R⁰, -(CR^fR^f)_r-C0₂R^c, -(CRfRf)_rC(O)NR¹²R¹³, -C(O)NR¹⁴(CR^fR^f)_tN¹²R¹3₅ -(CRfRf)_rOC(O)NR¹²R¹³, -(CRfRf)₁-NR¹⁴C(O)NR¹²R¹³, -(CR^fR^f)_rNR¹⁴C(0)R^d, -(CR^fRf)_rNR¹⁴C(O)OR^h, -NR¹⁴(CR^fRf)_nC(0)R^d, -NR¹⁴CO(CRfR^f)_nOR^c, -(CH₂V-CR¹³O=NOR⁰), -S(O)pNR¹²R¹³, -(CRfRf)_rNR¹⁴S(O)_pNR¹²R¹³, -NR¹⁴SO₂CF₃, -NR¹⁴S(0)_pR^d -S(O)₂CF₃, -S(O)Rd, -S(O)₂R^d, -OP(O)(OEt)₂, -O(CH₂)₂OP(O)(OEt)_2; 4,4,5,5-tetramethyl-l,3,2-dioxabprolarryl, C_1-8 alkyl substituted with 0-2 R^a, C₂-S alkenyl substituted with 0-2 R^a, C₂_8 alkynyl substituted with 0-2 R^a,

-(CR^fRf)_r-C₃.i3 carbocycle substituted with 0-5 R^b, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)p, wherein said heterocycle is substituted with 0-5 R^b; alternatively, two R¹S on two adjacent carbon atoms are combined with the carbon atoms to which they are attached, form a 5- to 10-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR^{1 1} _J O, and S(O)_p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 R^b;

R^6a is, independently at each occurrence, =0, F₅ Cl, Br, I, -(CR¹R¹VOR⁰, SR⁰, CN, NO₂, CF₃, OCF₃, -CF₂CF₃, -OCF₂CF₂H, -OCF₂CF₃, -(CRfR^f)_rNR¹²R¹³, -C(O)R⁰, -(CRfRf)_r-C(O)OR°, -(CRfRf)₁-C(O)NR¹²R¹³, -(CR^fRf)_rNR¹⁴C(O)R^d, -S(O)_pNR¹²R¹³, -S(O)R^d, -S(O)₂R^d, Si(Me)₃, Si(Ci_₄ alkyl)₃, Cμ₄ haloalkyl, Ci_4 haloalkyloxy-, C1-4 alkyloxy-, C₁^ alkylthio-, Ci-C₄ alkyl-C(O)-, Ci_₄ alkyl-O-C(O)-, C]_₄ allcyl-C(O)NH-, C_μ8 alkyl substituted with 0-1 R^a, C2-8 alkenyl substituted with 0-1 R^a, C2-8 alkynyl substituted with 0-1 R^a,

carbocycle substituted with 0-2 R^e, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹ *, O₅ and S(O)p, wherein said heterocycle is substituted with 0-2 R^e; alternatively, when two R^^a groups are attached to the same carbon atom or silicon atom, together with the carbon atom or silicon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N₅ NR¹¹, O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b; alternatively, when two R^6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR¹¹, O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b;

R⁷ is, independently at each occurrence, H, =0, F, Cl, Br, I₅ OCF3, CF₃, OR^C, - SR^C, CN, NO₂, -NR¹²R¹³, _c(0)R^c, -C(O)OR^C, -C(O)NR¹²R¹³, -NR¹⁴C(0)R^d, -S(O)pNR¹²R¹³, -S(O)R^d, -S(O)₂R^d, C_{1 -8} alkyl substituted with 0-2 R^a, C₂-S alkenyl substituted with 0-2 R^a, C₂-S alkynyl substituted with 0-2 R^a, -(CR^fR^f)_r-C₃_io carbocycle substituted with 0-3 R^b, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR^7b, O₅ and S(O)_p, wherein said heterocycle is substituted with 0-3 R^b; alternatively, two R⁷S on two adjacent carbon atoms form a 5- to 7-membered carboc3'clic or heterocyclic ring comprising: carbon atoms and 0-3 ring heteroatoms selected from O, N₅ NR^7b, and S(O)_p, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^7c;

R^7b is H, C₁₄ alkyl, -C(O)(Ci_4 alkyl), -C(O)phenyl, -C(O)benzyl, or benzyl; R^7c is, independently at each occurrence, H, F, Cl, Br₅ 1₅ OCF₃, CF₃, OR^C, SRc, CN, NO₂, -NR¹²R¹³, -C(O)R⁰, -C(O)ORc, -C(O)NR¹²R¹³, -NR^C(O)Rd -S(CO_pNR¹²R¹³, -S(O)R^d, -S(O)₂R^d, _C]_₄ ^i phenyl substituted with 0-3 Rb, or benzyl substituted with 0-3 R^b;

R¹¹ is, independently at each occurrence, H, Cj_-4 alkoxy, C_j.g alkyl substituted with 0-2 R^a, C2-4 alkenyl substituted with 0-1 R^a, C2-4 alkynyl substituted with 0- 1 R^a, -C(O)(C i^ alkyl), -C(O)(CH₂)_n(C₃_6 cycloalkyl),

-C(0)(CH₂)_Π(C₆-JO aryl), -C(O)(CH₂)_n(5- to 10-membered heteroaryl), -C(O)O(CL₈ alkyl), -C(O)O(CH₂)_n(C₃_₆ cycloalkyl), -C(0)0(CH₂)_n(C₆.io aryl), -C(O)O(CH₂)n(5- to 10-memberedheteroaryl), -C(O)O(CH₂)₂_4(Ci_₄ alkyl), -C(O)NH(C i_8 alkyl), -C(O)NH(CH₂)_n(C₃-₆ cycloalkyl), -C(0)NH(CH₂)_n(C₆-io aryl), -C(O)NH(CH₂)_n(5- to 10-membered lieteroaryl), -S(O)₂(CL₈ alkyl), -S(O)₂(CH₂)_n(C₃-6 cycloalkyl), -S(O)₂(CH₂)_n(C₆_₁₀ aryl), -S(O)₂(CH₂)_n(5- to 10-membered heteroaryl), -(CR^fR^f)_rC₃.io carbocycle, or -(CR^fR^f)_r-5- to 10-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, aryl, and carbocycle are substituted with 0-2 R^, and said heteroaryl and heterocycle are substituted with 0-2 R^b and comprise: carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p;

