Heterocyclic spiro compounds and methods of use

A compound of Formula I

• or a pharmaceutically acceptable salt thereof, wherein
• R1 at each occurrence independently is H, C1-4alkoxy, —(CH2)—C1-4dialkylamino, aziridin-1-yl-methyl, azetidin-1-yl-methyl, pyrrolidine-1-yl-methyl, piperidin-1-yl-methyl, or morpholin-1-yl-methyl;
• R2 is H, halogen, —CN, C1-4alkyl, C1-4haloalkyl, —CH2CN, —CH2OH, C1-4alkoxy, or C1-4 haloalkoxy;
• wherein, optionally, one R1 and R2 together with the carbon atoms to which they are attached form a
• group;
• R3 at each occurrence independently is H, halogen, CN, OH, —CH2OH, C1-4alkyl, C1-4 haloalkyl, —CH2CN, or C1-4alkoxy, wherein two substituents R3 attached to the same carbon atom optionally form together with said carbon atom a C3-6cycloalkyl or a carbonyl group;
• A at each occurrence independently is CR3R3 or absent;
• R4 is Z1—CH(Z2—R5)—CH2—R6;
• Z1 is O, NH, N(C1-4alkyl), or CH2;
• Z2 is absent or CH2;
• R5 is C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, C3-6heterocycloalkyl, phenyl, or 5 to 6 membered heteroaryl,
• wherein the phenyl is optionally substituted with 1 to 3 substituents selected from halogen, —CN, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, and C1-3haloalkoxy,
• wherein the heteroaryl is optionally substituted with 1-3 substituents selected from —CN, C1-4alkyl, C1-4haloalkyl C1-4alkoxy, and C1-4haloalkoxy;
• R6 is —CO(NR7R7), phenyl, 5,5-dimethyl-3,5-dihydro-4H-imidazol-4-one-2-yl, or 5 to 6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1-3 substituents selected from —CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy;
• R7 at each occurrence independently is H or C1-4alkyl;
• X1 is CR8 or N;
• X2 is CH, or N;
• X3 is C or N;
• X4 is C or N;
• R8 is H, halogen, CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5cycloalkyl, or C3-5cyclohaloalkyl;
• B together with the atoms to which it is attached forms a 4 to 7 membered fully saturated, fully unsaturated, or partially unsaturated carbocyclic or heterocyclic ring system,
• wherein the heterocyclic ring system comprises 1 to 5 heteroatoms selected from N, O, and S,
• wherein the ring system is optionally substituted with 1 to 5 substituents R9;
• R9 at each occurrence independently is halogen, OH, —CN, —NH2, C(═O)C1-6alkyl, C1-6 alkyl, C1-6haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-5cycloalkyl, C3-5cyclohaloalkyl, phenyl, or 5 to 6 membered heteroaryl,
• wherein the C1-6alkyl is optionally substituted with —CO(C1-4alkylamino) or —CO(C1-4 dialkylamino),
• wherein the phenyl is optionally substituted with 1 to 3 independently selected halogens,
• wherein the heteroaryl is optionally substituted with 1 to 3 substituents selected from halogen, C1-4alkyl, and C1-4haloalkyl,
• wherein two substituents R9 together optionally form a —(CH2)n— group creating a ring together with the ring atom or ring atoms to which the two substituents R9 are attached, wherein the —(CH2)n— group optionally has one —CH2— group substituted with one heteroatom selected from N, O and S;
• and
• n is 1, 2, 3, or 4.