US 2026/0216175 A1 · COMPLEMENT INHIBITION

or a pharmaceutically acceptable salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-II:

or a pharmaceutically acceptable salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG), or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-III:

or a pharmaceutically acceptable salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-XII′:

or a salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

RRX1 is —OH or —C(O)RRX1 is an activated carboxyl group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-X′:

or a pharmaceutically acceptable salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4 is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-X″:

or a pharmaceutically acceptable salt thereof, wherein:

RPG is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

R1 is hydrogen, halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, amino C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkoxy, C3-C6 cycloalkyl C1-C6 alkoxy, halo C1-C6 alkoxy, —S(O)pC1-C6 alkyl, —CH2NHC(O)C1-C4 alkyl or —OCH2C(O)R7;

p is 0, 1, or 2;

R2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, hydroxy C1-C6 alkyl, or halogen;

R3 is hydrogen, halogen, cyano, C1-C4 alkyl, halo C1-C4 alkyl, —CH2C(O)R7;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

R7 is hydroxyl, C1-C4 alkoxy, amino, or mono- or di-C1-C4 alkylamino;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-IV:

or a pharmaceutically acceptable salt thereof, wherein:

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, oxo

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-IV′:

or a pharmaceutically acceptable salt thereof, wherein:

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, oxo

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6 is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-VI:

or a pharmaceutically acceptable salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

RPG2 is an amino protecting group;

R4 is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5 and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5 is —C(O)R8, —CH2C(O)R8, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-VII:

or a salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

RPG2 is an amino protecting group;

R4a is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5a and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5a is —CHO, —CH2CHO, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-VIII:

or a salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

R4a is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5a and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5a is —CHO, —CH2CHO, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-IX:

or a salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

R4b is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5b and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5b is —CH2OH, —CH2 CH2OH, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6 or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-X:

or a salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG), or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

p is 0, 1, or 2;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6 or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-XI:

or a salt thereof, wherein:

m is 1, or 2;

n is 1, or 2;

RPG3 is —H or an amino protecting group;

RPG4 is —OH or —C(O)RPG4 is a protected carboxyl group;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5 is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5 are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

p is 0, 1, or 2;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-XII:

or a salt thereof, wherein:

n is 1, or 2;

RPG3 is —H or an amino protecting group;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

p is 0, 1, or 2;

RRX1 is —OH or —C(O)RRX1 is an activated carboxyl group;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-XIII:

or a salt thereof, wherein:

m is 1, or 2;

RPG4 is —OH or —C(O)RPG4 is a protected carboxyl group;

R6′PG is R6′ or an amino protecting group;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

or

R4′ and one R6 are taken together to form C2-C4 alkylene;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

t is 0, 1, 2, 3 or 4;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound having the structure of formula M-XIV:

or a salt thereof, wherein:

n is 1, or 2;

RPG3 is —H or an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

p is 0, 1, or 2;

—C(O)RPG5 is protected carboxyl;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

and

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

or

a compound, wherein the compound has the structure of formula M-XV:

or a pharmaceutically acceptable salt thereof, wherein:

RPG2 is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, oxo

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-XVI:

or a pharmaceutically acceptable salt thereof, wherein:

RPG2 is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG), or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

p is 0, 1, or 2;

R4 is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, oxo

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur;

or

a compound, wherein the compound has the structure of formula M-XVII:

or a pharmaceutically acceptable salt thereof, wherein:

RPG2 is an amino protecting group;

R4PG is phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl and 5-10 membered heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalenyl, or heteroaryl is optionally substituted with R5PG and further optionally substituted with one or two R5′;

each R5′ is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy C1-C4 alkyl, hydroxyl, R10, —OR6′, —N(R51)2, halo C1-C6 alkyl, cyano, and cyanomethyl;

or

two R5′ are taken together with their intervening atoms to form a 4-8 membered monocyclic partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R51 is independently R6′;

R5PG is —C(O)R8PG, —CH2C(O)R8PG, R9, —C(O)NHSO2C1-C4alkyl, —SO2NHC(O)C1-C4alkyl, —SO2N(H)p(C1-C4alkyl)2-p, —SO(NH)C1-C4alkyl, —SO2C1-C4alkyl, cyano, halogen, hydroxy C1-C4 alkyl, —B(R8PG)2 or 5-membered heteroaryl having 1-4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom;

each R8PG is independently R8, or —C(O)R8PG is a protected carboxylic acid group;

m is 1, or 2;

n is 1, or 2;

p is 0, 1, or 2;

R4′ is hydrogen, C1-C4 alkyl, or hydroxy C1-C4 alkyl;

each R6 is independently hydrogen, halogen, hydroxyl, amino, mono- and di-C1-C6 alkylamino, C1-C6 alkyl, halo C1-C6 alkyl, hydroxy C1-C6 alkyl, cyano C1-C6 alkyl or C1-C6 alkoxy, or:

two R6 on a carbon atom are taken together to form ═O, or two R6 on a carbon atom are taken together with the carbon atom to form a 3-membered monocyclic saturated ring having 0-1 ring atoms independently selected from nitrogen, sulfur and oxygen;

or

two R6 are taken together with their intervening atoms to form a 3-8 membered monocyclic saturated or partially unsaturated ring having 0-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, oxo

R4′ and one R6 are taken together to form C2-C4 alkylene;

t is 0, 1, 2, 3 or 4;

R6′PG is R6′ or an amino protecting group;

R6′ is hydrogen, C1-C6 aliphatic, R10, —CH2—C3-C6 cycloaliphatic, —CH2—R10, —CH2-(hydroxy C1-C4 alkyl), phenyl, —C(O)—C1-C6 aliphatic, —SO2—C1-C6 aliphatic, —CH2-phenyl, —CH2-(amino C1-C4 alkyl), or —CH2-(mono- and di-C1-C4 alkylamino C1-C4 alkyl) wherein each of the C1-C6 aliphatic and phenyl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein each of the alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally and independently substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur wherein each ring nitrogen is optionally and independently substituted with C1-3 acyl;

or:

R6 and R6′ are taken together with their intervening atoms to form a 3-8 membered monocyclic or bicyclic saturated, partially unsaturated or aromatic ring having 1-3 ring atoms independently selected from nitrogen, sulfur and oxygen, wherein the ring is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo;

each R8 is independently hydroxyl, C1-C4 alkoxy, amino or a 5-7 membered saturated heterocyclyl having 1, 2, or 3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur;

or mono- and di-C1-C4 alkylamino which is optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C4 alkyl;

R9 is a 5-membered heteroaryl having 1 to 4 ring nitrogen atoms and 0 or 1 ring oxygen or sulfur atom, which heteroaryl is optionally substituted with 0 to 2 C1-C4 alkyl groups;

and

R10 is 3-6 membered heterocyclyl or 5-6 membered heteroaryl having 1-3 ring atoms independently selected from nitrogen, oxygen and sulfur, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, C1-C4 alkyl, halo C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, and oxo, and wherein each nitrogen ring atom of the heterocyclyl or heteroaryl is optionally and independently substituted with C1-3 acyl, cyano C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl having 1-4 ring atoms independently selected from nitrogen, oxygen and sulfur.

Complement inhibition

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Complement inhibition

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Abstract

Claims32