R¹² is, independently at each occurrence, H₅ CL6 alkyl, -C(O)(Ci_6 alkyl), -C(0)(CH₂)_n(C6-io aryl), -C(O)(CH₂)_n(5- to 10-membered heteroaryl), -C(O)O(CL₄ alkyl), -C(O)OCH₂(C₆-I₀ aryl), -(CH₂)_nC(O)OCH₂(5- to 10-membered heteroaryl), -(CH₂)_nOC(0)(Ci .4 alkyl), -(CH₂)_nOC(0)(C6-io aryl), -(CH₂)_nOC(O)(5- to 10-membered heteroaryl), -(CH₂)_nC(O)O(CL4 alkyl), -(CH₂)_nC(O)O(C₆-_{] 0} aryl), -(CH₂)_nC(O)O(5- to 10-membered heteroaryl), -(CH₂)_nC(O)NH(Ci_₆ alkyl), -(CH₂)_aC(0)NH(C_6-io aryl), -(CH₂)_nC(O)NH(5- to 10-membered heteroaryl), -(CH₂)tOC(O)NH(Ci.₆ alkyl), -(CH₂)_tOC(0)NH(C₆_io aryl),

-(CH₂)_tOC(O)NH(5- to 10-membered heteroaryl), -S(O)₂(CL₆ alkyl), -S(0)₂(CH₂)_n(C6-io aryl), -S(O)₂(CH₂)_n(5- to 10-membered heteroaryl),

aryl), or -(CR^fR^f)_n- 5- to 10-membered heteroaryl; wherein said alkyl, and aryl are substituted with 0-2 RS; and said heteroaryl is substituted with 0-2 RS and comprises: carbon atoms and 1-4 heteroatoms selected from N, NR^{1 !}, O, and S(0)_p;

R¹³ is, independently at each occurrence, H, Cμg alkyl, or -(CH2)n-pb-enyl; alternatively, R¹² and R¹³, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising: carbon atoms and 1-2 additional heteroatoms selected from N, NR¹¹, O, and S(O )_p;

R¹⁴ is, independently at each occurrence, H, C_\.β alkyl substituted with 0-2 R^14a, C₂-6 alkenyl substituted with 0-2 R^14a, C₂-6 alkynyl substituted with 0-2 R^14a, -(CH2)_r-C34o carbocycle substituted with 0-3 RS, or -(CH₂)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)p, wherein said heterocycle is substituted with 0-3 RS;

R^14a is, independently at each occurrence, H, Ci_4 alkyl, OR^f, Cl, F, Br, I, =0, CF₃, CN₅ NO₂, -C(O)Rf -C(O)OR^f, -C(O)NR¹²R¹³, or -S(O)_pR^f;

R¹⁶ is, independently at each occurrence, H, F₅ C_j_6 alkyl substituted with 0-2 R^a, C2-6 alkenyl substituted with 0-2 R^a, C2-6 alkynyl substituted with. 0-2 R^a, or -(CH₂)_r-phenyl substituted with 0-2 R^b;

R¹⁷ is, independently at each occurrence, H, OH, Cμg alkyl, or -(CH₂)n-plienyl; alternatively, R¹⁶ and R¹⁷ on the same carbon atom combine to form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR¹¹, O, and S(O)_p, 0-1 carbonyl, and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b; alternatively, two R¹⁶ groups on adjacent atoms combine to form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR¹ *-, O, and S(O)_p, 0-1 carbonyl, and 0-3 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b;

R^a is, independently at each occurrence, H, =0, F, OCF3, CF3, OR^C, SR^C, CN₅ -NRl²Rl³, _c(0)R^c, -C(O)OR^C, -C(O)NR¹²R¹³, -NR¹⁴C(O)R^d, -S(O)_pNR'²R¹³, -S(O)R^d, -S(O)₂R^d, -(CH₂)r-C₃.io carbocycle substituted with 0-3 R^e, or -(CH₂)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR/, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^e;

R^b is, independently at each occurrence, H, =0, F, Cl, Br, I, -(CH2)_rOR^c, SRc, CN, NO₂, CF₃, OCF₃, -(CH₂VNR¹²R¹³, -C(O)R^C, ~(CH₂)_r-C(O)ORc, -(CH₂VC(O)NR¹²Rl³, -NR^C(O)Rd, -S(O)_pNR¹²R³³, -S(O)R^d, -S(O)₂R^d, Ci_4 haloalkyl, C1-4 haloalkyloxy-, Cj_4 alkyloxy-, C3-4 alkylthio-, C1.4 alkyl-C(O)-, C_M alkyl-O-C(O)-, CM alkyl-C(O)NH-_? C_1-8 alkyl substituted with 0-2 R^a, C₂.₈ alkenyl substituted with 0-2 R^a, C₂.g allcynyl substituted with 0-2 R^a, -(CH₂VC₃-Io carbocycle substituted with 0-3 R^e, or -(CH₂)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf O, and S(O)p, wherein said heterocycle is substituted with 0-3 R^e;

R^c is, independently at each occurrence, H, -0P(0)(0Et)2, Cμg alkyl substituted with 0-2 R^e. C₂-S alkenyl substituted with 0-2 R^e, C₂_8 alkynyl substituted with 0-2 R^e, -(CR^fR^r)_r-C₃-8 cycloalkyl substituted with 0-2 R^e, -(CR^fR^f)_r-C₆-io aryl substituted with 0-2 R^e, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N₅ NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e;

