N-9 substituted purine compounds, compositions and methods of use

A compound of Formula I:

• wherein
• R1 is selected from the group consisting of 6- to 10-membered aryl, 5- to 9-membered heteroaryl, 3- to 12-membered heterocycloalkyl, 3- to 12-membered cycloalkyl, wherein R1 is substituted with from 0 to 5 RR1 substituents selected from the group consisting of halogen, F, Cl, Br, I, —NRaRb, —SRa, —ORa, —C(O)ORa, —C(O)NRaRb, —C(O)Ra, —NRaC(O)Rb, —OC(O)Rc, —NRaC(O)NRaRb, —OC(O)NRaRb, —NRaS(O)2NRaRb, —S(O)2Ra, —S(O)2NRaRb, —Rc—NO2, —N3, ═O, —CN, Rcl, —X1—NRaRb, —X1—SRa, —X1—ORa, —X1—C(O)ORa, —X1—C(O)NRaRb, —X1—C(O)Ra, —X1—NRaC(O)Rb, —X1—OC(O)Ra, —X1—NRaC(O)NRaRb, —X1—OC(O)NRaRb, —X1—NRaS(O)2NRaRb, —X1—S(O)2Ra, —Xi—S(O)2NRaRb, —X1—NO2, —X1—N3, —X1—CN, and X1—Rc1;
• wherein Ra and Rb are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-7 heterocycloalkyl, phenyl and —(CH2)1-4-phenyl, optionally Ra and Rb, when attached to the same nitrogen atom are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S;
• Rc is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-7 heterocycloalkyl, phenyl and —(CH2)1-4-phenyl;
• X1 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene;
• and Rc1 is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, 2-indolyl, 1-naphthyl, 2-naphthyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 2-furanyl and 3-furanyl, and wherein Rc1 is substituted with from 0 to 3 substituents selected from F, Cl, Br, I, —NRaRb, —SRa, —ORa, —S(O)2Ra, —S(O)2NRaRb, —NO2, —N3, ═O, —CN, pyridyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C1-6 heteroalkyl;
• R2 is selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, a 6- to 10 membered aryl, 5- to 10-membered heteroaryl, a 3- to 12-membered heterocycloalkyl, a 3- to 12 membered cycloalkyl, -L-C6-10 aryl, -L-C1-9 heteroaryl, -L-C3-12 cycloalkyl and -L-C2-12 heterocycloalkyl, wherein L is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene and C1-6 heteroalkylene, and wherein R2 is substituted with from 0 to 5 RR2 substituents selected from the group consisting of halogen, F, Cl, Br, I, —NRdRe, —SRd, —ORd, —C(O)ORd, —C(O)NRdRe, —C(O)Rd, —NRdC(O)Re, —OC(O)Rf, —NRdC(O)NRdRe, —OC(O)NRdRe, —NRdS(O)2NRdRe, —S(O)2Rd, —S(O)2NRdRe, —Rf, —NO2, —N3, ═O, —CN, —X2—NRdRe, —X2—SRd, —X2—ORd, —X2—C(O)ORd, —X2—C(O)NRdRe, —X2—C(O)Rd, —X2—NRdC(O)Re, —X2—OC(O)Rd, —X2—NRdC(O)NRdRe, —X2—OC(O)NRdRe, —X2—NRdS(O)2NRdRe, —X2—S(O)2Rd, —X2—S(O)2NRdRe, —X2—NO2, —X2—N3 and —X2—CN;
• wherein Rd and Re are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-7 heterocycloalkyl, phenyl and —(CH2)1-4-phenyl, optionally Rd and Re, when attached to the same nitrogen atom are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S;
• Rf is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C2-7 heterocycloalkyl, phenyl and —(CH2)1-4-phenyl;
• and X2 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene;
• R3 is a 5- to 12-membered monocyclic or bridged heterocycloalkyl ring, wherein the R3 group is substituted with from 0 to 3 RR3 substituents selected from the group consisting of —C(O)ORg, —C(O)NRgRh, —NRgRh, —ORg, —SRg, —S(O)2Ri, —S(O)Ri, —Ri, halogen, F, Cl, Br, I, —NO2, —CN and —N3, wherein Rg and Rh are each independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C2-6 alkenyl and C3-6 cycloalkyl, wherein optionally Rg and Rh, together with the nitrogen atom to which each is attached, are combined to form a 3- to 6-membered heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O and S, and Ri is selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C3-6 cycloalkyl;
• and if R3 is a monocyclic heterocycloalkyl ring then any two RR3 groups attached to the same atom of R3 is optionally combined to form at 3- to 7-membered carbocyclic or 3- to 7-membered heterocyclic ring comprising 1 to 2 atoms selected from N, O and S as ring vertices;
• A1, A2, A3 and A4 are each a member independently selected from N, C(RA) or C(H), wherein at least three of A1, A2, A3 and A4 is each independently C(H) or C(RA), wherein RA at each occurrence is independently selected from the group consisting of F, Cl, Br, I, —NO2, —CN, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or any two RA groups attached to adjacent atoms are optionally combined to form a C2-6 heterocyclic ring comprising from 1 to 2 heteroatoms selected from N, O and S as ring vertices, C3-7 cycloalkyl ring, a C1-5 heteroaryl ring comprising from 1 to 4 heteroatoms selected from N, O and S as ring vertices, or phenyl ring;
• and
• D is a member selected from the group consisting of —NR4C(O)NR5R6, —NR5R6, —C(O)NR5R6, —OC(O)OR5, —OC(O)NR5R6, —NR4C(═N—CN)NR5R6, —NR4C(═N—OR5)NR5R6, —NR4C(═N—NR5)NR5R6, —NR4C(O)R5, —NR4C(O)OR5, —NR4S(O)2NR5R6 and —NR4S(O)2R5, wherein R4 is selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl and C2-6 alkenyl;
• R5 and R6 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C2-10 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl, and R5 and R6, when attached to the same nitrogen atom, are optionally combined to form a 5- to 7-membered heterocyclic or a 5- to 9-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O and S as ring vertices and substituted with 0-3 RD substituents;
• and wherein R4, R5 and R6 are further substituted with from 0 to 3 RD substituents, wherein RD is independently selected from the group consisting of halogen, F, Cl, Br, I, —NO2, —CN, —NRjRk, —ORj, —SRj, —C(O)ORj, —C(O)NRjRk, —NRj(O)Rk, —NRj(O)ORm, —X3—NRjRk, —X3—ORj, —X3—SRj, —X3—C(O)ORj, —X3—C(O)NRjRk, —X3—NRjC(O)Rk, —X3—NRjC(O)ORk, —X3—CN, —X3—NO2, —S(O)Rm, —S(O)2Rm, ═O, and —Rm;
• wherein Rj sand Rk is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl;
• and Rm, at each occurrence, is independently selected from C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C6-10 aryl and C1-9 heteroaryl;
• X3 is selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene;
• and wherein D and a RA substituent attached to an atom that is adjacent to the atom to which D is attached are optionally combined to form an optionally substituted 5- to 6-membered heterocyclic or heteroaryl ring substituted with from 0 to 4 RD substituents.