R^d is, independently at each occurrence, CF₃, OH, C1.4 alkoxy, Ci_6 alkyl, -(CH₂)_r-C₃_io carbocycle substituted with 0-2 R^e, or -(CH₂VS- to 10- membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR^f, O₅ and S(O)p, wherein said heterocycle is substituted with 0-2 R^e;

R^e is, independently at each occurrence, H, =0, -(CH2)_r-0R^f, F, Cl, Br, I, CN, NO₂, -(CH₂VNR¹²R¹³, -C(O)R^f, -(CH₂VC(O)ORf -NR¹⁴C(O)Rf -(CH₂VC(O)NR¹²R¹³, -SO₂NR¹²R¹³, -NRWSO₂NR¹²R¹³, -NR¹⁴SO₂-Ci-₄ alkyl, -NRWSO₂CF₃, -NR¹⁴SO₂-phenyl, -S(O)₂CF₃, -S(O)_p-OR\ -(CF₂)_rCF₃, Si(Me)₃, Si(Me)₂(^-Bu), Si(Ci-4 alkyl)₃, Cχ_8 alkyl substituted with 0-2 Rg, C₂-8 alkenyl substituted with 0-2 RS₅ C₂_8 alkynyl substituted with 0-2 RS, -(CH₂)_rC₃.g cycloalkyl substituted with 0-2 RS, -(CH₂)_rC6-io aryl substituted with 0-2 R^§, or -(CH2)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR/, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 RS;

Rf is, independently at each occurrence, H, Cμg alkyl, or -(CH2)_n-phenyl; Rg is, independently at each occurrence, H, =0, OR^f, F, Cl, Br, I, CN, NO2,

-NR^fR^f, -C(O)Rf -C(O)ORf, -NR^fC(0)R^f, -C(O)NRfRf -SO₂NRfRf -NRfSO₂NRfRf -NR^fSO₂-Ci_4 alkyl, -NR^fSO₂CF₃, -NR^fSO₂-phenyl, -S(O)₂CF₃, -S(0)_P-CM alkyl, -S(O)_p-phenyl, -(CF₂)_rCF₃, C).₆ alkyl, C₂-6 alkenyl, or C₂.₆ alkynyl;

R*¹ is, independently at each occurrence, C]_g alkyl substituted with 0-2 RS, -(CH2)_trphenyl substituted with 0-2 RS, or -(CH₂)_n-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf O, and S(0)_p, wherein said heterocycle is substituted with 0-2 R8;

R" is, independently at each occurrence, H, C_]__$ alkyl substituted with 0-2 R^§. -(CH₂)_n-phenyl substituted with 0-2 RS, or -(CH₂)_n-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRf O, and S(O)_p, wherein said heterocycle is substituted with 0-2 RS; n, at each occurrence, is selected from 0, 1, 2, 3, and 4; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, and 4; s, at each occurrence, is selected from 0, 1, 2, and 3; and t, at each occurrence, is selected from 1, 2, 3, and 4; provided that when ring D is dihydroindolyl, ring A is other than thiazolyl.

2. A compound according to Claim 1, wherein: W is O; and X₂ is a bond, -CH₂-, -CH₂CH₂-, -CH₂CHMe-, -CH₂CO-, or

ompound according to Claim 1, wherein: ring B is substituted with 0-3 K7 and selected from:

ring D is substituted with 0-5 R^6a and selected from:

wherein D₁ is selected from: cyclopentyl, cylohexyl, piperidiii}4, tetrahydropyi"aiiyl, phenyl, pyridinyl, pyrimidinyl, thiophenyl, pyrrolyl, fuxanyl and thiazolyl;

W is O; and

X2 is a bond.

4. A compound according to Claim 1, wherein: ring A is substituted with 0-5 R¹ and selected from: phenyl, pyridinyl, pyrimidinyl, furanyl, isoxazolyl, thiazolyl, thiadiazqlyl, benzothiazolyl, indolyl, and benziniidazolyl.

5. A compound according to Claim 1, wherein: ring A is substituted with 0-4 R¹ and selected from: phenyl, pyridyl, isoxazolyl, furanyl, thienyl, thiazolyl, and benzothiazolyl; and ring B is substituted wititi 0-3 R⁷ and selected from:

6. A compound according to Claim 1, wherein: R¹ is, independently at each occurrence, F, Cl, Br, I, CF3, -CF2CF3, OCF3,

-OCF₂CF₂H, -OCF₂CF₃, SiMe₃, -(CR^fR^f)_rOR^c, SR^C, CN₅ NO₂, -(CR^fRf)_rNR¹²R¹³, -(CR^fR^f)_rC(O)R^c, -(CR^fR^f)_r-CO₂R^c, -(CR^fR^f)_r-C(O)NR¹²R¹³, -OP(O)(OEt)₂, 4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl, C₁ _g alkyl substituted with 0-2 R^a, C2-8 alkenyl substituted with 0-2 R^a, C₂-S alkynyl substituted with 0-2 R^a, -(CRfRf)₁-C₃.13 carbocycle substituted with 0-5 R^b, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR* 1, O, and S(O)p, wherein said heterocycle is substituted with 0-5 Rb; alternatively, two R¹S on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or • heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR¹¹ _J O, and S(O)_p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 R^b.

7. A compound according to Claim 1, wherein:

180 005/016525

R^6a is, independently at each occurrence, F₅ Cl, Br, I, -(CRiRVOR⁰, SR^C, CN, CF₃, OCF₃, -CF₂CF₃, -OCF₂CF₂H, -OCF₂CF₃, -NR¹²R¹³, -C(O)Rc, -(CR^fR^f)_rC(O)OR^c, -Si(Me)₃, CM haloalkyl, C_{] -4} haloalkyloxy-, C 1-4 alkyloxy-, CM alkylthio-, Ci-C₄ alkyl-C(O)-, Cμ alkyl-O-C(O)-, CM alkyl-C(O)NH-, C_1-8 alkyl substituted with 0-2 R^a ₅ C2-8 alkenyl substituted with 0-2 R^a, C2-8 alkynyl substituted with 0-2 R^a, -(CR^fR^f)_r-C_3-1o carbocycle substituted with 0-2 R^e, or -(CRfRf)₁-S- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹ *, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e; and alternatively, when two R^^a groups are attached to the same carbon atom or silicon atom, together with the carbon atom or silicon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N, NR¹ ' , O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b; alternatively, when two R^6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR^{1 ]} , O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b.

8. A compound according to Claim 1, wherein:

R¹¹ is, independently at each occurrence, H, Cμg alkyl substituted with 0-2 R^a ₅ -C(O)(CH₂)_n(C₃.₆ cycloalkyl), -C(O)(CH₂)_πphenyl, -C(O)O(C_1-8 alkyl),

-C(O)O(CH₂)_n(C₃.6 cycloalkyl), -C(O)O(CH₂)nphenyl, -C(O)O(CH₂)₂-4(Ci-4 alkyl), -C(O)NH(CL₆ alkyl), -S(O)₂(C_1-6 alkyl), -S(O)₂(CH₂)_πphenyl, -(CRfRf)₁-C_3-7 cycloalkyl, -(CR^fR^f)_r-phenyl, or -(CRfRf)₁-S- to 6-membered heterocycle; wherein said alkyl, cycloaUcyl, phenyl, and aryl are substituted with 0-2 R^b, and said heteroaryl

181 and heterocycle are substituted with 0-2 R^b and comprise: carbon atoms and 1-4 heteroatoms selected from N, NR/, O, and S(O)_p.

9. A compound according to Claim 1, wherein: ring A is substituted with 0-4 Rl and selected from: phenyl, pyridyl, isoxazolyl, fαranyl, thienyl, thiazolyl, and benzothiazolyl; ring B is substited with 0-3 R⁷ and selected from:

ring D is substituted with 0-5 R^^a and selected from:

182

wherein D₁ is selected from: cyclopentyl, cyiohexyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, thiophenyl, pyrrolyl, furanyl and thiazolyl;

W is 0;

X₂ is a bond; R¹ is, independently at each occurrence, F, Cl, Br, I₅ CF3, -CF₂ CF3, OCF3,

-OCF₂CF₂H, -OCF₂CF₃, SiMe₃, -(CR^fR^f)_rOR^c, SR^C, CN, NO₂, -(CR^fR^f)_rNR¹²R^{] 3}, -(CR^fR^f)_r-C(0)R^c, -(CRfR^f)_r-CO₂R^c, -(CR^fR^f)_r-C(O)NR¹²R¹³, -OP(O)(OEt)₂, 4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl, C_μ8 alkyl substituted with 0-2 R^a, C2-8 alkenyl substituted with 0-2 R^a, C₂_s alkynyl substituted with 0-2 R^a, -(CR^fR^f)_rC3.i3 carbocycle substituted with 0-5 R^b, or -(CR^fR^f)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N₅ NR¹ ', O₅ and S(O)_p, wherein said heterocycle is substituted with 0-5 BP; alternatively, two R¹S on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising: carbon atoms and 0-3 additional heteroatoms selected from N, NR^{1 1}, O, and S(O)_p, and 0-2 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-4 R^b;

183 R^6a is, independently at each occurrence, F, Cl, Br, I, -(CRiROrOR⁰, SR^C, CN, CF₃, OCF₃, -CF₂CF₃, -OCF₂CF₂H₅ -OCF₂CF₃, -NR¹²R¹³, -C(O)R^C, -(CR^fR^f)_rC(0)0R^c, -Si(Me)₃, CM haloalkyl, C _M haloalkyloxy-, C 1-4 alkyloxy-, C1.4 alkylthio-, Ci-C₄ alkyl-C(O)-, C_M alkyl-O-C(O)-, C_M alkyl-C(O)NH-, C_1-8 alkyl substituted with 0-2 R^a, C2-8 alkenyl substituted with 0-2 R^a, C2-8 alkynyl substituted with 0-2 R^a, -(CR^fR^f)_rC₃-io carbocycle substituted with 0-2 R^e, or -(CRfRf)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatorns selected from N, NR¹ ' , O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e; alternatively, when two R^6a groups are attached to the same carbon atom or silicon atom, together with the carbon atom or silicon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N, NR^{1 3} , O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b; alternatively, when two R^6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR^{1 1} _J O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b; and

R¹¹ is, independently at each occurrence, H, Cμg alkyl substituted with 0-2 R^a, -C(θχCH₂)n(C₃-₆ cycloalkyl), -C(O)(CH₂)nphenyl, -C(O)O(CL₈ alkyl), -C(O)O(CH₂)n(C₃-6 cycloalkyl), -C(O)O(CH₂)_nphenyl, -C(O)O(CH₂)₂^(C_M alkyl), -C(O)NH(Ci^ alkyl), -S(O)₂(CL₆ alkyl), -S(O)₂(CH₂)_nphenyl₅ -(CRfRf)_rC₃-₇ cycloalkyl, -(CR^fR^f)_rphenyl, or -(CRfRf)₁-S- to 6-membered heteroc3'cle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 R^b, and said heteroaryl and heterocycle are substituted with 0-2 R^b and comprise: carbon atoms and 1-4 heteroatoms selected from N, NRf O, and S(O)_p.

184 10. A compound according to claim 1, wherein the compound is of Formula (Ia):

(Ia) or a stereoisomer or pharmaceutically acceptable salt, or solvate thereof, wherein: ring A is

ring B is substituted with 0-3 R⁷ and selected from:

185

ring D is substituted with 0-5 R^6a and selected from:

R¹, R^la, R^]b, and R^lc are, independently at each occurrence, H, F, Cl, Me, NH₂, or OH;

R², R^2a, R2b, R2c₅ R2d _R3₅ R3a _R3_{Cj R}3d_{5 R}4_{s R}4a_{5 R}4_{Cj R}5_{? R}5a_{? R}5_Cj ^d _R5d are, independently at each occurrence, H, F, Cl, Br, I, CF3, -CF2CF3, OCF3, -OCF₂CF₂H, -OCF₂CF₃, SiMe₃, -(CR^fRf)_r-OR^c, SR^C, CN, NO₂, -(CRfRf)₁-NR^RlS₅

186 -(CR^fR^f)_u-C(O)R^c, -(CR^fR^f)_r-CO₂R^c, -(CRfRf)₁₁-C(O)NR¹²R¹³, -OP(O)(OEt)₂, 4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl, C_1-8 alkyl substituted with 0-2 R^a, -(CR^fRf)_u-C3-6 carbocycle substituted with 0-2 R^b, or -(CR^fR^f)_u-5- to 6-membered lieterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^b; alternatively, Rl + R², R² + R³, R³ + R⁴, R⁴ + R⁵, R^la + R^2a, R^2a + R^3a, _R3a + _R4a _R4a _{+ R}5a _Rlb + _R2b_{s R}2b + _R5d _Rl c + _R3c_{5 R}2c + _R3c_{? R}2d + _R3d

_R3c + _R4c_{; or R}4c + _R5c_; combine with the carbon atoms to which they are attached, form 5- tolO-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N, NR¹ *, O, and S(O)_p, 0-1 carbonyl group, and additional 0-2 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b;

R^6a is, independently at each occurrence, F, Cl, Br, I, -(CR^fRf)_r-OR^c, SR^C, CN₅ CF₃, OCF₃, -CF₂CF₃, -OCF₂CF₂H, -OCF₂CF₃, -NRl²R¹³, -C(O)R^C, -(CRfRf)₁-C(O)OR⁰, -Si(Me)₃, Ci_₄ haloalkyl, Ci_₄ haloalkyloxy-, C1-4 alkyloxy-, CM alkylthio-, C₁-C₄ alkyl-C(O)-, C].₄ alkyl-O-C(O)-, Ci_₄ alkyl-C(O)NH-, Cμg alkyl substituted with 0-2 R^a, C₂_8 alkenyl substituted with 0-2 R^a C₂.g alkynyl substituted with 0-2 R^a, -(CR^fR^f)_r-C₃.io carbocycle substituted with 0-2 R^e, or -(CRfRf)_r-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NRl 1, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e; alternatively, when two R^^a groups are attached to the same carbon atom or silicon atom, together with the carbon atom or silicon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N, NR¹¹, O, Si, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b; alternatively, when two R^^a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocj'clic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N,

187 NR^{1 1}, O, Si, and S(0)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 R^b;

R⁷ is, independently at each occurrence, H, =0, F, Cl, Br, I, OCF3, CF3, OR^C, SRc, CN, NO₂, -NR¹²R¹³, -C(O)R^C, -C(O)OR^C, -C(O)NR¹²R¹³, -NR¹⁴C(0)R^d, -S(O)PNR¹²R¹³ , -S(O)R^d, -S(O)₂R^d, C_1-6 alkyl substituted with 0-2 R^a,

-(CH2)u-C3-io carbocycle substituted with 0-3 R^b, or -(CH2)_u-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR^7b, O, and S(O)p, wherein said heterocycle is substituted with 0-3 R^b;

R^7b is H, C_1-4 alkyl, -C(O)(Ci_₄ alkyl), -C(O)phenyl, -C(O)benzyl, or benzyl; R¹¹ is, independently at each occurrence, H, Cμg alkyl substituted with 0-2

Ra, -C(O)(CH₂)_n(C₃-6 cycloalkyl), -C(O)(CH₂)_πphenyl, -C(O)O(CL₈ alkyl), -C(O)O(CH₂)_n(C₃-6 cycloalkyl), -C(O)O(CH2)nphenyl, -C(O)O(CH₂)₂-4(Ci-4 alkyl), -C(O)NH(C_1-6 alkyl), -S(O)₂(Ci^ alkyl), -S(O)₂(CH₂)_nphenyl, -(CR^fR^f)_r-C₃_₇ cycloalkyL -(CR^fR^f)_rphenyl, or -(CR^fR^f)_r-5- to 6-membered heterocycle; wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 R^b, and said heteroaryl and heterocycle are substituted with 0-2 R^b and comprise: carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p;

R¹² is, independently at each occurrence, H, C 1-6 alkyl, -C(O)(C_1-6 alkyl), -C(O)(CH₂)_nphenyl, -C(O)(CH₂)_n(5- to 6-membered heteroaryl), -C(O)O(C_1-4 alkyl), -C(O)OCH₂phenyl, -(CH₂)_nC(O)OCH₂(5- to 6-membered heteroaryl), -(CH₂)_X1OC(O)(C_1-4 alkyl), -(CH₂)_nOC(O)phenyl, -(CH₂)_nOC(O)(5- to 6-membered heteroaryl), -(CH₂)_nC(O)O(C_1-4 alkyl), -(CH₂)_nC(O)Ophenyl, -(CH₂)_nC(O)O(5- to 6-membered heteroaryl), -(CH₂)_πC(O)NH(d.₆ alkyl), -(CH₂)_nC(O)NHphenyL -(CH₂)_πC(O)NH(5- to 6-membered heteroaryl), -(CH₂)_tOC(O)NH(Ci-₆ alkyl), -(CH₂)_tOC(O)NHphenyl, -(CH₂)_tOC(O)NH(5- to 6-membered heteroaryl), -S(O)₂(C_1-6 alkyl), -S(O)₂(CH₂)_nphenyl, -S(O)₂(CH₂)_n(5- to 6-membered heteroaryl),

or -(CRfRf)_n- 5- to 6-membered heteroaryl; wherein said alkyl, and arjd are substituted with 0-2 RS; and said heteroaryl is substituted with 0-2 Rg and comprises: carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)_p;

R¹³ is, independently at each occurrence, H, Cμg alkyl, or -(CH2)_n-phen}4; alternatively, R¹² and R¹³, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising: carbon atoms and 1-2 additional heteroatoms selected from N, NR¹¹, O, and S(O)_p;

R¹⁴ is, independently at each occurrence, H, Cμg alkyl substituted with 0-2 R^14a, C₂_6 alkenyl substituted with 0-2 R^14a, Ci-β alkynyl substituted with 0-2 R^14a, -(CH2)_U-C₃_6 cycloalkyl substituted with 0-3 RS, -(CH₂)_u-phenyl substituted with 0-3 Rg, or -(CH₂)_u-5- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR¹ *, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 Rg;

R^14a is, independently at each occurrence, H, C1-4 alkyl, ORf, Cl, F, Br, I, =0, CF₃, CN₅ NO₂, -C(O)Rf, -C(O)ORf -C(O)NR¹²R¹³, or -S(O)_pR^f; R^a is, independently at each occurrence, H₃ =0, F, OCF3, CF₃, OR^C, SR^C, CN,

-NR¹²R¹³, -C(O)R^C, -C(O)OR^C, -C(O)NR¹²R¹³, -NR¹⁴C(0)R^d, -S(O)_pNR¹²R¹³, -S(O)R^d, -S(O)2R^d, -(CH₂)u-C₃_io carbocycie substituted with 0-3 R^e, or -(CH2)u-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^e;

R^b is, independently at each occurrence, H, =0, F, Cl, Br, I, -(CH2)_r-OR^c, SR^C, CN, NO₂, CF₃, OCF₃, -(CH₂)_r-NR¹²R¹³, -C(O)R⁰, -(CH₂)_rC(O)OR^c, -(CH₂VC(O)NR¹²R¹³, -NR¹⁴C(O)R^d, -S(O)_pNR¹²R¹³, -S(O)R^d, -S(O)₂R^d Ci-4 haloalkyl, Ci_4 haloalkyloxy-, C1-4 alkyloxy-, Cχ_4 alkylthio-, Ci_4 alkyl-C(O)-, C 1.4 alkyl-O-C(O)-, C j .4 alkyl-C(O)NH-, C_1-6 alkyl substituted with 0-2 R^a, C2-4 alkenyl substituted with 0-2 R^a, C2-4 alkynyl substituted with 0-2 R^a, -(CH2)u-C₃_io carbocycie substituted with 0-3 R^e, or -(CH₂)u-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^e;

189 R^c is, independently at each occurrence, H, -0P(0)(0Et)₂, Ci_8 alkyl substituted λvith 0-2 R^e, C2-4 alkenyl substituted with 0-2 R^e, C2-4 alkynyl substituted with 0-2 R^e, -(CH2)u-C3-8 cycloalkyl substituted with 0-2 R^e, -(CH₂)_u-C6-io ^Y¹ substituted with 0-2 R^e, or -(CH₂)_u-5- to 10-membered heterocycle comprising: carbon, atoms and 1-4 heteroatorns selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e;

R^d is, independently at each occurrence, CF3, OH₅ C] .4 alkoxy, Cj.6 alkyl, -(CH2)u-C3-io carbocycle substituted with 0-2 R^e, or -(CH₂)_u-5- to 10- membered heterocycle comprising: carbon atoms and 1-4 heteroatorns selected from N, NRf, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e;

R^e is, independently at each occurrence, H, =0, -(CH2)_r-0R^f, F, Cl, Br, I, CN, NO₂, -(CH₂)_U-NR¹²R¹³, -C(O)Rf -(CH₂)_r-C(O)OR^f, -NR¹⁴C(0)R^f, -(CH₂VC(O)NR¹²RlS₅ -SO₂NRl²Rl³, -NRl⁴SO₂NR¹²Rl³, -NRWSO₂-C_1-4 alkyl, -NRl⁴SO₂CF₃, -NR¹⁴SO₂-ρhenyl, -S(O)₂CF₃, -S(O)_p-Cμ₄ alkyl, -S(O)_p-phenyl, ~(CF₂)_UCF3, Ci_6 alkyl substituted with 0-2 RS, C₂_4 alkenyl substituted with 0-2 Rg, C2-4 alkynyl substituted with 0-2 RS₅ -(CH₂)_U-C₃-S cycloalkyl substituted with 0-2 RS, -(CH2VC6-10 aryl substituted with 0-2 RS, or -(CH₂)_u-5- to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatorns selected from N, NR^f, O, and S(O)_p, Λvherein said heterocycle is substituted with 0-2 RS; R^f is, independently at each occurrence, H, or C_j-4 alkyl;

RS is, independently at each occurrence, H, =0, OR^f, F, Cl, Br, I, CN, NO₂, -NRfRf -C(O)Rf -C(O)ORf -NRfC(O)R^f, -C(O)NRfRf -SO₂NR^fR^f, -NR^fSO₂NR^fR^f ₅ -NR^fSO₂-Ci_₄ alkyl, -NRfSO₂CF₃, -NR^fSO₂-phenyl, -S(O)₂CF₃, -S(0)_p-Ci-4 alkyl, -S(O)_p-phenyl, -(CF₂)uCF₃, Cχ_6 alkyl, C_2-4 alkenyl, or C₂.₄ alkynyl; Rh is, independently at each occurrence, C^g alkyl substituted with 0-2 Rg, or

-(CH₂)n-phenyl substituted with 0-2 Rg; n, at each occurrence, is selected from 0, 1, and 2; p, at each occurrence, is selected from O₅ I₅ and 2; r₅ at each occurrence, is selected from O₅ 1, 2, 3₅ and 4;

190 s, at each occurrence, is selected from O, 1, 2, and 3; t, at each occurrence, is selected from 1 and 2; and u, at each occurrence, is selected from O, 1, and 2; provided that when ring D is dihydroindolyl, ring A is other than thiazolyl.

11. A compound according to claim 1, wherein the compound is of Formula (Ia):

ring B is

191

ring D is selected from:

192

wherein the phenyl ring in each of the structures is substituted with 0-2 R^6a;

R¹, R^la, and R^lb ai-e, independently at each occurrence, H, F, Cl, Me, NH2,

OH,

or phenoxy substituted with 0-2 R^e;

. R², R^2b, R^2c, and R^2d are, independently at each occurrence, H, F, Cl, Br,

193 Ci_-6 alkyl, Ci_₆ aUcoxy, -O(CH₂)₈CO₂Me, -O(CH₂)₂C(Me)2θMe₃ -O(CH₂)₂OCOMe, NO₂, CF₃, CF₂CF₃, 2-CH₂N(Me)₂-Ph, Ph, cyclohexoxy, 4-Me-cyclohexoxy, cyclohexyhnethoxy, (1 -Bn-pyrrolidin-3-3'l)oxy, (1 -Bn-pyrrolidin-3-yl)methoxy, (1 H-pyrrol-1 -yl)ethoxy, (2-Bu-l H-irαidazol-4-yl)methoxy, (1 -Ph- IH-1, 2,3 -triazol-4-yl)methoxy, l-Bn-piperidin-3-oxy, l-Bn-piperidin-4-oxy, 4-Bn-morpholiii-2-yl-methoxy, benzoxy, 4-CO₂Me-benzoxy or SiMe₃;

R³, R^3a ₅ R^3c, and R^3d are, independently at each occurrence, H, F, Cl, Br, Ci_6 alkyl, Ci_₆ alkoxy, -OCH(Me)CH₂O-^-Bu, CF₃, OCF₃, -OCF₂CF₂H, -OCF₂CF₃, SiMe₃, NH₂, NMe₂, -CH₂NMe₂, NEt₂, -NHPh, -N(Me)Ph, -NH(4-0Me-Ph), -NH(2-CF₃-Ph), -NH(2-f-Bu-Ph), -CH(Me)N(Me)(3-CF₃-Bn), -CH(Me)N(Me)(4-CF₃-Bn), -CH(Me)N(Me)(furan-2-ylmethyl),

-CH(Me)N(Me)(tliien-2-ylmethyl), -CH(Me)NHCH(Me)Ph, -CH(Me)OH, -CH(Me)O(Z-Pr)₅ -CH(Me)O(Z-Bu), -CH(Me)O(3-CF₃-Bn), -CH(Me)O(4-CF₃-Bn),

-CH(Me)O(l-Bn-pyrrolidm-3-ylmethyl), -CH(Me)OCH₂C(Me)₂CH₂NMe₂, -CH(Me)OBn, -CH(Me)0(4-z-Pr-Bn), -CH(Me)0(4-0Ph-Bn),

-CH(Me)O(3,5-diCl-Bn), -CH(Me)OCH₂(l-Bn-piperidin-4-yl), -CH₂NHBn, -CH₂NH(4-CF₃-Bn), -CH₂N(Me)Bn, -CH(Me)NHCH₂-pyridin-2-yl, -CH(Me)NHCH₂-p>τidin-4-yl, -CH(Me)NHCH₂(6-Cl-pyridin-3-yl), -CH(Me)N(Me)(Z-Bu), -CH(Me)N(Me)Bn, -CH(Me)N(Me)(4-0Me-Bn), -CH(Me)N(Me)(4-F-Bn), -CH(Me)N(Me)(3-Cl-Bn), -CH(Me)N(Me)(4-Cl-Bn), -CH(Me)N(Me)(3,4-diCl-Bn), -CH(Me)N(Me)CH₂CH₂Ph, -CH(Me)N(Me)CH₂-pyridin-2-yl, -CH(Me)N(Me)CH₂-pyridin-3-yl, -CH(Me)N(Me)CH₂-pyridin-4-yl, -CH(Me)N(Me)CH₂-fui-an-2-yl, -CH(Me)N(Me)CH₂-thien-2-yl, -CH(Me)N(Me)CH₂-(5-Me-thien-2-yl), -CH(Me)N(Me)CH₂-(5-Cl-thien-2-yl), -CH(Me)N(Et)Bn, -CH(Me)N(Et)(4-Me-Bn), -CH(Me)N(Et)(2-Cl-Bn), -CH(Me)N(Bn)CH₂CN, -CH(Me)N(Bn)CH₂CH₂OH, -CH(Me)N(Bn)CH₂CO₂Me₅ -CH(Me)N(Bn)CH₂CONMe₂, -CH(Me)N(Bn)CH₂CON(Me)(Bn), -CH(Me)-isoindolin-2-yl, -CH(Me)-(1 ,2,3, 4-tetrah3^droisoquinolin-2-yl), -CH(Me)(4-Bn-piρerazin-l -yl), COMe, CO₂Me, CO₂Et, -CH₂CO₂Me₅ -C(Me)₂CO₂Me, -O(CH₂)₅CO₂Et₅

194 -0(CH₂)SCO₂Me, -O(CH₂)₂C(Me)₂OMe, -O(CH₂)₂OCOMe, -OCH₂C(Me)₂CH₂NMe₂, Ph, 2-CH₂OH-Ph, 2-CH₂N(Me)₂-Ph, 3-CH₂N(Me)₂-Ph, 4-CH₂N(Me)₂-Ph, 2-((3-OH-pyrrolidin-l-yl)methyl)-Ph, phenoxy, 2-f-Bu-phenoxy, 2-CF3-phenoxy, Bn, benzoxy, 3-OMe-benzoxy, 4-CO₂Me-benzoxy, 4-OCF3 -benzoxy, 2,4-diF-benzoxy, cyclohexyknethoxy, cyclohexylethoxy, cyclopentoxy, 3-Me-cycIopentoxy, cyclohexoxy, 4-Me-cyclohexoxy, 4-CO₂Et-cyclohexoxy, l-Bn-pyrrolidin-3-oxy, (l-Bn-pyrrolidin-3-yl)methoxy, 1 H-pyrazol- 1 -yl, 3-CO₂Et-5-Me- 1 H-pyrazol- 1 -yl, 4-CO₂Et-5-Me- 1 H-pyrazol- 1 -yl, 5-Cθ2Et-3-Me-lH-ρyrazol-l-yl, (2-Bu-lH-iraidazol-4-yl)methoxy, lH-l,2,4-triazol-l-yl, (l-Ph-lH_rl,2,3-triazol-4-yl)methoxy, 2-(lH-pyrrol-l-yl)ethoxy₅ 1 -piperidinyl, 1 -Bn-piperazin-4-yl, (2,2-diinethyl- 1 ,3-dioxolan~4-yl)methoxy, 1 -Bn-piperidin-3-oxy, 1 -Bn-piperidin-4-oxy, ( 1 -(z-Bu)-piperidin-4-yl)methoxy, (1 -isopentyl-piperidin-4-yl)methoxy, (1 -CO₂(^-Bu)-piperidin-4-yl)methoxy, (1 -CO₂Bn-piperidin-4-yl)methoxy, (1 -Bn-piperidin-4-yl)methoxy, (1 -phenethyl-piperidui-4-yl)methoxy, (1 -(4-phenylbutyl)~pipεridin-4-yl)methoxy, ( 1 -cyclohexylmetliyl-piperidin-4-yl-methoxy, (l-((pyridin-2-yl)methyl)-piperidin-4-yl)metlioxy, ( 1 -((pyridin-4-yl)metliyl)-piperidin-4-yl)methoxy, (1 -((1₅3-dioxolan-2-yl)methyl)piperidin-4-yl)methoxy, N-morpholinyl, 4-Bn-morpholin-2-yl-methoxy_J C3-6 cycloalkyl substituted with -CO₂Me, -CH₂OH₅ or -CH₂OMe, 4,4,5,5-tetramethyl-l,3,2-dioxaboiOlanyl, or -OP(O)(OEt)₂;

R⁴, R^4a, aiαd R^4c are H;

R⁵, R^5a, R^5c, and R^5d are, independently at each occurrence, H, Me, F or Cl; alternatively, R¹ + R², R² + R³, R³ + R⁴, R⁴ + R⁵, R^3a + R^4a, R^4a + R^5a,

Rib + _R2b_{5 R}2c + _R3c_{5 R}3c + _R4c_{5 R}4c + _R5c_{} R}lb + _R2b_{; R}2d + _R3d_{? or R}2b + _R5d_; combine with the carbon atoms to which they attached, form 5- tolO-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 heteroatoms selected from N, NR¹¹, O, and S(0)_p, 0-1 carbonyl group, and additional 0-2 double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b;

R^6a is, independently at each occurrence, H, F, Cl, Br, I, CN, -C(Me)₂CN,

195 C i_8 alkyl, C_2-8 alkenyl, OH, SMe, S(Z-Pr), -C(Me)₂OMe, -C(Me)₂OEt, -C(Me)₂OPr, -CHMeO(CH₂)₂OMe, -C(Me)₂O(CH₂)₂OMe, -C(Et)₂OMe, -C(Et)₂OEt, COPh, -CH=CHCO₂(^-Bu), CF₃, OCF₃, Ci_-4 alkyloxy, CO₂Me, -CH₂CO₂Me, C₃_7 cycloalkyl, Ph, Bn, 1-pyrrolidinyl, 5-isoxazolyl, N-morpholinyl, 4-Bn-piperazinyl, 1-piperidinyl, l-Bn-piperidin-4-yl, Or -Si(Me)₃; alternatively, when two R^6a groups are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3- to 7- membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR^{1 ]}, O, and S(0)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b; alternatively, when two R^^a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms selected from N, NR¹¹, O, and S(O)_p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 R^b;

R⁷, R^7a R^7b, and R^7d, independently at each occurrence, H, Me, Cl, Br, CN, OMe, SMe, or NHMe;

R⁸, R^8a , R^8b and R^8e are, independently at each occurrence, H, Me, Cl, or CN;

R¹¹ is, independently at each occurrence, Cμg alkyl, -CH₂CH₂OH, -CH₂CH₂OMe, -C(O)(C] -6 alkyl), -C(O)phenyl, -C(O)benzyl, -C(O)O(Ci_-6 alkyl), -C(O)Obenzyl, -CH₂CO₂H, -CH₂CO₂(Ci_-6 alkyl), -C(O)NH(Ci_-6 alkyl), -C(O)NHbenzyl, -S(O)₂(Ci_₆ alkyl), -S(O)₂phenyl, -S(O)₂benzyl, phenyl, or benzyl;

Y is O, S, or NH;

R^b is, independently at each occurrence, H, F, Cl, Br, C] .4 alkyl, OH, CO₂H, NH₂, CF₃, OCF₃, Ci-4 alkyloxy, C₃_7 cycloalkyl, phenyl, or benzyl;

R^e is, independently at each occurrence, H, F, Cl, Cj .4 alkyl, OH, CO₂H, NH₂, CF₃, OCF₃, or CM alkyloxy; and p, at each occurrence, is selected from 0, 1, and 2; provided that when ring D is dihydroindolyl, ring A is other than thiazolyl.

196